ADENOVIRUS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Adenovirus: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00028-8 1. Adenovirus-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on adenovirus. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON ADENOVIRUS ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Adenovirus.................................................................................... 7 E-Journals: PubMed Central ....................................................................................................... 71 The National Library of Medicine: PubMed .............................................................................. 113 CHAPTER 2. NUTRITION AND ADENOVIRUS ................................................................................ 161 Overview.................................................................................................................................... 161 Finding Nutrition Studies on Adenovirus ................................................................................ 161 Federal Resources on Nutrition ................................................................................................. 170 Additional Web Resources ......................................................................................................... 170 CHAPTER 3. ALTERNATIVE MEDICINE AND ADENOVIRUS .......................................................... 173 Overview.................................................................................................................................... 173 National Center for Complementary and Alternative Medicine................................................ 173 Additional Web Resources ......................................................................................................... 187 General References ..................................................................................................................... 187 CHAPTER 4. DISSERTATIONS ON ADENOVIRUS ............................................................................ 189 Overview.................................................................................................................................... 189 Dissertations on Adenovirus ..................................................................................................... 189 Keeping Current ........................................................................................................................ 192 CHAPTER 5. PATENTS ON ADENOVIRUS ....................................................................................... 193 Overview.................................................................................................................................... 193 Patents on Adenovirus............................................................................................................... 193 Patent Applications on Adenovirus........................................................................................... 228 Keeping Current ........................................................................................................................ 263 CHAPTER 6. BOOKS ON ADENOVIRUS........................................................................................... 265 Overview.................................................................................................................................... 265 Book Summaries: Federal Agencies............................................................................................ 265 Book Summaries: Online Booksellers......................................................................................... 266 Chapters on Adenovirus ............................................................................................................ 266 CHAPTER 7. PERIODICALS AND NEWS ON ADENOVIRUS ............................................................. 269 Overview.................................................................................................................................... 269 News Services and Press Releases.............................................................................................. 269 Academic Periodicals covering Adenovirus ............................................................................... 272 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 275 Overview.................................................................................................................................... 275 NIH Guidelines.......................................................................................................................... 275 NIH Databases........................................................................................................................... 277 Other Commercial Databases..................................................................................................... 279 APPENDIX B. PATIENT RESOURCES ............................................................................................... 281 Overview.................................................................................................................................... 281 Patient Guideline Sources.......................................................................................................... 281 Finding Associations.................................................................................................................. 283 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 285 Overview.................................................................................................................................... 285 Preparation................................................................................................................................. 285 Finding a Local Medical Library................................................................................................ 285 Medical Libraries in the U.S. and Canada ................................................................................. 285 ONLINE GLOSSARIES................................................................................................................ 291
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Online Dictionary Directories ................................................................................................... 291 ADENOVIRUS DICTIONARY................................................................................................... 293 INDEX .............................................................................................................................................. 385
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with adenovirus is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about adenovirus, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to adenovirus, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on adenovirus. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to adenovirus, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on adenovirus. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON ADENOVIRUS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on adenovirus.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and adenovirus, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “adenovirus” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Acute Viral Hemorrhagic Cystitis: Alarming Symptoms with a Benign Cause Source: Journal of the American Academy of Physician Assistants. 16(11): 25-27. November 2003. Summary: Acute viral hemorrhagic cystitis (AVHC), a subset of acute hemorrhagic cystitis (AHC), is one of the few urinary tract infections that does not have a bacterial etiology. Although most patients who have AHC are immunocompromised adults, the disease can occur in children who have no underlying disease, often when it is preceded by a viral illness. Estimates are that more than 70 percent of cases of AVHC in children occur in boys. This article presents a case report of a 10 year old boy diagnosed with AVHC. The author reviews the typical symptoms, course, and treatment for AVHC. AVHC caused by an adenovirus is a self-limiting disease that lasts 2 to 6 days in the immunocompetent patient. In an otherwise healthy child, the disease requires only
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simple hydration to safely run its course. After the more serious causes of hematuria (blood in the urine) are ruled out by physical exam and diagnostic studies, the clinician can reassure the child's parents that no lasting damage occurred to the child's urinary tract. 1 table. 15 references. •
New Clinical Issues in Celiac Disease Source: Gastroenterology Clinics of North America. 27(2): 453-465. June 1998. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 654-2452 or (407) 345-4000. Summary: Celiac disease is a condition of permanent gluten intolerance in which a gluten-free diet results in complete clinical and histologic recovery. There has been considerable progress in genetic and immunobiologic research, and this article focuses on evolving issues in the diagnosis and management of patients with celiac disease. The first section addresses cause and pathogenesis, discussing toxic gluten fractions, genetics, the adenovirus 12 hypothesis, the peptide HLA complex hypothesis, the lectin hypothesis, and the enzyme deficiency hypothesis. The author notes that serial studies of the small bowel mucosa of genetically susceptible individuals after gluten challenge suggest that there is a spectrum of histologic changes induced by gluten. These lesions are briefly defined as they are classified: preinfiltrative, infiltrative, hyperplastic, destructive, and hypoplastic. In children, the onset of celiac disease is between the first and third years of life after gluten interaction, and they present with a classic syndrome of chronic diarrhea, failure to thrive, and abdominal distention. Adult patients may present at any age, although there appears to be a bimodal peak noted in the 30s or 40s in women and 40s or 50s in men. Celiac disease can be overt in presentation with classic symptoms of diarrhea, weight loss, and weakness or may present with constitutional symptoms or metabolic, neurologic, or psychological disturbances without any gastrointestinal complaints. The author discusses malignancy and lymphoma, noting that the risk of lymphoma associated with celiac disease necessitates lifelong observation of celiac disease patients. However, preliminary research shows that the overall cancer risk in patients with celiac disease who follow a gluten-free diet is not significantly higher than that of the general population. The author includes a detailed section on serologic testing, discussing antigliadin antibodies, antiendomysial antibody, and antireticulin antibody. Two final sections cover the role of oats in celiac therapy and the problem of refractory disease (disease that does not respond to the gluten-free diet). Small bowel biopsy remains the gold standard for diagnosing celiac disease, but antibody tests are a useful adjunct in deciding whom to biopsy and for screening groups at high risk before initiating a lifelong gluten-free diet. 2 tables. 90 references.
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Celiac Disease: A Review Source: Gastroenterology Nursing. 17(3): 100-105. November-December 1994. Contact: Available from Williams and Wilkins. 428 E. Preston Street, Baltimore, MD 21202-3993. Summary: In this article, the author provides a review of celiac disease, with an emphasis on the nursing care and intervention required in this patient population. Topics include the incidence of celiac disease; an historical perspective; the differential diagnosis of celiac disease; environmental stressors, including enzyme deficiency, genetic factors, and the adenovirus theory; the clinical presentation of the disease; immunopathology; pathophysiology; and the nursing care of the patient with celiac disease, including assessment, nursing diagnosis, plan, implementation, and evaluation.
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The author stresses that nursing intervention in celiac disease requires careful nutritional assessment and dietary instruction. 3 figures. 26 references. (AA-M). •
Gastrointestinal Infections in Childhood Source: Current Opinion in Gastroenterology. 12(1): 88-94. January 1996. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 700, Philadelphia, PA 19106. (215) 574-2266. Fax (215) 574-2292. Summary: This article reviews recent publications concerning clinical, epidemiologic, diagnostic, and therapeutic aspects of emerging and established pathogens pertaining to children. Diarrheagenic pathogens are emphasized. The review is intended to familiarize primary care physicians with new developments in this area and acquaint gastroenterologists with pediatric considerations in approaching gastrointestinal infections. Topics include bacterial infections, including Escherichia coli, vibrio cholerae, salmonella, and shigella; viral infections, including rotavirus, adenovirus, and calicivirus; parasitic infections, including cyclospora, cryptosporidium, giardia, and other pathogenic parasites; daycare centers and gastrointestinal infections; miscellaneous disorders, including persistent diarrhea, and necrotizing enterocolitis; the laboratory diagnosis of enteric infections; and treatment of gastrointestinal infections, including immunotherapy and probiotic therapy for rotavirus, oral rehydration solutions, and treatment of persistent diarrhea. 75 references (25 annotated).
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Risk of Transmission of Viruses in the Dental Office Source: Journal of the Canadian Dental Association. 66(10): 554-555, 557. November 2000. Contact: Available from Canadian Dental Association. 1815 Alta Vista Drive, Ottowa, ON K1G 3Y6. (613) 523-1770. E-mail:
[email protected]. Website: www.cda-adc.ca. Summary: This article reviews the risk of transmission of viruses in the dental office. In addition to the bloodborne pathogens such as HIV and hepatitis B and C viruses, other viruses of concern in the dental office include rubella, mumps and measles viruses; the herpes viruses, including varicella zoster, Epstein Barr, and cytomegalovirus; human papilloma viruses; adenovirus; coxsackie viruses; and the upper respiratory tract pathogens, including influenza. Most of these viruses are far more prevalent than the bloodborne pathogens and many are of particular concern to nonimmune pregnant women and immunocompromised patients. The author discusses the evidence for viral transmission in the dental office, and dentists' exposure to bloodborne pathogens. The author notes that many cases of transmission of infection are not documented. Many are not recognized because of subclinical infection (no apparent symptoms), the difficulty of linking isolated sporadic cases with a health care worker, and the variation in completeness of surveillance among jurisdictions. 29 references.
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Viral Infection as a Cause of Arthritis Source: American Family Physician. 54(6):2009-2015. November 1, 1996. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail:
[email protected]. Website: www.aafp.org. Summary: This journal article for health professionals discusses viral infection as a cause of arthritis. Theories concerning the pathogenesis of viral rheumatic illnesses are
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presented. The features of arthritis associated with various viral infections are described, focusing on rubella virus; parvovirus B19; enteroviruses, adenovirus, and arboviruses; and hepatitis A, B, and C viruses. Rheumatic complaints secondary to viral infections are usually brief, self-limited, and nondestructive. They may accompany almost any type of viral illness, and the arthritic presentation is nonspecific. Often the cause of the rheumatic complaint remains elusive because of the prompt resolution of the viral infection. Evaluation for autoimmune diseases should be postponed until the symptoms have been present for at least 6 weeks. However, some viral diseases, such as parvovirus and chronic hepatitis B and C virus infections, can produce long-lasting rheumatic symptoms. Since the arthritis associated with hepatitis C infection has only recently been recognized, it is important to search for this association in patients who have atypical rheumatic complaints, risk factors for hepatitis, and alterations in liver enzymes, so that an accurate diagnosis can be established and the pathophysiology can be better understood. 26 references and 1 table. •
Epidemiology, Etiology, Diagnostic Evaluation, and Treatment of Low Back Pain Source: Current Opinion in Orthopedics. 11(3): 225-231. June 2000. Summary: This journal article provides health professionals with information on the epidemiology, etiology, diagnosis, and treatment of low back pain. Low back pain is a common medical problem that has decreased in frequency in the occupational setting over the past decade. The weather affects low back pain but to a minor degree. Obesity has been implicated as a cause, but epidemiologic studies have reported both positive and negative associations. Physical factors, as well as job satisfaction, play a role in the development and perpetuation of low back pain. Contrary to previous measurements, intradiskal pressure has been determined in vivo to be greater in the standing than in the sitting position. Degenerative disk disease and associated spondylolisthesis are a common finding on lumbar radiographs. Adenovirus mediated gene transfer to nucleus pulposus cells may be the initial stage of a new form of therapy for degenerative disk disease. Bed rest is not more helpful than activity as tolerated for the treatment of sciatica. Percutaneous transcutaneous electrical stimulation may offer additional pain relief in combination with other modalities. The role of opioid analgesics for chronic noncancer pain engenders considerable differences of opinion. Fusion of the lumbar spine should be reserved for those patients who have failed conservative therapy. The outcome of spinal stenosis surgery is more closely associated with the patient's perception of improvement than with the degree of canal narrowing. 2 figures and 29 references. (AA-M).
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Viral Connection to Obesity Source: Healthy Weight Journal. 14(6):83. November/December 2000. Summary: University of Wisconsin researchers found that the role of a virus infection in the development of obesity must be considered. In four distinct experiments, published in the International Journal of Obesity, the researchers inoculated chickens and mice with a human adenovirus (AD-36) and found that visceral fat, total body fat, and/or body weight were significantly greater compared with control groups. Increased fatness could be seen as early as 3 weeks and persisted for 13 and 22 weeks when the studies concluded. It was previously believed that these viruses could not infect across species. The Wisconsin researchers verified earlier that obesity could be induced by an avian adenovirus in four animal models. They cite research that demonstrated that canine distemper virus can produce obesity in mice and that it was believed to be related to
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hypothalamic damage. They also cite reports that some obese humans have antibodies to avian adenovirus.
Federally Funded Research on Adenovirus The U.S. Government supports a variety of research studies relating to adenovirus. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to adenovirus. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore adenovirus. The following is typical of the type of information found when searching the CRISP database for adenovirus: •
Project Title: A MAX-AD VACCINE FOR MUCOSAL IMMUNITY TO HIV Principal Investigator & Institution: Sauter, Sybille L.; Vice President of Research & Development; Corautus Genetics, Inc. 75 5Th St Nw, Ste 313 Atlanta, Ga 303081037 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-MAR-2003 Summary: (Provided by Applicant): To date there is no effective HIV vaccine available. Development of a beneficial HIV vaccine has been challenging due to the high mutation rate of the virus, in particular the envelope protein. Many of the 25 or more different HIV vaccines now in clinical trials target the envelope protein in an effort to raise an antibody response to that protein. New insight into effective anti-viral vaccines has focused attention on eliciting cellular immune responses. In addition, mucosal immunity to HIV is desirable for an effective HIV vaccine, since mucosal tissues are the common sites of initial infection. The vaccine being developed by GenStar targets these two issues by the inclusion of the HIV components known to elicit the best cellular immune responses and the ability of adenovirus to produce excellent mucosal immunity. GenStar's proprietary adenoviral vector, Max-Ad, is particularly suited for this approach, since it is a gutless adenovirus with a very large insert capacity. This capacity not only allows the inclusion of multiple HIV components but also the gene for the immunostimulatory cytokine, GM-CSF. In addition, this virus offers efficient transduction of most cells including dendritic cells, excellent high titer large-scale production, and the lack of synthesis of any adenoviral proteins. In the proposed studies we intend to determine the ability of a Max-Ad/HIV vaccine to elicit cellular immune responses to HIV through mucosal delivery. PROPOSED COMMERCIAL APPLICATION: HIV is a world-wide health problem with over 30 million people infected and 15,000 new cases of HIV infections diagnosed each day. Clearly, a prophylactic vaccine for this infectious disease is urgently needed and would produce
2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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significant financial and social returns. The potential for effective immunization via a mucosal route such as intranasal spray is particularly attractive in view of the large population at risk and the ease of administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A NOVEL ADENOVIRUS-BASED TETRAVALENT DENGUE VACCINE Principal Investigator & Institution: Deitz, Stephen B.; Genphar, Inc. 871 Lowcountry Blvd Mount Pleasant, Sc 294643025 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JAN-2003 Summary: (provided by applicant): The deliberate attempts to infect political figures and high profile members of the 'the media' with anthrax after the attacks of Sept. 11, 2001 highlight the need for an effective strategy to deal with bioterrorism. The threat of bioterrorism is no longer just a threat. There are a large number of disease-causing agents that have the potential to be used as weapons and we must be prepared to neutralize their effectiveness whether they are ultimately used or not. For many potential bioweapons, the best defense is preemptive vaccination. Unfortunately, there are more disease-causing agents than there are vaccines. We have chosen to focus our attention on one potential bioweapon: dengue virus. Dengue fever and dengue hemorrhagic fever are incapacitating, potentially lethal diseases that are caused by dengue virus infection. Dengue infection has been problematic for American military personnel stationed in tropical or subtropical countries and there is some concern that the virus could be weaponized in the future. There are four common serotypes of dengue virus and immunity against one serotype can enhance the severity of disease following infection with another serotype. Therefore, an effective dengue virus vaccine must elicit a broad response that is capable of neutralizing all four serotypes. We will use a unique adenovirus-based expression system to create a novel tetravalent dengue virus vaccine. Phase I of this project will focus on subcloning genes from all four dengue virus serotypes into adenovirus vectors and characterizing the vectors with respect to protein expression. Three dengue virus genes, prM, E, and NS1, from each serotype will be inserted into adenovirus vectors. Expression of the dengue virus genes from the adenovirus vectors is expected to elicit both humoral and cellular immune responses. The first generation vaccine will consist of a mixture of two adenovirus vectors - each vector expressing six genes from two dengue virus serotypes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AAV VECTORS FOR MUSCULAR DYSTROPHY (LGMD) GENE THERAPY Principal Investigator & Institution: Xiao, Xiao; Associate Professor; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 28-APR-1999; Project End 31-MAR-2004 Summary: Duchenne muscular dystrophies (DMD) and Limb-girdle muscular dystrophies (LGMD) are common inherited degenerative muscle diseases caused by mutations in genes coding for memberance associated proteins in muscle cells. DMD and LGMD often manifest themselves in young age and lead to severe morbidity and fatality, with no currently available effective treatment. In addition, the diseases are usually genotypically recessive, which makes them suitable for gene replacement therapy with vectors. Recombinant adeno-associated virus (rAAV) is one such vector
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based on defective human parvoviruses. rAAV system has attracted attention due to its non-pathogenicity, genomic integration, transduction of quiescent cells, and apparent lack of cellular immune reactions. In contrast to other viral vectors, rAAV is capable of efficiently bypassing the myofiber basal lamina and tranducing mature muscle cells. We have demonstrated that rAAV vectors harboring a foreign gene can achieve highly efficient and sustained gene transfer in mature muscle of immunocompetent animals for more than 1.5 years without detectable toxicity. Recently, significant improvement in vector production methodology has made it possible to generate high titer and high quality rAAV vectors completely free of helper adenovirus contamination. However, no experiments using rAAV vectors to restore the functional deficits in muscle tissue itself have been reported to date. In this proposal, we will use delta-SG as the target disease gene, the delta-SG deficient hamster as the LGDM animal model, and rAAV as the gene delivery vector to test our general hypothesis that safe, efficient and sustained functional rescue of muscle deficiency can be achieved by genetic complementation of inherited muscular dystrophies with rAAV vectors. Specifically, we would like to achieve the following aims: 1) To study gene transfer efficiency and functional rescue in the LGMD hamster model by local intramuscular delivery of delta-SG-rAAV vectors and examine their short term ability to correlate the genetic defect in both skeletal and cardiac muscle. 2) To evaluate the gene therapy efficacy after systemic delivery of rAAV vectors through intra-artery or intra-ventricle injection. 3) To investigate the molecular kinetics and fate of rAAV vectors, especially after systemic vector delivery. 4) To develop new generation, high titer, helper-virus-free rAAV producer cells, which not only harbor vector and packaging genes, but also contain the necessary helper genes from adenovirus in a highly regulated and inducible manner. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ABLATION OF IMMUNE RESPONSE TO ADENOVIRUS VECTORS Principal Investigator & Institution: Mountz, John D.; Professor of Medicine; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: (from the abstract) The investigator writes that most applications of gene therapy will depend on prolonged expression and readministration of the transgene. Although design of viral vectors with extensive deletions of the genome has resulted in prolonged expression, this approach does not completely abrogate the immune response. It is their contention that a combined strategy that includes tolerization to the vectors, as well as low immunogenicity vectors, will be absolutely necessary for successful long-term gene therapy in humans. He proposes a tolerization strategy that will be applicable clinically and is supported by preliminary data indicating prolonged expression of the transgene and the absence of an immune response. The investigators have shown that antigen presenting cells expressing adenovirus/Fas ligand (Ad/Fas L) and antigen induces systemic tolerance to the Ad antigens without toxicity. Here, they will use APCs that express Fas ligand and have been infected with low-immunogenicity adenovirus-LacZ and other transgenes to induce systemic tolerance to the gene therapy. In Aim 1, the investigators will determine if the mouse CD11b promoter can specifically up-regulate Fas L in APCs infected with adenovirus with extensive DNA deletions. Expression of Fas L specifically in macrophages using the CD11b promoter has been demonstrated after transient transfection and in transgenic mice. In Aim II, they will determine if ex-vivo infected APC with adenovirus with extensive DNA deletions can be used to induce T-cell tolerance to adenovirus vector and transgene antigens. APCs will be infected ex-vivo and analyzed for tolerance induction in vivo. The tolerance to
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transgenes of low and high immunogenicity will be determined. In Aim III, they will determine if survival of normal APCs will be prolonged using the Fas apoptoss inhibitor CrmA gene and a soluble TNF-receptor to enhance APC and adenovirus survival and tolerization after infection with adenovirus. In Aim IV, the investigators will develop adenovirus with modified tropism to target Fas L expression to antigen presenting cells for in vivo tolerance induction. This will be accomplished by enhanced targeting to APC using the mannose receptor and by pre-infusion of Ad fiber knob protein to inhibit endogenous tropism of Ad/Fas L to the liver. These experiments should accomplish the objective of devising adenovirus-transgene tolerance methods that are safe and efficiently deliver Fas L to APCs, either by in vivo transfer with relatively high targeting to APCs or in vitro transfer into cells and then transfer of cells that express Fas L. Infection of APCs ex-vivo with Ad/FasL has now been demonstrated to be safe and feasible, and does not induce toxicity upon transfer of these macrophages in vivo. Dr. Mountz and his colleagues believe that the studies will provide a feasible and safe method to enable prolonged and repeated administration of gene therapy that will be required for successful treatment of human diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADENOVIRUS MODULATION OF LACRIMAL GLAND FUNCTION Principal Investigator & Institution: Hamm-Alvarez, Sarah F.; Associate Professor; Pharmaceutical Sciences; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): Tear proteins play key roles in combating viral and bacterial infections and in supporting cornea and conjunctiva. A primary function of the acinar cells of the lacrimal gland is the production and release of a variety of proteins including hormones, lactoferrin and lysosomal hydrolases into tear fluid. Many of these proteins are stored in large sub-apical secretory vesicles which release their contents at the apical membrane once appropriate intracellular signaling pathways have been activated. We have found that transduction of primary cultured rabbit lacrimal acini with adenovirus serotype 5 (Ad5) vector decreases the secretagogue-stimulated release of tear proteins in parallel with depletion of rab3D-enriched mature secretory vesicles in the sub-apical cytoplasm. The Ad5 capsid proteins, penton and fiber, mediate virus binding and endocytosis through interactions with `v integrins and coxsackievirus and adenovirus receptor, respectively. Integrin ligation is associated with major changes in intracellular signaling pathways including those which may regulate biosynthetic/secretory membrane traffic. Penton proteins may also participate in the intracellular trafficking of internalized virus by recruitment of host membrane trafficking proteins, diminishing the availability of these proteins for other essential membrane trafficking functions. Two specific aims are proposed utilizing primary cultured rabbit lacrimal acini as our experimental system: 1) Is Ad5-mediated impairment of lacrimal acinar secretion caused by capsid proteins and 2) Is Ad5mediated impairment of lacrimal acinar secretion due to sequestration of clathrin and adaptor proteins by the penton dileucine motif? These unique hypotheses will be tested using recombinant assembly-competent wild type and mutant Ad5penton and fiber proteins, and will utilize a variety of techniques including confocal fluorescence and electron microscopy analysis of secretory vesicle content, subcellular membrane fractionation, immunoprecipitation and measurements of stimulated protein secretion. Considerable recent interest has focused on ocular gene therapy using Ad5 or Ad5derived materials. However, exposure of the lacrimal gland to Ad-derived materials
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may severely compromise its ability to maintain adequate protein secretory capacity. The studies proposed here will be essential in evaluating the feasibility of ocular gene therapy using Ad-derived materials and in improving the safety of such delivery systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION
ADENOVIRUS-RECEPTOR
INTERACTION--STRUCTURE,
Principal Investigator & Institution: Freimuth, Paul I.; Professor; Brookhaven Science Assoc-Brookhaven Lab Brookhaven National Lab Upton, Ny 11973 Timing: Fiscal Year 2002; Project Start 01-JUL-1996; Project End 31-DEC-2004 Summary: Our structure of the adenovirus-12 fiber knob domain in complex with a soluble fragment of CAR, the cellular receptor for group B coxsackieviruses and many adenoviruses, challenges established models of the mechanism of virus-receptor binding. The CAR binding site on knob is formed from surface loops, which are the most variable parts of the knob protein and account for serological differences, rather than from more highly conserved regions that were proposed as candidate binding sites based on an earlier crystal structure of the Ad5 knob. The overlap of a receptor binding site of conserved specificity and antigenically variable regions strongly suggests that aspects of the molecular mechanism of virus-receptor binding may be unique and without precedent in non-viral systems. Both the knob-CAR and HIV gp120-CD4 interfaces contain unusual large water-filled cavities, allowing for indirect watermediated binding in addition to direct contact of amino acids across the interface. This feature may be part of a mechanism to buffer binding site specificity against overlapping antigenic variation. We will analyze the mechanism of knob-CAR binding in detail, using the combined approaches of x-ray crystallography, mutagenesis and biochemistry. The structures of fiber knobs from different adenovirus serotypes will be solved alone and in complex with CAR to study the impact of antigenic variation on the structure and activity of the receptor binding site. The contribution of individual knob amino acids that contact CAR directly or indirectly through cavity-bound water molecules will be assessed by mutagenesis and quantitative binding assays. Knobspecific monoclonal antibodies which interfere with knob-CAR binding will be isolated to characterize the antigenic structure of the receptor binding sites. Knowledge gained from our studies may be broadly applicable to understanding mechanisms of receptor binding in other virus systems, including HIV. Our results also may have application to the development of vaccines and anti- viral drugs, and they will impact efforts to retarget the tropism of adenovirus-based vectors for gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALPHA-V INTEGRINS AND ADENOVIRUS CELL ENTRY Principal Investigator & Institution: Nemerow, Glen R.; Associate Member; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 20-JAN-1995; Project End 31-DEC-2003 Summary: Adenovirus (Ad) represent a significant causes of human respiratory, gastrointestinal and ocular infections; however, replication-defective forms of Ad are currently in use in clinical trials for gene therapy. Despite some success with this approach, a lack of knowledge of how Ad recognizes host cell co-receptors (alphav integrins) and how alphav integrins promote virus uptake has prevented optimal use of Ad vectors in the clinic. This proposal seeks to define the precise integrin binding events
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Adenovirus
and intracellular signaling pathways involved in adenovirus entry into host cells. The goals of this proposal are to 1) determine the three-dimensional architecture of Ad and the kinetics of alphav integrin binding, 2) to characterize the mechanism of Ad-mediated endosome disruption and the role of alphav integrins in this process, 3) to define the signaling molecules that regulate Ad internalization and 4) to exploit cell signaling pathways to enhance Ad-mediated gene delivery in vitro and in vivo. Cryoelectron microscopy and kinetic analyses will be used to define the structural elements responsible for alphav integrin association with different Ad serotypes and extracellular matrix proteins. A panel of epithelial cells lines expressing modified forms of alphav integrins will be used to identify the precise sequences and mechanisms involved in Admediated endosome disruption, a key step required for virus penetration into the cell. Biochemical and molecular genetic approaches will be used to investigate the role of signaling molecules in virus internalization (endocytosis). Finally, a modified adenovirus vector with the capacity to trigger multiple cell signaling pathways will be used to enhance gene delivery to neovascular tissue and solid tumors in vivo. If successful, these studies have the potential to increase our understanding of several fundamental cell and molecular biological processes as well as optimize the use of Ad vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIBODY-MODIFIED ADENOVIRAL VECTORS FOR TUMOR TARGETING Principal Investigator & Institution: Li, Erguang; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The overall goal of this project is to generate antibody-modified adenoviral vectors for cell/tissue specific gene delivery. Adenovirusbased vectors are widely used for gene delivery and gene therapy clinical trials. These vectors are advantageous in that they can be prepared to high titers with high purity and can deliver gene to a variety of cell types. The low tissue specificity of Ad-based vectors has restricted the potential application of these vectors as a treatment for acute and chronic diseases. Ad infection is initiated by high affinity interaction of viral fiber protein with its cellular receptor CAR (coxsackie adenovirus receptor). Modification of the fiber protein (the determinant for virus tropism) has been a major strategy to improve gene delivery specificity. Ad fiber is a homotrimeric protein that contains an Nterminal tail, responsible for its non-covalent attachment to virus surface, a shaft region, and a C-terminal knob, essential for cell surface attachment. The trimerization domain was proposed to be in the knob region of the C-terminus. Thus, fiber modification to improve tissue specificity has mainly focused on this region, although such modification tends to disrupt fiber trimer, resulting in the assembly of incomplete virions. This proposal focuses on the modification of Ad vectors by fusing cell specific ligands such as antibodies to the N-terminal shaft of Ad fiber protein. Three specific aims are proposed to address the design and gene delivery efficiency of these vectors. AIM 1. To develop reporter Ad vectors by replacing fiber protein with chimeric TEF-tumor targeting single chain antibody. AIM 2. To determine gene delivery selectivity in in vivo tumor models by measuring reporter gene expression in tumor and organs. AIM 3. To construct and to determine the efficacy of therapeutic genes delivered by antibodymodified vectors by measuring tumor growth in colorectal tumor murine transgenic models. The new Ad vectors would have combined advantages of high delivery efficiency (by Ad) and high tissue specificity (by antibodies).
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASSESSMENT OF RECOMBINANT CHIMPANZEE ADENOVIRUS VACCINES IN CYNOMOLGOUS MONKEYS Principal Investigator & Institution: Letvin, Norman L.; Chief, Div of Viral Pathogenesis; Wistar Institute Philadelphia, Pa 191044268 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: With accruing data indicating the critical importance of cytotoxic T lymphocytes (CTL) in containing the replication of HIV-1 in infected individuals, AIDS vaccine strategies are being evaluated in pre-clinical studies that elicit high frequency cell-mediated immune responses. Among the most impressive of these HIV-1 vaccine modalities that have been assessed to date in nonhuman primate models are the genedeleted human adenovirus vectors. However, there is concern that pre-existing immunity to adenoviruses in vaccinees may substantially decrease the immunogenicity of such vaccine constructs. Pre-existing immunity to common serotype adenoviruses is, in fact, quite common in human populations. Therefore, these vaccine constructs may prove to be less than optimal immunogens in humans. Adenoviruses from nonhuman primate species may provide vectors that elicit immunity comparable to that elicited by recombinant human adenovirus constructs. These constructs may prove particularly useful as human immunogens since immunity to these vectors should not exist in human populations. The studies described in the present proposal assess the immunogenicity of recombinant chimpanzee adenovirus vaccine constructs in macaques. The immunogenicity of these vectors will be determined, strategies for their optimal use will be explored, and their protective efficacy will be examined. Specifically, we will assess the: I. Immunogenicity of recombinant chimpanzee adenoviruses in macaques; I1.Prime/boost strategies for vaccination using recombinant chimpanzee adenovirus constructs; II1.Impact of pre-existing immunity to human adenoviruses on immunogenicity of recombinant chimpanzee adenovirus vaccines; IV. Relative immunogenicity of various prime/boost strategies; V. Protection of recombinant chimpanzee adenovirus immunized monkeys against challenge with a) athogenic clade C SHIV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CAR & ADENOVIRAL GENE THERAPY FOR DIABETIC RENAL DISEASE Principal Investigator & Institution: Bhatt, Udayan Y.; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Replication deficient recombinant adenoviruses (rAv) are potent vectors for DNA transfer (transduction). Diabetic glomerulosclerosis is a potential target for rAv-based forms of gene therapy. The coxsackie adenovirus receptor protein (CAR) mediates rAv infection. Despite widespread use of rAv, the mechanisms of CAR-mediated viral entry into cells are not well characterized. Therefore, the scientific objective of this proposal is to define CAR receptor expression, function, and utility in controlling transduction. The project has 3 Specific Aims. Aim #1 will further characterize the expression of CAR in normal and diabetic kidney. Aim #2 will investigate the functional consequences of rAv engagement of CAR under normal and diabetic conditions. Beginning with DNA microarray analysis followed by confirmatory studies using quantitative PCR, the gene activation profile resulting from
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Adenovirus
CAR engagement by rAv will be elucidated. Aim #3 will explore the clinical utility of CAR in regulating rAv mediated gene transfer. The goal of this aim is to control rAv transduction by using a doxycycline-responsive CAR transgene. Taken together, these studies will define CAR expression, function, and utility in the development of rAvbased forms of gene therapy for diabetic glomerulosclerosis. The scientific goals of this project are a natural extension of the candidate's current studies (NIH 1F32 DK1006401). The educational curriculum developed by the candidate and his sponsors will complement the scientific studies in developing a comprehensive training experience. The educational curriculum employs a multi-faceted approach consisting of didactics, seminars, and meetings. These activities provide the foundation for the applicant in the pursuit of a career as a physician scientist. The long-term career goal is to develop into a translational scientist with all of the clinical and basic investigative tools necessary to design and apply novel forms of gene therapy for kidney disease. In this regard, the candidate will continue his relationship with his current mentor, N. S. Nahman, Jr., M.D. Dr. Nahman provides an excellent role model as a clinician scientist. Chandan K. Sen, Ph.D., serves as a cosponsor on the project and brings a diverse background in the basic sciences for the candidate's training plan. Thus, the candidate's scientific plan, educational curriculum, and association with effective mentors ensure an excellent career development experience. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARBON MONOXIDE AND VASCULAR SMOOTH MUSCLE CELL FUNCTION Principal Investigator & Institution: Durante, William; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-DEC-1998; Project End 31-MAR-2007 Summary: (provided by applicant): The broad long-term objective of this research proposal is to establish heme oxygenase-1 (HO-1)-derived carbon monoxide (CO) as a novel and biologically important gas that regulates homeostasis at sites of vascular injury. We have measured the release of CO from vascular smooth muscle cells (SMC) and found that SMC-derived CO functions in an autocrine and paracrine fashion to inhibit SMC proliferation and platelet aggregation, respectively. The central hypothesis of this proposal is that HO-1-derived CO is a critical regulator of the SMC response to vascular injury. To test our hypothesis we plan to pursue the following three complementary and linked specific aims. In aim 1, we will examine the role of CO in regulating vascular SMC migration, collagen synthesis, and the secretion of vascular endothelial growth factor (VEGF) utilizing cultured vascular SMC. The effect of exogenously administered and endogenously derived CO will be studied. SMC will be exposed to CO via an exposure chamber while endogenous CO production will be induced by adenovirus-mediated transfer of the HO-1gene. The role of HO-1-derived CO in regulating SMC function will also be examined by harvesting SMC from the aorta of HO-1 knockout animals and comparing their functional properties with SMC from wild type animals. If CO is found to alter these SMC functions, we will determine the involvement of the cGMP or p38 mitogen activated protein kinase signaling pathways. In aim 2, we will elucidate the actions of HO-1 in regulating collagen deposition and VEGF expression following arterial injury using transgenic mice deficient in HO-1. In addition, we will investigate if CO inhalation can substitute for HO-1 in preventing collagen deposition and VEGF expression in these animals. In aim 3, we will explore the effect of adenovirus-mediated HO-1 gene delivery on collagen accumulation and VEGF expression in these animals. Finally, we will determine if CO-mediated VEGF release
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functions in a paracrine manner to stimulate endothelial cell growth both in vitro and in vivo. It is anticipated that these studies will (a) establish CO as a novel regulator of the vessel wall's response to injury and (b) implicate the HO-1/CO system as a promising new therapeutic target in treating vascular fibroproliferative disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELL TARGETING LIGANDS AND VECTORS FOR CLL Principal Investigator & Institution: Barry, Michael A.; Associate Professor; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: The inability to deliver therapeutic agents to chronic lymphocytic leukemia (CLL) cells in vitro or in vivo is a fundamental impediment to any drug or gene therapy for this disease. For CLL, gene therapy approaches to deliver immunostimulatory gene products to CLL cells hold great promise for treating this disease, however, current gene therapy vectors are not optimal for this application. In particular, most gene therapy vectors fail to effectively deliver genes into CLL cells making ex vivo approaches inefficient. By contrast, most vectors mediate robust, but non-specific gene delivery to many non-CLL cells in the body. This inability to deliver genes into CLL cells combined with a robust ability to deliver genes into the liver and immune cells makes current vectors unsafe for in vivo applications against CLL. Given that current vectors are inadequate for these CLL applications, this project proposes to develop CLL-targeting ligands and vectors to increase CLL transduction in vitro and mediate CLL-specific gene delivery in vivo. Towards this goal, the project will pursue the following Specific Aims: Specific Aim 1: To generate cell-targeting ligands against human CLL cells. Specific Aim 2. To translate CLL- targeting ligands onto adenovirus gene therapy vectors and test for improved CLL transduction in vitro. Specific Aim 3. To optimize the affinity and specificity of CLL-binding and CLL- targeting peptides. Specific Aim 4. To test the ability of CLL- targeting adenoviral vectors to mediate CLL-specific gene delivery in mouse xenografts of human CLL cells. We will use our peptide libraries to select targeting ligands against a panel of primary patient CLL cancer cells with the rationale that ligands generated here can be translated directly into clinical application against human tumors. As targeting ligands are identified, they will be optimized and tested for their ability to increase CLL transduction and CLL-specific transduction by adenoviral gene therapy vectors in vitro. Promising targeting vectors will then be tested in vivo in mouse xenografts for their ability to mediate human CLL-specific transduction in the context of a living organism. If successful, this work will lay the foundation for future applications of these CLL-targeting ligands and vectors for gene therapy for CLL patients through the clinical arm of the Center for Cell and Gene Therapy at Baylor College of Medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CEREBRAL CIRCULATION: NO AND REACTIVE OXYGEN SPECIES Principal Investigator & Institution: Heistad, Donald D.; Director; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 31-MAR-2006 Summary: (Verbatim from the application): The goal of this project is to evaluate effects of inducible nitric oxide synthase (iNOS) on vascular function. The investigators have been studying effects of iNOS, using pharmacological inhibitors and iNOS-deficient mice, and have made a recombinant adenovirus, which will provide a novel approach
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Adenovirus
to study vasomotor effects of iNOS. Preliminary data are the first studies of vasomotor effects of iNOS, using adenovirus-mediated gene transfer. Studies are proposed (based on preliminary data) to test the hypothesis that iNOS at high levels of expression, produces superoxide in blood vessels and thereby impairs endothelial function. Studies also are proposed to test the hypothesis that, at low levels of expression, gene transfer of iNOS may generate primarily nitric oxide (NO) that quenches superoxide and thereby improves endothelial function. These latter studies will be performed in vessels with high levels of superoxide, after exposure to lipopolysaccharide or from diabetic rabbits. Studies are proposed to study vessels in vitro and in vivo, and to examine mechanisms by which iNOS impairs vasomotor function. Approaches that will be used to address these aims are gene transfer of iNOS in vitro and in vivo, generally to the carotid or basilar artery of rabbits; measurement of vasomotor responses ex vivo in vascular rings in an organ bath, and responses in vivo using sonimicrometry; measurement of activity of nitric oxide synthase with labeled citrulline; detection of superoxide with hydroethidine in the vessel wall in situ; and quantitation of superoxide with lucigenin (5 uM). It is well recognized that iNOS is expressed in vessels in response to injury and in disease states, and that these disease states generally are associated with endothelial dysfunction. The use of gene transfer of iNOS to vessels to study vasomotor function is novel, and is likely to provide new insight into mechanisms by which iNOS alters vasomotor function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION AND SORTING OF ZYMOGEN GRANULE PROTEINS Principal Investigator & Institution: Lowe, Anson W.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-FEB-1991; Project End 31-JAN-2005 Summary: (provided by applicant): The exocrine pancreas is responsible for the synthesis and secretion of digestive enzymes into the intestine. The acinar cell is responsible for the pancreas' exocrine functions and can be characterized as a polarized secretory epithelia. Digestive enzyme secretion is also regulated and can be stimulated with acetylcholine and cholecystokinin. The key subcellular organelle responsible for regulated secretion in the acinar cell is the zymogen granule; a secretory vesicle that stores and concentrates digestive enzymes until secretion is stimulated. The focus of this project has been the characterization of zymogen granule membrane proteins as a means toward understanding the mechanisms underlying the formation of secretory granules and the targeting of proteins to the regulated secretory pathway. GP2 is the dominant protein in the zymogen granule membrane and accounts for 35 percent of the total granule membrane protein. In vitro studies have demonstrated that GP2 is able to aggregate with other exocrine regulated secretory proteins in acidic conditions designed to mimic the trans-Golgi network and immature secretory granule where sorting occurs. GP2 is initially bound to the membrane through a glycosylphosphotidylinositol linkage, which by itself confers membrane protein sorting to the apical plasma membrane. Because GP2 exhibits binding to the soluble digestive enzymes within the granule and contains a sorting determinant for the apical plasma membrane, it is likely that the protein plays a significant role in sorting digestive enzymes into the zymogen granule and the regulated pathway. The goal of this application for the next funding period is to define GP2's function. Transgenic knockout techniques will be employed to produce a mouse with a GP2 null allele. Because GP2 is specifically expressed in the pancreatic zymogen granule and the exocrine pancreas is not functional until after birth, it is
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unlikely that an embryonic lethal will result from the mutation. Thus preparations have been made to analyze the resultant mutant mice using biochemical, morphological, and physiological approaches. Electron microscopy will be used to study GP2's role on the formation of the zymogen granule. Primary pancreatic cultures will be used to study the integrity of the regulated secretory pathway in the mutants. To establish that any resultant phenotypes are truly secondary to the GP2 null mutant, preparations have been made for the reconstitution of wild-type GP2 in primary pancreatic cultures using adenovirus mediated gene delivery. Adenovirus expression of a variety of mutant GP2 constructs will be used to identify important functional domains in the protein. Last, studies will be performed on the effects of the GP2 mutation in experimentally induced pancreatitis. The model we propose to generate will provide important information on GP2 biology and may also provide potential models for human acute and chronic pancreatic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZING VIRUSES WITH MASS SPECTROMETRY Principal Investigator & Institution: Siuzdak, Gary E.; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2005 Summary: The goal of our proposed research is to develop novel approaches for characterizing viruses, initially we will focus on human rhinovirus (HRV), flock house virus (FHV) and adenovirus, and further, use this technology as a general assay for the identification of viruses as well as viral cellular receptors. One approach is the selective extraction of HRV viruses from solution onto a plate using antibodies or nucleic acid reactive tethers followed by analysis of the proteolyzed capsid proteins. Essentially, this would be developed as a two-step assay (binding combined with mass spectrometry) to extract and identify viruses from biofluids. Furthermore, by tethering HRV and adenovirus to a surface we plan to perform affinity experiments with cellular protein extracts with the goal of identifying cellular receptors via protein mass mapping. A more specific outline of our research aims are as follows: 1. Develop affinity approaches attached to a solid support to selectively capture viruses. The target virus systems will be extracted from the solution and identified by proteolytic mass mapping of their capsid proteins. Desorption/ionization techniques such as matrix-assisted laser desorption/ionization (MALDI) and desorption/ionization on silicon (DIOS) will be used initially. Liquid chromatography tandem mass spectrometry will also be used for these analyses to allow for the analyses of heterogeneous protein samples. As there are no rapid, inexpensive screens for most viral infections this approach will be further developed as a general method for identifying viruses. 2. Identify cellular protein receptors using immobilized virus. Whole immobilized adenovirus and HRV will be subjected to cellular extracts, followed by removal of unbound material and subsequent analysis of the proteins bound to the virus. Proteolysis followed by mass analysis and database searching will allow for the characterization of viral receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHIMERIC ADENOVIRUS VACCINE VECTORS FOR HIV/SIV Principal Investigator & Institution: Barouch, Dan H.; Instructor in Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006
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Adenovirus
Summary: (provided by applicant): The development of a safe and effective HIV-1 vaccine is a global health priority. Recombinant adenovirus serotype 5 (rAd5) vectorbased vaccines have been shown to elicit potent cellular immune responses in animal models and are being developed as candidate HIV-1 vaccines. However, the high prevalence of preexisting immunity to Ad5 in human populations will likely substantially limit the immunogenicity and clinical utility of rAd5 vaccines. Recombinant adenovirus serotype 35 (rAd35) vector-based vaccines are therefore being developed as potential alternatives to rAd5 vaccines. Our preliminary studies demonstrate that a rAd35-Gag vaccine effectively evades anti-Ad5 immunity but is substantially less immunogenic than a rAd5-Gag vaccine in mice. The development of improved vaccine vectors is therefore urgently needed. In this Innovation Grant, we propose to construct novel chimeric rAd vectors that combine the desirable properties of rAd5 and rAd35. The Ad5 fiber protein may be critical for rAd5 immunogenicity, whereas the Ad5 hexon protein is the primary target of Ad5-specific neutralizing antibodies. We therefore hypothesize that chimeric rAd vectors containing the Ad5 fiber and the Ad35 hexon will both retain the immunogenicity of rAd5 and effectively evade anti-Ad5 immunity. If successful, these novel vectors could be developed rapidly as improved adenovirus vaccines for HIV-1. We propose the following three Specific Aims: I. To construct and assess the immunogenicity of rAd35 vectors containing the Ad5 fiber in mice; II. To construct and assess the immunogenicity of rAd5 vectors containing the Ad35 hexon in mice; and III. To assess the immunogenicity of the optimal chimeric rAd vector in a pilot study in rhesus monkeys. This project is consistent with the goals of PA-03-082, which aims to support the entrance of innovative, exploratory, high risk/high impact prophylactic vaccine concepts into the research pipeline. Within the two-year time frame of this award, sufficient data will be generated with candidate chimeric rAd vaccines to justify further vaccine/challenge studies in rhesus monkeys. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLINICAL AND LABORATORY STUDIES OF MALIGNANT LYMPHOMAS Principal Investigator & Institution: Levy, Ronald; Professor; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 27-JUN-1997; Project End 31-MAR-2005 Summary: (provided by applicant): Accumulated experience towards recruiting a patient's immune system to battle malignant lymphomas suggest that polypeptide vaccines offer the best combination of safety and efficacy. The adenovirus approach proposed in the original project application for the treatment of T-cell lymphomas has been abandoned. However, we are now faced with the major challenge of producing these patient-specific polypeptide therapeutics rapidly and at an acceptable cost. A new and unique product is required for each patient. Recent and exciting advances in the Swartz laboratory in the Department of Chemical Engineering at Stanford suggest the feasibility of using cell-free protein synthesis technology. Preliminary results show reliable synthesis of a variety of vaccine candidates and also suggest promise for producing bioactive immune stimulators such as GMCSF. The research proposed in this application will continue to develop technology that will eventually lead to production of vaccines within a week of specimen acquisition and at costs that are a fraction of those required for competing technologies. These capabilities are essential for the general adoption of this promising therapy for treating T-cell malignancies. The specific aims for this project are: 1. Increase the stability of linear DNA templates in cell-free synthesis reactions to allow efficient vaccine production from PCR products. 2. Develop
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reliable and inexpensive technology for the consistent expression of 5 mg of insoluble vaccine polypeptide per batch reaction. 3. Develop reliable and inexpensive technology for the expression and purification of 5 mg of properly folded vaccine antigen per batch reaction. 4. Produce a variety of insoluble and soluble fusion proteins as vaccine candidates suitable for efficacy and safety tasting in animal models. This is a supplemental project to complement Project 2 of the Ronald Levy Program Grant entitled "Clinical and Laboratory Studies of Malignant Lymphomas" and focuses specifically on T-cell malignancies. It is required because of the abandonment of the adenovirus approach and is motivated by the opportunity presented by recent advances in cell-free protein synthesis technology. It is projected to have a two-year duration and will be directed by James R. Swartz, Professor, Department of Chem. Engineering, Stanford University. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONDITIONAL REPLICATING ADENOVIRUS FOR GLIOMA TREATMENT Principal Investigator & Institution: Fueyo, Juan; Assistant Professor; Neuro-Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Due to lack of effective therapy, primary brain tumors are the focus of intense investigation of novel experimental approaches that use vectors and recombinant viruses. Therapeutic approaches have been both indirect, whereby vectors are used, or direct to allow for direct cell killing by the introduced virus. Promising therapies can be designed by targeting fundamental molecular defects of the glioma cells. The function of p16-Rb-E2F pathway is abnormal in most malignant gliomas and therefore constitutes a suitable target for anti-cancer therapies. We have previously generated a conditional replicating adenovirus, D24, unable to bind to and inactivate the retinoblastoma protein (Rb). This tumor-selective adenovirus is able to replicate in glioma cells but not in normal cells. Although, the adenovirus induces a potent cytopathic effect in vitro, its anti-cancer effect in vivo is less dramatic. In this project, we propose a series of modifications in the D24 adenovirus in order to render the oncolytic virus more efficient infecting and killing glioma cells in vivo. In addition, experiments will be designed to introduce the necessary modifications in the D24 adenovirus to increase its specificity and to control pharmacologically its replication and spread. In vivo cancer gene therapy approaches for gliomas based on adenoviral vector-mediated gene delivery and oncolytic adenoviruses can be limited by the suboptimal efficacy of adenoviruses to infect tumor cells. This issue is mainly due to deficiency of the primary adenoviral receptor on the tumor targets. To circumvent this deficiency, we propose the construction of a tumor-selective adenoviral targeted to a tumor cell marker. In this regard, RGD-related integrins are frequently overexpressed in gliomas. Furthermore, these integrins recognize the RGD peptide motif. On this basis, we will construct an adenoviral vector genetically modified to contain such a peptide within the HI loop of the fiber protein as a means to alter viral tropism. This RGD-D24 adenovirus should infect glioma cells in vivo with extraordinary efficiency, increasing dramatically the oncolytic power of the D24. In Specific Aim 1. We propose to characterize the anticancer effect of D24-RGD in vitro in comparison with D24. In Specific Aim 2, the D24-RGD construct will be characterized in vivo using an orthotopic glioma animal model. In addition, we will examine the correlation between the anticancer effect of the D24-RGD ant its spread throughout the tumor. The experiments will require pathological examination of the tumors, viral protein expression, as well as
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examination of spread of the virus throughout the tumor. We will asses the replication of the virus within the tumor and titer the viral production in vivo. Finally, we will analyze how the administration of anti-adenoviral drugs influence the growth of D24RGD-infected tumors. In Specific Aim 3, we will combine a high-effective oncolytic adenovirus with a regulatory system that can be used to control viral replication in vivo in a selected site and at a desired time. The D24-RGD construct will be genetically modified to include drug response elements sensitive to the effect of tetracycline. To obtain tissue-specific expression of the target gene, we will coupled the regulator to a cancer specific (E2F-1) promoter to drive the early viral genes. The combination of an inducible system and a tissue-specific promoter will allow the development of an innovative oncolytic system, which is able to kill cancer cells and spread within the tumor in a cell type-specific and time- and level-controllable fashion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--GENE TRANSFER Principal Investigator & Institution: Mcdermott, Paul J.; Associate Professor; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: The function of the Gene Transfer Core is to provide a facility for the construction, screening, large-scale purification, and titrating of replication-defective, recombinant adenoviruses. Recombinant adenoviruses provide a reliable method for high efficiency gene transfer into adult cardiocytes and for directly altering the phenotype. Specifically, the core will 1) maintain lines of human 293 endothelial kidney cells [HEK], 2) amplify and maintain purified stocks of adenovirus shuttle plasmids and adenovirus backbone plasmids, 3) transfect recombinant adenoviral DNA into 293 HEK cells, 4) propagate recombinant adenoviruses in 293 HEK cells, 5) plaque-purify recombinant adenoviruses and perform large-scale purifications, and 6) titer purified adenoviruses by plaque assays in 293 HEK cells. The core will also be responsible for long-term storage of recombinant adenoviruses and will assist individual investigators in carrying out gene transfer protocols in adult cardiocytes. A full-time research specialist has been trained in all of the procedures and techniques involved in running this core, and will be supervised by the core director. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--IMMUNOLOGY/PATHOLOGY FACILITY Principal Investigator & Institution: Atkinson, Mark A.; Professor; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: The Immunology/Pathology of The University of Florida Gene Therapy enter has been formed to assist investigators participating in gene therapy projects aimed at reversing and/or preventing phenyhlketonuria (PKU), alpha-1-anti-trypsin (AAT) deficiency, disorders of glycogen storage, and pilot projects related to diseases of the liver. Specifically, the Core will support these investigations by performing immunological and pathological analyses that characterize the host's immune system and cell/tissue response to agents proposed for or actively used in clinical trials based on gene therapy. This goal will be accomplished by performance of two specific aims: 1) Determine the immunogenicity of recombinant adeno-associated virus (rAAV) transgene products and capsid protein administered to animals in studies investigating long-term therapeutic gene transfer and expression; 2) Determine the tissue
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compartment of engraftment in host tissue, both with respect to site(s) of engraftment and toxicity of endogenous host tissues. Such studies Are vital in order to evaluate whether engraftment and toxicity to endogenous host tissues. Such studies are vital in order to evaluate whether methods for limiting/eliminating immune responses against vector capsid proteins and transgene products or directing engraftment/reducing cellular toxicity (were they identified) require development. Specific examples of vector based systems to which these services will be provided/applied include the rAAV, rAAV-green fluorescent protein, rAAV-acid alpha- glucosidase, and adenovirus infection based systems. In addition to providing a critical element for assurance of therapeutic safety, the Immunology/Pathology Core should provide information that will enhance the feasibility and efficacy of gene delivery trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CRYO-EM STRUCTURAL STUDIES OF ADENOVIRUS CELL ENTRY Principal Investigator & Institution: Stewart, Phoebe L.; Associate Professor; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2004; Project Start 01-AUG-1997; Project End 31-DEC-2008 Summary: (provided by applicant): The long-term objective of this project is to understand the events involved in adenovirus (Ad) cell entry at the molecular level. The specific goals for the next funding period are to undertake high resolution structural studies of Ad and Ad/integrin complexes, to investigate the geometry of the interaction between Ad and its host cell receptors, and to define the conformational changes induced in alpha-v beta-5 integrin by binding to monovalent and multivalent ligands. The proposed research will definitively test the paradigm that Ad has evolved efficient pathways for infecting specific cell types and for inducing integrin cell signaling events. The results will bridge the knowledge gap between our understanding of Ad molecular biology and the rapidly expanding field of Ad vector based gene therapy. In the previous funding period, we have made exciting new discoveries that have provided a better characterization of Ad structure and its interaction with host cell receptors. An emerging concept is that the precise three-dimensional orientation of the virus with its associated receptors is a contributing factor to viral tropism. The proposed higher resolution studies will enable us to characterize the tertiary protein fold of the Ad penton base protein, which interacts with alpha-v integrins during viral cell entry, as well as the conformation of alpha-v integrin when bound and clustered by the multivalent Ad penton base protein. The specific aims are designed to address two fundamental questions: 1) What structural features of Ad are critical for efficient binding to host cell receptors? 2) What conformational changes does Ad induce in alpha-v beta-5 integrin to initiate signaling pathways? Advances in cryo-electron microscopy (cryoEM) have made determining a high resolution structure of an icosahedral virus and cryoelectron tomography of Ad/receptor vesicle complexes feasible. These advances include the development of automated data acquisition software, computer-controlled tomography software, parallelized image processing software, and microscopes with liquid-helium-cooled specimen stages. Cryo-EM methods have also recently been extended to detergent solubilized membrane proteins and we will apply this approach to determine structures of alpha-v beta-5 integrin and an Ad/alpha-v beta-5 integrin complex. Increased knowledge of the Ad cell entry process may provide an opportunity to develop antivirals that block viral cell entry and will facilitate the rational design of targeted Ad vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CTL EFFECTOR MECHANISMS IN ADENOVIRAL HEPATITIS Principal Investigator & Institution: Thiele, Dwain L.; Professor of Internal Medicine and Chief; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 31-MAY-2004 Summary: We hypothesize that Fas/Fas ligand-dependent cytotoxic T lymphocyte (CTL) effector mechanisms are critically important in killing of virally infected hepatocytes. This contrasts with CTL responses to allogeneic or virally infected target cells of non- hepatic origin, where perforin-dependent mechanisms play a more prominent role. The hypothesis is based on preliminary studies indicating that defects in Fas/Fas ligand-dependent immune effector mechanisms greatly prolong in vivo expression of adenovirus encoded genes in the liver. Moreover, CTL killing of hepatocyte targets appears to be largely Fas ligand-dependent and is not dramatically impaired by perforin deficiency. In the proposed studies, we will test this hypothesis by examining mechanisms involved in CTL-mediated killing of hepatocyte targets and silencing of virally encoded genes expressed in hepatocytes. We will isolate intrahepatic CTL from adenovirus infected mice and directly examine the cytolytic effector mechanisms utilized in killing adenovirus-infected hepatocytes. The adhesion and other co-stimulatory molecules that are expressed by adenovirus-specific CTL and play a role in interactions with adenovirus-infected hepatocytes will be identified. We will determine whether different CTL effector mechanisms silence adenovirally transduced foreign genes encoding cytosolic, cell surface or secreted proteins. The hypothesis, that selective modulation of Fas-dependent effector mechanisms by adenovirus encoded immunomodulatory proteins will significantly alter the duration of hepatic expression of other virally encoded genes, will be tested. These studies will provide insights into CTL effector mechanisms involved in clearance of viral infections from the liver and have the potential to direct strategies that enhance and prolong expression of liverdirected gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CYTOTOXIC T CELL TRANSFER FOR THERAPY OF EBV LYMPHOMA Principal Investigator & Institution: Rooney, Cliona M.; Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-1993; Project End 31-JAN-2004 Summary: (Adapted from Applicant's Abstract): Adenovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the three commonest causes of lethal viral disease in patients immunocompromised by allogeneic stem cell transplantation (SCT). No drugs are available to treat adenovirus or EBV infections, and conventional agents for CMV have many limitations. Hence there is considerable interest in the use of T-cell based therapies to restore immunity to these pathogens. The current application builds on this group's earlier work, showing that EBV specific CTL generated by culture of donor T cells with donor EBV-transformed lymphoblastoid cell lines (LCL) can be safely administered to SCT recipients and act as effective EBV prophylaxis. Moreover, gene marking the CTL before infusion showed that these cells persisted long term and infiltrated and destroyed sites of active EBV lymphoma. This grant now proposes to use the excellent antigen presenting properties of EBV-LCL to present additional antigens, derived from adenovirus and CMV, ultimately generating a CTL line from a single culture that has specificity for all three viruses. The three Specific Aims are based on substantial pre-clinical feasibility data. In Aim 1, patients will continue to receive EBV-
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specific CTL but will receive in addition gene marked adenovirus specific CTL in a dose escalation study, to establish their safety and persistence. In Aim 2, EBV-LCL themselves will be pulsed with adenovirus and used to generate bi-specific lines recognizing both EBV and CMV. These will be infused into patients and their persistence and anti-viral immune activity measured. In Aim 3, EBV-LCL will be pulsed with both adenovirus and CMV, and tri-specific CTL lines prepared. Following infusion, their safety, persistence and anti-viral immune activity will be determined. This plan to develop a cell based anti-viral therapeutic that derives from a single culture system, will offer a practical and cost-effective means of preventing these three lethal infections after SCT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF NOVEL ADENOVIRUS-LENTIVIRUS HYBRID VECTOR Principal Investigator & Institution: Margalit, Ruth; Intragene Sciences, Inc. 2775 Monterey Rd San Marino, Ca 91108 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2003 Summary: (provided by applicant): The overall goal of these studies is to develop a novel adenovirus-lentivirus hybrid vector system for efficient gene delivery and longterm gene expression, and to use this hybrid vector as a vehicle for stable transduction of therapeutic genes for cancer gene therapy. To this end, we will construct and test helper-dependent adenovirus vectors that contain a complete packaging system for production of lentivirus vectors in situ. We will first test the hybrid vectors in cell culture studies to optimize the vector-associated parameters that might affect in situ second-stage lentivirus vector production and subsequent stable transduction efficiency. To explore the potential of these hybrid vectors for use in therapeutic applications, we will test their ability to achieve efficient in vivo gene delivery and long-term expression of an anti-angiogenic factor, endostatin, in an animal model of prostate cancer. Although previous studies have demonstrated tumor inhibition by endostatin, significant problems with systemic administration of this peptide have been encountered, including difficulty in producing adequate amounts of functional protein for in vivo use, and instability resulting in a very short circulating half-life, which necessitates highdose bolus or continuous infusion schedules to maintain effective serum concentrations. We hypothesize that the adenovirus-lentivirus hybrid vector system has the potential to achieve high-level and long-term anti-angiogenic gene expression in vivo, and may thereby reduce local tumor growth and metastatic potential after intra-tumoral administration. We will first develop adenovirus-lentivirus hybrid vectors for stable gene expression, and evaluate the therapeutic efficacy of the anti-angiogenic gene in vitro. Subsequently, by using a mouse model of prostate cancer, we will evaluate the therapeutic efficacy of adenovirus--lentivirus hybrid-mediated gene transfer after intratumoral administration. These studies should ultimately lead to development of more efficient and widely applicable cancer gene therapy protocols. PROPOSED COMMERCIAL APPLICATION: Highly efficient and permanent delivery of therapeutic genes for cancer treatment or gene replacement therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DOUBLE STRAND BREAK REPAIR--INHIBITION BY ADENOVIRUS E4 Principal Investigator & Institution: Ketner, Gary W.; Professor; Molecular Microbiol and Immun; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218
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Timing: Fiscal Year 2002; Project Start 19-JAN-2001; Project End 31-DEC-2005 Summary: Adenovirus early region 4 (E4) encodes proteins critical in a variety of processes required for a successful viral infection. While E4 is not required for DNA replication, three E4 proteins (E4 11k, product of E4 ORF3; E4 34k, product of E4 ORF6; and the product of E4 ORF4) regulate replication in infected cells. In addition, most of the viral DNA produced by E4 mutants lacking E4 11k and E4 34k is structurally abnormal, consisting of concatemers of the viral genome up to 6 or more monomers in length. Concatemeric viral DNA is not observed in cells infected by wild-type virus. Eukaryotic cells possess efficient double strand break repair (DSBR) systems for rejoining DNAs broken by radiation and other agents. To test the hypothesis that the concatenated viral DNA seen in E4 mutant infections arises by end-to-end joining of linear intracellular viral DNAs by DSBR, concatemer formation was examined in cells lacking the DNA-dependent protein kinase (DNA PK), an essential component of the cellular DSBR system. No concatemers were observed in E4 mutant infections of DNA PK- cells, consistent with the hypothesis that concatemers arise by DSBR and suggestion that in wild-type infections, E4 prevents concatenation by inhibiting DSBR. Further, E4 34k inhibited V(D)J recombination, a process that requires DSBR, in a plasmid-based assay. Finally, immunoprecipitation experiments showed that both the E4 11k and E4 34k proteins associate physically with DNA PK. Together, these data strongly suggest that both E4 proteins inhibit DSBR, possibly by a mechanism that involves binding to DNA PK. It is likely that suppression of concatemer formation increases the efficiency of viral DNA replication. Additionally, since DNA PK is a proximal element in the pathway that induces p53 activity in response to DNA, inhibition of DNA PK may be anti-apoptotic in infected cells. Thus, the interaction of E4 with DSBR may contribute in two distinct and novel ways to the success of an adenoviral infection. The goal of the work proposed here is to develop an understanding of the physical nature of the interactions between these E4 products and DNA PK, and to determine the significance to the viral life cycle of this newly-recognized aspects of E4 function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENHANCED CRAD FOR ESOPHAGEAL ADENOCARCINOMA Principal Investigator & Institution: Yamamoto, Masato; Surgery; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Esophageal adenocarcinoma is now the fastest growing cancer category in western men. Additionally, the prognosis of locally advanced disease has remained static despite current management advances. These facts clearly indicate the necessity of developing novel therapeutic approaches for esophageal adenocarcinoma. Even though conditionally replicative adenoviruses (CRAds) offer a novel and potent modality to approach solid tumors of the gastrointestinal tract, esophageal adenocarcinoma cells are extremely resistant to adenoviral infection due to minimal expression of the adenoviral primary receptor (coxsackie-adenovirus receptor, CAR). Furthermore, the lack of promoters with selectivity for esophageal adenocarcinoma has hindered the construction of CRAds that can selectively replicate in target tumor cells to achieve a useful therapeutic index for clinical utility. Lastly, absence of a non-invasive in vivo imaging method to detect CRAd replication and spread has hampered an understanding of CRAd biology in vivo. To achieve full therapeutic potential of CRAds for esophageal adenocarcinoma, we propose the construction of promoter-driven, infectivity-enhanced CRAds with imaging capabilities. To address the first issue, we have identified three promising promoters that exhibit
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favorable "tumor versus liver" and "tumor versus normal mucosa" differentials which are critical for utility in an adenoviral context. As well, we have developed methods to alter the tropism of adenoviruses, thereby achieving infectivity enhancement of tumor target ceils. The incorporation of an RGD4C motif in the HI loop of the fiber-knob region and Ad5/3 chimeric fiber modification has been shown to dramatically improve the infectious potency of adenovirus on esophageal adenocarcinoma cells. These findings offer solutions to the problem of esophageal adenocarcinoma cell resistance to adenoviral infection. In addition, we will configure optical and radiological imaging functions into our infectivity enhanced CRAds driven by optimal promoter. These features provide minimally invasive detection of CRAd replication and spread in a clinical setting, serving as a monitoring system with relevance to patient safety. Thus, it is obvious that infectivity-enhanced CRAds controlled by an optimal promoter element and possessing an imaging capability will be a therapeutic agent with great clinical utility for esophageal adenocarcinoma. The applicability of these modalities will be established from both toxicological and tumoricidal effect standpoints along with confirmation of CRAd functionality by optical and radiological imaging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESTROGEN DEPENDENCY OF UTERINE LEIOMYOMA Principal Investigator & Institution: Al-Hendy, Ayman; Obstetrics and Gynecology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2003; Project Start 24-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Uterine leiomyoma arise from the uterine smooth muscle compartment (myometrium) and are the most common gynecologic tumor in premenopausal women, occurring in up to 77% of all women. They are all significant cause of pelvic pain, menorrhagia, infertility, and pregnancy-related complications. These estrogen-dependent tumors are the leading indication for hysterectomy in reproductive age women. Currently, no medicinal therapy exists. Prolonged use of GnRH agonists, which can shrink tumors but induce a chemical menopause, is restricted due to serious side effects. The hormone-dependent phenotype of uterine leiomyoma suggests that interventions targeting the estrogen receptor (ER)-signaling pathway may have therapeutic efficacy. Proof-of-principal experiments have now established that treatment with anti-estrogen medications (e.g., tamoxifen and raloxifene) can significantly reduce tumor incidence, size, and proliferative index in the Eker rat, the only animal model known to acquire spontaneous uterine leiomyoma. Adenovirusmediated delivery of a mutated dominant-negative ER (Ad-ER-DN) inhibited cell proliferation and induced apoptosis in human and rat leiomyoma cell lines. In a pilot experiment, Ad-ER-DN injected directly intratumor in nude mice with pre- existing fibroids induced immediate arrest and regression of tumor growth due to extensive apoptosis. explants in nude In this project, we will (Specific Aim 1) determine if Ad-ERDN transduction inhibits endogenous ER signaling in estrogen-responsive rat and human leiomyoma cells, (Specific Aim 2) expand pilot results and evaluate the ability of Ad-ER-DN to ablate pre-established subcutaneous leiomyoma mice, and (Specific lira 3) conduct a pre-clinical trial to assess the ability of Ad-ER-DN to ablate uterine leiomyoma when delivered by direct intratumor injection in the immune-competent Eker rat. Tumor response will be correlated to proliferative and apoptotic indices, to markers of tumor angiogenesis, and to several estrogen-regulated genes. We will examine immune response and the safety of single vs. repeated recombinant adenovirus treatment alone or in combination with SERM (Raloxifene). Evident therapeutic potential aside, this project will add to our understanding of the molecular mechanisms
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of estrogen-dependence in this common uterine tumor. It will also show, in a wellcharacterized natural rat model, the effects of specific perturbing of ER signaling on several cellular functions (i.e., angiogenesis, apoptosis, and cell cycle). This knowledge will impact many other estrogen-related conditions (e.g., breast and endometrial cancer, cardiovascular disease, osteoporosis). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EXPRESSION OF THE COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR Principal Investigator & Institution: Cohen, Christopher J.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): As a pediatrician with a background in cell biology and infectious diseases, my interest in the host-pathogen interaction has been longstanding. The development of new therapeutic modalities that will ultimately lead to improvements in healthcare is dependent on the continued investment in welldesigned biomedical research. Tissue-specific expression of viral receptor molecules is an important determinant of viral tropism. Group B coxsackieviruses and many adenoviruses initiate infection by binding to the coxsackievirus and adenovirus receptor (CAR). We believe that detailed understanding of virus entry and its relation to virus tropism will require us to understand the biology of viral receptors- including their subcellular localization, their intracellular trafficking, and their interactions with other proteins that may function in virus entry, or restrict receptor accessibility to virus. This belief is grounded in the recent unexpected observation that, despite CAR expression on respiratory epithelial cells, intact respiratory epithelium is impervious to adenovirus entry. Our collaborators and we have found that in well-differentiated epithelium, signals within the CAR cytoplasmic domain target receptor expression to the basolateral cell surface, where it is inaccessible to virus. CAR's primary biologic function remains uncertain, and its cell biology remains poorly understood. We have found that CAR localizes to intercellular contacts where it may be involved in adhesion, intercellular recognition, or contact-dependent signaling. In polarized epithelium, CAR is expressed at the tight junction--a specific epithelial structure regulating paracellular transport of molecules and inflammatory cells--in association with the protein ZO-l. The recently identified reovirus receptor is also a tight junction component, raising questions about why three unrelated virus groups, all of which traverse epithelial surfaces in the course of infection, have evolved to interact with molecules that may be sequestered in intercellular contacts. The experiments outlined below will define CAR's function in virus infection of epithelial cells, and its contribution to the formation and structure of the epithelial tight junction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EXTRACELLULAR BARRIERS TO GENE TRANSFER IN THE LUNG Principal Investigator & Institution: Boucher, Richard C.; Director; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (provided by applicant) Dosing patients with gene transfer vectors for the treatment of lung disease likely will require intraluminal delivery strategies. We hypothesize that vector delivery via this route will confront two major barriers prior to any potential vector interaction with a cell surface receptor: (1) the transported mucus
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layer; (2) the cell surface tethered mucin/glycocalyx layer. Surprisingly little is known about the relative efficiencies (defined as percent of delivered vectors reaching epithelial cell surfaces) of the two principal delivery modes (aerosolization; lavage) for topical airways vector delivery. Thus, prior to further human clinical studies, we propose first to quantitate the barriers to vector penetration to the epithelial cell surface afforded by mucus clearance after aerosol vs. lavage vector delivery. Because we speculate that clearance of topically delivered vector will be rapid, and hence delivery to epithelial cell surfaces inefficient, we propose strategies to increase the efficiency for both aerosol and lavage administration, and use these data to select an optimal delivery system for our mouse studies (see below). Next, we hypothesize that vectors that escape mucus clearance will confront a second barrier, the cell surface -glycocalyx. Thus, we propose to identify the components of the glycocalyx that contribute to the functional barrier to gene transfer and design strategies to abrogate these barriers in studies with welldifferentiated and freshly excised human airway epithelial preparations. The concepts and strategies to abrogate the barrier function of the glycocalyx, particularly the contribution of the tethered mucins MUC1 and MUC4, will be extended to in vivo conditions using transgenic mice. Employing a defined target (GPI-CAR) for adenovirus mediated gene transfer in the apical membrane of airway epithelia in transgenic mice, we will systematically explore the role of the glycocalyx as a barrier to gene transfer in wild-type mice and mice deficient in MUC1 and MUC4. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONAL GENOMICS OF THE BETA-CELL Principal Investigator & Institution: Kaestner, Klaus H.; Associate Professor; Genetics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-JUL-2007 Summary: (provided by applicant): Diabetes mellitus is a significant health problem, affecting approximately 16 million people in the United States. Future therapeutic approaches to diabetes will benefit greatly from a complete understanding of the expression profile of the beta cell under normal and pathological conditions and the functional annotation of differentially expressed genes. The goal of this application is to pool the complementary expertise available in three laboratories for mining of an exciting new resource-the more than 7,700 unique cDNAs cloned by the prior NIDDKfunded consortium on "Functional Genomics of the Developing Endocrine Pancreas". Our goals are three-fold: Aim 1 of this proposal will establish a large cDNA microarray enriched for genes expressed in the endocrine pancreas by combining the 7,700 nonredundant cDNAs described above with the 3,400 clones of our current PancChip 2.0. We will employ this microarray for the screen of six paradigms of perturbed P-cell function to identify candidate genes to be analyzed further in aims 2 and 3. Aim 2 will transfer 1,000 selected cDNA clones from our collection into the FLEXGene repository. This repository will allow for high-throughput transfer of cDNAs into multiple expression vectors. In addition, we will select antigens for the production of antisera to derive marker antibodies of beta cells and their precursors. In Aim 3 we will functionally evaluate 500 selected cDNAs for their potential role in beta-cell biology. Clones transferred into the FLEXGene repository and sequence verified (Aim 2) will be subcloned into adenovirus vectors to allow for efficient transduction of INS-1 cells. In some cases, the sequence of differentially expressed genes will be used for design of interference RNA (RNAi) oligonucleotides to allow suppression of target gene expression. The effect of modulation of target gene expression will then be tested in various models of R-cell function. Candidate cDNAs that are positive in this screen will
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be further evaluated in adenovirus-transduced islets and/or transgenic animals. Genes identified in this fashion may become candidate drug targets or could be useful in development of surrogate p-cells for cell-based insulin replacement therapy. This project will serve as a valuable gene discovery effort that will complement the program implemented by the NIDDK-funded beta-cell biology consortium. The new resources generated through this project will be made available to the NIDDK-funded biotechnology centers and the diabetes research community at large. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE MODIFICATION OF ADENOVIRUS CAPSID PROTEINS Principal Investigator & Institution: Falck-Pedersen, Erik S.; Professor; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: Uptake by a specific target cell is a critical first step in gene transfer, which in most systems is limited by the endogenous entry pathway used by a particular gene transfer vector/virus. We have successfully engineered the Ad 5 vector to bind to a target cell through a different high affinity receptor than that normally used by the subgroup C viruses. Although we have made considerable progress in this area, there is still a considerable need for continuing our efforts to target Ad vectors. This is especially true if we are to target tissues such as well differentiated airway epithelium which have been reported to lack the high affinity as well as low affinity receptors that are used by subgroup C viruses for entry. Steps essential to Ad-mediated gene transfer: 1) attachment to the cell via the high affinity receptor (fiber binding to CAR, MHC-1), 2) facilitated internalization mediated by penton interaction with the alphavbeta3,5 integrins, and 3) endosomal escape which is a function of conformational changes in the major capsid protein hexon, are the aspects of Ad vectors which make them the most efficient gene transfer vector available. These proteins are also the primary targets of innate and acquired immune systems which are responsible for the lack of persistence of gene transfer by Ad vectors as well as the neutralizing immunity which compromises the effectiveness of repeat administration of Ad vectors. The focus of this project is to genetically modify the major capsid proteins of Adenovirus (Ad): hexon, fiber, and penton to the advantage of gene transfer of gene transfer to airway epithelial cells. It is our position that these proteins are the key mediators of both positive and negative attributes of Ad gene transfer vectors and our ability to genetically manipulate to genetically manipulate them will result in more efficient gene transfer, a greater degree of target cell specificity and finally a decreased in imunogenicity. Developing the capacity to modify the capsid proteins in our vectors will have direct application to any Ad vector system, including the "gutless vectors", chimeric virus vectors, and Ad vectors used to piggyback large DNA molecules. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GM-CSF & ALVEOLAR MACROPHAGE ANTIVIRAL LUNG DEFENSE Principal Investigator & Institution: Trapnell, Bruec C.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: This application will test the hypothesis that granulocyte-macrophage-colony stimulating alveolar macrophage (AM) innate antiviral mechanisms and by limiting inflammation during viral lung infection. GM is a hematopoietic growth factor recently
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shown to be vital to lung homeostasis and host defense. The role of GM in early hematopoiesis appears to be redundant, however, its role in the lung is unique. While the mechanism(s) through which GM regulates lung host defense are unclear, GM modulates multiple, diverse function of AM. Based on our preliminary data and published reports, we propose that GM interacts with AM precursors in the lung, stimulating their terminal differentiation, and increases their capacity to internalize and degrade viral pathogens from the respiratory surface (i.e., GM increases intrinsic clearance of AM (ICAM). By increasing ICAM, GM increases primary pathogen clearance (i.e., by resident AM) thus reducing or obviating the need for chemotactic/proinflammatory cytokine signaling and secondary clearance (i.e., by recruited leukocytes). Murine models will be used in which the synthesis of GM is: 1) normal (GM+/+; 2) absent (GM-/-); 3) constitutively over- expressed in the lung (SPCGM/GM-/-); or 4) conditionally expressed in the lung under positive external control using a novel bitransgenic system (BTx-GM or BTx-GM/GM-/-. In the latter model, GM expression can be induced or extinguished, temporally, by addition or withdrawal of oral, aqueous doxycycline resulting in lung GM levels ranging from absence to overexpression. GM-deficient and replete mice will be used to study the in vivo role of GM in: (Aim 1) stimulating AM receptor expression and internalization of adenovirus; (Aim 2) trafficking and degradation of adenovirus in AM; and (Aim 3) limitation of inflammation during adenovirus infection of the respiratory tract. We will identify and characterize the mechanisms by which AM internalize and degrade adenovirus in vivo and in vitro. We will also discern the temporal relationship between GM expression in the lung and AM differentiation, ICAM (for adeno-virus), and the relationship between ICAM and limitation of lung inflammation. Our studies will help clarify the critical role of GM in modulating AM function, stimulation of innate lung host defense, and in limitation of lung inflammation and thus, will help establish the feasibility of the therapeutic use of recombinant GM for prevention or treatment of common acute and chronic lung infection and lung inflammation in various clinical disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMATOPOIETIC STEM CELL THERAPY FOR MYOCARDIAL REGENERAT Principal Investigator & Institution: Bolli, Roberto; Chief; Medicine; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Recent reports that HSCs can regenerate infarcted myocardium have unleashed a tidal wave of enthusiasm for translating these findings to the clinical arena. A number of institutions have already initiated studies of cytokine or HSC therapy in patients with acute MI. It is our opinion that this rush to clinical trials is not only premature but possibly counterproductive, and that further, careful preclinical investigation is necessary to establish the efficacy of various treatment protocols and the underlying mechanisms. For example, nothing is currently known regarding whether i.v. HSC administration is effective, which cytokine or combination of cytokines is more likely to succeed, how long the window of efficacy is, and whether HSCs are effective in the context of reperfusion. Similarly, nothing is known regarding the nature of the integrin/adhesion molecule interactions that underlie the homing of HSCs or the potential synergistic role of accessory calls, specifically, the FCs. Our fundamental hypothesis is that both i.v. injected and cytokine-mobilized HSCs can regenerate infarcted myocardium and that this process is mediated by a well-defined cascade of molecular interactions that involve specific adhesion molecules (ICAM-1, VCAM-1, P-
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selectin, and E-selectin), integrins (VLA-4, VLA-5, and LFA-1), chemokines (SDF-1), and chemokine receptors (CXCR-4). We further propose that FCs exert an important potentiating effect on HSC-dependent cardiac reqeneration and that this process can be further enhanced by FL These hypotheses will be tested in a well-established murine model using a broad multidisciplinary approach that will encompass diverse techniques (integrative physiology, protein chemistry, biochemistry, pathology, confocal microscopy, immunohistochemistry, molecular immunology, molecular biology, and gene therapy). Aim I will assess the effectiveness of two clinically-relevant forms of HSC therapy (i.v. HSCs and cytokines) in two different models designed to simulate reperfused and nonreperfused MI and will define the time-window of efficacy. Three clinically-applicable cytokines (G-CSF, SCF, FL) will be tested, alone or in combination. Using gene targeted mice and immunologic blockade of integrins, Aim 2 will systematically investigate the role of four specific adhesion molecules (VCAM-1, ICAM1, P-selectin, and E-selectin) and three specific integrins (VLA-4, VLA-5, and LFA-1) in HSC migration to the infarcted myocardium. Aim 3 will decipher the role of SDF1/CXCR-4 interactions in HSC homing and infarct repair, using adenovirus-mediated gene transfer of SDF-1 and CXCR-4. Aim 4 will explore the differential regenerative capacity of HSCs and FCs harvested from bone marrow vis-a-vis peripheral blood and the underlying mechanisms. Aim 5 will determine whether FCs induce allogeneic graft tolerance to HSCs via a Th2 cytokine (IL-4 and IL-10)-dependent mechanism. This proposal will yield novel information regarding the ability of i.v. HSCs and various cytokine regimens to regenerate infarcted myocardium, the molecular mechanisms for HSC homing, the potential role of FCs, and the beneficial effects of FL. The results may eventually lead to the development of novel therapeutic strategies in patients with ischemic heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HUMAN PAPILLOMAVIRUS GENE EXPRESSION Principal Investigator & Institution: Broker, Thomas R.; Professor; Biochem & Molecular Genetics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-1984; Project End 31-MAY-2004 Summary: (provided by applicant): A safe oncolytic virus, suitable as a therapeutic agent, must target cancer cells for destruction but not propagate in normal tissues. We have recently reported the first use of organotypic "raft" cultures of primary human keratinocytes, which form fully stratified and differentiated epithelia, to test the properties of a conditional replication-competent adenovirus (CRAD) CB016 targeted to tissues expressing the human papillomavirus (HPV) oncogenes E6 and E7 (Balague et al., 2001). Mucosotropic HPVs cause a spectrum of hyper-proliferative ano-genital and oral lesions, including condylomata, papillomas, dysplasias, and carcinomas of cervical, penile, anal, and tonsillar epithelia with no effective treatment or vaccine. HPV E7 protein shares considerable functional homology with the adenovirus E1A proteins, in inactivating the host tumor suppressor protein pRB and related p107 and p130. This functional homology forms the conceptual basis for the development and investigation of Ad5 CB016. This virus is deleted of conserved regions CR1 and CR2 of E1A. It replicates and is cytolytic in raft cultures that express the HPV-18 oncogenes, but not in control raft cultures. However, in carefully conducted time course experiments, we further demonstrated that productive infection of CB016 was considerably delayed, but not eliminated, in normal raft cultures. Our long-term goal is to build upon these initial findings and design new safer CRAD having minimal cytopathic effects in normal raft cultures, but oncolytic in HPV oncogene-expressing raft cultures that simulate benign
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papillomas, dysplasias and cancers. Emphasis will be placed on the deletion of 19 kDa Ad E4-E6/7 protein, which complements E1A mutations by forming transcriptionally active complexes with the E2F/DP1 family of transcription factors, and on additional domains of the E1A protein, which also activate other early adenovirus promoters. We also intend to investigate the incorporation of Ad E1B deletions as an additional safety feature for normal tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMAGING TRANSGENE EXPRESSION IN GENE THERAPY PROTOCOLS Principal Investigator & Institution: Blasberg, Ronald G.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 30-JUL-2002; Project End 31-MAR-2006 Summary: (Applicant's Description) We propose to assess transgene expression by noninvasive imaging in patients undergoing gene therapy. Four separate components, involving four different clinical trials, are included in this proposal in order to provide a broad clinical spectrum for assessing the benefits and limitations of imaging transgene expression in a clinical setting. Three different viral vectors (adenovirus, Herpes Simplex Virus, and retrovirus) will be used in these clinical trials and this will provide the opportunity to obtain comparable imaging data for each of the three vectors. Two of the components will involve patients in existing clinical trials at Mount Sinai Medical School in New York. One clinical trial involves patients with hepatic metastases from colorectal cancer, and the other involves patients with local prostate cancer; both trials involve direct intratumoral injection of an adenoviral vector (ADV-tk) expressing the Herpes Simplex Virus thymidine kinase gene (HSV1-tk), followed by intravenous ganciclovir treatment. The third and fourth components will involve both preclinical and clinical imaging studies at MSKCC, and will also involve patients with colorectal hepatic metastases. The third component involves an experimental treatment protocol where a replication restricted Herpes Simple Virus type-1 (mHSV1; G207 or R7020) is injected into the hepatic artery to induce selective cytolysis of dividing tumor cells (hepatic metastases). The fourth component will involve hepatic artery injection of a retrovirus (DCSV or SFG) containing a fusion gene which includes dihydrofolate reductase (DHFR) and HSV1-tk cDNA. The treatment rationale is based on data showing that exposure of transduced tumor cells to trimethotrexate (TMTX) will lead to amplification of DHFR and consequently, to amplification of the HSV1-TK as well; in turn, this will make the transduced cells more sensitive to ganciclovir. HSV-TK imaging will be performed using positron emission tomography (PET) and 124-I labeled FIAU (2'-fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil); we have previously demonstrated that [124I]-FIAU PET imaging of HSV-TK activity following retroviral and adenoviral (ADV-tk) transduction is feasible, selective and quantitative. The preclinical studies in this proposal will: 1) extend these studies and demonstrate selective vector imaging, 2) provide a comparison between mHSV1 (G207 and R7020) and retroviral (DCSV and SFG) vectors in appropriate experimental animal models, and 3) provide imaging data that could support and justify the initiation of clinical trials. The clinical studies are the focus of this proposal and will demonstrate that noninvasive imaging of transgene expression in target tissue can be used to monitor and facilitate the evaluation of gene therapy by defining the location, magnitude and persistence of transgene expression over time. It would also provide the opportunity to assess the spread of the vector to nontarget tissue and organs using whole body imaging techniques, and it could define the optimal time and duration of time for effective pro-drug administration.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOPATHOGENESIS OF ADENOVIRUS KERATITIS Principal Investigator & Institution: Chodosh, James; Associate Professor; Ophthalmology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: (provided by applicant): Ocular infection by subgroup D adenovirus serotypes 8, 19, or 37 causes epidemic keratoconjunctivitis, manifest by acute pseudomembranous conjunctivitis, punctate and macro-epithelial corneal erosions, and delayed-onset subepithelial corneal stromal infiltrates. Subepithelial infiltrates, the hallmark of epidemic keratoconjunctivitis, cause photophobia, foreign body sensation, and reduced vision, and may persist for months to years. On the basis of evidence from our laboratory that adenovirus type 19 infection of human corneal fibroblasts in vitro induces the potent neutrophil chemotactant interleukin-8 (IL-8), we hypothesize that adenoviral subepithelial infiltrates result when infection of superficial keratocytes induces secretion of IL-8 and migration of neutrophils into the corneal stroma. Our long term goal is to understand the interplay between adenoviruses and mechanisms of innate immune response in the human cornea. The specific aims of this proposal are: 1) to test the hypothesis that IL-8 gene transcription in adenovirus-infected human corneal fibroblasts occurs before onset of adenoviral gene transcription, 2) to test the hypothesis that an intracellular signaling cascade mediates adenovirus-induced IL-8 gene transcription in human corneal fibroblasts, and 3) to test the hypothesis that inhibitors of intracellular signaling can be applied to prevent IL-8-induced conical inflammation. The National Plan for Vision Research (1999-2003) by the National Advisory Eye Council noted the "high morbidity and economic costs" of epidemic keratoconjunctivitis (p. 42). Our proposal bridges the gap between studies of corneal immunobiology and corneal infectious diseases and meets a major program objective of the Council: to "analyze the molecular nature of corneal inflammation" (p. 51). The proposed studies are significant because they test novel mechanisms of viral pathogenesis and innate immune defense in the human cornea. Chronic discomfort and reduced vision in epidemic keratoconjunctivitis relate directly to the presence of subepithelial corneal infiltrates. The gaps in our knowledge that this grant intends to fill are: 1) by what mechanism does adenovirus infection stimulate IL-8 production by human corneal fibroblasts; and 2) can signal transduction inhibitors be used to inhibit the innate immune response to adenovirus infection of the human cornea? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPORT OF ADENOVIRUS DNA INTO THE NUCLEUS Principal Investigator & Institution: Gerace, Larry R.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Adenoviruses are non-enveloped DNA viruses with an -36 kb genome. In humans, adenoviruses cause a significant number of gastrointestinal and respiratory infections. They also are a major cause of viral conjunctivitis, including epidemic keratoconjunctivitis (EKC), a condition that can threaten long-term visual function and for which there is no effective treatment. In addition, adenoviruses are being intensively investigated as vectors for human gene therapy because of their broad tissue tropism. Although significant insight has been
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obtained on how adenovirus penetrates the cell to reach the cytoplasm, little is known about the molecular mechanism of nuclear import of the adenovirus genome, which is critical for virus reproduction. This proposal is directed at obtaining detailed molecular insight on adenovirus DNA import. The aims are: 1) The mechanism for docking of adenovirus to the nuclear pore complex will be investigated, focusing on an analysis of the adenovirus hexon protein and its interaction with specific nucleoporins. 2) The role of protein VII in the transport of adenovirus DNA through the nuclear pore complex will be analyzed, and the possibility that protein VII can be used as a nonviral method for achieving efficient gene transfer will be investigated. 3) The role of cytosolic factors, including hsc70 and its cofactors, in virus uncoating at the pore complex and in DNA import, will be analyzed. Considered together, this work will provide a valuable model for understanding the nuclear import of the genomes of pathogenic DNA viruses. The work also could potentiate the development of new therapies for EKC in humans. Finally, it could provide the basis for developing efficient means for nonviral gene transfer, which would be useful for gene therapy and functional studies of cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMPROVED ADENOVIRAL VECTORS FOR HEPATIC GENE THERAPY Principal Investigator & Institution: Kay, Mark A.; Professor; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-MAR-2003 Summary: Recombinant adenovirus vectors offer potential for human gene therapy because of their ability to transduce many tissues at high efficiency in vivo. The enthusiasm for use of these vectors has been tempered by a powerful immunologic response directed against vector containing cells because of the low level synthesis of vector derived antigens. The fact that adenovirus-mediated gene transfer is persistent in animals lacking antigen-dependent immunity establishes the need to produce a less antigenic vector. Dr. Kay and his colleagues recently developed a method for creating high titer adenovirus vectors that were devoid of vector genomic sequences responsible for producing the immune response. Unexpectedly, these deleted vectors, although efficient at gene transfer, with minimal or no toxicity, do not persist in vivo in immunocompetent or immunodeficient animals. This occurred because these deleted vectors could not replicate their genome in transduced cells in vitro and in vivo. Thus it is hypothesized that persistence of adenoviral DNA is inherently related to its ability to replicate. The major goals of this proposal are: 1) to determine the minimal number of adenovirus genes needed for stability and place these back into the vector to make a minimal vector that can persist; 2) determine the mechanism(s) allowing for vector genome persistence; 3) determine the acute toxicity and antigen-dependent immunological responses directed against the new vector; and 4) develop the deleted vector system to produce an integrating vector system. The results of these studies will have important implications for the development of adenoviruses for gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPROVED EFFICACY OF ADENOVIRUS MEDIATED GENE TRANSFER TO AIRWAY EPITHELIA Principal Investigator & Institution: Zabner, Joseph; Associate Professor; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003
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Summary: Gene transfer to airway epithelia has the potential to become an important new treatment for cystic fibrosis (CF) lung disease. However, the poor efficiency of binding and infecting differentiated airway epithelia is a major barrier for adenovirus, as well as for most other vectors. This proposal builds on our earlier work to answer the specific aims. 1) What is the role of the serotype 2 adenovirus (Ad2) receptors in adenovirus infection of human airway epithelia? Our earlier work indicated that the apical membrane of differentiated human airway epithelia lacks receptor activity for adenovirus fiber. With the recent identification of type 2/5 adenovirus receptors, CAR and MHC class Ia2, it is now possible to investigate the cellular and molecular bases for limited adenovirus type 2/5 binding. The results of these studies will tell us why adenovirus infection is relatively inefficient and will help us enhance gene transfer with adenovirus and other vectors. 2) Will genetic modifications of the adenovirus fiber increase vector binding and infection of airway epithelia? In preliminary studies we discovered that serotype 17 adenovirus (Ad17) bound to and infected differentiated airway epithelia more efficiently than Ad2 and Ad5 serotypes, which are currently used as vectors. We will investigate the mechanisms responsible for increased binding and infection. Our preliminary data with a chimeric type 2 adenovirus expressing Ad17 fiber are very encouraging; we will test the hypothesis that this novel chimeric vector can enhance gene transfer to human airway epithelia and correct the CF defect. 3) Will provide modifications of the adenovirus fiber protein improve binding and infection? Our preliminary data and earlier work suggest that if adenovirus binding to the apical surface of airway epithelia can be improved, then gene transfer will be increased. To find new ligands for the unknown apical receptors, we will build on our preliminary work using phage display libraries. This combinatorial approach will identify novel peptide ligands which bind to and are internalized by the apical membrane. We will insert the peptides into the adenovirus fiber protein of recombinant adenovirus fiber protein of recombinant adenovirus vectors and investigate their interaction with the epithelium and ability to enhance gene transfer. These studies using adenovirus vectors will increase our understanding of the mechanisms of gene transfer, improve knowledge of interactions between vectors and the airways, and will suggest new approach to enhance efficiency. Importantly, the results will have immediate application to new generations of adenovirus vectors, as well as other vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INNATE IMMUNE RESPONSE TO ADENOVIRAL VECTORS Principal Investigator & Institution: Nociari, Marcelo M.; Medicine; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (Applicant's abstract) Well known drawbacks, of the adenovirus vector (AdV) gene therapy system are largely associated with the antiviral inflammatory response of the host. Vector induced inflammation, the transient expression of transgenes due to the generation of cytotoxic T-cells, and the development of adenovirus specific neutralizing antibodies have clearly limited the usefulness of AdV gene transfer applications. Results from our laboratory have identified TNF-alpha as a key antiviral molecule, involved in orchestration of inflammation, the generation of cytotoxic T-cells and production of anti-AdV neutralizing antibodies. The activation of macrophages by AdV, provides the early antiviral response responsible for secretion of TNF-alpha, which contributes to the activation of the immune cascade that currently compromises AdV gene therapy applications. In this proposal, we are hypothesizing that specific ligands present in the vision are stimulating unknown macrophage
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receptors (such as toll like receptors), resulting in activation of macrophage and induction of anti-AdV immunity. We are proposing to identify the specific AdV ligandreceptor pathways involved in the macrophage activation cascade, and based on our understanding of these pathways, we will generate viral vectors that are less potent at macrophage activation. These studies will provide basic insight into viral vector-host interactions as well as provide strategies to greatly diminish AdV inflammation/immune activation resulting in enhanced success of AdV gene transfer strategies. 1) Identify the signaling molecules that mediate AdV induction of TNF-alpha in macrophages. 2) Identify the adenoviral molecules that trigger TNF-alpha. 3) Design adenovirus vector mutants that do elicit and at the same time interfere with AdVmediated TNF-alpha induction; and 4) Test the adenovirus vector mutants in gene transfer experiments to the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION Principal Investigator & Institution: Chicoine, Louis G.; Pediatrics; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Pulmonary hypertension (PH) is a significant cause of morbidity and mortality affecting a broad range of patients. Neonatal pulmonary hypertension is the second leading cause for admission to neonatal intensive care units for respiratory support. In adults, PH causes significant morbidity and mortality in patients with chronic obstructive pulmonary disease. In all patients, PH is characterized by cellular proliferation and altered vasoreactivity in the pulmonary vascular bed. The objectives of this proposal are to evaluate the vasodilator efficacy and toxicity of NO produced by virally mediated inducible nitric oxide synthase (iNOS) gene transfection in the lung and to determine the effect of virally transfected iNOS on the pathogenesis of PH. The general hypothesis is that virally transfected iNOS will result in sufficient NO formation to modulate pulmonary vasoconstriction and attenuate pulmonary vascular changes associated with pulmonary hypertension, but insufficient NO formation to result in toxicity. Utilizing human iNOS gene and, as a control, the E. coli lac Z reporter gene coding for beta-galactosidase (beta-gal) adenovirus constructs our goals set forth in this proposal are: 1) to optimize iNOS gene delivery and expression in the rat lung, 2) to determine the role of transfected iNOS on the development of pulmonary hypertension, and 3) to compare intravascular and intratracheal delivery of the iNOS gene in terms of gene expression, vascular reactivity and toxicity. These goals are addressed in the following specific aims: Specific Aim number 1: Assess the effectiveness of adenovirusmediated iNOS gene transfection in attenuating acute pulmonary vasoconstrictor responses. Specific Aim number 2: Assess iNOS gene transfection-mediated effects on the development of chronic hypoxia-induced pulmonary hypertension. Specific Aim number 3: Assess the efficacy and toxicity of intravascularly and intratracheally administered adenoviral iNOS constructs. The methods will involve using adenovirus constructs containing the gene for iNOS or beta-gal that will be administered intravascularly; the lungs will then be studied to determine vascular reactivity, NO production, and localization of transfected iNOS. Some rats will be transfected and exposed to chronic hypoxia. Finally, intravascular and intratracheal delivery will be compared in terms of gene localization and toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LOCAL ANGIOGENIC THERAPY FOR DIABETIC ULCERS Principal Investigator & Institution: Brem, Harold; Director; Surgery; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-DEC-2006 Summary: (provided by applicant) Diabetic foot ulcers are the primary etiology resulting in over 1,000 amputations per week in the United States. The cost of these ulcers is measured in the billions, and the morbidity is excessive. No patient therapy is currently available that significantly stimulates angiogenesis in a wound. The goal of this Mentored Clinical Scientist Development Award is to allow the Principal Investigator to obtain the expertise necessary to develop, coordinate and translate laboratory findings on gene therapy, growth factors, angiogenesis, and diabetes into practical clinical applications for developing new local angiogenic gene therapy for treatment of diabetic foot ulcers. Since angiogenesis maintains a critical role in wound healing, an angiogenic molecule such as Vascular Endothelial Growth Factor (VEGF) may provide an effective treatment either alone or as part of combination therapy for patients with diabetic wounds. Systemic therapy may, however, be limited by side effects such as possible induction of retinopathy. The primary objective is to determine the minimal dose of the angiogenic molecule, VEGF delivered by either adenovirus (ADV), or recombinant VEGF, which will result in statistically significant acceleration of time to 100% closure in experimental diabetic wounds. Furthermore, insights into the mechanism by which VEGF exerts its acceleration of healing in experimental diabetic ulcers will be gained. The role of collagen synthesis and angiogenesis synthesis in the closure rates of diabetic ulcers will be delineated after treatment with VEGF. Any toxicity will be established by evaluating the: a) local inflammatory response at the wound site after VEGF therapy, b) the systemic absorption of VEGF after VEGF therapy, and c) the effect on distant organs that may be particularly susceptible to VEGF therapy. If VEGF therapy fails to be safe or effective, alternative methods of growth factor release have been proposed, e.g., a polymer delivery system. The major goal of the research will be to ascertain that local angiogenic gene therapy with selected growth factors is safe and has minimal system toxicity. Working in an academic environment during the period of this award, the PI will continue his involvement in the clinical and basic research training and teaching of medical students and housestaff on diabetic foot ulcers. Support from this proposal will allow the applicant to use knowledge from the fields of gene therapy, angiogenesis and wound healing to develop a safe angiogenic gene therapy for diabetic foot ulcers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF CRANIAL SUTURE FUSION & PATENCY--TGF-B & FG Principal Investigator & Institution: Longaker, Michael T.; Professor of Surgery; Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Craniosynostosis, the premature fusion of cranial growth plates, can lead to severe functional and morphologic problems in children. The functional problems include increased intracranial pressure, mental retardation, blindness and death. The morphologic problems may include a severely dysmorphic cranial shape and mid-face hypoplasia. Craniosynostosis represents a substantial biomedical burden with an estimated incidence as high as 1:2000 births. Recent advances have documented an association between fibroblast growth factor receptor mutations and syndromic
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craniosynostoses. To elucidate the molecular mechanisms underlying suture fusion, we have developed a murine model in which the posterior frontal suture has been shown to undergo programmed sutural fusion shortly after birth. Our preliminary studies have implicated transforming growth factor beta (TGF-beta1) and fibroblast growth factor (FGF) signaling in the regulation of dura mater-suture interaction. These findings have led to the central hypothesis to be tested in this proposal: regional differentiation and growth factor expression by the dura mater directly underlying a cranial suture regulates the fate of the overlying cranial suture. The specific roles of transforming growth factor and fibroblast growth factors in fusing and patent sutures will be examined using adenovirus-mediated gene therapy. Specifically, we will evaluate the ability of adenovirus vectors encoding a dominant negative TGF-beta receptor or a dominant negative FGF receptor (i.e. down-regulation of the biologic activities of TGFbeta or FGF, respectively) to prevent programmed posterior frontal suture fusion. Similarly, the ability of adenovirus vectors capable of increasing TGF-beta1 or FGF-2 biologic activities to cause cranial suture will be evaluated in the normally patent sagittal suture. Sutures will be assessed histologically for temporal and spatial changes in suture fusion/patency and we will assess molecular effects of alterations in TGF-beta or FGF biologic activity by analyzing mRNA and protein expression of extracellular matrix products, TGF-beta isoforms, TGF-beta receptors, FGF-2, and FGF receptors. Finally, cellular proliferation and programmed cell death will be evaluated in experimental and control sutures. This proposal is important and timely because it addresses the basic etiopathogenesis of a common craniofacial disorder. The long-term objective of this work is to understand the mechanisms underlying sutural fusion so we can develop biomolecular strategies to treat or reverse prematurely fused sutures nonsurgically. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF P53 SILENCING BY ADENOVIRUS E2B 55K PROTEIN Principal Investigator & Institution: Berk, Arnold J.; Professor; Microbiol & Molecular Genetics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-FEB-1995; Project End 31-DEC-2004 Summary: Mechanisms will be analyzed by which adenovirus E1B-55K in vitro indicated that a cellular co-repressor(s) is required to inhibit a step in basal transcription specifically from promoters with p53-binding sites. We propose to purify this corepressor and analyze the mechanism by which it represses transcription. In a p53minus cell line, the principal defect in the replication of the E1B- 55K null mutant d11520 at 32 degrees is failure to efficiently translate viral late mRNAs. Remarkably, this defect is largely complemented by incubation at 39 degrees. This observation suggests that induction of the heat-shock stress response can largely substitute for the E1B-55K late function. This possibility will be tested by determining if chemical agents that induce the stress response at 32 degrees also relieve the requirement for E1B-55K. During the late phase of infection by wtAd5, host cell mRNA translation is inhibited by the dephosphorylation of the translation initiation factor eIF-4E, the cap binding complex. An E1B- 55K mutant has been reported to be defective in inducing this eIF-4E dephosphorylation. Since heat shock also indues eIF-4E dephosphorylation and elevated temperature largely relieves the requirement for E1B-55K, we propose studies to test the model that the dephosphorylation of eIF-4E is required for the efficient translation of viral late mRNAs. We will also test the model that dephosphorylation of eIF-4E
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indirectly causes the late phase inhibition of cellular mRNA nucleocytoplasmic transport by preventing the release of shuttling hnRNP proteins from newly transported mRNAs. These studies may provide a simple means for predicting which tumor cells would be effective hosts for the replication of E1B-55K mutants and, therefore, might be candidates for therapy by infection with an E1B-55K mutant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM ADENOVIRUS-36
OF
PROMOTION
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ADIPOGENESIS
BY
Principal Investigator & Institution: Dhurandhar, Nikhil V.; Nutrition and Food Science; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): Obesity is a chronic condition with multiple causes, which has reached epidemic proportions in the U.S. The problem is compounded by a relative lack of effective treatments. Identifying and understanding various etiological factors involved may help in designing better treatments directed at the appropriate causes. Five viruses are reported to cause obesity in animal models, and viral infection may play an etiological role in some forms of human obesity. We recently reported adenovirus type-36 (Ad-36), the first human virus that increases adiposity in experimental animals including non-human primates and is associated with human obesity. Our in-vitro experiments with 3T3-L1 cells (rodent preadipocytes cell line) and human preadipocytes show Ad-36-induces up-regulation of fat cell differentiation and modulates the expression of several genes in fat cell differentiation pathway. Our central hypothesis is that up-regulation of fat cell differentiation contributes significantly to the adipogenic effect of Ad-36. The objective of this proposal is to identify the molecular interactions between fat cells and Ad-36, which will provide the basis to elucidate the mechanism of promotion of adipogenesis. Preliminary data suggested that the only a subset of viral genes are expressed in Ad-36 infected preadipocytes. In Specific Aim 1, we will begin by identifying the Ad-36 transcription units expressed during differentiation of infected preadipocytes. From these candidates, the Specific Aim 2 will identify the viral transcription unit(s) that enhance preadipocyte differentiation. Next, the Specific Aim 3 will determine the differentiation-associated changes in cellular gene expression prompted by the candidate transcription unit identified in Specific Aim 2 as well as Ad-36 virus. Ad-2, a non-adipogenic human adenovirus will be used as a negative control. Also, genes found to enhance the differentiation of 3T3-L1 cells will be tested for their effect on differentiation of human preadipocytes. Identifying the interacting viral and cellular genes will help in future for elucidating novel signaling controls of fat cell differentiation and molecular pathway(s) for Ad-36 induced adiposity. Such an understanding of the mechanism of Ad-36 induced adiposity will help in determining the contribution of Ad-36 infections in human obesity. We believe that determining the role of viral infections in human obesity may influence the treatment, management, and possible prevention of such type of obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION OF CD4+ T CELLS IN AUTOIMMUNE UVEITIS Principal Investigator & Institution: Li, Wei; Ophthalmology; University of MiamiMedical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2004
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Summary: (Applicant's Abstract) Autoimmune uveitis is an inflammatory disease mediated by autoreactive CD4+ T cells. The animal model of the disease, experimental autoimmune uveitis (EAU), can be triggered by immunization with several identified retinal antigens, including interphotoreceptor retinoid binding protein (IRBP). IRBP peptide 1-20 (IRBP 1-20) has been identified to be one of the major uveitogenic epitopes in a mouse model. The purpose of this study is to develop a novel strategy to selectively turn on or turn off T cells recognizing this epitope according to our choice. We hypothesize that co-expression of a covalent peptide/MHC class 11 molecule complex and an accessory molecule will allow activation or deletion of peptide-specific, uveitogenic CD4+ T cells in a T cell receptor (TCR) guided fashion. In this study, recombinant adenoviruses will be engineered to express a fusion protein of MHC class Il and IRBP 1 -20. The covalent IRB 1-20/class II complex expressed by the adenovirus on the surface of infected cells will serve as bait or molecule-capturing device, as it will selectively bind to TCRs recognizing this antigen. In addition, the same adenovirus will express either a co-stimulatory molecule (137-1) necessary for T cell activation or a death molecule (FasL) that will trigger T cell apoptosis. Therefore, only the T cells specifically bound to the covalent IRBPl-20/class 11 complex will be selectively activated or deleted, while the T cell population that does not recognize the antigen will be left untouched, remaining nalve or immune competent to other antigens. In Specific Aim 1, recombinant adenovirus co-expressing IRBPl-20/class II complex and 137-1 will be generated and characterized. IRBP 1-20-sPecific T cell activation and possible induction of EAU in adenovirusinfected mice will be defined. In Specific Aim 2, recombinant adenovirus coexpressing IRBP 1-20/class 11 complex and FasL will be generated and characterized. IRBPl-20-specific T cell deletion and possible reduction of EAU in mice infected by this FasL-expressing adenovirus will be defined. These studies will not only yield new insights for the underlying causes and pathogenesis of autoimmune uveitis, but may also lead to a more selective immunotherapy for the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR AND FUNCTIONAL ANALYSIS OF HUMAN APOA-1 Principal Investigator & Institution: Zannis, Vassilis I.; Professor of Medicine & Biochemistry; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JUL-1994; Project End 31-JAN-2007 Summary: (provided by applicant): ApoA-I is the major protein component of HDL and is required both for the biogenesis and the functions of HDL. Lipid-free apoA-1 and different HDL species formed by sequential lipidation of apoA-I by ABCA1 appear to have distinct functions in cholesterol efflux, selective uptake of lipids, activation of LCAT, and possibly other functions of HDL. It is our hypothesis based on our recent findings, that subtle changes in the apoA-l structure may affect HDL biogenesis and functions including ABCA1- and SR-BI-mediated cholesterol efflux, SR-Bl-mediated selective uptake of lipids, and activation of the LCAT. In this application we will use in vitro and in vivo approaches to elucidate the structure and functions of apoA-I. The in vitro studies will utilize mutant forms of apoA-I and HDL produced in apoA-l-/- mice following adenovirus infection. The in vivo studies will utilize adenovirus-mediated gene transfer in apoA-l-/- mice and transgenic mice expressing apoA-l mutants. Our specific aims are: 1) To determine by physicochemical methods the contribution of specific domains and residues of apoA-l that are responsible for stabilizing the conformation and structure of apoA-l through intra- or intermolecular interactions in solution, or when bound to lipids. Structural changes of the apoA-I mutants will be
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correlated with the in vitro and in vivo functions of apoA-l, including LCAT activation and lipid and lipoprotein binding. 2) To investigate the functional interactions of lipidbound apoA-l with SR-Bl and the effect of apoA-l mutations in SR-Bl-mediated cholesterol efflux and selective lipid uptake. 3) To investigate the effect of apoA-I mutations in cholesterol efflux and the functional interactions of lipid-free apoA-I with ABCA1 that leads to efflux of cellular phospholipid and cholesterol. 4) To investigate the implications of apoA-l mutations on the biogenesis and the function of different HDL species using adenovirus-mediated gene transfer in apoA-l-/- mice as well as transgenic mice. Epidemiological and genetic data, combined with recent transgenic experiments, suggest that increased apoA-I and HDL levels protect from atherosclerosis. In contrast, low apoA-I and HDL levels predispose humans to coronary artery disease (CAD), a leading cause of mortality worldwide. Understanding the molecular structure and the various biological functions of apoA-I may lead to new pharmacological approaches to prevent and/or treat these conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR NEUROMODULATION
BASES
FOR
MOTONEURONAL
Principal Investigator & Institution: Bayliss, Douglas A.; Assistant Professor; Pharmacology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-FEB-1995; Project End 31-MAR-2006 Summary: Multiple ion channels influence neuronal excitability, and these are often subject to modulation by neurotransmitters. Prominent among these is a background or 'leak' K+ channel that is targeted for inhibition by neurotransmitters, leading to membrane depolarization and increased excitability. G protein-coupled receptors capable of mediating this effect have been identified for many transmitters (invariably those that couple via Gaq/l 1-family subunits), and whereas it represents a predominant mechanism for slow synaptic excitation throughout the brain, this phenomenon is particularly well described in motoneurons. Despite its widespread presence, the molecular identity of leak K+ channel(s) targeted for inhibition are unknown in most native systems, and the mechanisms of receptor-mediated channel inhibition remain obscure. A major goal of the current proposal is to identify the molecular substrate for a motoneuronal leak K about current. Evidence from our laboratory indicates that the two-pore domain K+ channel, TASK-1 (KCNK3), contributes to a pH- and neurotransmitter-sensitive leak K+ channel in hypoglossal motoneurons. New observations indicate that the closely related TASK-3 (KCNK9) subunit is also expressed in motoneurons. Moreover, preliminary data suggest that it may form heterodimers with TASK-1. We hypothesize that TASK-1 and TASK-3 form functional heterodimers that contribute to motoneuronal pH- and neurotransmitter-sensitive leak K+ currents. The second major goal is to characterize molecular mechanisms involved in receptormediated inhibition of these channels, focusing in turn on the molecules that represent the beginning (i.e., G proteins) and end points (TASK channels) of the receptor-activated signaling pathway. We hypothesize that Gag-family subunits provide the initial receptor-activated signal and that key determinants located in cytoplasmic domains of TASK channels are required for receptor-mediated TASK channel inhibition. For these studies, we utilize two experimental systems: a model system, based on heterologous expression of Gaq-coupled receptors and TASK channel subunits in mammalian cells, which recapitulates this modulatory mechanism; and a native neuronal system, in which heterologous gene expression is obtained in motoneurons using adenovirus
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vectors. The following Specific Aims are proposed: To determine if TASK channels can form functional heterodimers; To determine G protein subunits and channel domains involved in receptor-mediated TASK inhibition; and To determine contributions of TASK channels to motoneuronal currents and mechanisms of their modulation. These experiments will characterize molecular substrates underlying a native neurotransmitter-modulated leak K+ current and test key aspects of the mechanisms by which they are modulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR EGRESS IN GENE DELIVERY Principal Investigator & Institution: Giordano, Frank J.; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (the applicant's description verbatim): The circulatory system, via the microcirculation, accesses every cell in the body. Exploitation of this to deliver therapeutic genes and other molecules to target organs is limited by endothelial barrier function and selective permeability. The mechanisms regulating selective endothelial permeability are poorly defined, and a better understanding may lead to enhanced methods for delivering genes and macromolecules to tissues and organs. We hypothesize that specific peptide sequence motifs are associated with targeting macromolecular translocation across continuous endothelia, such as that lining the coronary microvasculature. We further hypothesize that specific peptide motifs are also involved in intracellular targeting and trafficking of macromolecules. We contend that definition of these pathways could lead to viable strategies to efficiently deliver therapeutic genes and molecules to the heart. We will use the power of peptide phage display in a model of endothelial barrier function to identify peptide motifs associated with translocation of macromolecules across the endothelium. We will also use phage display to investigate the role such peptide motifs play in endocytosis of macromolecules and their subsequent intracellular trafficking. We will use a complimentary combination of biochemical, immunohistochemical, molecular and ultrastructural approaches, to investigate these events. Finally, we will engineer targeted AAV and adenovirus vectors to investigate the ability of these defined peptide motifs to direct macromolecule translocation and intracellular trafficking in the context of these gene therapy vehicles. We will fulfill the following specific aims: 1) To identify peptide sequences capable of overcoming endothelial barrier function and facilitating macromolecular translocation across continuous endothelia; and to investigate the mechanisms by which this translocation occurs; 2) To identify peptide sequences capable of binding and internalization into cardiac. myocytes, investigate the internalization pathways targeted by these peptide motifs, and determine the role of caveolin 3 in cardiomyocyte endocytosis. 3) To investigate the ability of specific peptide targeting motifs to direct intracellular trafficking and facilitate macromolecular translocation across the continuous endothelia in the context of targeted AAV and adenovirus vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: MOLECULAR FUNCTIONS OF THE ADENOVIRUS E1A ONCOGENE Principal Investigator & Institution: Green, Maurice; Chairman and Professor; Inst for Molecular Virology; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-JUL-1996; Project End 31-MAR-2007
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Adenovirus
Summary: (provided by applicant): The human adenovirus E1A 243R oncoprotein encodes a transcription repression function that localizes to the N-terminal domain (E1A 1-80) and is required for induction of cell cycle progression and neoplastic cell transformation. Our goals are to understand the mechanism of E1A repression in molecular detail and to identify the natural cellular promoters targeted by the E1A repression domain during adenovirus infection. The first specific aim is to define mechanism(s) of E1A repression through in vitro studies using protein-protein interaction and a transcription-repression system. A large panel of EIA single amino acid substitution mutants will be used to define interactions among E1A, p300/CBP, and TBP and to establish their relevance to the E1A repression function. The 3D structure of the E1A N-terminal repression domain will be determined by NMR spectroscopy to help understand the interactions between E1A and its cellular partners. Our working model is that E1A accesses specific cellular promoters involved in growth regulation through p300/CBP as a molecular scaffold," where it then can disrupt interaction between TBP and the TATA box. To test this model, preinitiation complexes assembled in vitro and loaded with known amounts of p300/CBP will be analyzed for E1A repressibility. The second specific aim is to define the mechanism of E1A repression in vivo. Transient expression will be used (i) to establish whether E1A can utilize promoter-bound p300/CBP to access specific genes, (ii) to define the molecular determinants of E1A-repressible promoters by chromatin immunoprecipitation (CHIP), and (iii) to analyze the molecular basis of resistance to E1A repression by nonrepressible promoters. To provide genetic proof for the role of TBP as an ultimate target of E1A repression, detailed mutational analysis of TBP single amino acid substitution mutants will be performed in vivo and in vitro. Collectively, the findings from in vitro and in vivo studies will allow the development of a detailed molecular model(s) for the mechanism of E1A repression. The third specific aim will identify by CHIP analysis the natural cellular promoters targeted by the E1A repression domain during infection of quiescent human cells. The functional consequences of interaction between E1A and specific cellular promoters will be established by kinetic studies of the gene specific mRNA and protein products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR GENE AND RADIATION THERAPIES FOR CANCER Principal Investigator & Institution: Freytag, Svend O.; Division Head; Radiation Oncology; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp046 Detroit, Mi 48202 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): Adenovirus-medicated suicide gene therapy is an investigation cancer therapy that has produced impressive results in preclinical models. Despite these promising results, this approach has shown limited efficacy in the clinic largely due to a low efficiency of gene transfer in vivo. To overcome this limitation, our research program has developed a novel, trimodal approach that utilizes an oncolytic, replication-competent adenovirus to selectively and efficiently deliver a pair of therapeutic suicide genes to tumors. Preclinical studies have demonstrated that the replication-competent adenovirus itself generates a potent anti-tumor effect. The therapeutic efficacy of the adenovirus can be enhanced significantly by invoking two suicide gene systems (CD/5-FC and HSV-1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents and, importantly, sensitizes them to radiation. Two phase I clinical trials that evaluated the safety and efficacy of replicationcompetent adenovirus-mediated double suicide gene therapy without (BB-IND 8436)
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and with (BB-IND 9852) three-dimensional conformal radiotherapy (3D-CRT) in men with prostate cancer have been completed with excellent results. The results demonstrate that replication-competent adenovirus-mediated double suicide gone therapy can be combined safely with conventional dose 3D-CRT and is showing signs of biological activity. This Program Project builds on our previous preclinical and clinical accomplishments with a single-minded goal- to develop the technology of replicationcompetent adenovirus-mediated double suicide gene therapy to a point where it will be a safe and effective adjuvant to radiation therapy in the clinic. To accomplish this, we have assembled a highly interactive group of projects and cores that function as a comprehensive and cohesive unit that will advance gone therapy technology on three fronts: 1) by developing better adenoviral vectors and therapeutic genes, 2) by developing better means of vector delivery and monitoring of therapeutic gone expression in vivo, and 3) by evaluating the merit of these preclinical advancements in three Phase I/II clinical trials. The combined basic and clinical science described here will generate new important knowledge and may ultimately lead to more effective cancer treatments. COLLABORATING INSTITUTION (S): None OVERALL CRITIQUE: External beam radiation therapy (EBRT) is a primary treatment for prostate cancer and it has been estimated that about half of the 198,000 men diagnosed with this disease this year will receive radiation. Despite considerable improvements in beam delivery, clinical local failure is still a significant problem emphasizing the need for improved local control. Thus, strategies for enhancing the efficacy of the current treatment regimens are highly important. Investigators in this revised program project application propose a coordinated effort designed to enhance the effectiveness of EBRT through the use of a novel gene therapy approach. The three Project Leaders, Drs. Freytag, Kim and Brown, have been working together for nearly 10 years to develop what they refer to as a "trimodal" gene therapy approach for the treatment of cancer. This involves a modified, replication-competent adenovirus, Ad5-CD/Tkrep that delivers two "suicide" genes, cytosine deaminase and herpes simplex thymidine kinase, to tumors. Tumors are then treated with 5-fluoro cytosine (5-FC) and ganciclovir (GCV), both of which are converted to the cytotoxic agents, 5-FdUMP and GCV-MP, inside the tumor cells through the action of the transfected genes. Thus, when combined with EBRT, tumor cells are killed by a combination of virus-mediated cytolysis, the cytotoxic action of 5FdUMP and GCV-MP, and the radiosensitizing properties of these latter two agents. Compelling laboratory data have been published by this group demonstrating that this first generation vector essentially works as described both in vitro and in vivo. A total of 29 co-authored, peer-reviewed publications and several more either submitted or in preparation have resulted thus far. Moreover, a phase I study that evaluated the toxicity and efficacy of the vector in combination with the two pro-drugs in men with local recurrent prostate cancer was completed that demonstrated the safety and possible efficacy of these components of the trimodal therapy. A second phase I trial, evaluating the safety of this same strategy but now including the EBRT, has also been recently completed. Two laboratory-based projects will test a number of different improvements in the viral backbone that may either enhance transgene activity, enhance vector delivery, or allow monitoring of transgene expression. The third project will translate these laboratory findings into clinical trials. The program is supported by four core components. This amended application is significantly improved over the last submission. This has been accomplished through the removal of the original Project 2 that had not been favorably received in the prior reviews as well as through modifications to the remaining projects. The investigators have responded thoughtfully to the concerns raised in the previous critique. The previously identified strengths of the program remain the clinical significance of the research, the scientific expertise of the investigators, the solid record of past productivity, the highly integrated approach, and
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Adenovirus
the excellent resources available to conduct this research. Many of the prior concerns raised for Projects 1 and 2 have now been resolved and Project 3 that had been highly rated previously remains strong. The cores remain satisfactory. Overall, this highly integrated program addresses significant problems and has an outstanding level of merit. Five years of support is appropriate. Project 1, "Second-Generation Adenoviral Vectors for Cancer Therapy" (Svend O. Freytag, Ph.D., Project Leader). The major goals of this project are to generate and provide all the necessary novel replication competent adenoviruses, characterize their growth and suicide potential in prostate cancer cells both in vivo and in vitro, and assess their toxicity. The novel adenoviruses are designed to improve the efficacy of this gene therapy through: 1) modulation of the immune response, 2) enhanced viral induced oncolysis, 3) improved suicide genes, and 4) adenoviruses that can be used for in vivo imaging and potentially therapeutic radioactive compounds. The significance of the project is its potential to improve care of patients with prostate cancer or other cancers sensitive to external beam radiation therapy. The overall strengths of the project include the diverse adenoviruses that test distinct hypotheses, the high enthusiasm and the strong leadership ability of the Project Leader, the experience of the team in generating adenoviruses and their analysis, the extensive preliminary data including numerous publications, the highly productive and long standing collaborations, a defined decision tree for choosing the clinical candidate vector, assessment of potential toxicity on normal tissues as well as in tumor-bearing animals, and the clinical experience of the investigators. There are no major weaknesses in this project. The only minor weakness identified in the prior review was the RM-9 model and Dr. Freytag is working to obtain or develop more relevant models. In addition, the constructs represent cutting edge translational research, providing innovative potential therapies for clinical testing. This project will most likely greatly advance the technology and utility of gene therapeutic approaches to prostate cancer. There are no remaining concerns related to this project and it received a merit priority score of 1.3. Project 2, "Improved Gene Delivery and In vivo Imaging" (Steve Brown, Ph.D., Project Leader). Overall, this project seeks to optimize conditions for and monitoring of local delivery of adenoviral vectors within a specific target organ - in this case the prostate. The specific aims are: (1) To develop new noninvasive methods to determine the spatial distribution of viral spread following intraprostatic injection of replication competent adenovirus; (2) To optimize parameters affecting the viral spread to ensure complete organ coverage with vector; (3) To assess the extent of the bystander effect of CD gene therapy compared to the extent of gene expression. The proposed project addresses a technically challenging issue but one which is of critical importance to moving the field further. If the extent of gene expression following vector delivery can be measured accurately in vivo and non-invasively, clinical protocols will become more informative, more effective and critically safer. A significant strength is the impressive preliminary data showing both gene expression and function correlations. Another strength is the large animal model that more closely represents the human prostate in size. The investigative team is also a major strength; they have a proven record of publication and continued innovation. The project has no significant outstanding weaknesses. During the course of the review several issues were raised and satisfactorily answered by the applicant. The project seeks to define the optimal conditions by which a virus can be delivered to a specific site and achieve maximal coverage in terms of viral gene expression and therapeutic effects (bystander). Other groups have not addressed these issues in such depth. Therefore, the studies proposed here are innovative and valuable. Dr. Brown has generated extensive preliminary data to support this application and is a highly experienced investigator with the state of the art techniques that will be used. The availability of the technical software and hardware at the Henry Ford Science Center is a major strength. In summary, the merit of this
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project is very high; the practical value of these studies to the field is notable, and there is high confidence in this group of researchers to achieve the stated goals. This project received a merit priority score of 1.3. Project 3, "Suicide Gene and Radiation Therapy Clinical Trials" (Jae Ho Kim, M.D., Ph.D., Project Leader). Project 3 seeks to clinically apply a newer, hopefully more potent, replication competent, fusion gene adenoviral vector in combination with dual prodrugs and radiation therapy in the treatment of men with prostate cancer as well as to use a novel vector encoding the sodium iodide symporter for imaging vector delivery and transgene expression. Overall, this is a well crafted, well organized project, which logically extends the investigator's previous preclinical and clinical work and takes full advantage of the newer vectors developed in other projects of this application. The members of this project are well integrated into the fabric of the entire set of projects and their previous work demonstrates that they possess the commitment and expertise necessary for such clinical translation. A concern remains, that was not completely addressed by the investigators during the teleconference, regarding the trial design in Specific Aim 2. The proposed design is a classic phase I design, which may not be appropriate for the particular patient population being studied (previously irradiated patients) with regard to the nature of the combination treatment that will be employed (virus plus re-irradiation). Since the most important dose limiting side effects (i.e. the side effects that a phase I trial seeks to understand) from such therapy are not likely to be readily apparent within the first 6 months post treatment, the proposed trial design is not adequate to determine the MTD or DLT in this context. The design could be modified. Nonetheless, the project as a whole is very likely to provide meaningful and important new clinical data as to the benefits and limitations of the gene therapy approaches proposed, which will be useful in future studies in prostate cancer and other cancers types as well. The concern raised above did not dampen enthusiasm for this project, which remained very high. The project received an average merit score of 1.4. Core A, the "Administrative Core", will be led by Dr. Freytag. He will provide supervision over monthly meetings of all project participants. An internal and external review board will evaluate progress on the work plan on an every three month and annual basis, respectively. A specific fulltime grants administrator will be employed to tract all project costs and report information directly to Dr. Freytag, who in turn will be responsible for financial aspects of the trial. The Administrative Core is well designed and straightforward and overall, the core has a solid, basic administrative structure. It is rated Satisfactory. Core B, "Molecular Biology and Vector Core" (Svend Freytag, Ph.D., Core Director). This core will perform a number of important functions related to the construction, production and testing of the adenoviral vectors to be used in all of the projects in this program. In addition, it will provide some quality assurance testing of clinical grade vector and perform assays for monitoring the presence of viral DNA in patient's blood. These functions are well within the expertise of Dr. Freytag and his staff. This core is critical to the success of this program because, except for the production of clinical grade vector for Project 4 that will be obtained from appropriate outside sources, it will provide the vectors needed for all of the other studies in this program project. This core is rated Satisfactory. Core C, "Tumor/Cell Biology and Histology Core" (Steve Brown, Ph.D., Core Director). This core will perform several functions related to cells and tissues used or analyzed in the various projects. This includes expanding cultures of tumor cells for implantation into animals, perform necropsies and routine histology and immunohistochemistry, provide spleenocytes and hepatocytes for cytolytic assays, and analyze prostate biopsies for transgene expression. These functions are necessary to the success of the Program Project. Drs. Brown and Freytag are experienced in tumor biology and qualified to lead this core. This core is rated satisfactory. Core D, "Biostatistical and Data Management Core" (Mei Lu, Ph.D., Core Director). The objective of the Biostatistics Core is to provide
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professional expertise in biostatistics for all research projects, including experimental design, statistical data analysis and informative presentation of results. The revised core application clearly demonstrates that the core staff have worked closely with the individual project investigators to help design the studies, determine the appropriate sample sizes, and develop plans for statistical analysis and data management. Nearly each and every aim is discussed in sufficient detail in the description of the core. In summary, Dr. Lu has recruited an able team to support the program project, and the core has made a thorough, systematic and highly competent review of all the research projects. Modern data analysis technologies as proposed are appropriate; the core is technically strong. This core is rated as Satisfactory. PROGRAM AS AN INTEGRATED EFFORT: The program is highly integrated as evidenced by a number of factors. These include the fact that the leaders of the three projects have worked together for several years to generate the extensive background data in support of this application. These interactions are documented in a series of twenty-nine previous publications jointly coauthored by this group with several additional papers submitted. The scientific interactions among the projects with regard to sharing of data, techniques, and materials are very obvious. It is recognized that the prior accomplishments of this group would not have been possible without a high degree of integration. This high level of integration is one of the strongest elements of this program project. RECOMMENDED RATING: Highly Integrated SRG NOTE: Written comments were received from the applicant in response to the Draft Review Report. These comments were considered by the committee members during the discussion and final assessment and scoring of the application. Clarifications and corrections of text have been made, where appropriate. PRINCIPAL INVESTIGATOR: The Principal Investigator is Svend O. Freytag, Ph.D. He is currently a Senior Staff Scientist in the Molecular Biology Research Program and the Department of Radiation Oncology at the Henry Ford Health System. He holds the Wendell W. Anderson Chair in Cancer and serves as Division Head for Research in Radiation Oncology and Director of Molecular Biology. He is Principal Investigator on several peer-reviewed grants in the area of gene therapy and has published seventeen papers in this field over the last nine years. He, along with Dr. Kim, co-sponsored and wrote the approved IND applications associated with the gene therapy vector system that is the subject of this application. Dr. Freytag's leadership capabilities are impressive and his high degree of commitment to this research program is evident. This coupled with his experience in laboratory and clinical activities related to the goals of this application are considered notable strengths and clearly support his role as Principal Investigator. BUDGETARY OVERLAP: None HUMAN SUBJECTS RESUME: THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW ADMINISTRATOR TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: PROTECTION OF HUMAN SUBJECTS (Resume): Concerns for Project 3. The research plan includes a detailed description of the required human subject issues. Projects 1 and 2 and Core C propose using cultured human cell lines. These cell lines are routinely obtained from public repositories and data from these studies cannot be associated in any way with patient identifiers. Project 3 proposes three different clinical trials: (1) a randomized, prospective phase I/II study to determine whether replication-competent adenovirusmediated double suicide gene therapy in combination with intensity modulated radiotherapy (IMRT) is superior to IMRT alone in patients with newly diagnosed, intermediate-to-high risk prostate cancer, (2) a phase I/II study to determine the safety and efficacy of replication-competent adenovirus-mediated double suicide gene therapy in combination with salvage IMRT in patients with locally recurrent prostate cancer, and (3) a phase I trial to determine the efficiency of gene transfer and vector persistence in vivo following intraprostatic injection of adenovirus prepared in saline or an improved
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vector formulation. The protocols and informed consent documents for these trials were provided. Some of these documents were presented as drafts and are pending IRB and NIH RAC approval. Some design issues and human subjects concerns are evident for Project 3. The proposed consent form for the Specific Aim 1 trial does not address the "abbreviated" phase I patient population. There should be a separate consent form for the phase I patient population. The design, and number of necessary patients, to define the optimal dose of repeat RT for patients with recurrent prostate cancer in the Specific Aim 2 trial should be modified. This is not a limiting weakness, and the design can be easily corrected. The consent form language for the Specific Aim 2 trial does not provide enough detailed language regarding the risks of re-irradiation and also does not reflect the non-standard use of radiation in this trial and the responsibility for payment for radiation therapy services. The protocol and consent form for Specific Aim 3 trial requires some corrections because the draft protocol is not in concert with language detailing the trial in the application. Correction regarding the non-use of pro-drugs, and clear explanation to the patients of the potential risk in the delay of prostatectomy in order to obtain scanning data for cohort 2 is needed. It should be emphasized that during the teleconference review, the applicant group adequately addressed all these issues and will include the appropriate modifications in the final version of the documents. The data safety and monitoring plan is acceptable. There is an adequately described process of monitoring of patient eligibility, provision of concern, definition of Serious Adverse Events (SAE), and a separate Data and Safety Monitoring Board (DSMB), comprised of other physicians at the Cancer Center. The DSMB reviews the submitted data on a quarterly basis at a minimum, or more often, if problems arise. There is an adequate process of adverse event reporting and communication of information to the local IRB, the NIH and FDA. A process for modification of protocols and approval is in place. The benefits of these trials are to future patients and the knowledge to be gained from these studies could support the use of gene therapy in combination with EBRT for improving therapeutic response and provide understanding of the mechanisms behind the interactions of these therapeutic agents. The project is very likely to provide meaningful new clinical data and set the basis for useful future clinical studies in prostate cancer. INCLUSION OF WOMEN PLAN (Resume): Acceptable. Prostate cancer only affects men. G3A. INCLUSION OF MINORITIES PLAN (Resume): Acceptable. Approximately two thirds of the recruited population will be of African-American origin. M1A. INCLUSION OF CHILDREN PLAN (Resume): Acceptable. Prostate cancer is a disease of the adult population. C3A. VERTEBRATE ANIMALS (Resume): This program project will use mice and dogs. Project 1 will use intact male C57Bl/6 and SCID mice. Project 2 will use adult male dogs. The use of these animals is justified for the proposed research. The procedures are in accordance with standard animal care procedures under appropriate veterinary supervision. The Bioresources Facility is AAALAC certified. Internal IACUC approval has been obtained. INDIVIDUAL PROJECTS AND CORES For each project and core, the critiques from individual reviewers are provided in essentially unedited form. Please note that these critiques were prepared prior to the review and may not have been revised to reflect any updated information obtained from the applicant group. The "RESUME AND SUMMARY OF DISCUSSION" and "OVERALL CRITIQUE" sections above summarize the final assessment of the proposed studies. PROJECT 1: Second-Generation Adenoviral Vectors for Cancer Therapy (Svend O. Freytag, Ph.D., 20 percent effort) (provided by applicant): Our research program has developed a novel, trimodal gene therapy-based approach for the treatment of cancer. Our approach utilizes a cytolytic, replication-competent adenovirus (Ad5-CD[TKrep) to selectively and efficiently deliver a pair of therapeutic "suicide" genes to tumors. Our preclinical studies have demonstrated that the Ad5-CD/TKrep virus itself, via its cytolytic activity, has potent
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anti-tumor activity. The efficacy of Ad5-CD/TKrep viral therapy can be enhanced significantly by invoking two suicide gene systems (CD/5-FC and HSV-1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents and importantly, sensitizes them to radiation. A major objective of Project 1 is to develop second-generation adenoviruses that may be more efficacious and less toxic than the parental Ad5-CD/TKrep virus. We will determine whether second-generation adenoviruses containing various E3 genes demonstrate greater anti-tumor activity in an immune-competent host relative to the parental Ad5-CD/TKrep virus. We will test the hypothesis that suppression of the host immune response by E3 genes will result in longer-term therapeutic gene expression and improved tumor control. Anti-tumor activity will be correlated with the duration of therapeutic gene expression in vivo and the extent, and nature, of the immune response. We will determine whether secondgeneration adenoviruses expressing a more catalytically active yeast CD/mutant HSV-1 TKSR39 transgene results in better tumor control than the parental Ad5-CD/TKrep virus. We will examine the toxicity of second-generation adenoviruses in the immunecompetent mouse following intraprostatic and intravenous administration. Finally, we will develop a series of second-generation adenoviruses expressing the human sodium iodide symporter (hNIS). We will test the hypothesis that expression of hNIS will enable virus-infected cells to take up 99mTcO4-and 123I and allowing for non-invasive monitoring of vector biodistribution and therapeutic gene expression in vivo. All of the second-generation adenoviruses developed in Project 1 will be used in the other projects of this Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR STRUCTURE OF THE ADENOVIRUS CAPSID Principal Investigator & Institution: Burnett, Roger M.; Professor; Wistar Institute Philadelphia, Pa 191044268 Timing: Fiscal Year 2002; Project Start 01-AUG-1988; Project End 31-DEC-2005 Summary: (Applicant's abstract) Virion structures will be determined for adenovirus and the adenovirus-like bacteriophage PRD1 in atomic detail and correlated with viral functions. Both virions are large with a relatively complicated, but similar, icosahedral architecture including specialized vertex structures responsible for recognition and entry. The experimental approach combines X-ray crystal structures of the coat proteins with cryo-electron microscopy (EM) image reconstructions of virions to obtain initial models. The molecular positions are then refined by computational methods to define intermolecular interactions and reveal other virion components. Adenovirus causes various human diseases and is an important vector for human gene therapy. The crystal structure of hexon, the major coat protein, was recently determined at 2.5A resolution for type 5 (ad5). The model of the 951-residue chain is better than an earlier 2.3A model for the 967-residue ad2 hexon. Although the overall fold is maintained, sequence assignments in two regions differ significantly. The new refinement methods used for ad5 will be applied to ad2, and structures for the more distantly related ad12 and avian hexons determined. These structures will be compared to find the basis for hexon's extraordinary molecular stability, and to show how different serotypes have evolved. The final hexon model will facilitate engineering to produce virions with modified outer hexon surfaces as immunologically distinct variants for gene delivery. The computational model of the 240-hexon capsid will define the binding sites for minor "cementing" proteins that play a key role in stabilizing the virion and suggest how analogs could be designed to disrupt infection. PRD1 is an unusual membranecontaining dsDNA bacteriophage. The recently-determined crystal structure of its 394-
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residue major coat protein, P3, has revealed an unexpected evolutionary relationship between PRD1 and adenovirus. A rigid-body model of P3 will be fitted to EM images of virions, empty capsids, and P3 shells to improve the current capsid model and reveal how P3 interacts with the internal membrane. Two other PRD1 proteins have been crystallized and their structures will be determined. The 64 kDa monomeric vertex protein, P2, is responsible for attachment and so is analogous to the receptor-binding adenovirus fiber. A structure for the 38 kDa tetrameric assembly factor, P17, that is essential for virion formation, will shed light on proteins that are poorly understood despite their critical and possibly general role in viral assembly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NO/CGMP SIGNAL TRANSDUCTION SYSTEM IN VASCULAR INJURY Principal Investigator & Institution: Bloch, Kenneth D.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: The objective of this proposal is to characterize the roles of nitric oxide (NO)/cGMP signal transduction in the neointimal response to vascular injury. Vascular injury induces smooth muscle cells in the media to migrate into the intima, where they proliferate and synthesize extracellular matrix, ultimately compromising the lumen. Recent studies in animal models and in patients with coronary artery disease have suggested that increasing NO levels at the site of vascular injury inhibits neointima formation. NO acts, in part, by stimulating soluble guanylate cyclase (sGC), a heterodimer composed of alpha and beta subunits, to produce cGMP leading to activation of cGMP-dependent protein kinase Z(cGDPK). In vitro, NO appears to modulate many vascular cell functions, inhibiting smooth muscle cell proliferation, migration, and extracellular matrix synthesis and stimulating endothelial cell proliferation and smooth muscle cell apoptosis. Preliminary evidence suggests that sGC and cGDPK are decreased in neointimal smooth muscle cells of injured blood vessels. We hypothesize that vascular cell NO/cGMP signal transduction has an important role in attenuating neointima formation and that decreased sGC and cGDPK limit the ability of NO to inhibit neointima formation. To test these hypothesis, adenovirus-mediated gene transfer will be used to determine the effect of altering NO/cGMP signal transduction on the neointimal response to vascular injury. In Specific Aim 1, vascular cells in culture will be infected with adenoviral vectors specifying a mutant dominantnegative sGC alpha1 subunit, wild-type cGDPK, and a mutant constitutively-active cGDPK. The effects of altering NO/cGMP signal transduction on vascular cell functions which contribute to neointima formation will be identified. In Specific Aim 2, sGC and cGDPK expression will be correlated with the changes in vascular cell functions associated with balloon-induced vascular injury in a rat carotid artery model. In Specific Aim 3, adenovirus-mediated gene transfer will be used to investigate the effect of modulating NO/cGMP signal transduction on vascular injury-induced neointima formation, as well as re- endothelialization, and smooth muscle cell proliferation, apoptosis and extracellular matrix synthesis. Neointima formation contributes to the restonosis process which frequently follows percutaneous angioplasty. Understanding the roles of the NO/cGMP signal transduction system in modulating the response to vascular injury may provide novel therapeutic approaches for the treatment of restonosis that percutaneous angioplasty. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NON-INVASIVE DELIVERY OF SKIN-TARGETED TETANUS VACCINES Principal Investigator & Institution: Tang, De-Chu C.; Vaxin Inc. 500 Beacon Pky W Birmingham, Al 352093144 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 31-MAY-2004 Summary: (Adapted from Applicant's Abstract) A major limitation with the contemporary vaccination program as a preventative measure against tetanus is the encumbrance associated with multiple needle-dependent injections. Our aim is to develop a simple method for the delivery of tetanus vaccines by topical application of an adenovirus-vectored vaccine patch. The hypothesis is that the expression of the tetanus toxin C-fragment (tetC) in the outer layer of skin can induce a systemic immune response against the toxin molecule. We have demonstrated that a protective immune response against live Clostridium tetani infection could be elicited in mice by a single topical application of a patch containing an adenovirus vector encoding tetC. These studies will further develop the vectored vaccine patch, and specifically determine whether this novel approach for the delivery of vaccines can mobilize the immune repertoire against tetanus in humans. In this project, the potential for a vectored vaccine patch to elicit a protective immune response against tetanus in animals with pre-existing immunity to adenovirus will be investigated. A new generation of adenovirus vectors with reduced immunogenicity as well as enhanced transduction efficiency for the outer layer of skin will be developed as novel vaccine carriers. Efficacy of NIVS will be compared to those induced by other means. The interaction between vectors and the host will be studied by determining the fate of vector DNA. A Phase I human clinical trial for evaluating the safety of a vectored vaccine patch will be conducted. The overall goal of these experiments is to determine whether tetanus vaccines can be effectively and safely delivered by a skin patch that requires a lower level of skill in a needle-free manner. PROPOSED COMMERCIAL APPLICATION: Non-invasive vaccination onto the skin may boost vaccine coverage against tetanus because the procedure is simple, effective, painless, and safe, The development may also make vaccination programs less dependent upon medical resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL ADENOVIRUS TRANSFER TO AIRWAY EPITHELIA
COMPLEXES--EFFICACY
OF
GENE
Principal Investigator & Institution: Welsh, Michael J.; Professor; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: Gene transfer to airway epithelia could provide an important new treatment for cystic fibrosis (CF) lung disease. A common problem with current vector systems is that the efficiency of gene transfer to differentiated human airway epithelia is limited. In work supported by this Program, we have investigated the advantages and limitations of adenoviral and non-viral vectors. By combining the two systems, we have utilized their unique advantages and avoided many of the limitations. In so doing, we have developed novel vector systems, including Ad:CaPi co- precipitates. This vector shows markedly enhanced gene transfer to differentiated airway epithelia. Moreover, preliminary data suggest that the Ad:CaPi co-precipitates do not produce additional toxicity. In this Project we focus on six questions. 1) How do Ad:CaP co-precipitates infect cells? 2) What properties of Ad:CaPi co-precipitates are important for gene transfer? 3) What cells are targeted by Ad:CaPi co- precipitates and other complexes? 4)
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Can complexes shield adenovirus from neutralizing antibodies? 5) Can other vectors, including AAV, be incorporated into CaPi co-precipitates? The results of these studies will improve our understanding of the mechanisms and barriers and gene transfer, will have application of several different vector systems, and should ultimately lead to improved gene transfer for CF airway disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL CELL CYCLE REGULATION BY ADENOVIRUS E1B 55K Principal Investigator & Institution: Ornelles, David A.; Associate Professor; Microbiology and Immunology; Wake Forest University Health Sciences WinstonSalem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: The adenovirus E1B 55-kDa (55K) protein functions during virus growth and virus-mediated cellular transformation. During virus growth, the 55K protein binds the E4orf6 protein and regulates mRNA biogenesis. During transformation, the 55K protein binds the tumor suppressor p53 and blocks transcription from p53-responsive genes including those that promote apoptosis and induce G1 growth arrest. However, most cells infected with the 55K-mutant virus do not undergo apoptosis, do not arrest in G1, and do not fail to replicate mutant viral DNA. Consequently, the link between 55K function in virus growth and transformation remains unclear. This work will elucidate this link as part of the larger goal of understanding the means by which adenovirus targets mechanisms of cellular growth control for virus growth. Because 55K-mutant viruses grow only in HeLa cells that were infected in early S phase but not in G1, the 55K protein overcomes a restriction imposed on virus growth by the cell cycle. This restriction and the 55K function that overcomes this restriction will be determined by three specific aims. First, the hypothesis that adenovirus must usurp the control of mRNA for cell cycle-independent growth will be evaluated by comparing the growth of related G1-restricted adenovirus mutants and the control of mRNA transport among infected cells that are permissive and restrictive for virus growth. Second, heterokaryons of permissive and restrictive cells will be used to elucidate the cellular basis for this restriction and determine the dominance of the restrictive phenotype. Third, cellular proteins targeted by 55K/E4orf6 complex for cell cycle-independent virus growth will be identified and the cell cycle- regulation of these proteins determined. This study will determine how the 55K protein subverts cell cycle controls for virus growth. This may represent the first link between the roll of the 55K protein in lytic growth and viral transformation. These studies will increase our understanding of the mechanisms of viral pathogenesis and viral oncogenesis as well as fundamental mechanisms of cellular growth control. Furthermore, this study will identify adenovirus mutants that are restricted for growth in S phase cells. Such replication competent viruses can be used as oncolytic agents to treat rapidly growing human tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ORGANIZATION AND EXPRESSION OF ADENOVIRUS GENES Principal Investigator & Institution: Ricciardi, Robert P.; Professor; Microbiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-1981; Project End 31-MAR-2007 Summary: (provided by applicant): Adenovirus E1A studies have contributed significantly towards understanding viral gene regulation and tumorigenesis. The modular nature of the E1A coding region has made it possible to examine these
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functions independently. The CR3 zinc finger region of E1A serves to activate transcription by interacting with three cellular proteins: TBP, hTAF135 and the newly discovered mediator protein, hSur-2. Mutational analyses and binding studies suggest that these three proteins require different residues of CR3 for activation. Solution of the 3-D structure of the CR3 region alone and complexed to these individual target proteins will provide the first detailed view of the E1A activation complex. In Ad12-tumor cells, a different region of E1A mediates down-regulation of MHC class I transcription enabling these tumor cells to escape lysis by cytotoxic T lymphocytes. This shut-off of MHC class I transcription is regulated by two factors (NF-KB and COUP-TFII) that affect the class I enhancer. NF-KB (p65/p50) fails to bind the class I enhancer and activate transcription because the p50 subunit is hypophosphorylated. This finding is novel in that it is the first example to show that p50 can regulate DNA binding of NF-KB and control its ability to activate transcription. To unravel this mechanism, the phosphoresidues of p50 that regulate DNA binding will need to be defined and the cellular kinase identified. By contrast, COUP-TFII binds strongly to the class I enhancer and represses transcription through its association with a HDAC complex that presumably causes chromatin compaction. This is the only known example in which a COUP-TF protein has been shown to regulate the MHC class I promoter. It will be essential to define the components of the COUP-TFII DNA complex by chromatin histone immunoprecipitation assays and to investigate whether Ad12 E1A is one of these components. In addition, a new understanding of Ad12 E1A mediated tumorigenesis will be acquired from analyzing genes which have been shown to be differentially expressed in Ad12 tumorigenic vs Ad5 non-tumorigenic cells. A recent discovery revealed that in addition to mediating MHC class I down-regulation, Ad12 EIA encodes a second tumorigenic function that is contained within a 20 amino acid region called the Spacer. Mutation of the Spacer prevents tumorigenesis without interfering with class I down-regulation. Screening a phage display library against the Spacer identified a protein with homology to a Natural Killer (NK) cell protein NKTR-l, consistent with the ability of Adl2-tumor cells to resist NK lysis. To investigate Spacer function, wt and mutant E1As will be tested for binding to NKTR-1. Finally, Wt E1A and mutant Spacer E1A cell lines will be compared for resistance to NK lysis and for differential gene expression by microarray analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHOSPHORYLATION IN RENAL CELL INJURY Principal Investigator & Institution: Choudhury, Goutam G.; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Abstract): Platelet-derived growth factor receptor b (PDGFR) is expressed in injured glomeruli and in activated cultured mesangial cells. Activation of PDGFR stimulates mesangial cell proliferation and migration, phenotypes manifest in many glomerular diseases including mesangioproliferative glomerulonephritis (GN). We recently demonstrated that PDGFRstimulated phosphatidylinositol 3 kinase (PI 3K) activity is necessary for proliferation and migration of cultured mesangial cells. A serine threonine kinase, Akt, has been identified as a downstream target of PI 3K. Our hypothesis is that Akt regulates mesangial cell activation which includes proliferation and migration of these cells during glomerular injury. We propose to characterize pathways by which Akt functions in cultured mesangial cells and in vivo in a model of anti-Thy-1-induced GN in rats. Akt kinase activity will be determined during progression of GN. The role of Akt kinase in
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mesangial cell activation will be determined by examining the effect of dominant negative and constitutively active versions of this protein on mesangial cell proliferation and migration. Proteins that regulate Akt kinase activity or represent substrates for this enzyme will be identified using a yeast two-hybrid protein-protein interaction strategy. Open reading frames of interacting proteins will be determined by nucleotide sequencing. Characterization of these proteins will be carried out by raising antipeptide and GST-fusion protein antibodies. Regulation of the Akt activity by these Aktassociated proteins will be studied in vitro and in cultured mesangial cells. The role of these proteins in pathways involving Akt and regulating mesangial cell proliferation and migration will be determined. Our preliminary data indicate that cross-talk between PDGFR tyrosine kinase and bone morphogenetic protein receptor serine threonine kinases exists in mesangial cells. We have recently demonstrated that activation of receptor serine threonine kinase by bone morphogenetic protein 2 (BMP-2), a member of TGFb superfamily, inhibits PDGF-induced DNA synthesis in the absence of matrix expansion. This inhibition is due to inhibition of PDGF-induced Erk1/2 type of MAPK (mitogen-activated protein kinase). In our second specific aim, we will use BMP-2 in a therapeutic approach to treat mesangioproliferative GN in rats. An adenovirus vector expressing BMP-2 will be constructed. Adenovirus-mediated gene transfer and engineered mesangial cell vectors will be used to express BMP-2 in vivo to inhibit mesangial cell proliferation in GN, without inducing extracellular matrix expansion. Activities of PI 3 kinase, MAPK and Akt will be determined in the glomerular lysates from vector-targeted animals. These studies will identify important signaling mechanisms involved in glomerular pathology and help to establish effective therapeutic modalities for treatment of proliferative forms of GN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT--PHOTON MICROSCOPY ADENOVIRAL INFECTION/ PROSTATIC TUMOR
VISUALIZATION
OF
Principal Investigator & Institution: Raikwar, Sudhanshu; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: The goal of this proposal is to develop a novel intravital imaging modality for androgen-independent prostate cancer. It is estimated that over 198,100 American men will be diagnosed with prostate cancer in year 2001 and 34,000 of them will die from this disease. For advanced prostate cancers, hormonal ablation is the only effective therapy available; however, the majority of patents will experience cancer recurrence and develop androgen-independent tumors. The mean survival of patients with androgen independent prostate cancer is about 18 months and is incurable at present. Therefore, there is an urgent need to develop novel treatment strategies to control androgen independent prostate cancer. Gene therapy is an attractive alternative therapy for androgen independent prostate cancer. Several clinical trials have been launched to evaluate the safety and efficacy of adenoviral-based gene therapy on prate cancer. The most exciting results come from the study of tumor/tissue restricted replication competent adenovirus. This strategy allows virus to propagate from limited infected cells to the whole tumor mass and overcomes the main problem of inadequate in vivo infectivity and biodistribution of adenovirus. However, how the viruses distribute and propagate in the tumor is not well studied. The objective of this pilot study is to visualize the virus infection and propagation inside the tumor using Intravital Dual Photon Confocal Fluorescence Optical Imaging Technology. This pilot study will develop a model system for the investigation of a better strategy to improve adenovirus-
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based gene delivery to the tumor and, thus, help to improve adenovirus-based gene therapy. Specific Aims: Specific Aim I will test whether we can visualize adenovirus infection in subcutaneous tumors using adenovirus expressing red fluorescence protein. Subcutaneous green fluorescent protein expressing prostate cancers will be established in nude mice and infected with adenovirus through intra tumoral injection or systemic delivery. Red fluorescence protein expressed in infected cells will be visualized with Dual Photon Confocal Fluorescence Optical Imaging. Specific Aim II will test whether the expression of adenovirus E1A proteins will alter tumor vasculature. Adenovirus E1A protein has been demonstrated to inhibit tumor angiogenesis and induce apoptosis. This aim intends to further investigate and enhance the effect of E1A protein on tumor vasculature. Specific Aim III will visualize adenovirus replication in the tumors and analyze how virus replication affects tumor vasculature. Replication competent adenovirus expressing red fluorescence protein will be constructed and used in this aim. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RB4 INTRAVESICAL GENE THERAPY: MECHANISMS OF CELL DEATH Principal Investigator & Institution: Benedict, William F.; Professor; Gas Med Oncology & Digest Dis; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): A modified retinoblastoma gene construct utilizes the second start codon of the RB gene and encodes for a 94 KD protein (pRB94. It is a markedly more potent tumor suppressor and cytotoxic agent than the wild-type RB protein and has been effective against all tumor types tested to date irrespective of tissue type, RB or other gene status, except for that of telomerase. A long-term objective of this project is to understand the cellular and molecular pRB94 interactions that cause such potent effects. Preliminary results suggest that a key mechanism of pRB94 specific induced tumor cell death may involve the production of rapid telomere attrition and chromosomal crisis. These results make the mechanism(s) of RB94 cell kill and tumor suppression potentially unique from all other agents or modalities examined to date and has occurred in all telomerase positive tumors or immortalized cells but not in tumor or immortalized cells containing an ALT pathway, i.e. telomerase negative cells. RB94 also has been found not to be cytotoxic or growth inhibitory to normal human cells, including urothelial cells, which are also telomerase negative. One approach will therefore be to determine if interference with the normal telomere complex plays a key role in RB94 produced telomere attrition, with subsequent chromosomal instability and cell death. The role of centrosomes and changes in STK15 kinase activity will also be studied in depth. Techniques will be include the use of microarrays, confocal laser scanning, analysis of chromosomal and telomere status, examination of RB94 specific protein interactions by Western blotting and immunochemical staining as well as immunoprecipitation with sequencing of putative RB94-specific related proteins. Studies will be expanded to examine RB94 cell kill in additional telomerase positive or negative tumor cells and genetically altered, non-tumorigenic immortalized cells. Whether or not these changes are caspase dependent will also be studied. Another specific aim is to optimize intravesical gene therapy and determine the effect of AdRB94 on superficial bladder cancer. An intravesical human bladder cancer model developed by us using GFP expressing cells will be utilized for this purpose. To increase adenovirus-mediated transfer the reagent, Syn3, will be used. Syn3 has been found to
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markedly increase adenoviralmediated gene transfer without being toxic itself. If these studies are successful, it could have a significant influence in developing a new modality of treatment for recurrent superficial bladder cancer and potentially for other tumor types as well as provide the molecular basis for the unique properties of RB94. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATABLE EXPRESSION OF TRAIL AND VIRAL ONCOLYSIS Principal Investigator & Institution: Doronin, Konstantin; Virrx, Inc. 1609 Adgers Wharf Dr St. Louis, Mo 63017 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2005 Summary: (provided by applicant): We have constructed an oncolytic adenovirus vector named "KD3" that replicates selectively in cancer cells as opposed to normal cells because of a mutation in the adenovirus E1A gene that prevents E1A proteins from deregulating the cell cycle in normal cells. KD3 was designed to overexpress the E311.6K protein (Adenovirus Death Protein, ADP). Overexpression of ADP allows for efficient egress of KD3 from infected cancer cells and the spread of KD3 from cell-to-cell. We also have constructed and partially characterized in cell culture a replicationdefective vector named "Tet-On-TRAIL" that expresses TNFrelated apoptosis-inducing ligand (TRAIL) under the control of a tetracycline-regulatable cassette. TRAIL is a member of the TNF family of death ligands that has been shown to induce apoptosis in a majority of cancer cells but not in most normal cells. When cells are co-infected with Tet-On-TRAIL and KD3, KD3 complements the replication and spread of Tet-OnTRAIL. When the Tet promoter is induced by doxyclycline (DOX), Tet-On-TRAIL synthesizes TRAIL very abundantly. We propose to characterize this "binary" vector system in cell culture and xenografts in nude mice with the long-term goal of obtaining preclinical data for a clinical trial. Tumors should be destroyed by two independent mechanisms, the replication and cell-to-cell spread of KD3 plus Tet-On-TRAIL, and the apoptosis-inducing ability of TRAIL on uninfected cancer cells. The vector system should be restricted to tumors by virtue of the E 1A mutation in KD3 and the cancer cell specificity of TRAIL. In cell culture experiments, we will examine TRAIL protein by immunoblot and immunofluorescence and TRAIL function by apoptosis assays. In order to determine if there is a bystander effect, cells infected with Tet-On-TRAIL+KD3+DOX will be mixed with uninfected cells and the death of the latter will be assayed. In vivo, we will inject Tet-On-TRAIL+KD3+DOX plus control vectors into subcutaneous human Hep3B liver cancer tumors in nude mice and examine the growth and apoptosis of the tumors, including uninfected contralateral tumors which may be destroyed by TRAIL released from the infected tumors. The possible toxicity to the mouse liver will be studied. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REPLICATIVE ADENOVIRUSES WITH ENHANCED INFECTIVITY Principal Investigator & Institution: Curiel, David T.; Director; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 10-JAN-2000; Project End 31-DEC-2003 Summary: Adenoviral vectors have been broadly used in cancer gene therapy but their utility has been limited by the insufficient transduction levels achieved. One factor that contributes to this limitation is the poor infectability of primary tumors due to low levels of the primary adenovirus receptor CAR. As a possible solution to this problem, our group has developed methods to increase adenovirus infectivity based on the
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modification of the virus tropism. We have demonstrated that the modification of the adenovirus fiber by genetic manipulation increases infectivity of primary tumors several orders of magnitude by the achievement of CAR-independent gene transfer. As a different solution, conditional replicative adenoviruses that propagate selectively in tumors have been used to achieve extensive lysis and transduction of tumors. For this replicative viruses is important to achieve tumor-selective replication to reduce their toxicity. Our group has developed methods of specific trans-complementation of replication defective adenoviral vectors cased on co-delivery of plasmids that enable replication. Using these methods we have achieved replication of viruses defective in essential early regions E1 and E4. It is our hypothesis that improving the infectivity and specificity of conditional replicative vectors will improve their therapeutic efficacy. We intend to modify the fiber of replicative adenovirus with an RGD motif that binds to integrins. This will provide an additional infectivity pathway different from the natural adenovirus receptor. In a second part of this project, we intend to combine this fiber modification with new methods to achieve tumor-selective replication on the transcriptional control of E4 or/and E2. Finally, we intend to demonstrate the oncolytic efficacy of these enhanced-infectability tumor- selective adenoviruses in murine models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RNA-SPECIFIC LIGANDS: AN APPROACH TO NEW ANTIVIRALS Principal Investigator & Institution: Beal, Peter A.; Associate Professor; Chemistry; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2003 Summary: Ribonucleic acid (RNA) function is central to all life, including that of viruses and bacteria. Antibacterial agents such as neomycin and erythromycin are examples of existing drugs that target sites in bacterial ribosomal RNAs. Unfortunately, bacteria are becoming increasingly resistant to these compounds via adaptation that allows for the modification of the RNA target or modification of the antibiotic. Human immunodeficiency virus (HIV), adenovirus (AV) and Epstein-Barr virus (EBV) are examples of human pathogens that all have unique RNA structures that appear necessary for replication. Each of these RNAs are potential targets for drug intervention. Unfortunately, our lack of understanding of the recognition of RNA by small molecules limits our ability to design high affinity ligands. The goal of this project is to identify low molecular weight ligands (<-l000 Da) that bind selectively to predefined RNA structures and inhibit the formation of protein-RNA complexes. This will be accomplished via the generation of structurally diverse libraries of molecules and the selection of library members with the requisite affinity and selectivity properties. The libraries are designed to contain intercalating ligands with appended functional groups capable of making specific contacts in the grooves of an RNA double helix. These experiments will ultimately lead to the ability to design and synthesize molecules that bind selectively to specific sequences of duplex RNA. In addition, these new compounds would have the potential to be developed into therapeutics for viral and bacterial infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF GLUTATHIONE REDUCTASE AND MACROPHAGE ONCOSIS Principal Investigator & Institution: Asmis, Reto Hr.; Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506
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Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): We hypothesize that increased glutathione reductase activity protects human macrophages from OxLDL-induced mitochondrial dysfunction and cell death, thereby decreasing the severity of atherosclerosis. Macrophage and foam cell death by oncosis plays a crucial role in the development of atherosclerotic lesions. We propose to study the molecular mechanism of glutathione reductase-mediated protection of macrophages from oncosis.Specific Aim 1: To determine the effect of OxLDL on the thiol redox state of mitochondria. Our preliminary data demonstrate that OxLDL induces mitochondrial depolarization and loss of ATP synthesis. We will use human monocyte-derived macrophages to determine if OxLDL promotes oncosis by 1) altering the thiol redox status of mitochondria, 2) inactivating mitochondrial glutathione reductase and 3) increasing mitochondrial inner membrane permeability.Specific Aim 2: To determine the role of mitochondrial and cytosolic glutathione reductase in preventing OxLDL-induced oncosis. Mitochondria do not synthesize glutathione (GSH) and therefore rely on GSH uptake and the reduction of GSSG to maintain the appropriate thiol redox state. We will use human monocytederived macrophages to determine 1) if adenovirus-mediated doxycycline-controlled expression of mitochondrial or cytosolic glutathione reductase (GR) prevents GSSG accumulation and protein thiol oxidation and 2) if increasing glutathione reductase activity restores mitochondrial function and protects macrophages from OxLDLinduced oncosis.Specific Aim 3: To determine whether increased macrophage glutathione reductase activity decreases the severity of atherosclerosis. Foam cell death promotes the formation of the necrotic core and the progression of atherosclerotic lesions. We will perform bone marrow transplantation studies to determine in vivo whether augmented expression of glutathione reductase (GR) in macrophages prevents foam cell death and lesion progression. GR-overexpressing bone marrow cells, generated by retroviral gene transfer, will be used to repopulate irradiated LDL receptor null mice and apoE null mice. We will measure both lesion size and lesional cholesterol/cholesterol ester content. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SELECTIVE THERAPY OF TUMORS THAT OVEREXPRESS C MYC Principal Investigator & Institution: Potter, Philip M.; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-MAR-2007 Summary: (provided by applicant): The anticancer prodrug CPT-11 is activated by esterases to yield the potent topoisomerase I inhibitor SN-3S. Expression of a rabbit liver carboxylesterase (rCE) that can efficiently activate CPT-11 confers sensitivity to the drug both to cells in culture and when grown as xenografts in immune-deprived mice. Since the activation of this agent in humans is poor, this affords the potential to use rCE in combination with CPT- 11 in a virus directed enzyme prodrug therapy approach (VDEPT). This proposal expands on previous studies to determine the effectiveness of VDEPT in eliminating human tumor cells from immune-deprived animals in a selective fashion. The premise for these studies is that tumor cells frequently overexpress the oncogene c-MYC, a transcription factor. By designing appropriate expression vectors based upon the omithine decarboxylase promoter, a gene specifically upregulated by cmyc, we propose to achieve tumor selective expression of the rCE (or hiCE) and hence selectively sensitize these cells to CPT-11. The experiments in this application propose to identify the most efficient carboxylesterase and transcriptional control elements to achieve tumor selective expression and to design adenovirus as delivery vehicles. The
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Adenovirus
Specific Aims of this application are, therefore: 1) To compare the abilities of the previously described rabbit CE (rCE) and a recently isolated human intestinal CE (hi CE) to sensitize human tumor cells to CPT- 11; 2) To specifically sensitize human tumor cells that express c-MYC to CPT-11 by expression of rCE orhiCE under the control of a modified omithine ecarboxylase promoter; and 3) To eliminate minimal residual disease and bulk tumor in a human tumor xenograft animal model system using adenovirus demonstrating specific expression of rCE or hiCE in combination with CPT-11. These studies will assess the effectiveness of VDEPT with rCE or hiCE and CPT-11 at eliminating tumor cells from appropriate animal models of human disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SIGNALING PATHWAYS INTERACTIONS AND MAMMARY TUMOR Principal Investigator & Institution: Iyengar, Srinivas R.; Professor; Pharmacology/Biological Chem; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: This proposal focuses on the role of the Galphas/adenylyl cyclase pathway and how constitutive and conditional elevation of cAMP affects cell proliferation and transformation. We have found that mutant (Q227L) activated Gas (alphas ) extensively inhibited H-Ras induced transformation of NIH-3T3 fibroblasts. We studied the effects of alphas expression on human breast cancer cell lines, since transformation of mammary epithelial cells is often associated with increases in receptor-tyrosine kinases that transmit their signals through Ras to MAP-kinase 1,2. Expression of alphas or elevation of cAMP results in a decrease in the intrinsic MAP-kinase (ERK1,2) activity of MCF-7 cell line and increased expression of the cell cycle inhibitor p27kip in MDA-231 and MDA-435 cell lines. This accompanied by inhibition of colony formation in soft agar and tumor formation in Nu/Nu mice. We constructed recombinant adenovirus that contains a FLAG epitope tagged alphas (ADV-alphas ). Infection of several types of human breast cancer cells representative of the latter stages of the disease, with the ADV-alphas in vitro, results in an inhibition of ability to form tumors in Nu/Nu mice. We find that application of ADV-alphas into established tumors results in blockade of their growth. These observations indicate that interactions between signaling pathways may regulate mammary carcinogenesis. We will expand these studies to include several human cell lines representing the later stages of breast cancer. We will test if adenovirus direction expression of alphas in combination with low doses of taxol causes full regression of tumors. We will determine the molecular mechanisms by which expression of alphas inhibits expression of the transformed phenotype in human mammary epithelial cells. We will look for inhibition of signal flow through the RafMAP kinase pathway as well as alterations in the expression of the cell cycle regulators. We will study the molecular consequences of expressing adenylyl cyclase 2 which can be stimulated by protein kinase C, in mammary epithelial cells and determine if such expression blocks proliferative signals conditionally and suppresses tumorigenesis. We will develop transgenic mice that express alphas or adenylyl cyclase 2 in mammary tissue to determine if this expression lowers the incidence of mammary tumors caused by expression of oncogenes such as erbB2 (HER2). From these studies we hope to gain an understanding of the mechanisms involved in the interactions between signaling pathways in regulating the proliferation and transformation of mammary epithelia. We also hope to determine whether such interactions can be used in the treatment of breast
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cancer and the feasibility of expressing components of the Galphas pathways as "germline therapy" for prevention of breast cancers in high-risk populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SITE SPECIFIC ALKYLATION OF THE HER2/NEU PROMOTER Principal Investigator & Institution: Ebbinghaus, Scot W.; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (PROVIDED BY APPLICANT): The HER-2/neu oncogene appears to play an important role in the initiation and progression of many types of human cancer, including approximately 25 percent of non-small cell lung cancer (NSCLC), the leading cause of cancer death in both men and women in the U.S. The overall goal of this project is to find novel ways to specifically inhibit HER-2/neu expression by developing triplex forming oligonucleotide (TFO)-alkylator conjugates what will bind in a site-specific manner to the HER-2/neu promoter by triplex DNA formation and lead to covalent DNA modification at specific guanine bases by the DNA alkylating agent. The specific aims of this proposal are designed to address the major obstacles to the successful development of a TFO-based DNA binding drug. Site-specific alkylation with TFOs conjugated to nitrogen mustards will be demonstrated in the HER-2/neu promoter. These data will be rationalized by molecular modeling, and these models will be used to further refine the design of the TFO-alkylator conjugates (Specific Aim 1). Much of this work has now been accomplished, and future work will focus on the design of novel conjugates with a minor groove DNA binding agent and the investigation of nuclease resistant oligonucleotide backbone modifications. The ability of these compounds to inhibit transcription initiation will be studied by triple helix formation in a reporter plasmid transiently transfected into NSCLC cell lines, and the ability of NSCLC cells to recognize and repair triplex directed DNA alkylation will be characterized after transfection (Specific Aim 2). Our preliminary data demonstrates that a TFO conjugated to a nitrogen mustard at both the 3' and 5' ends can direct two guanine adducts adjacent to both ends of the triple helix to resist DNA repair and suppress HER-2/neu promoter activity in NSCLC cells. An adenovirus based ODN delivery system will be developed, and the ability of adenoviruses to mediate ODN uptake and nuclear localization will be determined when adenovirus-ODN complexes are formed by a semi-stable chemical linker (Specific Aim 3). The ability of triplex forming ODNs to bind to the endogenous HER-2/neu gene and direct site-specific DNA alkylation will be studied by Southern blot and ligation mediated-PCR after the treatment of NSCLC cells with the TFOalkylator conjugates (Specific Aim 4). The therapeutic potential of these compounds to inhibit HER-2/neu expression and alter the malignant and invasive phenotype of NSCLC cells will be evaluated in tissue culture (Specific Aim 5). The development of a HER-2/neu specific anti-gene compound will provide a great deal of information about the role of the HER-2/neu gene in the initiation and progression of NSCLC and may lead to novel treatment approaches for HER-2/neu expressing cancers such as NSCLC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SPREAD OF REPLICATING ADENOVIRUS IN PANCREATIC TUMORS Principal Investigator & Institution: Hay, John G.; Professor; Medicine; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008
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Adenovirus
Summary: (provided by applicant): An increased understanding of the cellular and molecular mechanisms that lead to cancer, has lead to an expectation that biological agents will play an increasing role in cancer therapy. The ability of a replicating virus to multiply its genetic "pay-load" up to several thousand-fold within a target cell, and then spread from cell-to-cell within a tumor, is an important characteristic to be harnessed in the development of a molecular therapy. However, in the few clinical trials to date replicating adenoviruses have only achieved limited clinical success. It has also become apparent that stroma plays a very important role in the development of tumors, and particularly so in pancreatic cancer which often has an intense stromal response. The foundation for this proposal is our recently published work showing that replicating adenovirus can persist for several weeks at high level within xenograft tumors without totally eliminating these tumors. This proposal is therefore directed towards understanding how the replicating adenovirus interacts with tumor cells, stromal cells and the tumor physiologic environment within pancreatic xenograft tumors. A better understanding of these factors may enable improvements to be made in the design of replicating adenoviral gene therapy vectors to facilitate their spread and efficacy in pancreatic tumors. Aim one will determine if stromal cellular or matrix components limit the spread of replicating adenoviral vectors through pancreatic xenograft tumors. Aim two will determine if areas of hypoxia within the tumor limit adenoviral replication. Aim three will determine if the intensity or permeability of the tumor vasculature influences viral distribution and spread within pancreatic xenograft tumors, and whether this can be modified for therapeutic advantage. Aim four will determine if xenograft tumor cells or the infecting virus change during the course of a persistent infection, and if these changes reduce the efficacy of the replicating adenovirus vector. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SRCAP TRANSCRIPTION
REGULATION
OF
CREB
AND
GR-MEDIATED
Principal Investigator & Institution: Chrivia, John C.; Associate Pharmacological & Physiol Scis; St. Louis University St. Louis, Mo 63110
Professor;
Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): CREB-binding protein (CBP) functions as a coactivator for many transcription factors and is able to respond to extracellular signals to specifically regulate gene expression. Mutations within CBP have been found in patients with mental retardation and growth defects (Rubinstein-Taybi syndrome) and have been demonstrated in patients with acute myelogenous leukemia. Several viruses that cause diseases in humans (HTLV-l, HIV-1, CMV, HBV, and adenovirus) also use CBP to regulate gene expression. Regulation of transcription by CBP occurs in part through its ability to function as a histone acetylase transferase (HAT), and in part through contact with other molecules which themselves function as HATs or which function as general transcription factors such as TBP. Recent work indicates that CBP contacts a specific subset of proteins to activate transcription at different promoters. We have identified a novel protein termed SRCAP (SNF2-Related-CBP-Activator Protein) that binds to a region within CBP shown to be important for CBP to function as a coactivator for CREB. SRCAP regulates the ability of CREB and CBP to activate transcription and we have found that SRCAP regulates transcription of several promoters (PEPCK, somatostatin, and enkephalin) that utilize CREB and CBP to activate transcription. In addition, we have found that SRCAP enhances glucocorticoid receptormediated transcription of the MMTV-promoter. Recent studies indicate that SRCAP (like CBP) is targeted by several viral proteins. These include: the HCV core protein that
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inhibits CREB-mediated transcription; the HCV NS5A protein that in conjunction with SRCAP represses transcription of the p21 gene; the adenovirus protein, DBP, that blocks CBP-SRCAP interaction and inhibits transcription mediated by SRCAP; and the adenovirus protein, Ela that binds CBP and blocks binding of CBP to SRCAP. The proposed studies will determine whether interaction of CBP and SRCAP is needed for CREB-mediated transcription of endogenous genes. They will determine the mechanism(s) through which SRCAP activates CREB-mediated transcription and by which SRCAP activates GR-transcription of the MMTV promoter. These studies will also determine whether SRCAP binding proteins regulate the ATPase and transcriptional activities of SRCAP. For example, we have found that the Dead box RNA helicase protein (DBX) binds to SRCAP and represses CREB-mediated transcription. We propose to determine whether this repression of CREB-mediated transcription occurs through formation of a DBX-SRCAP complex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SSDNA OLIGONUCLEOTIDES
EXPRESSION
OF
TRIPLEX-FORMING
Principal Investigator & Institution: Chen, Yin; Cytogenix, Inc. 9881 S Wilcrest Houston, Tx 77099 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2003 Summary: We propose here to use a transgenic mouse model containing a reporter gene that has a target region amenable to triplex formation as a test system to determine the in vivo efficacy of intracellular ssDNA generation from a ssDNA expression system. 1. Adenovirus vector construct to deliver ssDNA expression cassette with a triplexforming sequence. a. A double-stranded DNA (dsDNA) sequence encoding for the AG30 triplex-forming ODN (TFO) sequence will be inserted into a second generation ssDNA generation of ssDNA expression system (single- vector), and the expression cassette will be subsequently removed and subcloned into an adenovirus vector. A series of control vectors also will be constructed. b. The new adenovirus vector constructs will be tested for their ability to express TFOs in cell culture (FL-10 cells and fibroblasts derived from transgenic mice) in anticipation of mouse experiments. 2. Test of in vivo targeting in mice. a. We will use an established transgenic mouse-based assay system to investigate triplex-mediated gene targeting via in vivo production of ssDNA. b. Comparison will be made between adenovirus vectors expressing ssDNA versus systemic administration of synthetic ODNs. At the completion of these studies, our expectation os that we will have: (1) established the ability of ssDNA vectors to deliver and produce ssDNA molecules in vivo in order to mediate gene targeting in the cells and tissues of experimental animals. The success of this work may lead to a novel research tool and may eventually provide a new approach to gene therapy for human disease utilizing unmodified strands of ssDNA designed specifically for therapeutic interventions related to triplex, antisense, aptamer, and DNA enzyme applications. PROPOSED COMMERCIAL APPLICATIONS: The success of this work may lead to a novel research tool and may eventually provide a new approach to gene therapy for human disease utilizing unmodified strands of ssDNA designed specifically for therapeutic interventions related to triplex, antisense, aptamer, and DNA enzyme applications. Furthermore, it would provide the basis for Phase II work to develop ssDNA generating vectors as potential gene targeting and gene therapy reagents for clinically relevant genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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•
Adenovirus
Project Title: SURFACTANT PROTEINS AND TYPE II CELL DIFFERENTIATION Principal Investigator & Institution: Ballard, Philip L.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) A deficiency of pulmonary surfactant at birth is a major contributing cause of lung injury and long-term lung disease such as bronchopulmonary dysplasia (BPD). The severe respiratory distress associated with inherited deficiency of surfactant protein-B (SP-B), in both mice pups and infants born at term, indicates a key role for the hydrophobic SPs in differentiation of type II cells. In the absence of SP-B there is a failure of normal lamellar body genesis as well as incomplete processing of SP-C. Recently, isolated deficiency of SP-C has been described in infants with interstitial lung disease. Respiratory distress also occurs in newborn term BWB calves which lack mature SP-C and have reduced SP-B, and in rodents respiratory distress and acquired deficiency of SP-B/-C occurs with lung injury secondary to bleomycin or infection (P. carinii and endotoxin). Based on these and other findings, this project proposes that synthesis of SP-B, SP-C and lamellar bodies are closely linked and that relative levels of both SP-B and SP-C influence surfactant function. The objectives of this proposal are to characterize the biosynthetic pathway for human SP-C, determine the roles of SP-B and SP-C in lamellar body genesis, and investigate SP-B and SP-C in lung disease. Aim I will determine expression of mature SP-C during type II cell differentiation in vivo and in vitro in relationship to production of SP-B and lamellar bodies and also define targeting domains and cleavage events in SP-C processing. The studies will utilize antibody to mature SP-C and a recently developed culture system for hormonally induced type II cell differentiation in vitro. Aim II will investigate the role and interactions of SP-B and SP-C in lamellar body genesis and trafficking of surfactant components using cell culture models of SP deficiency. The studies will examine the hypothesis that expression of mature SP-B is required for both lamellar body formation and final processing of SP-C intermediates. Experiments will be carried out in the cultured type II cell model and SP-B or -C gene expression will be selectively inhibited using adenovirus expressing antisense mRNAs. Processing and intracellular trafficking of each SP will be studied using epitope specific antibodies, pulse/chase labeling, and tagged recombinant proteins. In addition, processing and effects of alternatively spliced SP-B and mutated SP-C will be determined. Aim III will investigate expression of SP-B and SP-C in surfactant from infants with lung disease and after treatment with inhaled nitric oxide. It is hypothesized that a deficiency of SP-B and/or SP-C occurs in infants with severe BPD, and that this process is modulated by anti-inflammatory effects of nitric oxide. In addition, the developmental pattern for alternative SP-B splicing in human lung and relationship of splicing variants to SP-B levels and newborn lung disease will be determined. The proposed studies will utilize both the Tissue Culture and Clinical Cores and involve collaboration with Projects 6, 4 and 7. The new information will provide further understanding of the role of the hydrophobic surfactant proteins in lung development and newborn lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETED DELIVERY OF R-ADV FOR TREATMENT OF GLIOBLASTOMA Principal Investigator & Institution: Li, Yibing; Genepharm, Inc. 136 S Wolfe Rd Sunnyvale, Ca 94086 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 31-DEC-2003
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63
Summary: (provided by applicant): Adenoviruses are efficient vectors for the in vivo gene delivery in gene therapy. Adenoviruses efficiently infect many cell/tissue types and express therapeutic genes. However, viral infection of healthy tissues can cause toxicity and adverse effects. A therapeutic approach that targets the virus to diseased tissue while preventing infection of surrounding healthy tissue would be optimal. Our proposal attempts to address both of these issues by blocking native adenoviral infection, and specifically redirecting virus to disease tissues using a fusion protein with an antibody Fc binding domain. This protein adaptor has a unique strength: it can be flexibly adapted to target any marker for which there is a specific antibody. Our studies have demonstrated in endothelial culture that adenovirus, fusion protein and antibody complex could target the ICAM-l receptor while blocking native infection pathway. We propose to test our strategy in vivo targeting glioblastoma, a fatal disease for which no effective therapy present. The interleukin-13 receptor was found overexpressed on many glioblastomas and thus can be used as a specific marker for targeting. The goal is to demonstrate the feasibility of our strategy to mediate specific adenoviral infection in a murine xenografted glioblastoma model. This technology may ultimately improve gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETING ADENOVIRUS VECTORS TO OVARIAN CANCER Principal Investigator & Institution: King, C Richter.; Vice President, Research; Genvec, Inc. 65 W Watkins Mill Rd Gaithersburg, Md 20878 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Despite significant improvements in the management of ovarian cancer, approximately 13,900 women per year in the United States are expected to ultimately fail standard therapies and die. Peritoneal spread is the major route of dissemination and leads to significant morbidity. Therefore, ovarian cancer is well suited for the application of adenoviral anti-cancer treatments because they permit a regional administration of the vector into the peritoneal cavity with exposure of disseminated lesions to a locally high concentration of vector. However, a major disadvantage of current adenovirus vectors is that they efficiently transduce nontarget, mesothelial cells that line all the major organs in the peritoneal cavity while inefficiently transducing ovarian cancer cells. This suboptimal efficiency and specificity results because the target cancer cells often do not express high levels of the primary adenovirus receptor, the Coxsackie-Adenovirus Receptor (CAR), while the non-target mesothelial cells are efficiently transduced in a CAR-dependent manner. We have made significant strides in increasing the specificity of adenovirus vectors for cancer applications. We have created two targeted adenovirus vectors that are simultaneously mutated to avoid binding to CAR and genetically redirected for binding to either alphavbeta3/5 or alphavbeta6 integrin receptors, which are both highly expressed in ovarian cancers. Our preliminary data indicates that these vectors will avoid CARmediated gene transfer to healthy mesothelial tissue while efficiently targeting tumor cells that express either alphavbeta3/5 or alphavbeta6 integrin receptors. Our overall objective in the proposed studies is to identify a targeted lead vector expressing the therapeutic transgene for tumor necrosis factor-alpha (TNF) for the treatment of ovarian cancer. This lead must demonstrate significant anti-tumor activity with an acceptable toxicity profile in at least 2 preclinical models designed to closely mimic the clinical application. We will first test the hypothesis that the in vitro and in vivo efficiency and specificity of gene delivery are improved through targeting using vectors carrying marker genes (Specific Aim 1). We will then construct alphavbeta3/5 or alphavbeta6 -
64
Adenovirus
targeted vectors carrying the transgene for TNF. We will test the feasibility of these vectors as clinical leads by determining whether they display appropriate anti-tumor activities and toxicity profiles according to predefined criteria (Specific Aim 2). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETING OF PKA BY AKAP100 IN AGING AND FAILING HEARTS Principal Investigator & Institution: Bond, Meredith; Professor and Chair; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 16-FEB-2000; Project End 31-JAN-2005 Summary: The severity of human heart failure parallels increased sympathetic drive, elevated circulating catecholamines and a diminished inotropic response to betaadrenergic stimulation. A dominant view has been that the observed down-regulation of beta- receptors in failing hearts predicts altered downstream activity of the betaadrenergic pathway. However recent evidence suggests that regulation distal to receptor activation of adenylyl cyclase may be equally or more important. The subcellular distribution of cAMP-dependent protein kinase (PKA) is regulated in many tissues by compartmentalization of PKA by A-kinase anchoring proteins (AKAPs). However, to date there is little information as to how AKAPs regulate PKA activity in the heart. We recently showed co-localization of RII, the regulatory subunit of PKA II, with the cardiac-specific A-kinase anchoring protein, AKAP100, at the junctional sarcoplasmic reticulum (jSR), nucleus and intercalated disc of cardiac muscle cells. We showed that AKAP binding of PKA is regulated by RII autophosphorylation and that RII autophosphorylation is decreased in failing human hearts. These findings implicate AKAP100 dependent PKA targeting in the regulation of substrate phosphorylation in the heart and provide evidence for altered AKAP targeting of PKA in failing hearts. Our goal is to investigate the role of AKAP100 in regulating PKA- dependent substrate phosphorylation in normal and failing hearts. In Specific Aim 1, we will investigate the distribution of AKAP100 and AKAP: RII binding in failing and non-failing human hearts, and will determine the effect on AKAP:RII interation of unloading the failing heart by implantation of a left ventricular assist device (LVAD). This Aim will be addressed by immunofluorescent confocal microscopy, immunogold EM, surface plasmon resonance and Western and Northern blotting. In Specific Aim 2 we will study the functional role of AKAP100 in the regulation of PKA-dependent substrate phosphorylation in cardiac muscle cells by inhibition of AKAP100: RII binding. This will be achieved by adenovirus expression of the inhibitory peptide Ht31. We will assess changes in substrate phosphorylation, cell function, myofibrillar Ca2+ sensitivity and subcellular distribution of RII by confocal microscopy. Specific Aim 3 will investigate molecular interactions between AKAP100, PKA and a PKA substrate, the ryanodine receptor (RyR). This will be carried out by fluorescence resonance energy transfer (FRET) of fusion proteins of RII, catalytic subunit of PKA (C), AKAP100, Ht31 and RyR, each linked to a variant of green fluorescent protein (GFP) and expressed in CHO cells. Overall these studies will allow us to determine the role of AKAP targeting of PKA in the heart and the implications of altered targeting of PKA in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETING PCD FOR CANCER THERAPY Principal Investigator & Institution: Clarke, Michael F.; Professor of Medicine, and Cell and Deve; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274
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65
Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-JAN-2004 Summary: Despite recent advances in the detection and treatment of most cancers, cancer related mortality has not decreased in the United States. In the near future, cancer is predicted to overtake heart disease as the number one cause of death. It is clear that new approaches are needed to treat these diseases. Cancer is the result of disruption of the pathways that regulate cell proliferation. These pathways include mitogenic signals, growth inhibitory signals, and cell survival signals. Preliminary evidence suggests that these latter signals differ between normal cells and cancer cells, as well as between cancers derived from solid tissue cells and hematopoietic cells. We postulate that better understanding these differences will allow the development of novel cancer therapies. The overall goals of this proposal are to understand the perturbations in the programmed cell death (PCD) pathway in cancer cells, and to determine whether the differences between cancer cells and normal cells can be exploited to develop new therapeutic agents. To accomplish these goals, adenovirus vectors will be used to specifically inactivate inhibitory components of the PCD pathway. Viruses that target three different points in the PCD pathway will be analyzed. These vectors, the bcl-x, adenovirus, the mbm-2 adenovirus, and the hrk adenovirus have several qualities that make them ideal agents that can be used to study both the biology and biochemistry of the PCD pathway and used as gene therapy agents. Cancers of Breast, Ovarian, Bladder and Hematopoietic origin will be analyzed. These cancers were chosen to explore differences in PCD pathways in these tumors, and because adenovirus vectors have therapeutic potential in these diseases. The projects in this proposal are integrated to achieve these goals. Project #1, Biochemistry and function of hrk, will examine the role of a new gene, hrk, in PCD in normal and cancer cells. An adenovirus vector that expresses hrk will be made and used by each project to determine the role of this gene in PCD in each respective type of cancer cell. Project #2, Targeting PCD in Breast and Ovarian cancer cells will utilize each of the adenovirus vectors for effects on normal and malignant breast cancer cells. Animal models to test the utility of these vectors are described. Clinical trials using the bcl-x/s adenovirus in high dose chemotherapy and autologous BMT in breast cancer and for treatment of ascites in patients with ovarian cancer are planned. Project #3, targeting PCD in Leukemia, will explore the regulation of PCD in normal and leukemic hematopoietic cells. Strategies to use adenovirus to specifically kill leukemia cells contaminating the bone marrow of cells used for autologous BMT will be tested. Project #4, Targeting PCD in bladder cancer, will determine the role of the bcl-2 family in bladder cancer. Clinical trials using the bcl-x/s adenovirus are envisioned. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETING THE P53 PATHWAY FOR REVERSAL OF ORAL PREMALIGNANCY Principal Investigator & Institution: Clayman, Gary L.; Associate Professor; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Premalignancies of the oral cavity and oropharynx have a high risk of progression to invasive squamous carcinomas. Our biochemoprevention studies suggest that these sites are tremendously resistant to our most active agents, including cis-retinoic acid, interferonalpha and alpha-tocopherol; while clinical and pathologic response rates approach 80% in the larynx, there is a response rate of only 15% in the oral cavity. We hypothesize that over-expression of the wild-type p53 tumor suppressor gene in premalignant cells will induce apoptosis,
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Adenovirus
allowing for repopulation with epithelial cells of normal genotype and phenotype. Clinical studies show that adenovirus-mediated p53 gene transfer induces apoptosis in squamous cell carcinoma; apoptosis is observed without dose-limiting toxicity and independent of endogenous p53 genotype; importantly, non-malignant fibroblasts and epithelial cells remain unaffected. To address the hypothesis that over-expression of wild-type p53 will reverse the malignant process, we propose to conduct a clinical trial with an adenovirus vector encoding Ad5CMVp53 (RPR/INGN 201) administered via intramucosal injection and multiple oral rinses to patients with oral premalignant carcinoma. The study will be conducted as a Phase I/II study, with determination of maximum tolerated dose and effect of p53 gene transfer in reversing the clinical and histologic appearance of oral and oropharyngeal premalignancies to be evaluated in Specific Aim 1. In Specific Aim 2, we will determine the effect of p53 gene transfer on expression of molecular biomarkers of p53 activity in preneoplastic lesions of the oral cavity and oropharynx. We will determine the relationship between expression of the Coxsackie adenovirus receptor (CAR) expression and p53 induction in response to adenovirus p53 gene transfer. Other biomarkers to be studied include MDM2, MDMX, ARF, bcl-2, bax, and apoptotic index. In Specific Aim 3, we will determine the role of the p53 inhibitors MDM2 and MDMX in the development of SCCHN and in response to adenovirus p53 gene transfer; for these studies, we will correlate MDM2 and MDMX levels with p53 levels in tissue biopsies from patients with oral premalignancies enrolled in the clinical trial and in archival tissue samples from patients with SCCHN. Finally, we will conduct laboratory studies to begin to evaluate the therapeutic potential of alterations in MDM2 and/or MDMX in SCCHN. The data collected in this project will expand our understanding of the role of p53 and the p53 inhibitors MDM2 and MDMX in progression of oral cavity and oropharynx premalignancies and development of squamous cell carcinoma of the head and neck. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF CAR AND ITS APPLICATION IN BLADDER CANCER Principal Investigator & Institution: Hsieh, Jer-Tsong; Surgery; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): With over 50,000 new cases and 10,000 deaths expected this year in the U.S, bladder cancer is a significant health concern. Variable morphology, natural history, and prognosis demonstrate that transitional cell carcinoma (TCC) of the bladder is not a single disease, but occurs in three distinct forms, each possessing characteristic features (i.e., low grade papillary, noninvasive; carcinoma in situ; high grade, invasive). Recent studies have begun to elucidate the underlying genetic determinants of the morphologic and biologic characteristics of these different presentations of bladder cancer. Molecular and genetic alterations that precede morphologic changes, and which are responsible for tumorigenesis and progression of TCC. Understanding these genetic changes should eventually lead to improved diagnosis and gene therapy for TCC. Identification of a coxsackie and adenovirus receptor (CAR), a high receptor for adenovirus type 5, was recently reported. The heterogeneous expression of CAR is detected in several TCC and prostate cancer cell lines. This expression resulted from the downregulation of CAR gene transcription. By increasing their CAR levels, resistant cells could become highly sensitive to adenoviral infection. Therefore, CAR not only is a surrogate marker to monitor the outcome of gene therapy, but also facilitate the efficiency of gene therapy. The Down-regulation of CAR is often seen in TCC lesions but not in adjacent normal tissue, which suggests that CAR
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may play a pathophysiologic role in the progression of TCC. Also, CAR is associated with a tight junction protein in differentiated polarized cell. Moreover, increased CAR gene expression can inhibit the in vitro and in vivo growth of tumor cells. On the other hand, decreasing CAR expression (using antisense vector) in several TCC cell lines can facilitate the in vitro and in vivo growth rate. These data indicate that CAR is a tumor inhibitor in TCC cells. To further elucidate the underlying mechanism of CAR in TCC cells, preliminary data indicated that (1) CAR is a typical cell adhesion molecule; (2) CAR is associated with tight junction complex; (3) adhesion activity of CAR parallels its growth inhibitory function; (4) the intracellular domain of CAR is critical for inducing its growth inhibitory signal in TCC cells; (5) CAR is able to inhibit cyclooxygenase 2 (COX-2) expression. Based on these results, we hypothesize that CAR can inhibit cell growth by reestablishing intercellular interactions of TCC, and the mechanism of CAR action is to inhibit COX-2 expression in TCC. Since the biology of CAR and COX-2 is largely unknown, we plan to (1) establish a reciprocal relationship between CAR and COX-2 from TCC specimens of different grades and stages; (2) unveil downstream pathway(s) elicited by CAR that activates its tumor inhibition and to determine any other ligand(s) capable of activating CAR signaling; (3) determine the biologic significance of the suppression of COX-2 by CAR; (4) increase therapeutic efficacy of TCC gene therapy by enhancing its endogenous CAR expression. The outcome of this study should help us understand the biologic role of CAR in the progression of TCC and develop a new strategy for TCC therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METASTASIS
TISSUE
SPECIFIC
GENE
THERAPY
FOR
PULMONARY
Principal Investigator & Institution: Kao, Chinghai; Associate Professor; Urology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 04-JAN-2001; Project End 31-DEC-2003 Summary: (Applicant's Abstract) The major goal of this application is to develop a new treatment modality for pulmonary metastasis. Malignant cells usually gain access to the bloodstream through thin-walled venous tumor vessels and grow in solid cores from which fragments or tumor cells may break off to form tumor emboli. Such emboli tend to lodge in the first capillary beds they encounter. Therefore, the lung is a common metastatic side of many human tumors that spread via the hematogenous route. Effective therapy for patients with pulmonary metastases is lacking. To improve the treatment of these lethal sequelae of cancer, the applicant developed a novel tissuespecific gene therapy modality to treat pulmonary metastasis using osteosarcoma as an ideal model system. The objective of this application is to enhance the efficacy of the applicant's tissue-specific gene-therapy approach and develop a novel gene-delivery technique for the treatment of pulmonary metastases. They hypothesis to be tested is: pulmonary metastases can be treated by tissue/tumor-specific promoter-based toxic gene therapy with recombinant adenovirus as a gene delivery vehicle. Treatment efficacy can be enhanced by 1) combining with chemotherapeutic agents, and 2) improving localized delivery of therapeutic agents using an isolated-single-lungperfusion technique. To test these hypotheses the applicant proposes the following studies. (I) To study the possible benefit of combining gene therapy with chemotherapy, the beneficial effect of four commonly used chemotherapeutic agents, methotrexate, ifosfamide, doxorubicin and cisplatin, on herpes simplex virus thymidine kinase mediated cell- and tumor-kill will be evaluated. The doses of adenovirus, prodrugs, and
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chemotherapeutic agents for optimal therapeutic efficacy and the sequence of treatment will be studied. (II) To investigate the interaction between toxic gene therapy and chemotherapy, he will study the effect of chemotherapeutic agents on adenovirus mediated transgene expression, the effect of adenoviral gene expression on chemotherapy, and the collaborative efficacy of TK/prodrug and chemotherapeutic agent mediated cell-kill. In particular, the applicant will investigate the potential interference of virus attachment to its receptor and transportation to the nuclei. (III) To increase the local virus concentration and virus-target cell contact time, he will establish an isolated-single-lung-perfusion technique for locoregional delivery of adenovirus and evaluate its therapeutic advantage. He will also evaluate gene transduction efficacy of adenovirus delivered by the isolated-single-lung-perfusion technique. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCRIPTION FACTORS & INFLAMMATORY MEDIATORS IN STROKE Principal Investigator & Institution: Vemuganti, Rao L.; Neurological Surgery; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Focal cerebral ischemia is associated with a robust inflammation that contributes to the progression of ischemic neuronal damage. The mechanisms, which modulate the inflammation after focal ischemia, are not wellunderstood. Suppressor of cytokine signaling (SOCS) family of proteins controls the inflammation in the peripheral organs. Binding of pro-inflammatory cytokine IL-6 (formed in excess after ischemia) to its receptors induces transphosphorylation of the receptor-associated Janus kinases (JAKs). Phosphorylated JAKs in turn phosphorylate the down-stream STAT family of transcription factors, which dimerize and translocate into nucleus. Binding of phosphorylated STAT to DNA stimulates cytokine gene expression to generate more interleukins. This cycle leads to sustained inflammation unless controlled. Phosphorylated STAT also stimulates SOCS gene expression. SOCS proteins act as intracellular negative feedback regulators to inhibit JAK-STAT phosphorylation and thereby dampen the cytokine signal transduction. In the adult brain, SOCS proteins are expressed at a very low level, but can be induced rapidly. Our preliminary data showed an upregulation of SOCS-3 and STAT-3 expression after focal ischemia. We hypothesize that SOCS-3 induction is an endogenous neuroprotective event to control post-ischemic inflammation and neuronal damage. We also hypothesize that in the ischemic brain, SOCS-3 actions are mediated by STAT-3. Using antisense knockdown and adenovirus-induced overexpression of individual proteins, we will analyze the mechanism of action of the 3 control points of SOCS-3 pathway (IL-6, STAT3 and SOCS-3) in modulating post-ischemic inflammation and neuronal damage. We will study (a) if SOCS-3 knockdown increases and overexpression decreases interleukin levels and STAT-3 phosphorylation after ischemia; (b) if IL-6 knockdown (starting point of the cascade) prevents STAT-3 phosphorylation and SOCS-3 expression after ischemia, and (c) if STAT-3 knockdown/overexpression modulates post-ischemic SOCS-3 induction. Using GeneChip in combination with antisense and adenovirus, we will analyze the ischemia-induced gene expression changes modulated by SOCS-3. The ultimate goal is to define the role of SOCS-3/STAT-3 in post-ischemic cerebral inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSCRIPTIONAL REGULATION OF ADENOVIRUS LATE GENES Principal Investigator & Institution: Flint, S J.; Professor; Molecular Biology; Princeton University 4 New South Building Princeton, Nj 085440036 Timing: Fiscal Year 2004; Project Start 01-DEC-1986; Project End 31-MAR-2008 Summary: (provided by applicant): Human adenoviruses are under intense scrutiny as vehicles for gene therapy and as anticancer agents in humans. Nevertheless, many basic aspects of the mechanisms by which these viruses replicate efficiently in permissive cells remain poorly understood. These processes include the co-ordination of synthesis of progeny viral DNA genome with production of the structural proteins of virus particles. In adenovirus-infected cells, transcription of the genes encoding the latter proteins requires viral DNA synthesis. The long term objective of these studies is elucidation of the mechanisms by which viral and cellular components co-operate in such temporal regulation of viral transcription. To this end, a cellular transcriptional repressor responsible for the viral DNA synthesis-dependent transcription of the late IVa2 gene will be identified and characterized, so that its normal function and mechanism of action can be investigated. The protein encoded by the IVa2 gene is a sequence-specific DNA binding protein that has been implicated in stimulation of transcription from the promoter of the major late transcription, which contains the coding sequences for all but one structural protein, and in virion assembly. Complementary biochemical, molecular and genetic methods will be used to establish the roles of this important viral protein in infected cells and investigate the mechanisms by which it acts. The possibility that a novel mechanism regulates the rate at which the viral replication proteins are produced will also be assessed by genetic methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRK-MEDIATED SIGNALING AT NEUROMUSCULAR SYNAPSES Principal Investigator & Institution: Balice-Gordon, Rita J.; Associate Professor; Neuroscience; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): This revised proposal is aimed at determining the role of neurotrophins that signal through Trk receptors in modulating synapse structure and function in the developing and adult nervous system. The mouse neuromuscular junction will be used as a model system. The cell types that comprise neuromuscular junctions, the perisynaptic Schwann cells, presynaptic motor neuron terminals, and postsynaptic muscle fibers, each express a complement of neurotrophins and Trks, suggesting that neurotrophin signaling at this synapse is multi‑directional and involves all three cell types. Similarly, CNS neurons express several neurotrophins and Trks, but the relative roles of each signaling pathway in synaptic maturation and maintenance are unclear. Recent work from our lab showed that TrkB isoforms (which bind the neurotrophins BDNF and NT4/5) is expressed primarily postsynaptically, in the muscle fiber membrane in and around acetylcholine receptor (AChR) rich regions, while TrkC isoforms are localized to perisynaptic Schwann cells and TrkA is not localized to neuromuscular junctions. Down-regulation of TrkB signaling in muscle fibers, via adenovirus-mediated over-expression of a truncated, non-signaling form of TrkB (TrkB.tl), induced the dismantling of postsynaptic AChR rich regions. These observations lead to the hypothesis that exchange of ligands that signal through TrkB or TrkC receptors play different roles in synaptic maturation and maintenance. To test this hypothesis, we will use adenovirus‑mediated manipulation of neurotrophin and
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Trk expression in different cell types at neuromuscular junctions in vivo. The effect of these manipulations on neuromuscular junction structure and function will be analyzed with in vivo imaging, immunostaining, confocal microscopy and electrophysiological characterization of synaptic strength. We will also explore the molecular mechanisms downstream of TrkB‑mediated signaling, and how these may interact with the agrin/MuSK signaling pathway that mediates AChR clustering. The results of these experiments will provide new insights into the functional role(s) of neurotrophin and Trk‑mediated signaling at developing and adult synapses, and extend our understanding of the relative roles of antero‑ and retrograde synaptic signaling in the peripheral as well as central nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VASCULAR SMOOTH MUSCLE GROWTH AND FIBRONECTIN MATRIX Principal Investigator & Institution: Getz, Godfrey S.; Professor and Chair; Pathology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: The proliferation of vascular smooth muscle cells (VSMCs) is controlled by growth factors and by the interaction of cells with the extracellular matrix (ECM). Our goal is to understand the role of the fibronectin matrix in controlling VSMC proliferation. We have found that a recombinant fragment of fibronectin (protein III1-C) inhibits VSMC fibronectin matrix assembly and also inhibits VSMC proliferation. Moreover, III1-C blocks both growth factor-induced and adhesion-induced MAP kinase activation in VSMCs. To determine whether inhibition of fibronectin matrix assembly blocks MAP kinase activation, we will test whether other methods of inhibiting fibronectin matrix assembly also inhibit VSMC proliferation and MAP kinase signaling. It is possible that III1-C inhibits VSMC proliferation by some activity other than inhibition of fibronectin matrix assembly. We will therefore test whether III1-C interacts with proteins other than fibronectin on the surface of VSMCs. This will be accomplished by several methods, including crosslinking of labeled III1-C to cell surface proteins and III1-C affinity chromatography to isolate and identify cell surface proteins that interact with III1-C. The molecular mechanism by which III1-C blocks MAP kinase signaling will be analyzed by systematically testing the effects of III1-C on the activities of the known members of the Ras/MAP kinase pathway, thereby allowing us to determine where III1C disrupts this signaling pathway. We will also test the effect of III1-C on VSMC proliferation in vivo in a restenosis model. III1-C will be inserted into an adenovirus expression construct that includes a recently discovered SMC-specific promoter. This will allow high levels of expression and secretion of III1-C specifically in VSMCs in vivo. The III1-C-adenovirus vector will be tested in the rat carotid artery balloon injury model. If III1-C has the same effect on VSMC proliferation in vivo as it does in cell culture, then the III1-C- adenovirus vector should inhibit neointima formation in this rat carotid artery restenosis model. The work proposed in this grant will help establish the importance of the ECM, and in particular of the fibronectin matrix in regulating VSMC growth both in culture and in vivo. By understanding the role of the ECM in pathological processes such as restenosis and atherosclerosis we may begin to design more effective treatments for these conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: VSV-BASED THERAPEUTIC PAPILLOMA VACCINE Principal Investigator & Institution: Brandsma, Janet L.; Associate Professor; Comparative Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 17-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Human papillomavirus (HPV) infection of the cervix initiates the development of cervical cancer. Vaccination has the potential to prevent cervical cancer by preventing primary HPV infection and by eliminating persistent lesions. The ideal vaccine would induce therapeutic as well as protective immunity. The best animal model for therapeutic vaccine development is the cottontail rabbit papillomavirus (CRPV)-rabbit model. Live recombinant vesicular stomatitis viruses (rVSV) expressing foreign viral proteins have successfully protected animals against challenges with several human viruses. We recently generated an rVSV vector expressing the CRPV E6 tumor antigen and used it to vaccinate rabbits with wellestablished tumors (papillomas) in a preliminary experiment. The treatment induced dramatic therapeutic outcomes including the complete and permanent regression of all disease in some rabbits with a total papilloma burden of 4 cm3, as compared to no regression in the controls. The hypothesis of this application is that the rVSV-E6 vaccine can be improved to induce more rapid and more universal regression. It is based on the observation that the original vaccine expressed a relatively low level of E6 protein and that revaccination with the same rVSV-E6 was probably not effective, due to VSVspecific neutralizing antibodies induced by primary vaccination. The efficacy of the rVSV-E6 could also be improved by modifying the E6 gene to encode a ubiquitin-E6 fusion protein (UbE6), based on our findings, using CRPV DNA vaccines, that a UbE6 fused gene was markedly more effective than the unfused E6 gene. The specific aims are to repeat the preliminary experiment with larger group size and all appropriate controls; to determine if more rapid and more universal tumor clearance can be obtained using VSV vectors giving higher-level expression of E6 or expressing UbE6, using an efficient VSV-E6 boosting vector with the VSV envelope gene from a heterologous serotype, or using a completely heterologous viral vector (adenovirus). We will determine if the most effective therapeutic vaccine also induces protective immunity. The data provided by this investigation are likely to aid in the development a highly effective HPV vaccine to protect women against cervical cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “adenovirus” (or synonyms) into the search box. This search gives you access to 3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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full-text articles. The following is a sample of items found for adenovirus in the PubMed Central database: •
"Reversion" of a Less Tumorigenic cyt Mutant of Adenovirus 12 in Induction of the Cell Surface Change. by Yamamoto H, Shimojo H.; 1973 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=356639
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A block in release of progeny virus and a high particle-to-infectious unit ratio contribute to poor growth of enteric adenovirus types 40 and 41 in cell culture. by Brown M, Wilson-Friesen HL, Doane F.; 1992 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=241087
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A carboxy-terminal region required by the adenovirus type 9 E4 ORF1 oncoprotein for transformation mediates direct binding to cellular polypeptides. by Weiss RS, Javier RT.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192143
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A helper-dependent system for adenovirus vector production helps define a lower limit for efficient DNA packaging. by Parks RJ, Graham FL.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191467
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A Helper-Independent Adenovirus Vector with E1, E3, and Fiber Deleted: Structure and Infectivity of Fiberless Particles. by Von Seggern DJ, Chiu CY, Fleck SK, Stewart PL, Nemerow GR.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103985
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A High-Capacity, Capsid-Modified Hybrid Adenovirus/Adeno-Associated Virus Vector for Stable Transduction of Human Hematopoietic Cells. by Shayakhmetov DM, Carlson CA, Stecher H, Li Q, Stamatoyannopoulos G, Lieber A.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135810
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A late adenovirus factor induces eIF-4E dephosphorylation and inhibition of cell protein synthesis. by Zhang Y, Feigenblum D, Schneider RJ.; 1994 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237141
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A mouse model for adenovirus gene delivery. by Tallone T, Malin S, Samuelsson A, Wilbertz J, Miyahara M, Okamoto K, Poellinger L, Philipson L, Pettersson S.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35442
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A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. by Ginsberg HS, Moldawer LL, Sehgal PB, Redington M, Kilian PL, Chanock RM, Prince GA.; 1991 Mar 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51082
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A New Type of Adenovirus Vector That Utilizes Homologous Recombination To Achieve Tumor-Specific Replication. by Bernt K, Liang M, Ye X, Ni S, Li ZY, Ye SL, Hu F, Lieber A.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136641
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A protein serologically and functionally related to the group C E3 14,700-kilodalton protein is found in multiple adenovirus serotypes. by Horton TM, Tollefson AE, Wold WS, Gooding LR.; 1990 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=249240
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A purified adenovirus 289-amino-acid E1A protein activates RNA polymerase III transcription in vitro and alters transcription factor TFIIIC. by Datta S, Soong CJ, Wang DM, Harter ML.; 1991 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=249009
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A recombinant adenovirus expressing an Epstein-Barr virus (EBV) target antigen can selectively reactivate rare components of EBV cytotoxic T-lymphocyte memory in vitro. by Morgan SM, Wilkinson GW, Floettmann E, Blake N, Rickinson AB.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190082
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A Replication-Incompetent Adenovirus Vector with the Preterminal Protein Gene Deleted Efficiently Transduces Mouse Ears. by Moorhead JW, Clayton GH, Smith RL, Schaack J.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103924
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A Single Amino Acid in the Adenovirus Type 37 Fiber Confers Binding to Human Conjunctival Cells. by Huang S, Reddy V, Dasgupta N, Nemerow GR.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104037
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Absence of an essential regulatory influence of the adenovirus E1B 19-kilodalton protein on viral growth and early gene expression in human diploid WI38, HeLa, and A549 cells. by Telling GC, Perera S, Szatkowski-Ozers M, Williams J.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236319
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Activation of a preexisting cellular factor as a basis for adenovirus E1A-mediated transcription control. by Reichel R, Kovesdi I, Nevins JR.; 1988 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279553
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Activation of Adenovirus Early Promoters and Lytic Phase in Differentiated Strata of Organotypic Cultures of Human Keratinocytes. by Noya F, Balague C, Banerjee NS, Curiel DT, Broker TR, Chow LT.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155017
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Activation of p38 and ERK Signaling during Adenovirus Vector Cell Entry Lead to Expression of the C-X-C Chemokine IP-10. by Tibbles LA, Spurrell JC, Bowen GP, Liu Q, Lam M, Zaiss AK, Robbins SM, Hollenberg MD, Wickham TJ, Muruve DA.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135878
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Adeno-Associated Virus (AAV) Rep Protein Enhances the Generation of a Recombinant Mini-Adenovirus (Ad) Utilizing an Ad/AAV Hybrid Virus. by Sandalon Z, Gnatenko DV, Bahou WF, Hearing P.; 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110912
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Adeno-Associated Virus RNAs Appear in a Temporal Order and Their Splicing Is Stimulated during Coinfection with Adenovirus. by Mouw MB, Pintel DJ.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102024
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Adenovirus Binding to the Coxsackievirus and Adenovirus Receptor or Integrins Is Not Required To Elicit Brain Inflammation but Is Necessary To Transduce Specific Neural Cell Types. by Thomas CE, Edwards P, Wickham TJ, Castro MG, Lowenstein PR.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136027
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Adenovirus DNA polymerase: domain organisation and interaction with preterminal protein. by Parker EJ, Botting CH, Webster A, Hay RT.; 1998 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147410
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Adenovirus DNA replication facilitates binding of the MLTF/USF transcription factor to the viral major late promoter within infected cells. by Toth M, Doerfler W, Shenk T.; 1992 Oct 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=334297
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Adenovirus Dodecahedron Allows Large Multimeric Protein Transduction in Human Cells. by Fender P, Schoehn G, Foucaud-Gamen J, Gout E, Garcel A, Drouet E, Chroboczek J.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152161
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Adenovirus E1A N-Terminal Amino Acid Sequence Requirements for Repression of Transcription In Vitro and In Vivo Correlate with Those Required for E1A Interference with TBP-TATA Complex Formation. by Boyd JM, Loewenstein PM, Tang QQ, Yu L, Green M.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135854
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Adenovirus E1A proteins inhibit activation of transcription by p53. by Steegenga WT, van Laar T, Riteco N, Mandarino A, Shvarts A, van der Eb AJ, Jochemsen AG.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231197
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Adenovirus E1B 19-kilodalton protein overcomes the cytotoxicity of E1A proteins. by White E, Cipriani R, Sabbatini P, Denton A.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240940
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Adenovirus E3 14.7K protein functions in the absence of other adenovirus proteins to protect transfected cells from tumor necrosis factor cytolysis. by Horton TM, Ranheim TS, Aquino L, Kusher DI, Saha SK, Ware CF, Wold WS, Gooding LR.; 1991 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240621
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Adenovirus E4-dependent activation of the early E2 promoter is insufficient to promote the early-to-late-phase transition. by Hemstrom C, Virtanen A, Bridge E, Ketner G, Pettersson U.; 1991 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239924
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Adenovirus E4orf6 oncoprotein modulates the function of the p53-related protein, p73. by Higashino F, Pipas JM, Shenk T.; 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28104
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Adenovirus early region 1A modulation of interferon antiviral activity. by Anderson KP, Fennie EH.; 1987 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=254021
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Adenovirus early region 4 encodes two gene products with redundant effects in lytic infection. by Huang MM, Hearing P.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=250738
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Adenovirus early region 4 is required for efficient virus particle assembly. by Falgout B, Ketner G.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255990
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Adenovirus Endocytosis Requires Actin Cytoskeleton Reorganization Mediated by Rho Family GTPases. by Li E, Stupack D, Bokoch GM, Nemerow GR.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110297
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Adenovirus Endocytosis via [alpha]v Integrins Requires Phosphoinositide-3-OH Kinase. by Li E, Stupack D, Klemke R, Cheresh DA, Nemerow GR.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109499
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Adenovirus Hexon Protein Is a Potent Adjuvant for Activation of a Cellular Immune Response. by Molinier-Frenkel V, Lengagne R, Gaden F, Hong SS, Choppin J, GaherySegard H, Boulanger P, Guillet JG.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135719
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Adenovirus Induction of an Interferon-Regulatory Factor during Entry into the Late Phase of Infection. by Feigenblum D, Walker R, Schneider RJ.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110345
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Adenovirus infection elevates levels of cellular topoisomerase I. by Chow KC, Pearson GD.; 1985 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397534
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Adenovirus infection enhances in vitro adherence of Streptococcus pneumoniae. by Hakansson A, Kidd A, Wadell G, Sabharwal H, Svanborg C.; 1994 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302872
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Adenovirus inhibition of cell translation facilitates release of virus particles and enhances degradation of the cytokeratin network. by Zhang Y, Schneider RJ.; 1994 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236732
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Adenovirus interaction with distinct integrins mediates separate events in cell entry and gene delivery to hematopoietic cells. by Huang S, Kamata T, Takada Y, Ruggeri ZM, Nemerow GR.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190385
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Adenovirus Late Gene Expression Does Not Require a Rev-Like Nuclear RNA Export Pathway. by Rabino C, Aspegren A, Corbin-Lickfett K, Bridge E.; 2000 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112182
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Adenovirus precursor to terminal protein interacts with the nuclear matrix in vivo and in vitro. by Fredman JN, Engler JA.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237682
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Adenovirus Protein V Induces Redistribution of Nucleolin and B23 from Nucleolus to Cytoplasm. by Matthews DA.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113999
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Adenovirus Serotype 30 Fiber Does Not Mediate Transduction via the CoxsackieAdenovirus Receptor. by Law LK, Davidson BL.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136819
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Adenovirus Strains of Subgenus D Associated with Nosocomial Infection as New Etiological Agents of Epidemic Keratoconjunctivitis in Japan. by Takeuchi S, Itoh N, Uchio E, Tanaka K, Kitamura N, Kanai H, Isobe K, Aoki K, Ohno S.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85580
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Adenovirus Type 11 Uses CD46 as a Cellular Receptor. by Segerman A, Atkinson JP, Marttila M, Dennerquist V, Wadell G, Arnberg N.; 2003 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187375
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Adenovirus type 12 DNA firmly associates with mammalian chromosomes early after virus infection or after DNA transfer by the addition of DNA to the cell culture medium. by Schroer J, Holker I, Doerfler W.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192150
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Adenovirus type 12 early region 1B 54K protein significantly extends the life span of normal mammalian cells in culture. by Gallimore PH, Lecane PS, Roberts S, Rookes SM, Grand RJ, Parkhill J.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191941
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Adenovirus type 12-induced fragility of the human RNU2 locus requires U2 small nuclear RNA transcriptional regulatory elements. by Bailey AD, Li Z, Pavelitz T, Weiner AM.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230876
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Adenovirus Type 37 Uses Sialic Acid as a Cellular Receptor on Chang C Cells. by Arnberg N, Pring-Akerblom P, Wadell G.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136979
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Adenovirus Type 37 Uses Sialic Acid as a Cellular Receptor. by Arnberg N, Edlund K, Kidd AH, Wadell G.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111511
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Adenovirus type 5 and 7 capsid chimera: fiber replacement alters receptor tropism without affecting primary immune neutralization epitopes. by Gall J, Kass-Eisler A, Leinwand L, Falck-Pedersen E.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190048
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Adenovirus type 5 early region 4 is responsible for E1A-induced p53-independent apoptosis. by Marcellus RC, Teodoro JG, Wu T, Brough DE, Ketner G, Shore GC, Branton PE.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190645
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Adenovirus Type 5 Viral Particles Pseudotyped with Mutagenized Fiber Proteins Show Diminished Infectivity of Coxsackie B-Adenovirus Receptor-Bearing Cells. by Jakubczak JL, Rollence ML, Stewart DA, Jafari JD, Von Seggern DJ, Nemerow GR, Stevenson SC, Hallenbeck PL.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115923
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Adenovirus type 5 virions can be assembled in vivo in the absence of detectable polypeptide IX. by Colby WW, Shenk T.; 1981 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171335
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Adenovirus type 7 associated with severe and fatal acute lower respiratory infections in Argentine children. by Carballal G, Videla C, Misirlian A, Requeijo PV, Aguilar MD.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126266
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Adenovirus Type 7 Induces Interleukin-8 Production via Activation of Extracellular Regulated Kinase 1/2. by Alcorn MJ, Booth JL, Coggeshall KM, Metcalf JP.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114368
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Adenovirus type 9 E4 open reading frame 1 encodes a transforming protein required for the production of mammary tumors in rats. by Javier RT.; 1994 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236897
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Adenovirus Type 9 Fiber Knob Binds to the Coxsackie B Virus-Adenovirus Receptor (CAR) with Lower Affinity than Fiber Knobs of Other CAR-Binding Adenovirus Serotypes. by Kirby I, Lord R, Davison E, Wickham TJ, Roelvink PW, Kovesdi I, Sutton BJ, Santis G.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114453
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Adenovirus Types 11p and 35p Show High Binding Efficiencies for Committed Hematopoietic Cell Lines and Are Infective to These Cell Lines. by Segerman A, Mei YF, Wadell G.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111481
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Adenovirus types 2, 8, and 37 associated with genital infections in patients attending a sexually transmitted disease clinic. by Swenson PD, Lowens MS, Celum CL, Hierholzer JC.; 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228564
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Adenovirus types 40 and 41 and rotaviruses associated with diarrhea in children from Guatemala. by Cruz JR, Caceres P, Cano F, Flores J, Bartlett A, Torun B.; 1990 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268047
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Adenovirus uncoating and nuclear establishment are not affected by weak base amines. by Rodriguez E, Everitt E.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190220
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Adenovirus VAI RNA prevents phosphorylation of the eukaryotic initiation factor 2 alpha subunit subsequent to infection. by Schneider RJ, Safer B, Munemitsu SM, Samuel CE, Shenk T.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390405
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Adenovirus Vector Designed for Expression of Toxic Proteins. by Edholm D, Molin M, Bajak E, Akusjarvi G.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114528
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Adenovirus Vector-Induced Expression of the C-X-C Chemokine IP-10 Is Mediated through Capsid-Dependent Activation of NF-[kappa]B. by Borgland SL, Bowen GP, Wong NC, Libermann TA, Muruve DA.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111907
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Adenovirus vector-infected cells can escape adenovirus antigen-specific cytotoxic Tlymphocyte killing in vivo. by Wadsworth SC, Zhou H, Smith AE, Kaplan JM.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191754
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Adenoviruses Activate Human Dendritic Cells without Polarization toward a THelper Type 1-Inducing Subset. by Rea D, Schagen FH, Hoeben RC, Mehtali M, Havenga MJ, Toes RE, Melief CJ, Offringa R.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113078
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Adenoviruses from Human Immunodeficiency Virus-Infected Individuals, Including Two Strains That Represent New Candidate Serotypes Ad50 and Ad51 of Species B1 and D, Respectively. by De Jong JC, Wermenbol AG, Verweij-Uijterwaal MW, Slaterus KW, Wertheim-Van Dillen P, Van Doornum GJ, Khoo SH, Hierholzer JC.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85850
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Adenoviruses in the immunocompromised host. by Hierholzer JC.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358244
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Adenovirus-Facilitated Nuclear Translocation of Adeno-Associated Virus Type 2. by Xiao W, Warrington KH Jr, Hearing P, Hughes J, Muzyczka N.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136768
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Adenovirus-induced alterations of the cell growth cycle: a requirement for expression of E1A but not of E1B. by Braithwaite AW, Cheetham BF, Li P, Parish CR, WaldronStevens LK, Bellett AJ.; 1983 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=256401
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Adenovirus-mediated Cre deletion of floxed sequences in primary mouse cells is an efficient alternative for studies of gene deletion. by Prost S, Sheahan S, Rannie D, Harrison DJ.; 2001 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55864
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Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. by Newman KD, Dunn PF, Owens JW, Schulick AH, Virmani R, Sukhova G, Libby P, Dichek DA.; 1995 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186007
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Adenovirus-pulsed dendritic cells stimulate human virus-specific T-cell responses in vitro. by Smith CA, Woodruff LS, Kitchingman GR, Rooney CM.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190716
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Adenovirus-specific translation by displacement of kinase Mnk1 from cap-initiation complex eIF4F. by Cuesta R, Xi Q, Schneider RJ.; 2000 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=313943
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Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees. by Mi Z, Ghivizzani SC, Lechman E, Glorioso JC, Evans CH, Robbins PD.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165041
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Alternative poly(A) site utilization during adenovirus infection coincides with a decrease in the activity of a poly(A) site processing factor. by Mann KP, Weiss EA, Nevins JR.; 1993 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=359562
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An Adenovirus Inhibitor of Tumor Necrosis Factor Alpha-Induced Apoptosis Complexes with Dynein and a Small GTPase. by Lukashok SA, Tarassishin L, Li Y, Horwitz MS.; 2000 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111992
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An adenovirus mutant unable to express VAI RNA displays different growth responses and sensitivity to interferon in various host cell lines. by Kitajewski J, Schneider RJ, Safer B, Shenk T.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=367233
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An Adenovirus Type 5 Mutant with the Preterminal Protein Gene Deleted Efficiently Provides Helper Functions for the Production of Recombinant Adeno-Associated Virus. by Maxwell IH, Maxwell F, Schaack J.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110217
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An Adenovirus Vector with Genetically Modified Fibers Demonstrates Expanded Tropism via Utilization of a Coxsackievirus and Adenovirus Receptor-Independent Cell Entry Mechanism. by Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G, Belousova N, Curiel DT.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110480
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Analyses of Single-Amino-Acid Substitution Mutants of Adenovirus Type 5 E1B-55K Protein. by Shen Y, Kitzes G, Nye JA, Fattaey A, Hermiston T.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114175
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Analysis of 15 adenovirus hexon proteins reveals the location and structure of seven hypervariable regions containing serotype-specific residues. by Crawford-Miksza L, Schnurr DP.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190011
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Analysis of 15 different genome types of adenovirus type 7 isolated on five continents. by Li QG, Wadell G.; 1986 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=253937
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Analysis of early region 3 mutants of mouse adenovirus type 1. by Beard CW, Spindler KR.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190604
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Analysis with restriction endonucleases recognizing 4- or 5-base-pair sequences of human adenovirus type 3 isolated from ocular diseases in Sapporo, Japan. by Itakura S, Aoki K, Sawada H, Shinagawa M.; 1990 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268181
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Anti-adenovirus type 5 cytotoxic T lymphocytes: immunodominant epitopes are encoded by the E1A gene. by Routes JM, Bellgrau D, McGrory WJ, Bautista DS, Graham FL, Cook JL.; 1991 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239925
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Antibody response to enteric adenovirus types 40 and 41 in sera from people in various age groups. by Shinozaki T, Araki K, Ushijima H, Fujii R.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269306
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Antibody to human adenovirus early antigens during acute adenovirus infections. by Gerna G, Cattaneo E, Revello MG, Battaglia M, Achilli G.; 1981 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351513
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Antigenically intermediate human adenovirus strain associated with conjunctivitis. by Hierholzer JC, Rodriguez FH Jr.; 1981 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273797
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Application of a Fas Ligand Encoding a Recombinant Adenovirus Vector for Prolongation of Transgene Expression. by Zhang HG, Bilbao G, Zhou T, Contreras JL, Gomez-Navarro J, Feng M, Saito I, Mountz JD, Curiel DT.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109549
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Artificial Extension of the Adenovirus Fiber Shaft Inhibits Infectivity in Coxsackievirus and Adenovirus Receptor-Positive Cell Lines. by Seki T, Dmitriev I, Kashentseva E, Takayama K, Rots M, Suzuki K, Curiel DT.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135866
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Assembly of Adenoviruses. by Sundquist B, Everitt E, Philipson L, Hoglund S.; 1973 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=355120
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Bak and Bax Function To Limit Adenovirus Replication through Apoptosis Induction. by Cuconati A, Degenhardt K, Sundararajan R, Anschel A, White E.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155112
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Binding of Adenovirus Capsid to Dipalmitoyl Phosphatidylcholine Provides a Novel Pathway for Virus Entry. by Balakireva L, Schoehn G, Thouvenin E, Chroboczek J.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152149
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Binding of CCAAT Displacement Protein CDP to Adenovirus Packaging Sequences. by Erturk E, Ostapchuk P, Wells SI, Yang J, Gregg K, Nepveu A, Dudley JP, Hearing P.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154998
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Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy. by Gao GP, Yang Y, Wilson JM.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190991
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Biology of E1-Deleted Adenovirus Vectors in Nonhuman Primate Muscle. by Zoltick PW, Chirmule N, Schnell MA, Gao GP, Hughes JV, Wilson JM.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114928
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Biology of Ovine Adenovirus Infection of Nonpermissive Cells. by Kumin D, Hofmann C, Rudolph M, Both GW, Loser P.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136640
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Bovine adenovirus type 10 identified in fatal cases of adenovirus-associated enteric disease in cattle by in situ hybridization. by Smyth JA, Benko M, Moffett DA, Harrach B.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228995
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Bovine Lactoferrin Inhibits Adenovirus Infection by Interacting with Viral Structural Polypeptides. by Pietrantoni A, Di Biase AM, Tinari A, Marchetti M, Valenti P, Seganti L, Superti F.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166106
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Canine Adenovirus Type 2 Attachment and Internalization: CoxsackievirusAdenovirus Receptor, Alternative Receptors, and an RGD-Independent Pathway. by Soudais C, Boutin S, Hong SS, Chillon M, Danos O, Bergelson JM, Boulanger P, Kremer EJ.; 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110938
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Cell-binding domain of adenovirus serotype 2 fiber. by Louis N, Fender P, Barge A, Kitts P, Chroboczek J.; 1994 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236926
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Cellular Components Interact with Adenovirus Type 5 Minimal DNA Packaging Domains. by Schmid SI, Hearing P.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109777
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Characterization of a low-molecular-weight virus-associated (VA) RNA encoded by simian adenovirus type 7 which functionally can substitute for adenovirus type 5 VA RNAI. by Larsson S, Svensson C, Akusjarvi G.; 1986 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=288936
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Characterization of a Temperature-Sensitive Fiber Mutant of Type 5 Adenovirus and Effect of the Mutation on Virion Assembly. by Chee-Sheung CC, Ginsberg HS.; 1982 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=256927
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Characterization of an Adenovirus Vector Containing a Heterologous Peptide Epitope in the HI Loop of the Fiber Knob. by Krasnykh V, Dmitriev I, Mikheeva G, Miller CR, Belousova N, Curiel DT.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109474
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Characterization of E3/49K, a Novel, Highly Glycosylated E3 Protein of the Epidemic Keratoconjunctivitis-Causing Adenovirus Type 19a. by Windheim M, Burgert HG.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136837
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Characterization of the Complete Genome of the Tupaia (Tree Shrew) Adenovirus. by Schondorf E, Bahr U, Handermann M, Darai G.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150671
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Characterization of the knob domain of the adenovirus type 5 fiber protein expressed in Escherichia coli. by Henry LJ, Xia D, Wilke ME, Deisenhofer J, Gerard RD.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236468
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Characterization of transgenic mice containing adenovirus early region 3 genomic DNA. by Fejer G, Gyory I, Tufariello J, Horwitz MS.; 1994 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236992
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Chicken adenovirus (CELO virus) particles augment receptor-mediated DNA delivery to mammalian cells and yield exceptional levels of stable transformants. by Cotten M, Wagner E, Zatloukal K, Birnstiel ML.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237742
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Chromosomal Integration Pattern of a Helper-Dependent Minimal Adenovirus Vector with a Selectable Marker Inserted into a 27.4-Kilobase Genomic Stuffer. by Hillgenberg M, Tonnies H, Strauss M.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114561
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Circumvention of Immunity to the Adenovirus Major Coat Protein Hexon. by Roy S, Shirley PS, McClelland A, Kaleko M.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109897
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Comparative Immunogenicity in Rhesus Monkeys of DNA Plasmid, Recombinant Vaccinia Virus, and Replication-Defective Adenovirus Vectors Expressing a Human Immunodeficiency Virus Type 1 gag Gene. by Casimiro DR, Chen L, Fu TM, Evans RK, Caulfield MJ, Davies ME, Tang A, Chen M, Huang L, Harris V, Freed DC, Wilson KA, Dubey S, Zhu DM, Nawrocki D, Mach H, Troutman R, Isopi L, Williams D, Hurni W, Xu Z, Smith JG, Wang S, Liu X, Guan L, Long R, Trigona W, Heidecker GJ, Perry HC, Persaud N, Toner TJ, Su Q, Liang X, Youil R, Chastain M, Bett AJ, Volkin DB, Emini EA, Shiver JW.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154996
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Comparative Inactivation of Enteroviruses and Adenovirus 2 by UV Light. by Gerba CP, Gramos DM, Nwachuku N.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126408
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Comparative Sequence Analysis of the Largest E1A Proteins of Human and Simian Adenoviruses. by Avvakumov N, Wheeler R, D'Halluin JC, Mymryk JS.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155151
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Comparison of monoclonal time-resolved fluoroimmunoassay with monoclonal capture-biotinylated detector enzyme immunoassay for adenovirus antigen detection. by Hierholzer JC, Johansson KH, Anderson LJ, Tsou CJ, Halonen PE.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269303
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Comparison of neutralization and DNA restriction enzyme methods for typing clinical isolates of human adenovirus. by Fife KH, Ashley R, Shields AF, Salter D, Meyers JD, Corey L.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268329
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Complementary functions of E1a conserved region 1 cooperate with conserved region 3 to activate adenovirus serotype 5 early promoters. by Wong HK, Ziff EB.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236431
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Conjunctivitis due to adenovirus type 19. by Taylor JW, Chandler JW, Cooney MK.; 1978 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=275188
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Conserved sequences of the adenovirus genome for detection of all human adenovirus types by hybridization. by Scott-Taylor TH, Hammond GW.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265367
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Constitutive episomal expression of polypeptide IX (pIX) in a 293-based cell line complements the deficiency of pIX mutant adenovirus type 5. by Caravokyri C, Leppard KN.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189571
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Constructing chimeric type 12/type 5 adenovirus E1A genes and using them to identify an oncogenic determinant of adenovirus type 12. by Telling GC, Williams J.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236524
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Construction and Characterization of Adenovirus Serotype 5 Packaged by Serotype 3 Hexon. by Wu H, Dmitriev I, Kashentseva E, Seki T, Wang M, Curiel DT.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136697
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Construction and Characterization of Hexon-Chimeric Adenoviruses: Specification of Adenovirus Serotype. by Gall JG, Crystal RG, Falck-Pedersen E.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110610
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Construction of a Pseudoreceptor That Mediates Transduction by Adenoviruses Expressing a Ligand in Fiber or Penton Base. by Einfeld DA, Brough DE, Roelvink PW, Kovesdi I, Wickham TJ.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112945
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Adenovirus
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Construction of a recombinant adenovirus for efficient delivery of the I-SceI yeast endonuclease to human cells and its application in the in vivo cleavage of chromosomes to expose new potential telomeres. by Anglana M, Bacchetti S.; 1999 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=148704
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Construction of Avian Adenovirus CELO Recombinants in Cosmids. by Francois A, Eterradossi N, Delmas B, Payet V, Langlois P.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114934
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Crystal structure of reovirus attachment protein [sigma]1 reveals evolutionary relationship to adenovirus fiber. by Chappell JD, Prota AE, Dermody TS, Stehle T.; 2002 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125343
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Defective synthesis of early region 4 mRNAs during abortive adenovirus infections in monkey cells. by Ross D, Ziff E.; 1992 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=241073
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Deletion mutation analysis of the adenovirus type 2 E3-gp19K protein: identification of sequences within the endoplasmic reticulum lumenal domain that are required for class I antigen binding and protection from adenovirus-specific cytotoxic T lymphocytes. by Hermiston TW, Tripp RA, Sparer T, Gooding LR, Wold WS.; 1993 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237927
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Dependence of Adenovirus Infectivity on Length of the Fiber Shaft Domain. by Shayakhmetov DM, Lieber A.; 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110901
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Detection of adenovirus in clinical specimens by polymerase chain reaction and liquid-phase hybridization quantitated by time-resolved fluorometry. by Hierholzer JC, Halonen PE, Dahlen PO, Bingham PG, McDonough MM.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265651
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Detection of Adenoviruses (AdV) in Culture-Negative Environmental Samples by PCR during an AdV-Associated Respiratory Disease Outbreak. by Echavarria M, Kolavic SA, Cersovsky S, Mitchell F, Sanchez JL, Polyak C, Innis BL, Binn LN.; 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87165
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Detection of Astroviruses, Enteroviruses, and Adenovirus Types 40 and 41 in Surface Waters Collected and Evaluated by the Information Collection Rule and an Integrated Cell Culture-Nested PCR Procedure. by Chapron CD, Ballester NA, Fontaine JH, Frades CN, Margolin AB.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110573
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Detection, typing, and subtyping of enteric adenoviruses 40 and 41 from fecal samples and observation of changing incidences of infections with these types and subtypes. by de Jong JC, Bijlsma K, Wermenbol AG, Verweij-Uijterwaal MW, van der Avoort HG, Wood DJ, Bailey AS, Osterhaus AD.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265578
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Deubiquitinating Function of Adenovirus Proteinase. by Balakirev MY, Jaquinod M, Haas AL, Chroboczek J.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136223
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Development and Characterization of Bovine x Human Hybrid Cell Lines That Efficiently Support the Replication of both Wild-Type Bovine and Human Adenoviruses and Those with E1 Deleted. by van Olphen AL, Mittal SK.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136187
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Differential Activation of Innate Immune Responses by Adenovirus and AdenoAssociated Virus Vectors. by Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155101
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Direct detection and differentiation of fastidious and nonfastidious adenoviruses in stools by using a specific nonradioactive probe. by Niel C, Gomes SA, Leite JP, Pereira HG.; 1986 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269029
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Distinct Domains in the Adenovirus E3 RID[alpha] Protein Are Required for Degradation of Fas and the Epidermal Growth Factor Receptor. by Zanardi TA, Yei S, Lichtenstein DL, Tollefson AE, Wold WS.; 2003 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=229367
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Distinct Roles of Adenovirus Vector-Transduced Dendritic Cells, Myoblasts, and Endothelial Cells in Mediating an Immune Response against a Transgene Product. by Mercier S, Gahery-Segard H, Monteil M, Lengagne R, Guillet JG, Eloit M, Denesvre C.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136003
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Distinct Roles of the Adenovirus E4 ORF3 Protein in Viral DNA Replication and Inhibition of Genome Concatenation. by Evans JD, Hearing P.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153982
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Distribution of Mouse Adenovirus Type 1 in Intraperitoneally and Intranasally Infected Adult Outbred Mice. by Kajon AE, Brown CC, Spindler KR.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124599
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E1A 12S and 13S of the transformation-defective adenovirus type 12 strain CS-1 inactivate proteins of the RB family, permitting transactivation of the E2F-dependent promoter. by Putzer BM, Rumpf H, Rega S, Brockmann D, Esche H.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230261
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E1a regions of the human adenoviruses and of the highly oncogenic simian adenovirus 7 are closely related. by Kimelman D, Miller JS, Porter D, Roberts BE.; 1985 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=254650
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E4orf3 Is Necessary for Enhanced S-Phase Replication of Cell Cycle-Restricted Subgroup C Adenoviruses. by Shepard RN, Ornelles DA.; 2003 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165245
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E4orf6 Variants with Separate Abilities To Augment Adenovirus Replication and Direct Nuclear Localization of the E1B 55-Kilodalton Protein. by Orlando JS, Ornelles DA.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135776
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Early region 3 of adenovirus type 19 (subgroup D) encodes an HLA-binding protein distinct from that of subgroups B and C. by Deryckere F, Burgert HG.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190140
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Ectodomain of Coxsackievirus and Adenovirus Receptor Genetically Fused to Epidermal Growth Factor Mediates Adenovirus Targeting to Epidermal Growth Factor Receptor-Positive Cells. by Dmitriev I, Kashentseva E, Rogers BE, Krasnykh V, Curiel DT.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112205
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Effects of adenovirus infection on rRNA synthesis and maturation in HeLa cells. by Castiglia CL, Flint SJ.; 1983 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=368582
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Efficient Generation of Recombinant Adenoviruses Using Adenovirus DNATerminal Protein Complex and a Cosmid Bearing the Full-Length Virus Genome. by Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K, Tokuda C, Saito I.; 1996 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40078
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Efficient, Repeated Adenovirus-Mediated Gene Transfer in Mice Lacking both Tumor Necrosis Factor Alpha and Lymphotoxin [alpha]. by Benihoud K, Saggio I, Opolon P, Salone B, Amiot F, Connault E, Chianale C, Dautry F, Yeh P, Perricaudet M.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110450
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Encapsidation of Viral DNA Requires the Adenovirus L1 52/55-Kilodalton Protein. by Gustin KE, Imperiale MJ.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110107
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Engineering of Adenovirus Vectors Containing Heterologous Peptide Sequences in the C Terminus of Capsid Protein IX. by Dmitriev IP, Kashentseva EA, Curiel DT.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136342
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Enhanced splicing of nonconsensus 3' splice sites late during adenovirus infection. by Muhlemann O, Kreivi JP, Akusjarvi G.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189663
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Enhancement of Adenovirus Vector Entry into CD70-Positive B-Cell Lines by Using a Bispecific CD70-Adenovirus Fiber Antibody. by Israel BF, Pickles RJ, Segal DM, Gerard RD, Kenney SC.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114927
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Enteric adenovirus infection among infants with diarrhea in rural Bangladesh. by Jarecki-Khan K, Tzipori SR, Unicomb LE.; 1993 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262806
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Entry of adenovirus 2 into HeLa cells. by Svensson U, Persson R.; 1984 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255830
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Evaluation of a commercial monoclonal antibody for detection of adenovirus antigen. by August MJ, Warford AL.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269453
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Evaluation of a commercial monoclonal antibody-based enzyme immunoassay for detection of adenovirus types 40 and 41 in stool specimens. by Wood DJ, Bijlsma K, de Jong JC, Tonkin C.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267518
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Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. by Mittereder N, March KL, Trapnell BC.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190817
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Evaluation of three types of cell culture for recovery of adenovirus from clinical specimens. by Krisher KK, Menegus MA.; 1987 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269206
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Evidence for transudation of specific antibody into the middle ears of parenterally immunized chinchillas after an upper respiratory tract infection with adenovirus. by Bakaletz LO, Holmes KA.; 1997 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=170506
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Exploiting features of adenovirus replication to support mammalian kinase production. by Cotten M, Stegmueller K, Eickhoff J, Hanke M, Herzberger K, Herget T, Choidas A, Daub H, Godl K.; 2003 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=275485
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Exploiting the Natural Diversity in Adenovirus Tropism for Therapy and Prevention of Disease. by Havenga MJ, Lemckert AA, Ophorst OJ, van Meijer M, Germeraad WT, Grimbergen J, van den Doel MA, Vogels R, van Deutekom J, Janson AA, de Bruijn JD, Uytdehaag F, Quax PH, Logtenberg T, Mehtali M, Bout A.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155076
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Expression of an Antigenic Adenovirus Epitope in a Group B Coxsackievirus. by Hofling K, Tracy S, Chapman N, Kim KS, Smith Leser J.; 2000 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111977
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Expression of gp19K increases the persistence of transgene expression from an adenovirus vector in the mouse lung and liver. by Bruder JT, Jie T, McVey DL, Kovesdi I.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192111
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Extensive Cross-Reactivity of CD4 + Adenovirus-Specific T Cells: Implications for Immunotherapy and Gene Therapy. by Heemskerk B, Veltrop-Duits LA, van Vreeswijk T, ten Dam MM, Heidt S, Toes RE, van Tol MJ, Schilham MW.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155022
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Fatty Acid Modification of the Coxsackievirus and Adenovirus Receptor. by van"t Hof W, Crystal RG.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136239
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Fiber Swap between Adenovirus Subgroups B and C Alters Intracellular Trafficking of Adenovirus Gene Transfer Vectors. by Miyazawa N, Leopold PL, Hackett NR, Ferris B, Worgall S, Falck-Pedersen E, Crystal RG.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112667
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Fiberless Recombinant Adenoviruses: Virus Maturation and Infectivity in the Absence of Fiber. by Legrand V, Spehner D, Schlesinger Y, Settelen N, Pavirani A, Mehtali M.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103910
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First Molecular Evidence for the Existence of Distinct Fish and Snake Adenoviruses. by Benko M, Elo P, Ursu K, Ahne W, LaPatra SE, Thomson D, Harrach B.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136508
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Flexibility of the Adenovirus Fiber Is Required for Efficient Receptor Interaction. by Wu E, Pache L, Von Seggern DJ, Mullen TM, Mikyas Y, Stewart PL, Nemerow GR.; 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164825
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Functional Analysis of Adenovirus Protein IX Identifies Domains Involved in Capsid Stability, Transcriptional Activity, and Nuclear Reorganization. by Rosa-Calatrava M, Grave L, Puvion-Dutilleul F, Chatton B, Kedinger C.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114442
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Functional Analysis of the CAAT Box in the Major Late Promoter of the Subgroup C Human Adenoviruses. by Song B, Young CS.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109786
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Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells. by Chiou SK, Tseng CC, Rao L, White E.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237076
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Functional importance of complex formation between the retinoblastoma tumor suppressor family and adenovirus E1A proteins as determined by mutational analysis of E1A conserved region 2. by Corbeil HB, Branton PE.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237091
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Generation of cytotoxic T lymphocytes against immunorecessive epitopes after multiple immunizations with adenovirus vectors is dependent on haplotype. by Sparer TE, Wynn SG, Clark DJ, Kaplan JM, Cardoza LM, Wadsworth SC, Smith AE, Gooding LR.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191336
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Genetic heterogeneity in response to adenovirus gene therapy. by Lefesvre P, Attema J, Lemckert A, Havenga M, Bekkum DV.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155537
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Genetic heterogeneity of recent isolates of adenovirus types 3, 4, and 7. by Bailey AS, Richmond SJ.; 1986 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268826
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Genetic Targeting of an Adenovirus Vector via Replacement of the Fiber Protein with the Phage T4 Fibritin. by Krasnykh V, Belousova N, Korokhov N, Mikheeva G, Curiel DT.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114163
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Genetically Targeted Adenovirus Vector Directed to CD40-Expressing Cells. by Belousova N, Korokhov N, Krendelshchikova V, Simonenko V, Mikheeva G, Triozzi PL, Aldrich WA, Banerjee PT, Gillies SD, Curiel DT, Krasnykh V.; 2003 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=229360
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Genome analysis of South American adenovirus strains of serotype 7 collected over a 7-year period. by Kajon A, Wadell G.; 1994 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263996
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Genome Type Analysis of Adenovirus Types 3 and 7 Isolated during Successive Outbreaks of Lower Respiratory Tract Infections in Children. by Kim YJ, Hong JY, Lee HJ, Shin SH, Kim YK, Inada T, Hashido M, Piedra PA.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254340
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Genome Typing of Adenovirus Type 34 Isolated in Two Cases of Conjunctivitis in Sapporo, Japan. by Saitoh-Inagawa W, Tanaka K, Uchio E, Itoh N, Ohno S, Aoki K.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88514
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Genomic variation of adenovirus type 5 isolates recovered from bone marrow transplant recipients. by Webb DH, Shields AF, Fife KH.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265888
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Group D Adenoviruses Infect Primary Central Nervous System Cells More Efficiently than Those from Group C. by Chillon M, Bosch A, Zabner J, Law L, Armentano D, Welsh MJ, Davidson BL.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104501
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Heparan Sulfate Glycosaminoglycans Are Receptors Sufficient To Mediate the Initial Binding of Adenovirus Types 2 and 5. by Dechecchi MC, Melotti P, Bonizzato A, Santacatterina M, Chilosi M, Cabrini G.; 2001 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115122
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High level of transgene expression in cell cultures and in the mouse by replicationincompetent adenoviruses harboring modified VAI genes. by Eloit M, Adam M, Gallais I, Fournier A.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191776
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High-efficiency receptor-mediated delivery of small and large (48 kilobase gene constructs using the endosome-disruption activity of defective or chemically inactivated adenovirus particles. by Cotten M, Wagner E, Zatloukal K, Phillips S, Curiel DT, Birnstiel ML.; 1992 Jul 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=49444
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Human adenovirus early region 4 open reading frame 1 genes encode growthtransforming proteins that may be distantly related to dUTP pyrophosphatase enzymes. by Weiss RS, Lee SS, Prasad BV, Javier RT.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191256
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Human adenovirus encodes two proteins which have opposite effects on accumulation of alternatively spliced mRNAs. by Nordqvist K, Ohman K, Akusjarvi G.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358393
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Human adenovirus serotypes 3 and 5 bind to two different cellular receptors via the fiber head domain. by Stevenson SC, Rollence M, White B, Weaver L, McClelland A.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=188980
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Human adenovirus type 9 E4 open reading frame 1 encodes a cytoplasmic transforming protein capable of increasing the oncogenicity of CREF cells. by Weiss RS, McArthur MJ, Javier RT.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189889
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Human Adenoviruses and Coliphages in Urban Runoff-Impacted Coastal Waters of Southern California. by Jiang S, Noble R, Chu W.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92541
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Human adenovirus-host cell interactions: comparative study with members of subgroups B and C. by Defer C, Belin MT, Caillet-Boudin ML, Boulanger P.; 1990 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=249659
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Human adenovirus-specific CD8+ T-cell responses are not inhibited by E3-19K in the presence of gamma interferon. by Flomenberg P, Piaskowski V, Truitt RL, Casper JT.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190657
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Identification of Conserved Residues Contributing to the Activities of Adenovirus DNA Polymerase. by Liu H, Naismith JH, Hay RT.; 2000 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112450
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Identification of Contact Residues and Definition of the CAR-Binding Site of Adenovirus Type 5 Fiber Protein. by Kirby I, Davison E, Beavil AJ, Soh CP, Wickham TJ, Roelvink PW, Kovesdi I, Sutton BJ, Santis G.; 2000 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111771
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Identification of the Hexon Region of an Adenovirus Involved in a New Outbreak of Keratoconjunctivitis. by Imai Y, Kameya S, Ohkoshi M, Yamaki K, Sakuragi S.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88273
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Identification of Three Functions of the Adenovirus E4orf6 Protein That Mediate p53 Degradation by the E4orf6-E1B55K Complex. by Querido E, Morisson MR, Chu-PhamDang H, Thirlwell SW, Boivin D, Branton PE.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113966
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Immune Response to Recombinant Adenovirus in Humans: Capsid Components from Viral Input Are Targets for Vector-Specific Cytotoxic T Lymphocytes. by Molinier-Frenkel V, Gahery-Segard H, Mehtali M, Le Boulaire C, Ribault S, Boulanger P, Tursz T, Guillet JG, Farace F.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112292
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Immunoassay diagnosis of adenovirus infections in children. by Meurman O, Ruuskanen O, Sarkkinen H.; 1983 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=272865
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Immunochromatography Test for Rapid Diagnosis of Adenovirus Respiratory Tract Infections: Comparison with Virus Isolation in Tissue Culture. by Tsutsumi H, Ouchi K, Ohsaki M, Yamanaka T, Kuniya Y, Takeuchi Y, Nakai C, Meguro H, Chiba S.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85010
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Immunoglobulin class-specific serological responses to adenovirus in respiratory infections of young adult men. by Julkunen I, Lehtomaki K, Hovi T.; 1986 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268843
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Importance of enteric adenoviruses 40 and 41 in acute gastroenteritis in infants and young children. by Uhnoo I, Wadell G, Svensson L, Johansson ME.; 1984 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271331
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Importance of rotavirus and adenovirus types 40 and 41 in acute gastroenteritis in Korean children. by Kim KH, Yang JM, Joo SI, Cho YG, Glass RI, Cho YJ.; 1990 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268162
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Importance of the Ser-132 phosphorylation site in cell transformation and apoptosis induced by the adenovirus type 5 E1A protein. by Whalen SG, Marcellus RC, Barbeau D, Branton PE.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190495
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Improved Adenovirus Packaging Cell Lines to Support the Growth of ReplicationDefective Gene-Delivery Vectors. by Amalfitano A, Begy CR, Chamberlain JS.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39611
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Improved Production of Gutted Adenovirus in Cells Expressing Adenovirus Preterminal Protein and DNA Polymerase. by Hartigan-O'Connor D, Amalfitano A, Chamberlain JS.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104313
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In Vitro and In Vivo Biology of Recombinant Adenovirus Vectors with E1, E1/E2A, or E1/E4 Deleted. by Lusky M, Christ M, Rittner K, Dieterle A, Dreyer D, Mourot B, Schultz H, Stoeckel F, Pavirani A, Mehtali M.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109495
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In Vitro and In Vivo Characterization of a Mouse Adenovirus Type 1 Early Region 3 Null Mutant. by Cauthen AN, Brown CC, Spindler KR.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112884
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In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. by Guzman RJ, Hirschowitz EA, Brody SL, Crystal RG, Epstein SE, Finkel T.; 1994 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45096
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Incidence of enteric adenoviruses among children in Thailand and the significance of these viruses in gastroenteritis. by Herrmann JE, Blacklow NR, Perron-Henry DM, Clements E, Taylor DN, Echeverria P.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266716
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Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins. by Wickham TJ, Tzeng E, Shears LL 2nd, Roelvink PW, Li Y, Lee GM, Brough DE, Lizonova A, Kovesdi I.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192279
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Induction of Endogenous Genes following Infection of Human Endothelial Cells with an E1[minus sign] E4 + Adenovirus Gene Transfer Vector. by Ramalingam R, Rafii S, Worgall S, Hackett NR, Crystal RG.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113071
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Induction of p53-Independent Apoptosis by the Adenovirus E4orf4 Protein Requires Binding to the B[alpha] Subunit of Protein Phosphatase 2A. by Marcellus RC, Chan H, Paquette D, Thirlwell S, Boivin D, Branton PE.; 2000 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112317
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Induction of the Cellular E2F-1 Promoter by the Adenovirus E4-6/7 Protein. by Schaley J, O'Connor RJ, Taylor LJ, Bar-Sagi D, Hearing P.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111689
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Inhibition of adenovirus DNA replication by vesicular stomatitis virus leader RNA. by Remenick J, Kenny MK, McGowan JJ.; 1988 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=253139
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Inhibition of Chemokine Expression by Adenovirus Early Region Three (E3) Genes. by Lesokhin AM, Delgado-Lopez F, Horwitz MS.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155150
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Inhibition of NF-[kappa]B Activation in Combination with Bcl-2 Expression Allows for Persistence of First-Generation Adenovirus Vectors in the Mouse Liver. by Lieber A, He CY, Meuse L, Himeda C, Wilson C, Kay MA.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110346
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Inhibition of TRAIL-Induced Apoptosis and Forced Internalization of TRAIL Receptor 1 by Adenovirus Proteins. by Tollefson AE, Toth K, Doronin K, Kuppuswamy M, Doronina OA, Lichtenstein DL, Hermiston TW, Smith CA, Wold WS.; 2001 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114456
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Inhibition of Tumor Necrosis Factor Alpha-Induced NF-[kappa]B Activation by the Adenovirus E3-10.4/14.5K Complex. by Friedman JM, Horwitz MS.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137041
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Initial Interactions of Subgenus D Adenoviruses with A549 Cellular Receptors: Sialic Acid versus [alpha]v Integrins. by Arnberg N, Kidd AH, Edlund K, Olfat F, Wadell G.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112295
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Insufficient levels of NFIII and its low affinity for the origin of adenovirus type 12 (Ad12) DNA replication contribute to the abortive infection of BHK21 hamster cells by Ad12. by Schiedner G, Doerfler W.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190873
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Interaction of an adenovirus 14.7-kilodalton protein inhibitor of tumor necrosis factor alpha cytolysis with a new member of the GTPase superfamily of signal transducers. by Li Y, Kang J, Horwitz MS.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191215
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Interaction of the Adenovirus IVa2 Protein with Viral Packaging Sequences. by Zhang W, Imperiale MJ.; 2000 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111758
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Interactions of Soluble Recombinant Integrin [alpha]v[beta]5 with Human Adenoviruses. by Mathias P, Galleno M, Nemerow GR.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110279
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Interferon induction by adenovirus type 12: stimulatory function of early region 1A. by Toth MI, Arya B, Pusztai R, Shiroki K, Beladi I.; 1987 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=283702
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Intermediate human adenovirus type 22/H10,19,37 as a new etiological agent of conjunctivitis. by Noda M, Miyamoto Y, Ikeda Y, Matsuishi T, Ogino T.; 1991 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270101
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Internalization of Adenovirus by Alveolar Macrophages Initiates Early Proinflammatory Signaling during Acute Respiratory Tract Infection. by Zsengeller Z, Otake K, Hossain SA, Berclaz PY, Trapnell BC.; 2000 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112398
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Involvement of topoisomerases in replication, transcription, and packaging of the linear adenovirus genome. by Wong ML, Hsu MT.; 1990 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=249162
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Isolation and characterization of six new genome types of human adenovirus types 1 and 2. by Fife KH, Ashley R, Corey L.; 1985 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271572
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Isolation and characterization of temperature-sensitive mutants of adenovirus type 7. by Praszkier J, Ginsberg HS.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255884
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Laboratory identification of adenoviruses associated with gastroenteritis in Canada from 1983 to 1986. by Brown M.; 1990 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267982
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Lack of effect of mouse adenovirus type 1 infection on cell surface expression of major histocompatibility complex class I antigens. by Kring SC, Spindler KR.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190507
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Lack of evidence of phenotypic complementation of E1A/E1B-deleted adenovirus type 5 upon superinfection by wild-type virus in the cotton rat. by Oualikene W, Gonin P, Eloit M.; 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189553
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Large E1B proteins of adenovirus types 5 and 12 have different effects on p53 and distinct roles in cell transformation. by van den Heuvel SJ, van Laar T, The I, van der Eb AJ.; 1993 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237920
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Link of the unique oncogenic properties of adenovirus type9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2. by Glaunsinger BA, Weiss RS, Lee SS, Javier R.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125668
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Localization of the adenovirus early region 1B 55-kilodalton protein during lytic infection: association with nuclear viral inclusions requires the early region 4 34kilodalton protein. by Ornelles DA, Shenk T.; 1991 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240533
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Long-lasting adenovirus transgene expression in mice through neonatal intrathymic tolerance induction without the use of immunosuppression. by DeMatteo RP, Chu G, Ahn M, Chang E, Barker CF, Markmann JF.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191770
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Lytic and transforming functions of individual products of the adenovirus E1A gene. by Moran E, Grodzicker T, Roberts RJ, Mathews MB, Zerler B.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=252804
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Mechanism of enhancement of DNA expression consequent to cointernalization of a replication-deficient adenovirus and unmodified plasmid DNA. by Seth P, Rosenfeld M, Higginbotham J, Crystal RG.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236531
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Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPApp: influence of the adenovirus DNA binding protein. by Mul YM, van Miltenburg RT, De Clercq E, van der Vliet PC.; 1989 Nov 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=335103
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Mechanism of the Arginine Requirement for Adenovirus Synthesis I. Synthesis of Structural Proteins. by Everitt E, Sundquist B, Philipson L.; 1971 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=376255
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Microtubule-Independent Motility and Nuclear Targeting of Adenoviruses with Fluorescently Labeled Genomes. by Glotzer JB, Michou AI, Baker A, Saltik M, Cotten M.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114825
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Minimal cis-Acting Elements Required for Adenovirus Genome Packaging. by Ostapchuk P, Hearing P.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153973
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Modulation of Adenovirus Vector Tropism via Incorporation of Polypeptide Ligands into the Fiber Protein. by Belousova N, Krendelchtchikova V, Curiel DT, Krasnykh V.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136983
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Molecular and Epidemiological Analyses of Human Adenovirus Type 7 Strains Isolated from the 1995 Nationwide Outbreak in Japan. by Noda M, Yoshida T, Sakaguchi T, Ikeda Y, Yamaoka K, Ogino T.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120110
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Molecular Architecture of Adenovirus DNA Polymerase and Location of the Protein Primer. by Brenkman AB, Breure EC, van der Vliet PC.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155156
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Molecular characterization of replication-competent variants of adenovirus vectors and genome modifications to prevent their occurrence. by Hehir KM, Armentano D, Cardoza LM, Choquette TL, Berthelette PB, White GA, Couture LA, Everton MB, Keegan J, Martin JM, Pratt DA, Smith MP, Smith AE, Wadsworth SC.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190936
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Molecular characterization of the type-specific gamma-determinant located on the adenovirus fiber. by Eiz B, Pring-Akerblom P.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191935
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Molecular epidemiology and restriction site mapping of adenovirus type 3 genome types. by Adrian T, Best B, Hierholzer JC, Wigand R.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267552
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Molecular epidemiology of adenovirus type 21 in the Netherlands and the Federal Republic of Germany from 1960 to 1985. by van der Avoort HG, Adrian T, Wigand R, Wermenbol AG, Zomerdijk TP, de Jong JC.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269103
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Molecular epidemiology of adenoviruses: alternating appearance of two different genome types of adenovirus 7 during epidemic outbreaks in Europe from 1958 to 1980. by Wadell G, de Jong JC, Wolontis S.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=350875
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Monoclonal antibodies specific for adenovirus early region 1A proteins: extensive heterogeneity in early region 1A products. by Harlow E, Franza BR Jr, Schley C.; 1985 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255001
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Monoclonal antibody enzyme-linked immunosorbent assay for specific identification and typing of subgroup F adenoviruses. by Singh-Naz N, Rodriguez WJ, Kidd AH, Brandt CD.; 1988 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266271
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Monomeric scAlu and nascent dimeric Alu RNAs induced by adenovirus are assembled into SRP9/14-containing RNPs in HeLa cells. by Chang DY, Hsu K, Maraia RJ.; 1996 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146241
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Mouse Adenovirus Type 1 Early Region 1A Is Dispensable for Growth in Cultured Fibroblasts. by Ying B, Smith K, Spindler KR.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109774
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Multiple adenovirus serotypes use alpha v integrins for infection. by Mathias P, Wickham T, Moore M, Nemerow G.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237109
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Multiplexed, Real-Time PCR for Quantitative Detection of Human Adenovirus. by Gu Z, Belzer SW, Gibson CS, Bankowski MJ, Hayden RT.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254346
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Murine adenovirus infection of SCID mice induces hepatic lesions that resemble human Reye syndrome. by Pirofski L, Horwitz MS, Scharff MD, Factor SM.; 1991 May 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51658
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Muscle-Specific Overexpression of the Adenovirus Primary Receptor CAR Overcomes Low Efficiency of Gene Transfer to Mature Skeletal Muscle. by Nalbantoglu J, Larochelle N, Wolf E, Karpati G, Lochmuller H, Holland PC.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114173
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Mutant adenovirus type 9 E4 ORF1 genes define three protein regions required for transformation of CREF cells. by Weiss RS, Gold MO, Vogel H, Javier RT.; 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191656
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Mutational Analysis of the Avian Adenovirus CELO, Which Provides a Basis for Gene Delivery Vectors. by Michou AI, Lehrmann H, Saltik M, Cotten M.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103964
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Mutations in the DG Loop of Adenovirus Type 5 Fiber Knob Protein Abolish HighAffinity Binding to Its Cellular Receptor CAR. by Kirby I, Davison E, Beavil AJ, Soh CP, Wickham TJ, Roelvink PW, Kovesdi I, Sutton BJ, Santis G.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112985
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Mutations that affect phosphorylation of the adenovirus DNA-binding protein alter its ability to enhance its own synthesis. by Morin N, Delsert C, Klessig DF.; 1989 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=251187
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Mutations within the ADP (E3-11.6K) Protein Alter Processing and Localization of ADP and the Kinetics of Cell Lysis of Adenovirus-Infected Cells. by Tollefson AE, Scaria A, Ying B, Wold WS.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161948
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Mutual Interference of Adenovirus Infection and myc Expression. by Lohr K, Hartmann O, Schafer H, Dobbelstein M.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161938
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n-Butyrate, a cell cycle blocker, inhibits the replication of polyomaviruses and papillomaviruses but not that of adenoviruses and herpesviruses. by Shadan FF, Cowsert LM, Villarreal LP.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236418
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New genome types of adenovirus types 1, 3, and 5 isolated from stools of children in Brazil. by Gomes SA, Candeias JA, Monteiro SP, Pereira HG, Niel C.; 1989 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267475
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New human adenovirus (candidate adenovirus type 35) causing fatal disseminated infection in a renal transplant recipient. by Stalder H, Hierholzer JC, Oxman MN.; 1977 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=274749
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New human adenovirus associated with respiratory illness: candidate adenovirus type 39. by Hierholzer JC, Kemp MC, Gary GW Jr, Spencer HC.; 1982 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=272287
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New human adenovirus isolated from a renal transplant recipient: description and characterization of candiate adenovirus type 34. by Hierholzer JC, Atuk NO, Gwaltney JM Jr.; 1975 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=275094
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Normal Development, Wound Healing, and Adenovirus Susceptibility in [beta]5Deficient Mice. by Huang X, Griffiths M, Wu J, Farese RV Jr, Sheppard D.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85191
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Nuclear factor I is specifically targeted to discrete subnuclear sites in adenovirus type 2-infected cells. by Bosher J, Dawson A, Hay RT.; 1992 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=241077
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Oncogenicity of human papillomavirus- or adenovirus-transformed cells correlates with resistance to lysis by natural killer cells. by Routes JM, Ryan S.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189704
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Optimization of the helper-dependent adenovirus system for production and potency in vivo. by Sandig V, Youil R, Bett AJ, Franlin LL, Oshima M, Maione D, Wang F, Metzker ML, Savino R, Caskey CT.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15501
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Overexpression of the E1B 55-kilodalton (482R) protein of human adenovirus type 12 appears to permit efficient transformation of primary baby rat kidney cells in the absence of the E1B 19-kilodalton protein. by Zhang S, Mak S, Branton PE.; 1992 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=289025
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Ovine Adenovirus Vectors Overcome Preexisting Humoral Immunity against Human Adenoviruses In Vivo. by Hofmann C, Loser P, Cichon G, Arnold W, Both GW, Strauss M.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112778
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p53 Status Does Not Determine Outcome of E1B 55-Kilodalton Mutant Adenovirus Lytic Infection. by Goodrum FD, Ornelles DA.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110444
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p53-Independent and -Dependent Requirements for E1B-55K in Adenovirus Type 5 Replication. by Harada JN, Berk AJ.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112589
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Packaging capacity and stability of human adenovirus type 5 vectors. by Bett AJ, Prevec L, Graham FL.; 1993 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=238011
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Pathogenesis of type II avian adenovirus infection in turkeys: in vivo immune cell tropism and tissue distribution of the virus. by Suresh M, Sharma JM.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189784
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Patients with enteric adenovirus gastroenteritis admitted to an Australian pediatric teaching hospital from 1981 to 1992. by Grimwood K, Carzino R, Barnes GL, Bishop RF.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227894
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PCR and Restriction Endonuclease Analysis for Rapid Identification of Human Adenovirus Subgenera. by Elnifro EM, Cooper RJ, Klapper PE, Bailey AS.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86727
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PCR Detection of Adenovirus in a Bone Marrow Transplant Recipient: Hemorrhagic Cystitis as a Presenting Manifestation of Disseminated Disease. by Echavarria MS, Ray SC, Ambinder R, Dumler JS, Charache P.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84519
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PCR Method for Detection of Adenovirus in Urine of Healthy and Human Immunodeficiency Virus-Infected Individuals. by Echavarria M, Forman M, Ticehurst J, Dumler JS, Charache P.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105322
100
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Peptide maps and N-terminal sequences of polypeptides from early region 1A of human adenovirus 5. by Downey JF, Evelegh CM, Branton PE, Bayley ST.; 1984 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255577
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Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with first-generation, but not with high-capacity, adenovirus vectors: Toward realistic long-term neurological gene therapy for chronic diseases. by Thomas CE, Schiedner G, Kochanek S, Castro MG, Lowenstein PR.; 2000 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16571
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Phage Display of Adenovirus Type 5 Fiber Knob as a Tool for Specific Ligand Selection and Validation. by Pereboev A, Pereboeva L, Curiel DT.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114439
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Phosphorylation at the carboxy terminus of the 55-kilodalton adenovirus type 5 E1B protein regulates transforming activity. by Teodoro JG, Halliday T, Whalen SG, Takayesu D, Graham FL, Branton PE.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236514
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Polymerase chain reaction for detection of adenoviruses in stool samples. by Allard A, Girones R, Juto P, Wadell G.; 1990 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268252
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Posttranscriptional control of DHFR gene expression during adenovirus 2 infection. by Yoder SS, Berget SM.; 1985 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=254762
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Posttranslational modification at the N terminus of the human adenovirus type 12 E1A 235R tumor antigen. by Lucher LA, Brackmann KH, Symington JS, Green M.; 1986 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=252949
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Preexisting Immunity to Adenovirus in Rhesus Monkeys Fails To Prevent VectorInduced Toxicity. by Varnavski AN, Zhang Y, Schnell M, Tazelaar J, Louboutin JP, Yu QC, Bagg A, Gao GP, Wilson JM.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137042
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Prevalence and Quantitation of Species C Adenovirus DNA in Human Mucosal Lymphocytes. by Garnett CT, Erdman D, Xu W, Gooding LR.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136639
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Prevalent enteric adenovirus variant not detected by commercial monoclonal antibody enzyme immunoassay. by Scott-Taylor T, Ahluwalia G, Klisko B, Hammond GW.; 1990 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268276
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Processing of vimentin occurs during the early stages of adenovirus infection. by Belin MT, Boulanger P.; 1987 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255697
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Prolonged Survival of Pancreatic Islet Allografts Mediated by Adenovirus Immunoregulatory Transgenes. by Efrat S, Fejer G, Brownlee M, Horwitz MS.; 1995 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41448
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Pseudopackaging of Adenovirus Type 5 Genomes into Capsids Containing the Hexon Proteins of Adenovirus Serotypes B, D, or E. by Ostapchuk P, Hearing P.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113896
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Psoralen-cross-linking study of the organization of intracellular adenovirus nucleoprotein complexes. by Wong ML, Hsu MT.; 1988 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=253131
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Quantifying Adenovirus-Neutralizing Antibodies by Luciferase Transgene Detection: Addressing Preexisting Immunity to Vaccine and Gene Therapy Vectors. by Sprangers MC, Lakhai W, Koudstaal W, Verhoeven M, Koel BF, Vogels R, Goudsmit J, Havenga MJ, Kostense S.; 2003 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262545
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Quantitative colorimetric microneutralization assay for characterization of adenoviruses. by Crawford-Miksza LK, Schnurr DP.; 1994 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263999
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rab5 GTPase Regulates Adenovirus Endocytosis. by Rauma T, Tuukkanen J, Bergelson JM, Denning G, Hautala T.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113007
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Rapid Assessment of Adenovirus Serum Neutralizing Antibody Titer Based on Quantitative, Morphometric Evaluation of Capsid Binding and Intracellular Trafficking: Population Analysis of Adenovirus Capsid Association with Cells Is Predictive of Adenovirus Infectivity. by Vincent T, Harvey BG, Hogan SM, Bailey CJ, Crystal RG, Leopold PL.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114056
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Rapid Detection of Adenovirus in Throat Swab Specimens by PCR during Respiratory Disease Outbreaks among Military Recruits. by Echavarria M, Sanchez JL, Kolavic-Gray SA, Polyak CS, Mitchell-Raymundo F, Innis BL, Vaughn D, Reynolds R, Binn LN.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149655
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Rapid diagnosis of respiratory adenovirus infections in young adult men. by Lehtomaki K, Julkunen I, Sandelin K, Salonen J, Virtanen M, Ranki M, Hovi T.; 1986 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268842
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Rapid subgenus identification of human adenovirus isolates by a general PCR. by Kidd AH, Jonsson M, Garwicz D, Kajon AE, Wermenbol AG, Verweij MW, De Jong JC.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228858
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Rapid Typing of Human Adenoviruses by a General PCR Combined with Restriction Endonuclease Analysis. by Allard A, Albinsson B, Wadell G.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87765
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Adenovirus
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Readthrough activation of early adenovirus E1b gene transcription. by Maxfield LF, Spector DJ.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192291
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Receptor Binding Sites and Antigenic Epitopes on the Fiber Knob of Human Adenovirus Serotype 3. by Liebermann H, Mentel R, Bauer U, Pring-Akerblom P, Dolling R, Modrow S, Seidel W.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110330
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Recombinant adenovirus induces antibody response to hepatitis B virus surface antigen in hamsters. by Morin JE, Lubeck MD, Barton JE, Conley AJ, Davis AR, Hung PP.; 1987 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=305143
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Recombinant adenoviruses with large deletions generated by Cre-mediated excision exhibit different biological properties compared with first-generation vectors in vitro and in vivo. by Lieber A, He CY, Kirillova I, Kay MA.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190992
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Recombinant, Replication-Defective Adenovirus Gene Transfer Vectors Induce Cell Cycle Dysregulation and Inappropriate Expression of Cyclin Proteins. by Wersto RP, Rosenthal ER, Seth PK, Eissa NT, Donahue RE.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110446
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Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers. by Weitzman MD, Fisher KJ, Wilson JM.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190012
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Redox Regulation of Adenovirus-Induced AP-1 Activation by Overexpression of Manganese-Containing Superoxide Dismutase. by Zhang HJ, Drake VJ, Xu L, Hu J, Domann FE, Oberley LW, Kregel KC.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135732
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Reducing the Native Tropism of Adenovirus Vectors Requires Removal of both CAR and Integrin Interactions. by Einfeld DA, Schroeder R, Roelvink PW, Lizonova A, King CR, Kovesdi I, Wickham TJ.; 2001 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114713
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Reduction of Natural Adenovirus Tropism to the Liver by both Ablation of FiberCoxsackievirus and Adenovirus Receptor Interaction and Use of Replaceable Short Fiber. by Nakamura T, Sato K, Hamada H.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141073
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Regulated adenovirus mRNA 3'-end formation in a coupled in vitro transcriptionprocessing system. by Wilson-Gunn SI, Kilpatrick JE, Imperiale MJ.; 1992 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=289098
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Regulation of Adenovirus Membrane Penetration by the Cytoplasmic Tail of Integrin [beta]5. by Wang K, Guan T, Cheresh DA, Nemerow GR.; 2000 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111763
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103
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Regulation of the biosynthesis of subgroup C adenovirus protein IVa2. by Winter N, D'Halluin JC.; 1991 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=249004
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Relevance of Commercial Diagnostic Tests to Detection of Enteric Adenovirus Infections in South Africa. by Moore PL, Steele AD, Alexander JJ.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86517
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Replicating Adenoviruses That Target Tumors with Constitutive Activation of the wnt Signaling Pathway. by Brunori M, Malerba M, Kashiwazaki H, Iggo R.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115912
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Replication of an E1B 55-Kilodalton Protein-Deficient Adenovirus (ONYX-015) Is Restored by Gain-of-Function Rather than Loss-of-Function p53 Mutants. by Hann B, Balmain A.; 2003 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=229311
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Replication of ONYX-015, a Potential Anticancer Adenovirus, Is Independent of p53 Status in Tumor Cells. by Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110441
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Replication-Defective Adenovirus Infection Reduces Helicobacter felis Colonization in the Mouse in a Gamma Interferon- and Interleukin-12-Dependent Manner. by Jiang B, Jordana M, Xing Z, Smaill F, Snider DP, Borojevic R, Steele-Norwood D, Hunt RH, Croitoru K.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96775
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Replication-Defective Bovine Adenovirus Type 3 as an Expression Vector. by Reddy PS, Idamakanti N, Chen Y, Whale T, Babiuk LA, Mehtali M, Tikoo SK.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112946
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Replication-Deficient Human Adenovirus Type 35 Vectors for Gene Transfer and Vaccination: Efficient Human Cell Infection and Bypass of Preexisting Adenovirus Immunity. by Vogels R, Zuijdgeest D, van Rijnsoever R, Hartkoorn E, Damen I, de Bethune MP, Kostense S, Penders G, Helmus N, Koudstaal W, Cecchini M, Wetterwald A, Sprangers M, Lemckert A, Ophorst O, Koel B, van Meerendonk M, Quax P, Panitti L, Grimbergen J, Bout A, Goudsmit J, Havenga M.; 2003 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165227
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Requirement of the Adenovirus IVa2 Protein for Virus Assembly. by Zhang W, Imperiale MJ.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149513
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Rescue, Propagation, and Partial Purification of a Helper Virus-Dependent Adenovirus Vector. by Mitani K, Graham FL, Caskey CT, Kochanek S.; 1995 Apr 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42060
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RGD Inclusion in the Hexon Monomer Provides Adenovirus Type 5-Based Vectors with a Fiber Knob-Independent Pathway for Infection. by Vigne E, Mahfouz I, Dedieu JF, Brie A, Perricaudet M, Yeh P.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112562
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Adenovirus
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RNA-Binding Activity of the E1B 55-Kilodalton Protein from Human Adenovirus Type 5. by Horridge JJ, Leppard KN.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110364
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Role of [alpha]v Integrins in Adenovirus Cell Entry and Gene Delivery. by Nemerow GR, Stewart PL.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103752
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Role of adenovirus type 2 early region 4 in the early-to-late switch during productive infection. by Yoder SS, Berget SM.; 1986 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=288957
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Role of early genes in pathogenesis of adenovirus pneumonia. by Ginsberg HS, Horswood RL, Chanock RM, Prince GA.; 1990 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54498
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Role of preterminal protein processing in adenovirus replication. by Webster A, Leith IR, Nicholson J, Hounsell J, Hay RT.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191911
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Role of the adenovirus E1B 19,000-dalton tumor antigen in regulating early gene expression. by White E, Denton A, Stillman B.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=253469
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Role of the type 5 adenovirus gene encoding the early region 1B 55-kDa protein in pulmonary pathogenesis. by Ginsberg HS, Moldawer LL, Prince GA.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17901
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Role of viral antigens in destructive cellular immune responses to adenovirus vectortransduced cells in mouse lungs. by Yang Y, Su Q, Wilson JM.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190774
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Roles for the E4 orf6, orf3, and E1B 55-Kilodalton Proteins in Cell Cycle-Independent Adenovirus Replication. by Goodrum FD, Ornelles DA.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104274
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Selection of nonfastidious adenovirus species in 293 cells inoculated with stool specimens containing adenovirus 40. by Brown M.; 1985 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268359
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Sensitive analysis of genetic heterogeneity of adenovirus types 3 and 7 in the Soviet Union. by Golovina GI, Zolotaryov FN, Yurlova TI.; 1991 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270319
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Sequence conversion during postreplicative adenovirus overlap recombination. by Bennett KL, Pearson GD.; 1993 Feb 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45880
Studies
105
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Sequence elements upstream of the 3' cleavage site confer substrate strength to the adenovirus L1 and L3 polyadenylation sites. by Prescott J, Falck-Pedersen E.; 1994 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358841
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Sequence homology between avian and human adenoviruses. by Alestrom P, Stenlund A, Li P, Bellett A, Pettersson U.; 1982 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=256073
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Sequence-mediated regulation of adenovirus gene expression by repression of mRNA accumulation. by Prescott JC, Liu L, Falck-Pedersen E.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232070
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Sequences regulating poly(A) site selection within the adenovirus major late transcription unit influence the interaction of constitutive processing factors with the pre-mRNA. by Gilmartin GM, Hung SL, DeZazzo JD, Fleming ES, Imperiale MJ.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190003
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Serotyping of Adenoviruses on Conjunctival Scrapings by PCR and Sequence Analysis. by Takeuchi S, Itoh N, Uchio E, Aoki K, Ohno S.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84965
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Several E4 Region Functions Influence Mammary Tumorigenesis by Human Adenovirus Type 9. by Thomas DL, Schaack J, Vogel H, Javier R.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113951
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Simplified Microneutralization Test for Serotyping Adenovirus Isolates. by Malasig MD, Goswami PR, Crawford-Miksza LK, Schnurr DP, Gray GC.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88276
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Simultaneous culture for adenovirus, cytomegalovirus, and herpes simplex virus in same shell vial by using three-color fluorescence. by Brumback BG, Wade CD.; 1994 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263985
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SJL/J Mice Are Highly Susceptible to Infection by Mouse Adenovirus Type 1. by Spindler KR, Fang L, Moore ML, Hirsch GN, Brown CC, Kajon A.; 2001 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116099
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Some adenovirus DNA is associated with the DNA of permissive cells during productive or restricted growth. by Tyndall C, Younghusband HB, Bellett AJ.; 1978 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=353894
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Species-Specific Identification of Human Adenoviruses by a Multiplex PCR Assay. by Xu W, McDonough MC, Erdman DD.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87550
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Specific detection and typing of adenovirus types 40 and 41 in stool specimens by dot-blot hybridization. by Kidd AH, Harley EH, Erasmus MJ.; 1985 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271854
106
Adenovirus
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Stimulation of the adenovirus major late promoter in vitro by transcription factor USF is enhanced by the adenovirus DNA binding protein. by Zijderveld DC, d'Adda di Fagagna F, Giacca M, Timmers HT, van der Vliet PC.; 1994 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237297
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Strain Variation in Adenovirus Serotypes 4 and 7a Causing Acute Respiratory Disease. by Crawford-Miksza LK, Nang RN, Schnurr DP.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88656
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Structural Analysis of a Fiber-Pseudotyped Adenovirus with Ocular Tropism Suggests Differential Modes of Cell Receptor Interactions. by Chiu CY, Wu E, Brown SL, Von Seggern DJ, Nemerow GR, Stewart PL.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114944
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Structural analysis of the adenovirus type 5 E1B 55-kilodalton-E4orf6 protein complex. by Rubenwolf S, Schutt H, Nevels M, Wolf H, Dobner T.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191163
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Structural and Phylogenetic Analysis of Adenovirus Hexons by Use of HighResolution X-Ray Crystallographic, Molecular Modeling, and Sequence-Based Methods. by Rux JJ, Kuser PR, Burnett RM.; 2003 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187380
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Structural organization and polypeptide composition of the avian adenovirus core. by Li P, Bellett AJ, Parish CR.; 1984 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=254568
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Structure of Adenovirus Complexed with Its Internalization Receptor, [alpha]v[beta]5 Integrin. by Chiu CY, Mathias P, Nemerow GR, Stewart PL.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112761
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Studies of Nondefective Adenovirus 2-Simian Virus 40 Hybrid Viruses V. Isolation of Additional Hybrids Which Differ in Their Simian Virus 40-Specific Biological Properties. by Lewis AM Jr, Levine AS, Crumpacker CS, Levin MJ, Samaha RJ, Henry PH.; 1973 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=355161
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Studies on fastidious adenoviruses in Ontario: a distinct strain associated with gastroenteritis. by Bishai FR, Yolken RH, Chernesky MA, Johnston S, Rossier E.; 1986 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268656
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Subgenomic viral DNA species synthesized in simian cells by human and simian adenoviruses. by Daniell E.; 1981 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171049
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Susceptibility and signs associated with mouse adenovirus type 1 infection of adult outbred Swiss mice. by Kring SC, King CS, Spindler KR.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189759
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T Cells Cause Acute Immunopathology and Are Required for Long-Term Survival in Mouse Adenovirus Type 1-Induced Encephalomyelitis. by Moore ML, Brown CC, Spindler KR.; 2003 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=224599
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Targeted adenovirus-mediated gene delivery to T cells via CD3. by Wickham TJ, Lee GM, Titus JA, Sconocchia G, Bakacs T, Kovesdi I, Segal DM.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192116
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Targeting Adenoviral Vectors by Using the Extracellular Domain of the CoxsackieAdenovirus Receptor: Improved Potency via Trimerization. by Kim J, Smith,* T, Idamakanti N, Mulgrew K, Kaloss M, Kylefjord H, Ryan PC, Kaleko M, Stevenson SC.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135917
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The 10,400- and 14,500-dalton proteins encoded by region E3 of adenovirus form a complex and function together to down-regulate the epidermal growth factor receptor. by Tollefson AE, Stewart AR, Yei SP, Saha SK, Wold WS.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240965
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The 11,600-MW protein encoded by region E3 of adenovirus is expressed early but is greatly amplified at late stages of infection. by Tollefson AE, Scaria A, Saha SK, Wold WS.; 1992 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=241146
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The activity of cytosolic phospholipase A2 is required for the lysis of adenovirusinfected cells by tumor necrosis factor. by Thorne TE, Voelkel-Johnson C, Casey WM, Parks LW, Laster SM.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190941
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The adenovirus death protein (E3-11.6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. by Tollefson AE, Scaria A, Hermiston TW, Ryerse JS, Wold LJ, Wold WS.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190071
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The adenovirus E1A-regulated transcription factor E4F is generated from the human homolog of nuclear factor phiAP3. by Fernandes ER, Rooney RJ.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232036
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The adenovirus E3 /10.4K --14.5K proteins down-modulate the apoptosis receptor Fas /Apo-1 by inducing its internalization. by Elsing A, Burgert HG.; 1998 Aug 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21463
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The adenovirus E3-14.7K protein and the E3-10.4K/14.5K complex of proteins, which independently inhibit tumor necrosis factor (TNF)-induced apoptosis, also independently inhibit TNF-induced release of arachidonic acid. by Krajcsi P, Dimitrov T, Hermiston TW, Tollefson AE, Ranheim TS, Vande Pol SB, Stephenson AH, Wold WS.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190440
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Adenovirus
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The adenovirus E4-6/7 protein transactivates the E2 promoter by inducing dimerization of a heteromeric E2F complex. by Obert S, O'Connor RJ, Schmid S, Hearing P.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358488
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The adenovirus L3 23-kilodalton proteinase cleaves the amino-terminal head domain from cytokeratin 18 and disrupts the cytokeratin network of HeLa cells. by Chen PH, Ornelles DA, Shenk T.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237697
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The adenovirus type 12 early-region 1B 58,000-Mr gene product is required for viral DNA synthesis and for initiation of cell transformation. by Shiroki K, Ohshima K, Fukui Y, Ariga H.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=252807
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The Adenovirus Type 5 E1B-55K Oncoprotein Actively Shuttles in Virus-Infected Cells, Whereas Transport of E4orf6 Is Mediated by a CRM1-Independent Mechanism. by Dosch T, Horn F, Schneider G, Kratzer F, Dobner T, Hauber J, Stauber RH.; 2001 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114281
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The amino-terminal region of the adenovirus serotype 5 E1a protein performs two separate functions when expressed in primary baby rat kidney cells. by Smith DH, Ziff EB.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=365447
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The complete DNA sequence and genomic organization of the avian adenovirus CELO. by Chiocca S, Kurzbauer R, Schaffner G, Baker A, Mautner V, Cotten M.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190152
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The Coxsackie B Virus and Adenovirus Receptor Resides in a Distinct Membrane Microdomain. by Ashbourne Excoffon KJ, Moninger T, Zabner J.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141093
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The Coxsackievirus-Adenovirus Receptor Protein Can Function as a Cellular Attachment Protein for Adenovirus Serotypes from Subgroups A, C, D, E, and F. by Roelvink PW, Lizonova A, Lee JG, Li Y, Bergelson JM, Finberg RW, Brough DE, Kovesdi I, Wickham TJ.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110119
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The CR1 and CR3 domains of the adenovirus type 5 E1A proteins can independently mediate activation of ATF-2. by Duyndam MC, van Dam H, van der Eb AJ, Zantema A.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190602
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The dynamics of coiled bodies in the nucleus of adenovirus-infected cells. by Rebelo L, Almeida F, Ramos C, Bohmann K, Lamond AI, Carmo-Fonseca M.; 1996 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=275964
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The E1A products of oncogenic adenovirus serotype 12 include amino-terminally modified forms able to bind the retinoblastoma protein but not p300. by Wang HG, Yaciuk P, Ricciardi RP, Green M, Yokoyama K, Moran E.; 1993 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237867
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The E1B 19,000-molecular-weight protein of group C adenoviruses prevents tumor necrosis factor cytolysis of human cells but not of mouse cells. by Gooding LR, Aquino L, Duerksen-Hughes PJ, Day D, Horton TM, Yei SP, Wold WS.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240964
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The E1B 19-kilodalton protein is not essential for transformation of rodent cells in vitro by adenovirus type 5. by Telling GC, Williams J.; 1993 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=237531
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The E4-6/7 Protein Functionally Compensates for the Loss of E1A Expression in Adenovirus Infection. by O'Connor RJ, Hearing P.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112076
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The early region 1B 55-kilodalton oncoprotein of adenovirus relieves growth restrictions imposed on viral replication by the cell cycle. by Goodrum FD, Ornelles DA.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191084
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The Early Region 4 orf4 Protein of Human Adenovirus Type 5 Induces p53Independent Cell Death by Apoptosis. by Marcellus RC, Lavoie JN, Boivin D, Shore GC, Ketner G, Branton PE.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109936
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The human papillomavirus type 16 E7 protein complements adenovirus type 5 E1A amino-terminus-dependent transactivation of adenovirus type 5 early genes and increases ATF and Oct-1 DNA binding activity. by Wong HK, Ziff EB.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189822
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The initiator element of the adenovirus major late promoter has an important role in transcription initiation in vivo. by Lu H, Reach MD, Minaya E, Young CS.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191029
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The Interaction between the Fiber Knob Domain and the Cellular Attachment Receptor Determines the Intracellular Trafficking Route of Adenoviruses. by Shayakhmetov DM, Li ZY, Ternovoi V, Gaggar A, Gharwan H, Lieber A.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149506
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The Murine CAR Homolog Is a Receptor for Coxsackie B Viruses and Adenoviruses. by Bergelson JM, Krithivas A, Celi L, Droguett G, Horwitz MS, Wickham T, Crowell RL, Finberg RW.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109389
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The Nuclear Export Signal within the E4orf6 Protein of Adenovirus Type 5 Supports Virus Replication and Cytoplasmic Accumulation of Viral mRNA. by Weigel S, Dobbelstein M.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111596
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The role of human adenovirus early region 3 proteins (gp19K, 10.4K, 14.5K, and 14.7K) in a murine pneumonia model. by Sparer TE, Tripp RA, Dillehay DL, Hermiston TW, Wold WS, Gooding LR.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190086
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The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. by Lieber A, He CY, Meuse L, Schowalter D, Kirillova I, Winther B, Kay MA.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=192346
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The Role of Mouse Adenovirus Type 1 Early Region 1A in Acute and Persistent Infections in Mice. by Smith K, Brown CC, Spindler KR.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110240
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The Subgenus-Specific C-Terminal Region of Protein IX Is Located on the Surface of the Adenovirus Capsid. by Akalu A, Liebermann H, Bauer U, Granzow H, Seidel W.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112689
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The transcriptionally competent U2 gene is necessary and sufficient for adenovirus type 12 induction of the fragile site at 17q21-22. by Gargano S, Wang P, Rusanganwa E, Bacchetti S.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230877
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The Tripartite Leader Sequence of Subgroup C Adenovirus Major Late mRNAs Can Increase the Efficiency of mRNA Export. by Huang W, Flint SJ.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109368
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Three adenovirus type 8 genome types defined by restriction enzyme analysis: prototype stability in geographically separated populations. by Kemp MC, Hierholzer JC.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268676
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Time-resolved fluoroimmunoassay for enteric adenoviruses using the europium chelator 4,7-bis(chlorosulfophenyl)-1,10-phenanthroline-2,9-dicarboxylic acid. by Brown M, Shami Y, Zywulko M, Singh-Naz N, Middleton PJ.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267939
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Tissue-Specific, Tumor-Selective, Replication-Competent Adenovirus Vector for Cancer Gene Therapy. by Doronin K, Kuppuswamy M, Toth K, Tollefson AE, Krajcsi P, Krougliak V, Wold WS.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114124
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Transcription of adenovirus RNA in permissive and nonpermissive infections. by Farber MS, Baum SG.; 1978 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=354147
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Transcriptional Organization of the Avian Adenovirus CELO. by Payet V, Arnauld C, Picault JP, Jestin A, Langlois P.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110347
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trans-dominant interference of type 5 adenovirus E1a mutants in cell transformation. by Tang Q, Ginsberg HS.; 1994 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236687
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Transduction of the Mammary Epithelium with Adenovirus Vectors In Vivo. by Russell TD, Fischer A, Beeman NE, Freed EF, Neville MC, Schaack J.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154007
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Transforming Growth Factor [beta]1 Receptor II Is Downregulated by E1A in Adenovirus-Infected Cells. by Tarakanova VL, Wold WS.; 2003 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187388
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Transforming Potential of the Adenovirus Type 5 E4orf3 Protein. by Nevels M, Tauber B, Kremmer E, Spruss T, Wolf H, Dobner T.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103984
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Transgenic Expression in Mouse Lung Reveals Distinct Biological Roles for the Adenovirus Type 5 E1A 243- and 289-Amino-Acid Proteins. by Yang Y, McKerlie C, Borenstein SH, Lu Z, Schito M, Chamberlain JW, Buchwald M.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136987
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Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver. by Kay MA, Meuse L, Gown AM, Linsley P, Hollenbaugh D, Aruffo A, Ochs HD, Wilson CB.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20785
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Transient Stimulation of Deoxyribonucleic Acid-Dependent Ribonucleic Acid Polymerase and Histone Acetylation in Human Embryonic Kidney Cultures Infected with Adenovirus 2 or 12: Apparent Induction of Host Ribonucleic Acid Synthesis. by Ledinko N.; 1970 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=376090
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Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. by Yang Y, Su Q, Grewal IS, Schilz R, Flavell RA, Wilson JM.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190663
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Tropism of human adenovirus type 5-based vectors in swine and their ability to protect against transmissible gastroenteritis coronavirus. by Torres JM, Alonso C, Ortega A, Mittal S, Graham F, Enjuanes L.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190253
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Tumor promoters alter the temporal program of adenovirus replication in human cells. by Fisher PB, Young CS, Weinstein IB, Carter TH.; 1981 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=369685
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Tumor-Specific, Replication-Competent Adenovirus Vectors Overexpressing the Adenovirus Death Protein. by Doronin K, Toth K, Kuppuswamy M, Ward P, Tollefson AE, Wold WS.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112113
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Tyrosine kinase-dependent release of an adenovirus preterminal protein complex from the nuclear matrix. by Angeletti PC, Engler JA.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190167
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Unusual Properties of Adenovirus E2E Transcription by RNA Polymerase III. by Huang W, Flint SJ.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150658
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Upregulation of Class I Major Histocompatibility Complex Antigens by Interferon [gamma] is Necessary for T-Cell-Mediated Elimination of Recombinant AdenovirusInfected Hepatocytes in vivo. by Yang Y, Xiang Z, Ertl HC, Wilson JM.; 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41318
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Use of Restriction Fragment Analysis and Sequencing of a Serotype-Specific Region To Type Adenovirus Isolates. by Li QG, Henningsson A, Juto P, Elgh F, Wadell G.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84580
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VA RNAs from avian and human adenoviruses: dramatic differences in length, sequence, and gene location. by Larsson S, Bellett A, Akusjarvi G.; 1986 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=252950
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Vaccine-Induced Immunity in Baboons by Using DNA and Replication-Incompetent Adenovirus Type 5 Vectors Expressing a Human Immunodeficiency Virus Type 1 gag Gene. by Casimiro DR, Tang A, Chen L, Fu TM, Evans RK, Davies ME, Freed DC, Hurni W, Aste-Amezaga JM, Guan L, Long R, Huang L, Harris V, Nawrocki DK, Mach H, Troutman RD, Isopi LA, Murthy KK, Rice K, Wilson KA, Volkin DB, Emini EA, Shiver JW.; 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164828
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Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation. by Peng Y, Falck-Pedersen E, Elkon KB.; 2001 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114207
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Viral DNA sequences and gene products in hamster cells transformed by adenovirus type 2. by Johansson K, Persson H, Lewis AM, Pettersson U, Tibbetts C, Philipson L.; 1978 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=354211
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Viral Pollution in the Environment and in Shellfish: Human Adenovirus Detection by PCR as an Index of Human Viruses. by Pina S, Puig M, Lucena F, Jofre J, Girones R.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106735
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Virus-associated RNAs of naturally occurring strains and variants of group C adenoviruses. by Mathews MB, Grodzicker T.; 1981 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171222
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The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with adenovirus, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “adenovirus” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for adenovirus (hyperlinks lead to article summaries): •
A novel E1A-E1B mutant adenovirus induces glioma regression in vivo. Author(s): Gomez-Manzano C, Balague C, Alemany R, Lemoine MG, Mitlianga P, Jiang H, Khan A, Alonso M, Lang FF, Conrad CA, Liu TJ, Bekele BN, Yung WK, Fueyo J. Source: Oncogene. 2004 March 11; 23(10): 1821-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15014451
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A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Author(s): Post DE, Van Meir EG. Source: Oncogene. 2003 April 10; 22(14): 2065-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12687009
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A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent. Author(s): Zou W, Luo C, Zhang Z, Liu J, Gu J, Pei Z, Qian C, Liu X. Source: Oncogene. 2004 January 15; 23(2): 457-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14724574
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A replication competent adenovirus 5 host range mutant-simian immunodeficiency virus (SIV) recombinant priming/subunit protein boosting vaccine regimen induces broad, persistent SIV-specific cellular immunity to dominant and subdominant epitopes in Mamu-A*01 rhesus macaques. Author(s): Malkevitch N, Patterson LJ, Aldrich K, Richardson E, Alvord WG, RobertGuroff M. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 April 15; 170(8): 4281-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682263
6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
114
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A single RNA recognition motif in splicing factor ASF/SF2 directs it to nuclear sites of adenovirus transcription. Author(s): Lindberg A, Gama-Carvalho M, Carmo-Fonseca M, Kreivi JP. Source: The Journal of General Virology. 2004 March; 85(Pt 3): 603-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14993643
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Activation of the early-late switch in adenovirus type 5 major late transcription unit expression by L4 gene products. Author(s): Farley DC, Brown JL, Leppard KN. Source: Journal of Virology. 2004 February; 78(4): 1782-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14747543
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Adenovirus core protein VII contains distinct sequences that mediate targeting to the nucleus and nucleolus, and colocalization with human chromosomes. Author(s): Lee TW, Blair GE, Matthews DA. Source: The Journal of General Virology. 2003 December; 84(Pt 12): 3423-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645923
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Adenovirus meningoencephalitis in a patient with large B-cell lymphoma. Author(s): Fianchi L, Scardocci A, Cattani P, Tartaglione T, Pagano L. Source: Annals of Hematology. 2003 May; 82(5): 313-5. Epub 2003 March 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679888
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Adenovirus nephritis in hematopoietic stem-cell transplantation. Author(s): Bruno B, Zager RA, Boeckh MJ, Gooley TA, Myerson DH, Huang ML, Hackman RC. Source: Transplantation. 2004 April 15; 77(7): 1049-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15087771
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Adenovirus type 7 genomic-type variant, New York City, 1999. Author(s): Calder JA, Erdman DD, Ackelsberg J, Cato SW, Deutsch VJ, Lechich AJ, Schofield BS. Source: Emerging Infectious Diseases. 2004 January; 10(1): 149-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078614
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Adenovirus type 7 induces interleukin-8 in a lung slice model and requires activation of Erk. Author(s): Booth JL, Coggeshall KM, Gordon BE, Metcalf JP. Source: Journal of Virology. 2004 April; 78(8): 4156-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15047831
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Adenovirus vectors: biology, design, and production. Author(s): Imperiale MJ, Kochanek S. Source: Curr Top Microbiol Immunol. 2004; 273: 335-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674606
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Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. Author(s): Germano IM, Fable J, Gultekin SH, Silvers A. Source: Journal of Neuro-Oncology. 2003 December; 65(3): 279-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14682378
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Adenovirus-mediated gene delivery to dendritic cells. Author(s): Timares L, Douglas JT, Tillman BW, Krasnykh V, Curiel DT. Source: Methods in Molecular Biology (Clifton, N.J.). 2004; 246: 139-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970589
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Adenovirus-mediated p53AIP1 gene transfer as a new strategy for treatment of p53resistant tumors. Author(s): Yoshida K, Monden M, Nakamura Y, Arakawa H. Source: Cancer Science. 2004 January; 95(1): 91-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14720333
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Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines. Author(s): Kleeff J, Kothari NH, Friess H, Fan H, Korc M. Source: Pancreas. 2004 January; 28(1): 25-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707726
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Adenovirus-transduced dendritic cells injected into skin or lymph node prime potent simian immunodeficiency virus-specific T cell immunity in monkeys. Author(s): Brown K, Gao W, Alber S, Trichel A, Murphey-Corb M, Watkins SC, Gambotto A, Barratt-Boyes SM. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 December 15; 171(12): 687582. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662894
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Altered tropism of recombinant bovine adenovirus type-3 expressing chimeric fiber. Author(s): Wu Q, Tikoo SK. Source: Virus Research. 2004 January; 99(1): 9-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687941
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An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Author(s): Zhang ZL, Zou WG, Luo CX, Li BH, Wang JH, Sun LY, Qian QJ, Liu XY. Source: Cell Research. 2003 December; 13(6): 481-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14728805
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Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. Author(s): Kurozumi K, Tamiya T, Ono Y, Otsuka S, Kambara H, Adachi Y, Ichikawa T, Hamada H, Ohmoto T. Source: Journal of Neuro-Oncology. 2004 January; 66(1-2): 117-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015777
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Bak and Bax function to limit adenovirus replication through apoptosis induction. Author(s): Cuconati A, Degenhardt K, Sundararajan R, Anschel A, White E. Source: Journal of Virology. 2002 May; 76(9): 4547-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11932420
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Bending of adenovirus origin DNA by nuclear factor I as shown by scanning force microscopy is required for optimal DNA replication. Author(s): Mysiak ME, Bleijenberg MH, Wyman C, Holthuizen PE, van der Vliet PC. Source: Journal of Virology. 2004 February; 78(4): 1928-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14747557
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Binding of adenovirus capsid to dipalmitoyl phosphatidylcholine provides a novel pathway for virus entry. Author(s): Balakireva L, Schoehn G, Thouvenin E, Chroboczek J. Source: Journal of Virology. 2003 April; 77(8): 4858-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663792
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Binding of CCAAT displacement protein CDP to adenovirus packaging sequences. Author(s): Erturk E, Ostapchuk P, Wells SI, Yang J, Gregg K, Nepveu A, Dudley JP, Hearing P. Source: Journal of Virology. 2003 June; 77(11): 6255-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12743282
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Binding of PKA-RIIalpha to the Adenovirus E1A12S oncoprotein correlates with its nuclear translocation and an increase in PKA-dependent promoter activity. Author(s): Fax P, Carlson CR, Collas P, Tasken K, Esche H, Brockmann D. Source: Virology. 2001 June 20; 285(1): 30-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11414803
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Biocompatibility of cardiovascular gene delivery catheters with adenovirus vectors: an important determinant of the efficiency of cardiovascular gene transfer. Author(s): Marshall DJ, Palasis M, Lepore JJ, Leiden JM. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2000 May; 1(5 Pt 1): 423-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10933963
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Biology of ovine adenovirus infection of nonpermissive cells. Author(s): Kumin D, Hofmann C, Rudolph M, Both GW, Loser P. Source: Journal of Virology. 2002 November; 76(21): 10882-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12368331
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Biophysical targeting of adenovirus vectors for gene therapy. Author(s): Silman NJ, Fooks AR. Source: Curr Opin Mol Ther. 2000 October; 2(5): 524-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11249755
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Biosafety of in vivo adenovirus-p53 intravesical administration in mice. Author(s): Perrotte P, Wood M, Slaton JW, Wilson DR, Pagliaro L, Price RE, Dinney CP. Source: Urology. 2000 July; 56(1): 155-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10869658
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Bladder cancer therapy using combined proliferating cell nuclear antigen antisense oligonucleotides and recombinant adenovirus p53. Author(s): Zhu Z, Xing S, Lin C, Zhang X, Fu M, Liang X, Zeng F, Lu G, Wu M. Source: Chinese Medical Journal. 2003 December; 116(12): 1860-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687474
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Bovine adenovirus type 3 containing heterologous protein in the C-terminus of minor capsid protein IX. Author(s): Zakhartchouk A, Connors W, van Kessel A, Tikoo SK. Source: Virology. 2004 March 15; 320(2): 291-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15016551
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Brain ischemia augments exo-focal transgene expression of adenovirus-mediated gene transfer to ependyma in hypertensive rats. Author(s): Kumai Y, Ooboshi H, Kitazono T, Takada J, Ibayashi S, Fujishima M, Iida M. Source: Experimental Neurology. 2003 December; 184(2): 904-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769382
118
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BS69, an adenovirus E1A-associated protein, inhibits the transcriptional activity of cMyb. Author(s): Ladendorff NE, Wu S, Lipsick JS. Source: Oncogene. 2001 January 4; 20(1): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11244510
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Budding and secretion of HIV Gag-Env virus-like particles from recombinant human adenovirus infected cells. Author(s): Luo L, Li Y, Yong Kang C. Source: Virus Research. 2003 March; 92(1): 75-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12606078
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Caspase-3 activation and ERK phosphorylation during CVB3 infection of cells: influence of the coxsackievirus and adenovirus receptor and engineered variants. Author(s): Cunningham KA, Chapman NM, Carson SD. Source: Virus Research. 2003 April; 92(2): 179-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12686427
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Centrifugation facilitates transduction of green fluorescent protein in human monocytes and macrophages by adenovirus at low multiplicity of infection. Author(s): Mayne GC, Borowicz RA, Greeneklee KV, Finlay-Jones JJ, Williams KA, Hart PH. Source: Journal of Immunological Methods. 2003 July; 278(1-2): 45-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957395
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Characterisation of hexon and fibre genes of a novel strain of adenovirus involved in epidemic keratoconjunctivitis. Author(s): Adhikary AK, Inada T, Numaga J, Suzuki E, Ushijima H, Banik U, Mukouyama A, Matsuno S, Okabe N. Source: Journal of Clinical Pathology. 2004 January; 57(1): 95-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14693847
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Characterization of adenovirus p21 gene transfer, biodistribution, and immune response after local ocular delivery in New Zealand white rabbits. Author(s): Wen SF, Chen Z, Nery J, Faha B. Source: Experimental Eye Research. 2003 September; 77(3): 355-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12907168
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Characterization of in vitro and in vivo gene transfer properties of adenovirus serotype 35 vector. Author(s): Sakurai F, Mizuguchi H, Yamaguchi T, Hayakawa T. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 November; 8(5): 813-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599815
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Chlorine inactivation of adenovirus type 40 and feline calicivirus. Author(s): Thurston-Enriquez JA, Haas CN, Jacangelo J, Gerba CP. Source: Applied and Environmental Microbiology. 2003 July; 69(7): 3979-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839771
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Cholesterol is required for endocytosis and endosomal escape of adenovirus type 2. Author(s): Imelli N, Meier O, Boucke K, Hemmi S, Greber UF. Source: Journal of Virology. 2004 March; 78(6): 3089-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990728
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Coexpression of p21(WAF1/CIP1) in adenovirus vector transfected human primary hepatocytes prevents apoptosis resulting in improved transgene expression. Author(s): Wolff G, Schumacher A, Nuessler AK, Ruppert V, Karawajew L, Wehnes E, Neuhaus P, Dorken B. Source: Gene Therapy. 2003 April; 10(8): 668-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692595
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Combination of adenovirus-mediated thymidine kinase gene therapy with cytotoxic chemotherapy in bladder cancer in vitro. Author(s): Freund CT, Tong XW, Rowley D, Engehausen D, Frolov A, Kieback DG, Lerner SP. Source: Urologic Oncology. 2003 May-June; 21(3): 197-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810206
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Combination radiation and adenovirus-mediated P16(INK4A) gene therapy in a murine model for head and neck cancer. Author(s): Rhee JG, Li D, O'Malley BW Jr, Suntharalingam M. Source: Orl; Journal for Oto-Rhino-Laryngology and Its Related Specialties. 2003 MayJune; 65(3): 144-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12925815
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Comparative analysis of the genome organization of human adenovirus 11, a member of the human adenovirus species B, and the commonly used human adenovirus 5 vector, a member of species C. Author(s): Mei YF, Skog J, Lindman K, Wadell G. Source: The Journal of General Virology. 2003 August; 84(Pt 8): 2061-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867636
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Comparison between the interactions of adenovirus-derived peptides with plasmid DNA and their role in gene delivery mediated by liposome-peptide-DNA virus-like nanoparticles. Author(s): Preuss M, Tecle M, Shah I, Matthews DA, Miller AD. Source: Organic & Biomolecular Chemistry. 2003 July 21; 1(14): 2430-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956058
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Comparison of PCR, enzyme immunoassay and conventional culture for adenovirus detection in bone marrow transplant patients with hemorrhagic cystitis. Author(s): Raboni SM, Siqueira MM, Portes SR, Pasquini R. Source: Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. 2003 August; 27(3): 270-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878091
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Conditional replication of a recombinant adenovirus studied using neomycin as a selective marker. Author(s): Xue F, Qi YP, Joshua MN, Lan P, Dong CY. Source: J Biochem Mol Biol. 2003 May 31; 36(3): 275-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12787482
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Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Author(s): van Beusechem VW, Mastenbroek DC, van den Doel PB, Lamfers ML, Grill J, Wurdinger T, Haisma HJ, Pinedo HM, Gerritsen WR. Source: Gene Therapy. 2003 November; 10(23): 1982-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14528322
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Corneal IL-8 expression following adenovirus infection is mediated by c-Src activation in human corneal fibroblasts. Author(s): Natarajan K, Rajala MS, Chodosh J. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 June 15; 170(12): 6234-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12794155
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Cre/loxP-mediated adenovirus type 5 packaging signal excision demonstrates that core element VI is sufficient for virus packaging. Author(s): Maeda Y, Kimura E, Uchida Y, Nishida Y, Yamashita S, Arima T, Uchino M. Source: Virology. 2003 May 10; 309(2): 330-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12758179
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Crystallographic structure at 1.6-A resolution of the human adenovirus proteinase in a covalent complex with its 11-amino-acid peptide cofactor: insights on a new fold. Author(s): McGrath WJ, Ding J, Didwania A, Sweet RM, Mangel WF. Source: Biochimica Et Biophysica Acta. 2003 May 30; 1648(1-2): 1-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12758141
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Cyclic AMP regulate adenovirus mediated inducible nitric oxide synthase expression and CMV promoter activity in cultured hepatocytes. Author(s): Zhang B, Liu Y, Harbrecht BG. Source: Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. 2003 June; 8(4): 262-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12895436
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Cytomegalovirus and adenovirus infections and diseases among 75 paediatric unrelated allogeneic bone marrow transplant recipients. Author(s): Morfin F, Boucher A, Najioullah F, Bertrand Y, Bleyzac N, Poitevin-Later F, Bienvenu F, Simonet V, Galambrun C, Philippe N, Aymard M, Thouvenot D, Souillet G. Source: Journal of Medical Virology. 2004 February; 72(2): 257-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695667
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Delivering antisense telomerase RNA by a hybrid adenovirus/ adeno-associated virus significantly suppresses the malignant phenotype and enhances cell apoptosis of human breast cancer cells. Author(s): Zhang X, Chen Z, Chen Y, Tong T. Source: Oncogene. 2003 April 24; 22(16): 2405-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12717417
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Delivery of peptide drugs to the brain by adenovirus-mediated heterologous expression of human oligopeptide transporter at the blood-brain barrier. Author(s): Toyobuku H, Sai Y, Kagami T, Tamai I, Tsuji A. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 April; 305(1): 40-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12649351
122
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Dendritic cells transduced with gp100 gene by RGD fiber-mutant adenovirus vectors are highly efficacious in generating anti-B16BL6 melanoma immunity in mice. Author(s): Okada N, Masunaga Y, Okada Y, Mizuguchi H, Iiyama S, Mori N, Sasaki A, Nakagawa S, Mayumi T, Hayakawa T, Fujita T, Yamamoto A. Source: Gene Therapy. 2003 October; 10(22): 1891-902. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502218
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Dependence of exogenous SERCA gene expression on coxsackie adenovirus receptor levels in neonatal and adult cardiac myocytes. Author(s): Sumbilla C, Ma H, Seth M, Inesi G. Source: Archives of Biochemistry and Biophysics. 2003 July 15; 415(2): 178-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831840
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Detailed analysis of the CD8+ T-cell response following adenovirus vaccination. Author(s): Yang TC, Dayball K, Wan YH, Bramson J. Source: Journal of Virology. 2003 December; 77(24): 13407-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645597
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Detection of infectious adenovirus in cell culture by mRNA reverse transcriptionPCR. Author(s): Ko G, Cromeans TL, Sobsey MD. Source: Applied and Environmental Microbiology. 2003 December; 69(12): 7377-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14660388
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Detection of influenza, parainfluenza, adenovirus and respiratory syncytial virus during asthma attacks in children older than 2 years old. Author(s): Azevedo AM, Durigon EL, Okasima V, Queiroz DA, de Moraes-Vasconcelos D, Duarte AJ, Grumach AS. Source: Allergologia Et Immunopathologia. 2003 November-December; 31(6): 311-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670285
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Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults. Author(s): Bowles NE, Ni J, Kearney DL, Pauschinger M, Schultheiss HP, McCarthy R, Hare J, Bricker JT, Bowles KR, Towbin JA. Source: Journal of the American College of Cardiology. 2003 August 6; 42(3): 466-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906974
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Development and validation of a real-time PCR assay for the detection and quantitation of p53 recombinant adenovirus in clinical samples from patients treated with Ad5CMV-p53 (INGN 201). Author(s): Saulnier P, Vidaud M, Gautier E, Motte N, Bellet D, Escudier B, Wilson D, Yver A. Source: Journal of Virological Methods. 2003 December; 114(1): 55-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599679
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Development of adenovirus serotype 35 as a gene transfer vector. Author(s): Seshidhar Reddy P, Ganesh S, Limbach MP, Brann T, Pinkstaff A, Kaloss M, Kaleko M, Connelly S. Source: Virology. 2003 July 5; 311(2): 384-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842627
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Direct antiviral effect of cycloferon (10-carboxymethyl-9-acridanone) against adenovirus type 6 in vitro. Author(s): Zarubaev VV, Slita AV, Krivitskaya VZ, Sirotkin AK, Kovalenko AL, Chatterjee NK. Source: Antiviral Research. 2003 April; 58(2): 131-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742573
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Direct comparison of efficiency and stability of gene transfer into the mammalian heart using adeno-associated virus versus adenovirus vectors. Author(s): Chu D, Sullivan CC, Weitzman MD, Du L, Wolf PL, Jamieson SW, Thistlethwaite PA. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 September; 126(3): 671-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502138
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Disseminated adenovirus infection in two premature infants. Author(s): Rieger-Fackeldey E, Aumeier S, Genzel-Boroviczeny O. Source: Infection. 2000 July-August; 28(4): 237-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10961532
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Distinct domains in the adenovirus E3 RIDalpha protein are required for degradation of Fas and the epidermal growth factor receptor. Author(s): Zanardi TA, Yei S, Lichtenstein DL, Tollefson AE, Wold WS. Source: Journal of Virology. 2003 November; 77(21): 11685-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557654
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Distinct roles of the Adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation. Author(s): Evans JD, Hearing P. Source: Journal of Virology. 2003 May; 77(9): 5295-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692231
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DNA damage response and MCL-1 destruction initiate apoptosis in adenovirusinfected cells. Author(s): Cuconati A, Mukherjee C, Perez D, White E. Source: Genes & Development. 2003 December 1; 17(23): 2922-32. Epub 2003 November 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633975
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DNA replication of first-generation adenovirus vectors in tumor cells. Author(s): Steinwaerder DS, Carlson CA, Lieber A. Source: Human Gene Therapy. 2000 September 1; 11(13): 1933-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10986565
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DNA synthesis-dependent relief of repression of transcription from the adenovirus type 2 IVa(2) promoter by a cellular protein. Author(s): Huang W, Kiefer J, Whalen D, Flint SJ. Source: Virology. 2003 September 15; 314(1): 394-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517091
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Double genetic modification of adenovirus fiber with RGD polylysine motifs significantly enhances gene transfer to isolated human pancreatic islets. Author(s): Contreras JL, Wu H, Smyth CA, Eckstein CP, Young CJ, Seki T, Bilbao G, Curiel DT, Eckhoff DE. Source: Transplantation. 2003 July 15; 76(1): 252-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865820
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Dr. Gary J. Becker Young Investigator Award: intraarterial adenovirus for metastatic gastrointestinal cancer: activity, radiographic response, and survival. Author(s): Sze DY, Freeman SM, Slonim SM, Samuels SL, Andrews JC, Hicks M, Ahrar K, Gupta S, Reid TR. Source: Journal of Vascular and Interventional Radiology : Jvir. 2003 March; 14(3): 27990. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631632
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E1A, E1B double-restricted adenovirus for oncolytic gene therapy of gallbladder cancer. Author(s): Fukuda K, Abei M, Ugai H, Seo E, Wakayama M, Murata T, Todoroki T, Tanaka N, Hamada H, Yokoyama KK. Source: Cancer Research. 2003 August 1; 63(15): 4434-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12907616
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Effect of adenovirus-mediated overexpression of decorin on metalloproteinases, tissue inhibitors of metalloproteinases and cytokines secretion by human gingival fibroblasts. Author(s): Al Haj Zen A, Lafont A, Durand E, Brasselet C, Lemarchand P, Godeau G, Gogly B. Source: Matrix Biology : Journal of the International Society for Matrix Biology. 2003 May; 22(3): 251-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853035
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Effects of adenovirus mediated gene transfer to mouse testis in vivo on spermatogenesis and next generation. Author(s): Kojima Y, Sasaki S, Umemoto Y, Hashimoto Y, Hayashi Y, Kohri K. Source: The Journal of Urology. 2003 November; 170(5): 2109-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532865
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Effects of adenovirus-mediated sorcin overexpression on excitation-contraction coupling in isolated rabbit cardiomyocytes. Author(s): Seidler T, Miller SL, Loughrey CM, Kania A, Burow A, Kettlewell S, Teucher N, Wagner S, Kogler H, Meyers MB, Hasenfuss G, Smith GL. Source: Circulation Research. 2003 July 25; 93(2): 132-9. Epub 2003 June 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12805242
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Effects of adenovirus-mediated SV5 fusogenic glycoprotein expression on tumor cells. Author(s): Gomez-Trevino A, Castel S, Lopez-Iglesias C, Cortadellas N, Comas-Riu J, Mercade E. Source: The Journal of Gene Medicine. 2003 June; 5(6): 483-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12797113
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Efficient gene transfer into human CD34+ cells by an adenovirus type 35 vector. Author(s): Sakurai F, Mizuguchi H, Hayakawa T. Source: Gene Therapy. 2003 June; 10(12): 1041-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12776162
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Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirusexpressing p53 homologue p73beta. Author(s): Das S, El-Deiry WS, Somasundaram K. Source: Oncogene. 2003 November 20; 22(52): 8394-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627980
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Electrophysiological studies of ion channels and therapeutic potential with adenovirus-mediated gene transfer. Author(s): Qu J, Pham TV, Obreztchikova MN. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 227: 179-212. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824650
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Enhanced adenovirus infection of melanoma cells by fiber-modification: incorporation of RGD peptide or Ad5/3 chimerism. Author(s): Volk AL, Rivera AA, Kanerva A, Bauerschmitz G, Dmitriev I, Nettelbeck DM, Curiel DT. Source: Cancer Biology & Therapy. 2003 September-October; 2(5): 511-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14614316
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Enhanced antitumor effect of combined replicative adenovirus and nonreplicative adenovirus expressing interleukin-12 in an immunocompetent mouse model. Author(s): Nagayama Y, Nakao K, Mizuguchi H, Hayakawa T, Niwa M. Source: Gene Therapy. 2003 August; 10(16): 1400-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883537
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Enhanced antitumor effects of a bicistronic adenovirus vector expressing both herpes simplex virus thymidine kinase and monocyte chemoattractant protein-1 against hepatocellular carcinoma. Author(s): Tsuchiyama T, Kaneko S, Nakamoto Y, Sakai Y, Honda M, Mukaida N, Kobayashi K. Source: Cancer Gene Therapy. 2003 April; 10(4): 260-9. Erratum In: Cancer Gene Ther. 2003 August; 10(8): 647. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679798
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Enhanced oncolytic potency of replicative adenovirus expressing p53. Author(s): Nemunaitis J, Cunningham C, Senzer N. Source: Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy. 2003 February; 6(1): 5-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654282
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Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability. Author(s): Huang Y, Tyler T, Saadatmandi N, Lee C, Borgstrom P, Gjerset RA. Source: Cancer Research. 2003 July 1; 63(13): 3646-53. Erratum In: Cancer Res. 2003 August 15; 63(16): 5171. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839954
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Epigenetic regulation of coxsackie and adenovirus receptor (CAR) gene promoter in urogenital cancer cells. Author(s): Pong RC, Lai YJ, Chen H, Okegawa T, Frenkel E, Sagalowsky A, Hsieh JT. Source: Cancer Research. 2003 December 15; 63(24): 8680-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695181
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Evaluating the role of CRM1-mediated export for adenovirus gene expression. Author(s): Carter CC, Izadpanah R, Bridge E. Source: Virology. 2003 October 10; 315(1): 224-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14592774
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Evaluation of a rapid quantitative diagnostic test for adenovirus type 4. Author(s): Faix DJ, Houng HS, Gaydos JC, Liu SK, Connors JT, Brown X, Asher LV, Vaughn DW, Binn LN. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 February 1; 38(3): 391-7. Epub 2004 January 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14727210
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Exploiting features of adenovirus replication to support mammalian kinase production. Author(s): Cotten M, Stegmueller K, Eickhoff J, Hanke M, Herzberger K, Herget T, Choidas A, Daub H, Godl K. Source: Nucleic Acids Research. 2003 November 1; 31(21): E128. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576328
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Expression and glycosylation of rotavirus strain SA11 VP4 protein in a recombinant adenovirus. Author(s): Sun M, Zan Y, Ma Y, Zhang G, Du Q, Dai C. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 2001 September; 16(3): 129-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899323
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Expression of the coxsackievirus and adenovirus receptor in musculoskeletal tumors and mesenchymal tissues: efficacy of adenoviral gene therapy for osteosarcoma. Author(s): Kawashima H, Ogose A, Yoshizawa T, Kuwano R, Hotta Y, Hotta T, Hatano H, Kawashima H, Endo N. Source: Cancer Science. 2003 January; 94(1): 70-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708477
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Extensive cross-reactivity of CD4+ adenovirus-specific T cells: implications for immunotherapy and gene therapy. Author(s): Heemskerk B, Veltrop-Duits LA, van Vreeswijk T, ten Dam MM, Heidt S, Toes RE, van Tol MJ, Schilham MW. Source: Journal of Virology. 2003 June; 77(11): 6562-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12743315
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Factors involved in the sensitivity of different hematopoietic cell lines to infection by subgroup C adenovirus: implication for gene therapy of human lymphocytic malignancies. Author(s): Colin M, Renaut L, Mailly L, D'Halluin JC. Source: Virology. 2004 March 1; 320(1): 23-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003860
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Fatal adenovirus infection during alemtuzumab (anti-CD52 monoclonal antibody) treatment of a patient with fludarabine-refractory B-cell chronic lymphocytic leukemia. Author(s): Cavalli-Bjorkman N, Osby E, Lundin J, Kalin M, Osterborg A, Gruber A. Source: Medical Oncology (Northwood, London, England). 2002; 19(4): 277-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12512923
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Fatal adenovirus type 7b infection in a child with Smith-Lemli-Opitz syndrome. Author(s): Beby-Defaux A, Maille L, Chabot S, Nassimi A, Oriot D, Agius G. Source: Journal of Medical Virology. 2001 September; 65(1): 66-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11505445
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Fatal disseminated adenovirus infections in immunocompromised patients. Author(s): Pham TT, Burchette JL Jr, Hale LP. Source: American Journal of Clinical Pathology. 2003 October; 120(4): 575-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14560569
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Fatty acid modification of the coxsackievirus and adenovirus receptor. Author(s): van't Hof W, Crystal RG. Source: Journal of Virology. 2002 June; 76(12): 6382-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12021372
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Feasibility of generating adeno-associated virus packaging cell lines containing inducible adenovirus helper genes. Author(s): Qiao C, Li J, Skold A, Zhang X, Xiao X. Source: Journal of Virology. 2002 February; 76(4): 1904-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11799185
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FGF2-Targeted adenovirus encoding platelet-derived growth factor-B enhances de novo tissue formation. Author(s): Chandler LA, Doukas J, Gonzalez AM, Hoganson DK, Gu DL, Ma C, Nesbit M, Crombleholme TM, Herlyn M, Sosnowski BA, Pierce GF. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2000 August; 2(2): 153-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10947943
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Fiber knob modifications overcome low, heterogeneous expression of the coxsackievirus-adenovirus receptor that limits adenovirus gene transfer and oncolysis for human rhabdomyosarcoma cells. Author(s): Cripe TP, Dunphy EJ, Holub AD, Saini A, Vasi NH, Mahller YY, Collins MH, Snyder JD, Krasnykh V, Curiel DT, Wickham TJ, DeGregori J, Bergelson JM, Currier MA. Source: Cancer Research. 2001 April 1; 61(7): 2953-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11306473
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Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications. Author(s): Leen AM, Sili U, Savoldo B, Jewell AM, Piedra PA, Brenner MK, Rooney CM. Source: Blood. 2004 February 1; 103(3): 1011-9. Epub 2003 October 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14525768
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Fiber-mutant technique can augment gene transduction efficacy and anti-tumor effects against established murine melanoma by cytokine-gene therapy using adenovirus vectors. Author(s): Okada Y, Okada N, Nakagawa S, Mizuguchi H, Kanehira M, Nishino N, Takahashi K, Mizuno N, Hayakawa T, Mayumi T. Source: Cancer Letters. 2002 March 8; 177(1): 57-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11809531
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Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression. Author(s): Pattison S, Pankarican M, Rupar CA, Graham FL, Igdoura SA. Source: Human Mutation. 2004 January; 23(1): 32-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695530
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Flexibility of the adenovirus fiber is required for efficient receptor interaction. Author(s): Wu E, Pache L, Von Seggern DJ, Mullen TM, Mikyas Y, Stewart PL, Nemerow GR. Source: Journal of Virology. 2003 July; 77(13): 7225-35. Erratum In: J Virol. 2004 February; 78(4): 2167. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12805421
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Fulminant adenovirus hepatitis following bone marrow transplantation. A case report and brief review of the literature. Author(s): Wang WH, Wang HL. Source: Archives of Pathology & Laboratory Medicine. 2003 May; 127(5): E246-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708923
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Fulminant hepatic failure due to disseminated adenovirus infection in a patient with chronic lymphocytic leukemia. Author(s): Haura EB, Winden MA, Proia AD, Trotter JE. Source: Cancer Control : Journal of the Moffitt Cancer Center. 2002 May-June; 9(3): 24853. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12060822
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Fulminant hepatic failure secondary to adenovirus following fludarabine-based chemotherapy for non-Hodgkin's lymphoma. Author(s): Hogan WJ, Edwards WD, Macon WR, Habermann TM. Source: Leukemia & Lymphoma. 2001 September-October; 42(5): 1145-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11697635
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Function and immunolocalization of overexpressed human intestinal H+/peptide cotransporter in adenovirus-transduced Caco-2 cells. Author(s): Hsu CP, Walter E, Merkle HP, Rothen-Rutishauser B, Wunderli-Allenspach H, Hilfinger JM, Amidon GL. Source: Aaps Pharmsci [electronic Resource]. 1999; 1(3): E12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11741208
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Functional analysis of adenovirus protein IX identifies domains involved in capsid stability, transcriptional activity, and nuclear reorganization. Author(s): Rosa-Calatrava M, Grave L, Puvion-Dutilleul F, Chatton B, Kedinger C. Source: Journal of Virology. 2001 August; 75(15): 7131-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11435594
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131
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Functional and selective targeting of adenovirus to high-affinity Fcgamma receptor Ipositive cells by using a bispecific hybrid adapter. Author(s): Ebbinghaus C, Al-Jaibaji A, Operschall E, Schoffel A, Peter I, Greber UF, Hemmi S. Source: Journal of Virology. 2001 January; 75(1): 480-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11119616
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Functional silencing of hepatic microsomal glucose-6-phosphatase gene expression in vivo by adenovirus-mediated delivery of short hairpin RNA. Author(s): Huang A, Chen Y, Wang X, Zhao S, Su N, White DW. Source: Febs Letters. 2004 January 30; 558(1-3): 69-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759518
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Functions and mechanisms of action of the adenovirus E3 proteins. Author(s): Lichtenstein DL, Toth K, Doronin K, Tollefson AE, Wold WS. Source: International Reviews of Immunology. 2004 January-April; 23(1-2): 75-111. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14690856
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Gene silencing by adenovirus-delivered siRNA. Author(s): Shen C, Buck AK, Liu X, Winkler M, Reske SN. Source: Febs Letters. 2003 March 27; 539(1-3): 111-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12650936
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Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1-5. Author(s): Hsieh JL, Wu CL, Lai MD, Lee CH, Tsai CS, Shiau AL. Source: British Journal of Cancer. 2003 May 6; 88(9): 1492-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12778082
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Gene therapy for choroideremia: in vitro rescue mediated by recombinant adenovirus. Author(s): Anand V, Barral DC, Zeng Y, Brunsmann F, Maguire AM, Seabra MC, Bennett J. Source: Vision Research. 2003 April; 43(8): 919-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12668061
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Gene therapy for pancreatic cancer targeting the genomic alterations of tumor suppressor genes using replication-selective oncolytic adenovirus. Author(s): Sunamura M, Oonuma M, Motoi F, Abe H, Saitoh Y, Hoshida T, Ottomo S, Horii A, Matsuno S. Source: Hum Cell. 2002 September; 15(3): 138-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12703544
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Adenovirus
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Gene therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor. Author(s): Hoshida T, Sunamura M, Duda DG, Egawa S, Miyazaki S, Shineha R, Hamada H, Ohtani H, Satomi S, Matsuno S. Source: Pancreas. 2002 August; 25(2): 111-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12142732
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Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. Author(s): Shinoura N, Hamada H. Source: Current Gene Therapy. 2003 April; 3(2): 147-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12653407
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Gene transfer by adenovirus-mimetic peptides in the presence of a cationic lipid and/or adenovirus. Analysis of the contribution of the viral and nonviral components. Author(s): Moritz S, Colin M, Keller M, Klonjkowski B, Capeau J, Coutelle C, Chroboczek J, Brahimi-Horn MC. Source: Archives of Virology. 2003 January; 148(1): 1-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12536292
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General strategy for broadening adenovirus tropism. Author(s): Fontana L, Nuzzo M, Urbanelli L, Monaci P. Source: Journal of Virology. 2003 October; 77(20): 11094-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512557
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Generation of adenovirus vectors devoid of all viral genes by recombination between inverted repeats. Author(s): Stecher H, Carlson CA, Shayakhmetov DM, Lieber A. Source: Methods in Molecular Medicine. 2003; 76: 135-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12526162
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Generation of fiber-modified adenovirus vectors containing heterologous peptides in both the HI loop and C terminus of the fiber knob. Author(s): Koizumi N, Mizuguchi H, Utoguchi N, Watanabe Y, Hayakawa T. Source: The Journal of Gene Medicine. 2003 April; 5(4): 267-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692861
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Genetic characterisation of adenovirus type 8 isolated in Hiroshima city over a 15 year period. Author(s): Adhikary AK, Numaga J, Kaburaki T, Kawashima H, Araie M, Ikeda Y, Ogino T, Suzuki E, Ushijima H, Mukoyama A, Matsuno S, Inada T, Okabe N. Source: Journal of Clinical Pathology. 2003 February; 56(2): 120-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12560390
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Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer. Author(s): Howard DS, Rizzierri DA, Grimes B, Upchurch D, Phillips GL, Stewart AK, Yannelli JR, Jordan CT. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 October; 13(10): 1608-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10516763
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Genetic modification of adenovirus 5 tropism by a novel class of ligands based on a three-helix bundle scaffold derived from staphylococcal protein A. Author(s): Henning P, Magnusson MK, Gunneriusson E, Hong SS, Boulanger P, Nygren PA, Lindholm L. Source: Human Gene Therapy. 2002 August 10; 13(12): 1427-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215264
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Genetic retargeting of adenovirus vectors: functionality of targeting ligands and their influence on virus viability. Author(s): Magnusson MK, Hong SS, Henning P, Boulanger P, Lindholm L. Source: The Journal of Gene Medicine. 2002 July-August; 4(4): 356-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12124978
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Genetic retargeting of adenovirus: novel strategy employing “deknobbing” of the fiber. Author(s): Magnusson MK, Hong SS, Boulanger P, Lindholm L. Source: Journal of Virology. 2001 August; 75(16): 7280-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11462000
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Genetically targeted adenovirus vector directed to CD40-expressing cells. Author(s): Belousova N, Korokhov N, Krendelshchikova V, Simonenko V, Mikheeva G, Triozzi PL, Aldrich WA, Banerjee PT, Gillies SD, Curiel DT, Krasnykh V. Source: Journal of Virology. 2003 November; 77(21): 11367-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557622
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Genome type analysis of adenovirus types 3 and 7 isolated during successive outbreaks of lower respiratory tract infections in children. Author(s): Kim YJ, Hong JY, Lee HJ, Shin SH, Kim YK, Inada T, Hashido M, Piedra PA. Source: Journal of Clinical Microbiology. 2003 October; 41(10): 4594-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532188
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Genome types of adenovirus type 7 isolated in Hiroshima City. Author(s): Ikeda Y, Yamaoka K, Noda M, Ogino T. Source: Journal of Medical Virology. 2003 February; 69(2): 215-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12683410
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Growth inhibition of prostate cancer by an adenovirus expressing a novel tumor suppressor gene, pHyde. Author(s): Steiner MS, Zhang X, Wang Y, Lu Y. Source: Cancer Research. 2000 August 15; 60(16): 4419-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10969787
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Growth suppression by a p14(ARF) exon 1beta adenovirus in human tumor cell lines of varying p53 and Rb status. Author(s): Saadatmandi N, Tyler T, Huang Y, Haghighi A, Frost G, Borgstrom P, Gjerset RA. Source: Cancer Gene Therapy. 2002 October; 9(10): 830-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12224024
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Heparan sulfate proteoglycan mediates the selective attachment and internalization of serotype 3 human adenovirus dodecahedron. Author(s): Vives RR, Lortat-Jacob H, Chroboczek J, Fender P. Source: Virology. 2004 April 10; 321(2): 332-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051392
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Heparin-interacting sites of bovine lactoferrin are involved in anti-adenovirus activity. Author(s): Di Biase AM, Pietrantoni A, Tinari A, Siciliano R, Valenti P, Antonini G, Seganti L, Superti F. Source: Journal of Medical Virology. 2003 April; 69(4): 495-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12601757
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Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Author(s): Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J, Randlev B, Heise C, Uprichard M, Hatfield M, Rome L, Rubin J, Kirn D. Source: Cancer Research. 2002 November 1; 62(21): 6070-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414631
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Hepatic DR5 induces apoptosis and limits adenovirus gene therapy product expression in the liver. Author(s): Zhang HG, Xie J, Xu L, Yang P, Xu X, Sun S, Wang Y, Curiel DT, Hsu HC, Mountz JD. Source: Journal of Virology. 2002 June; 76(11): 5692-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11991997
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Hepatitis B virus X protein sensitizes hepatocellular carcinoma cells to cytolysis induced by E1B-deleted adenovirus through the disruption of p53 function. Author(s): Hsieh JL, Wu CL, Lee CH, Shiau AL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 January; 9(1): 338-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538486
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High levels of adenovirus DNA in serum correlate with fatal outcome of adenovirus infection in children after allogeneic stem-cell transplantation. Author(s): Schilham MW, Claas EC, van Zaane W, Heemskerk B, Vossen JM, Lankester AC, Toes RE, Echavarria M, Kroes AC, van Tol MJ. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 September 1; 35(5): 526-32. Epub 2002 July 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173125
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High throughput creation of recombinant adenovirus vectors by direct cloning, greenwhite selection and I-Sce I-mediated rescue of circular adenovirus plasmids in 293 cells. Author(s): Gao G, Zhou X, Alvira MR, Tran P, Marsh J, Lynd K, Xiao W, Wilson JM. Source: Gene Therapy. 2003 October; 10(22): 1926-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502222
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Histone deacetylase 1 inactivation by an adenovirus early gene product. Author(s): Chiocca S, Kurtev V, Colombo R, Boggio R, Sciurpi MT, Brosch G, Seiser C, Draetta GF, Cotten M. Source: Current Biology : Cb. 2002 April 2; 12(7): 594-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11937030
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Histone deacetylase inhibitor FR901228 enhances adenovirus infection of hematopoietic cells. Author(s): Kitazono M, Rao VK, Robey R, Aikou T, Bates S, Fojo T, Goldsmith ME. Source: Blood. 2002 March 15; 99(6): 2248-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11877306
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Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes. Author(s): Davison AJ, Akter P, Cunningham C, Dolan A, Addison C, Dargan DJ, Hassan-Walker AF, Emery VC, Griffiths PD, Wilkinson GW. Source: The Journal of General Virology. 2003 March; 84(Pt 3): 657-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12604818
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Adenovirus
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Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys. Author(s): Dhurandhar NV, Whigham LD, Abbott DH, Schultz-Darken NJ, Israel BA, Bradley SM, Kemnitz JW, Allison DB, Atkinson RL. Source: The Journal of Nutrition. 2002 October; 132(10): 3155-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12368411
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Human adenovirus and human cytomegalovirus infections in preterm newborns: no association with bronchopulmonary dysplasia. Author(s): Prosch S, Lienicke U, Priemer C, Flunker G, Seidel WF, Kruger DH, Wauer RR. Source: Pediatric Research. 2002 August; 52(2): 219-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149499
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Human adenovirus serotypes 4 and 11 show higher binding affinity and infectivity for endothelial and carcinoma cell lines than serotype 5. Author(s): Zhang LQ, Mei YF, Wadell G. Source: The Journal of General Virology. 2003 March; 84(Pt 3): 687-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12604821
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Human adenovirus serotypes 4p and 11p are efficiently expressed in cell lines of neural tumour origin. Author(s): Skog J, Mei YF, Wadell G. Source: The Journal of General Virology. 2002 June; 83(Pt 6): 1299-309. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12029144
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Human adenovirus type 35: nucleotide sequence and vector development. Author(s): Gao W, Robbins PD, Gambotto A. Source: Gene Therapy. 2003 November; 10(23): 1941-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14528318
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Human coxsackie-adenovirus receptor is colocalized with integrins alpha(v)beta(3) and alpha(v)beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: implications for cardiotropic viral infections. Author(s): Noutsias M, Fechner H, de Jonge H, Wang X, Dekkers D, Houtsmuller AB, Pauschinger M, Bergelson J, Warraich R, Yacoub M, Hetzer R, Lamers J, Schultheiss HP, Poller W. Source: Circulation. 2001 July 17; 104(3): 275-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11457744
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Human mesenchymal stem cells transduced with recombinant bone morphogenetic protein-9 adenovirus promote osteogenesis in rodents. Author(s): Dayoub H, Dumont RJ, Li JZ, Dumont AS, Hankins GR, Kallmes DF, Helm GA. Source: Tissue Engineering. 2003 April; 9(2): 347-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740097
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Human papillomavirus E6E7-mediated adenovirus cell killing: selectivity of mutant adenovirus replication in organotypic cultures of human keratinocytes. Author(s): Balague C, Noya F, Alemany R, Chow LT, Curiel DT. Source: Journal of Virology. 2001 August; 75(16): 7602-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11462032
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Human urinary bladder carcinomas express adenovirus attachment and internalization receptors. Author(s): Loskog A, Hedlund T, Wester K, de la Torre M, Philipson L, Malmstrom PU, Totterman TH. Source: Gene Therapy. 2002 May; 9(9): 547-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11973630
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Hypopigmentation associated with an adenovirus-mediated gp100/MART-1transduced dendritic cell vaccine for metastatic melanoma. Author(s): Tsao H, Millman P, Linette GP, Hodi FS, Sober AJ, Goldberg MA, Haluska FG. Source: Archives of Dermatology. 2002 June; 138(6): 799-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12056962
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Identification of adenovirus (ad) penton base neutralizing epitopes by use of sera from patients who had received conditionally replicative ad (addl1520) for treatment of liver tumors. Author(s): Hong SS, Habib NA, Franqueville L, Jensen S, Boulanger PA. Source: Journal of Virology. 2003 October; 77(19): 10366-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970421
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Identification of contaminating adenovirus type 1 in the ATCC reference strain of respiratory syncytial virus A2 (VR-1302). Author(s): Cameron R, Buck C, Merrill D, Luttick A. Source: Virus Research. 2003 April; 92(2): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12686423
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Immune evasion by adenovirus E3 proteins: exploitation of intracellular trafficking pathways. Author(s): Windheim M, Hilgendorf A, Burgert HG. Source: Curr Top Microbiol Immunol. 2004; 273: 29-85. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674598
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In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy. Author(s): Le Gat L, Gogat K, Bouquet C, Saint-Geniez M, Darland D, Van Den Berghe L, Marchant D, Provost A, Perricaudet M, Menasche M, Abitbol M. Source: Gene Therapy. 2003 December; 10(25): 2098-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595383
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Inclusion of Moloney murine leukemia virus elements upstream of the transgene cassette in an E1-deleted adenovirus leads to an unusual genomic integration in epithelial cells. Author(s): Zheng C, O'Connell BC, Baum BJ. Source: Virology. 2003 September 1; 313(2): 460-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12954213
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Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1. Author(s): Cozar-Castellano I, Takane KK, Bottino R, Balamurugan AN, Stewart AF. Source: Diabetes. 2004 January; 53(1): 149-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14693709
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Induction of therapeutic T-cell responses to subdominant tumor-associated viral oncogene after immunization with replication-incompetent polyepitope adenovirus vaccine. Author(s): Duraiswamy J, Bharadwaj M, Tellam J, Connolly G, Cooper L, Moss D, Thomson S, Yotnda P, Khanna R. Source: Cancer Research. 2004 February 15; 64(4): 1483-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14973049
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Infectivity enhanced, cyclooxygenase-2 promoter-based conditionally replicative adenovirus for pancreatic cancer. Author(s): Yamamoto M, Davydova J, Wang M, Siegal GP, Krasnykh V, Vickers SM, Curiel DT. Source: Gastroenterology. 2003 October; 125(4): 1203-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517802
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Inhibition of adenovirus DNA synthesis in vitro by sera from patients with systemic lupus erythematosus. Author(s): Horwitz MS, Friefeld BR, Keiser HD. Source: Molecular and Cellular Biology. 1982 December; 2(12): 1492-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582191
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Inhibition of adenovirus-mediated p27kip1 gene on growth of esophageal carcinoma cell strain. Author(s): Wu QM, Yu JP, Tong Q, Wang XH, Xie GJ. Source: World Journal of Gastroenterology : Wjg. 2003 November; 9(11): 2404-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14606065
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Inhibitory effect of adenovirus-uteroglobin transduction on the growth of lung cancer cell lines. Author(s): Lee JC, Park KH, Han SJ, Yoo CG, Lee CT, Han SK, Shim YS, Kim YW. Source: Cancer Gene Therapy. 2003 April; 10(4): 287-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679801
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Insertion of an exogenous promoter in the E1A regulatory region of adenovirus does not disturb viral replication despite reduced E1A transcription. Author(s): Yu L, Hamada K, Namba M, Kadomatsu K, Muramatsu T, Matsubara S, Tagawa M. Source: Cancer Letters. 2004 January 8; 203(1): 51-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670617
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Insulation from viral transcriptional regulatory elements enables improvement to hepatoma-specific gene expression from adenovirus vectors. Author(s): Ye X, Liang M, Meng X, Ren X, Chen H, Li ZY, Ni S, Lieber A, Hu F. Source: Biochemical and Biophysical Research Communications. 2003 August 8; 307(4): 759-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878174
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Integrin alpha3beta1 is an alternative cellular receptor for adenovirus serotype 5. Author(s): Salone B, Martina Y, Piersanti S, Cundari E, Cherubini G, Franqueville L, Failla CM, Boulanger P, Saggio I. Source: Journal of Virology. 2003 December; 77(24): 13448-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645603
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Intestinal intussusception associated with adenovirus infection in Mexican children. Author(s): Guarner J, de Leon-Bojorge B, Lopez-Corella E, Ferebee-Harris T, Gooding L, Garnett CT, Shieh WJ, Dawson J, Erdman D, Zaki SR. Source: American Journal of Clinical Pathology. 2003 December; 120(6): 845-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671973
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Intratumoral expression of a fusogenic membrane glycoprotein enhances the efficacy of replicating adenovirus therapy. Author(s): Ahmed A, Jevremovic D, Suzuki K, Kottke T, Thompson J, Emery S, Harrington K, Bateman A, Vile R. Source: Gene Therapy. 2003 September; 10(19): 1663-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12923565
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Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points. Author(s): Sauthoff H, Hu J, Maca C, Goldman M, Heitner S, Yee H, Pipiya T, Rom WN, Hay JG. Source: Human Gene Therapy. 2003 March 20; 14(5): 425-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691608
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Is adenovirus a fetal pathogen? Author(s): Baschat AA, Towbin J, Bowles NE, Harman CR, Weiner CP. Source: American Journal of Obstetrics and Gynecology. 2003 September; 189(3): 758-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526309
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Isolation and expansion of human adenovirus-specific CD4+ and CD8+ T cells according to IFN-gamma secretion for adjuvant immunotherapy. Author(s): Feuchtinger T, Lang P, Hamprecht K, Schumm M, Greil J, Jahn G, Niethammer D, Einsele H. Source: Experimental Hematology. 2004 March; 32(3): 282-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003314
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IVIG treatment of adenovirus infection-associated macrophage activation syndrome in a two-year-old boy: case report and review of the literature. Author(s): Seidel MG, Kastner U, Minkov M, Gadner H. Source: Pediatric Hematology and Oncology. 2003 September; 20(6): 445-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14631618
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Killing effects of cytosine deaminase gene mediated by adenovirus vector on human pancreatic cancer cell lines in vitro. Author(s): Li ZS, Pan X, Xu GM, Cui L, Dai GR, Gong YF, Tu ZX. Source: Hepatobiliary Pancreat Dis Int. 2003 February; 2(1): 147-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607669
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Kinetics of iodide uptake and efflux in various human thyroid cancer cells by expressing sodium iodide symporter gene via a recombinant adenovirus. Author(s): Lee WW, Lee B, Kim SJ, Jin J, Moon DH, Lee H. Source: Oncol Rep. 2003 July-August; 10(4): 845-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792733
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141
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Large epidemic of adenovirus type 4 infection among military trainees: epidemiological, clinical, and laboratory studies. Author(s): Kolavic-Gray SA, Binn LN, Sanchez JL, Cersovsky SB, Polyak CS, MitchellRaymundo F, Asher LV, Vaughn DW, Feighner BH, Innis BL. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 October 1; 35(7): 808-18. Epub 2002 September 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228817
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Large epidemic of respiratory illness due to adenovirus types 7 and 3 in healthy young adults. Author(s): Ryan MA, Gray GC, Smith B, McKeehan JA, Hawksworth AW, Malasig MD. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 March 1; 34(5): 577-82. Epub 2002 January 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11803503
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Latent adenovirus infection in COPD. Author(s): Hayashi S. Source: Chest. 2002 May; 121(5 Suppl): 183S-187S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010848
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Lethal adenovirus infection in a patient who had undergone nonmyeloablative stem cell transplantation. Author(s): Ikegame K, Takimoto T, Takahashi R, Murakami M, Tamaki H, Fujioka T, Kawakami M, Hirabayashi N, Soma T, Sugiyama H, Ogawa H. Source: International Journal of Hematology. 2001 July; 74(1): 95-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11530814
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Light-induced adenovirus gene transfer, an efficient and specific gene delivery technology for cancer gene therapy. Author(s): Hogset A, Ovstebo Engesaeter B, Prasmickaite L, Berg K, Fodstad O, Maelandsmo GM. Source: Cancer Gene Therapy. 2002 April; 9(4): 365-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11960287
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Limited proteolysis of the coxsackievirus and adenovirus receptor (CAR) on HeLa cells exposed to trypsin. Author(s): Carson SD. Source: Febs Letters. 2000 November 3; 484(2): 149-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11068050
142
Adenovirus
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Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2. Author(s): Glaunsinger BA, Weiss RS, Lee SS, Javier R. Source: The Embo Journal. 2001 October 15; 20(20): 5578-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11598001
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Lipoproteins produced by ApoE-/- astrocytes infected with adenovirus expressing human ApoE. Author(s): Peng D, Song C, Reardon CA, Liao S, Getz GS. Source: Journal of Neurochemistry. 2003 September; 86(6): 1391-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950448
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Live viral vectors: construction of a replication-deficient recombinant adenovirus. Author(s): Fooks AR. Source: Methods in Molecular Medicine. 2003; 87: 37-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12958448
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Local character of readthrough activation in adenovirus type 5 early region 1 transcription control. Author(s): Shen L, Spector DJ. Source: Journal of Virology. 2003 September; 77(17): 9266-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915542
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Longitudinal follow-up of cellular and humoral immunity induced by recombinant adenovirus-mediated gene therapy in cancer patients. Author(s): Molinier-Frenkel V, Le Boulaire C, Le Gal FA, Gahery-Segard H, Tursz T, Guillet JG, Farace F. Source: Human Gene Therapy. 2000 September 1; 11(13): 1911-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10986563
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Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson's disease. Author(s): Corti O, Sanchez-Capelo A, Colin P, Hanoun N, Hamon M, Mallet J. Source: Proceedings of the National Academy of Sciences of the United States of America. 1999 October 12; 96(21): 12120-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10518586
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Long-term stable expression of human apolipoprotein A-I mediated by helperdependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Author(s): Belalcazar LM, Merched A, Carr B, Oka K, Chen KH, Pastore L, Beaudet A, Chan L. Source: Circulation. 2003 June 3; 107(21): 2726-32. Epub 2003 May 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742997
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Long-term transgene expression in proliferating cells mediated by episomally maintained high-capacity adenovirus vectors. Author(s): Kreppel F, Kochanek S. Source: Journal of Virology. 2004 January; 78(1): 9-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671083
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Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015). Author(s): Ries SJ, Brandts CH, Chung AS, Biederer CH, Hann BC, Lipner EM, McCormick F, Korn WM. Source: Nature Medicine. 2000 October; 6(10): 1128-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11017144
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Low-dose immunization with adenovirus expressing the thyroid-stimulating hormone receptor A-subunit deviates the antibody response toward that of autoantibodies in human Graves' disease. Author(s): Chen CR, Pichurin P, Chazenbalk GD, Aliesky H, Nagayama Y, McLachlan SM, Rapoport B. Source: Endocrinology. 2004 January; 145(1): 228-33. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576177
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Lower respiratory tract infections due to adenovirus in hospitalized Korean children: epidemiology, clinical features, and prognosis. Author(s): Hong JY, Lee HJ, Piedra PA, Choi EH, Park KH, Koh YY, Kim WS. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 May 15; 32(10): 1423-9. Epub 2001 April 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11317242
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Low-glutamine fed-batch cultures of 293-HEK serum-free suspension cells for adenovirus production. Author(s): Lee YY, Yap MG, Hu WS, Wong KT. Source: Biotechnology Progress. 2003 March-April; 19(2): 501-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12675594
144
Adenovirus
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Low-protein medium affects the 293SF central metabolism during growth and infection with adenovirus. Author(s): Nadeau I, Gilbert PA, Jacob D, Perrier M, Kamen A. Source: Biotechnology and Bioengineering. 2002 January 5; 77(1): 91-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11745177
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Lysosomal acid lipase deficiency: correction of lipid storage by adenovirus-mediated gene transfer in mice. Author(s): Du H, Heur M, Witte DP, Ameis D, Grabowski GA. Source: Human Gene Therapy. 2002 July 20; 13(11): 1361-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162818
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MAP kinases and NF-kappaB collaborate to induce ICAM-1 gene expression in the early phase of adenovirus infection. Author(s): Tamanini A, Rolfini R, Nicolis E, Melotti P, Cabrini G. Source: Virology. 2003 March 15; 307(2): 228-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667793
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Minimal cis-acting elements required for adenovirus genome packaging. Author(s): Ostapchuk P, Hearing P. Source: Journal of Virology. 2003 May; 77(9): 5127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692215
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Mode of transgene expression after fusion to early or late viral genes of a conditionally replicating adenovirus via an optimized internal ribosome entry site in vitro and in vivo. Author(s): Rivera AA, Wang M, Suzuki K, Uil TG, Krasnykh V, Curiel DT, Nettelbeck DM. Source: Virology. 2004 March 1; 320(1): 121-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003868
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Modified adenovirus penton base protein (UTARVE) as a non-replicating vector for delivery of antisense oligonucleotides with antiviral and/or antineoplastic activity. Author(s): Smith CC, Kulka M, Aurelian L. Source: International Journal of Oncology. 2000 October; 17(4): 841-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10995900
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Modulation of adenovirus infection in vitro by antisense oligodeoxynucleotides. Author(s): Whitehead BF, Schofield R, Rogers KM, Gustafsson K, Fabre JW. Source: Respirology (Carlton, Vic.). 2003 September; 8(3): 310-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911823
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Modulation of oncogenic transformation by the human adenovirus E1A C-terminal region. Author(s): Chinnadurai G. Source: Curr Top Microbiol Immunol. 2004; 273: 139-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674601
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Molecular anatomy of Tupaia (tree shrew) adenovirus genome; evolution of viral genes and viral phylogeny. Author(s): Bahr U, Schondorf E, Handermann M, Darai G. Source: Virus Genes. 2003 August; 27(1): 29-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913356
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Molecular basis of the inflammatory response to adenovirus vectors. Author(s): Liu Q, Muruve DA. Source: Gene Therapy. 2003 June; 10(11): 935-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756413
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Molecular monitoring of adenovirus in peripheral blood after allogeneic bone marrow transplantation permits early diagnosis of disseminated disease. Author(s): Lion T, Baumgartinger R, Watzinger F, Matthes-Martin S, Suda M, Preuner S, Futterknecht B, Lawitschka A, Peters C, Potschger U, Gadner H. Source: Blood. 2003 August 1; 102(3): 1114-20. Epub 2003 April 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702513
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Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer. Author(s): Tsunemitsu Y, Kagawa S, Tokunaga N, Otani S, Umeoka T, Roth JA, Fang B, Tanaka N, Fujiwara T. Source: Gut. 2004 April; 53(4): 554-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15016751
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Multigene expression from a replicating adenovirus using native viral promoters. Author(s): Bauzon M, Castro D, Karr M, Hawkins LK, Hermiston TW. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 April; 7(4): 526-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727116
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Multiplexed, real-time PCR for quantitative detection of human adenovirus. Author(s): Gu Z, Belzer SW, Gibson CS, Bankowski MJ, Hayden RT. Source: Journal of Clinical Microbiology. 2003 October; 41(10): 4636-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532195
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Mutations in the DG loop of adenovirus type 5 fiber knob protein abolish highaffinity binding to its cellular receptor CAR. Author(s): Kirby I, Davison E, Beavil AJ, Soh CP, Wickham TJ, Roelvink PW, Kovesdi I, Sutton BJ, Santis G. Source: Journal of Virology. 1999 November; 73(11): 9508-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10516059
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Mutations within the ADP (E3-11.6K) protein alter processing and localization of ADP and the kinetics of cell lysis of adenovirus-infected cells. Author(s): Tollefson AE, Scaria A, Ying B, Wold WS. Source: Journal of Virology. 2003 July; 77(14): 7764-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829816
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Mutual interference of adenovirus infection and myc expression. Author(s): Lohr K, Hartmann O, Schafer H, Dobbelstein M. Source: Journal of Virology. 2003 July; 77(14): 7936-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829833
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N-acetylcysteine augments adenovirus-mediated gene expression in human endothelial cells by enhancing transgene transcription and virus entry. Author(s): Jornot L, Morris MA, Petersen H, Moix I, Rochat T. Source: The Journal of Gene Medicine. 2002 January-February; 4(1): 54-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11828388
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Naturally occurring heterologous trans-splicing of adenovirus RNA with host cellular transcripts during infection. Author(s): Kikumori T, Cote GJ, Gagel RF. Source: Febs Letters. 2002 July 3; 522(1-3): 41-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12095616
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Neutralizing antibodies and CD8+ T lymphocytes both contribute to immunity to adenovirus serotype 5 vaccine vectors. Author(s): Sumida SM, Truitt DM, Kishko MG, Arthur JC, Jackson SS, Gorgone DA, Lifton MA, Koudstaal W, Pau MG, Kostense S, Havenga MJ, Goudsmit J, Letvin NL, Barouch DH. Source: Journal of Virology. 2004 March; 78(6): 2666-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990686
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Nitric oxide inhibits the adenovirus proteinase in vitro and viral infectivity in vivo. Author(s): Cao W, Baniecki ML, McGrath WJ, Bao C, Deming CB, Rade JJ, Lowenstein CJ, Mangel WF. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 December; 17(15): 2345-6. Epub 2003 October 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14525937
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No sequence variation in part of the hexon and the fibre genes of adenovirus 8 isolated from patients with conjunctivitis or epidemic keratoconjunctivitis (EKC) in Norway during 1989 to 1996. Author(s): Vainio K, Borch E, Bruu AL. Source: Journal of Clinical Pathology. 2001 July; 54(7): 558-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11429431
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Non-classical export of an adenovirus structural protein. Author(s): Trotman LC, Achermann DP, Keller S, Straub M, Greber UF. Source: Traffic (Copenhagen, Denmark). 2003 June; 4(6): 390-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12753648
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Nonneurotropic adenovirus: a vector for gene transfer to the brain and gene therapy of neurological disorders. Author(s): Lowenstein PR, Suwelack D, Hu J, Yuan X, Jimenez-Dalmaroni M, Goverdhana S, Castro MG. Source: Int Rev Neurobiol. 2003; 55: 3-64. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12968530
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Novel partner proteins of adenovirus penton. Author(s): Chroboczek J, Gout E, Favier AL, Galinier R. Source: Curr Top Microbiol Immunol. 2003; 272: 37-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12747546
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Nuclear matrix localization and SUMO-1 modification of adenovirus type 5 E1b 55K protein are controlled by E4 Orf6 protein. Author(s): Lethbridge KJ, Scott GE, Leppard KN. Source: The Journal of General Virology. 2003 February; 84(Pt 2): 259-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12560556
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Nuclear perturbations following adenovirus infection. Author(s): Russell WC, Matthews DA. Source: Curr Top Microbiol Immunol. 2003; 272: 399-413. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12747557
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Oncolysis of human gastric cancers by an E1B 55 kDa-deleted YKL-1 adenovirus. Author(s): Lee B, Choi J, Kim J, Kim JH, Joo CH, Cho YK, Kim YK, Lee H. Source: Cancer Letters. 2002 November 28; 185(2): 225-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169397
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Oncolytic activity of the E1B-55 kDa-deleted adenovirus ONYX-015 is independent of cellular p53 status in human malignant glioma xenografts. Author(s): Geoerger B, Grill J, Opolon P, Morizet J, Aubert G, Terrier-Lacombe MJ, Bressac De-Paillerets B, Barrois M, Feunteun J, Kirn DH, Vassal G. Source: Cancer Research. 2002 February 1; 62(3): 764-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11830531
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Oncolytic adenovirus: getting there is half the battle. Author(s): Ross PJ, Parks RJ. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 November; 8(5): 705-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14632023
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Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials. Author(s): Kirn D. Source: Expert Opinion on Biological Therapy. 2001 May; 1(3): 525-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11727523
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ONYX-015, an E1B gene-defective adenovirus, induces cell death in human anaplastic thyroid carcinoma cell lines. Author(s): Portella G, Scala S, Vitagliano D, Vecchio G, Fusco A. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 June; 87(6): 2525-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12050209
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ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus. Author(s): Ries S, Korn WM. Source: British Journal of Cancer. 2002 January 7; 86(1): 5-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11857003
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Osteogenesis in rats induced by a novel recombinant helper-dependent bone morphogenetic protein-9 (BMP-9) adenovirus. Author(s): Li JZ, Hankins GR, Kao C, Li H, Kammauff J, Helm GA. Source: The Journal of Gene Medicine. 2003 September; 5(9): 748-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950065
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Osteoinduction by ex vivo adenovirus-mediated BMP2 delivery is independent of cell type. Author(s): Gugala Z, Olmsted-Davis EA, Gannon FH, Lindsey RW, Davis AR. Source: Gene Therapy. 2003 August; 10(16): 1289-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883525
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Overexpression of essential splicing factor ASF/SF2 blocks the temporal shift in adenovirus pre-mRNA splicing and reduces virus progeny formation. Author(s): Molin M, Akusjarvi G. Source: Journal of Virology. 2000 October; 74(19): 9002-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10982344
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Overexpression of the ADP (E3-11.6K) protein increases cell lysis and spread of adenovirus. Author(s): Doronin K, Toth K, Kuppuswamy M, Krajcsi P, Tollefson AE, Wold WS. Source: Virology. 2003 January 20; 305(2): 378-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12573583
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Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Author(s): Freytag SO, Stricker H, Pegg J, Paielli D, Pradhan DG, Peabody J, DePeraltaVenturina M, Xia X, Brown S, Lu M, Kim JH. Source: Cancer Research. 2003 November 1; 63(21): 7497-506. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612551
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Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. Author(s): Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WK. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 July 1; 21(13): 2508-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839017
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Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. Author(s): Sangro B, Mazzolini G, Ruiz J, Herraiz M, Quiroga J, Herrero I, Benito A, Larrache J, Pueyo J, Subtil JC, Olague C, Sola J, Sadaba B, Lacasa C, Melero I, Qian C, Prieto J. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 April 15; 22(8): 1389-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084613
150
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Precursor of human adenovirus core polypeptide Mu targets the nucleolus and modulates the expression of E2 proteins. Author(s): Lee TW, Lawrence FJ, Dauksaite V, Akusjarvi G, Blair GE, Matthews DA. Source: The Journal of General Virology. 2004 January; 85(Pt 1): 185-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14718634
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Presence of prepackaged mRNA in virions of DNA adenovirus. Author(s): Chung SW, Arnott JA, Yang Y, Wong PM. Source: The Journal of Biological Chemistry. 2003 December 12; 278(50): 50635-40. Epub 2003 September 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522982
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Prevalence of rotavirus, adenovirus and astrovirus infection in young children with gastroenteritis in Gaborone, Botswana. Author(s): Basu G, Rossouw J, Sebunya TK, Gashe BA, de Beer M, Dewar JB, Steele AD. Source: East Afr Med J. 2003 December; 80(12): 652-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15018423
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Production and use of replication-deficient adenovirus for transgene expression in neurons. Author(s): Minamide LS, Shaw AE, Sarmiere PD, Wiggan O, Maloney MT, Bernstein BW, Sneider JM, Gonzalez JA, Bamburg JR. Source: Methods Cell Biol. 2003; 71: 387-416. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12884701
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Production of an EGFR targeting molecule from a conditionally replicating adenovirus impairs its oncolytic potential. Author(s): Hemminki A, Wang M, Hakkarainen T, Desmond RA, Wahlfors J, Curiel DT. Source: Cancer Gene Therapy. 2003 August; 10(8): 583-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12872139
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Prolonged and inducible transgene expression in the liver using gutless adenovirus: a potential therapy for liver cancer. Author(s): Wang L, Hernandez-Alcoceba R, Shankar V, Zabala M, Kochanek S, Sangro B, Kramer MG, Prieto J, Qian C. Source: Gastroenterology. 2004 January; 126(1): 278-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14699506
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151
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Propagation of infectious human papillomavirus type 16 by using an adenovirus and Cre/LoxP mechanism. Author(s): Lee JH, Yi SM, Anderson ME, Berger KL, Welsh MJ, Klingelhutz AJ, Ozbun MA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 February 17; 101(7): 2094-9. Epub 2004 Feb 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769917
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Quantification and characterization of the bystander effect in prostate cancer cells following adenovirus-mediated FasL expression. Author(s): Hyer ML, Sudarshan S, Schwartz DA, Hannun Y, Dong JY, Norris JS. Source: Cancer Gene Therapy. 2003 April; 10(4): 330-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679806
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Quantification of adenovirus DNA in plasma for management of infection in stem cell graft recipients. Author(s): Lankester AC, van Tol MJ, Claas EC, Vossen JM, Kroes AC. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 March 15; 34(6): 864-7. Epub 2002 February 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11850866
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Quantifying adenovirus-neutralizing antibodies by luciferase transgene detection: addressing preexisting immunity to vaccine and gene therapy vectors. Author(s): Sprangers MC, Lakhai W, Koudstaal W, Verhoeven M, Koel BF, Vogels R, Goudsmit J, Havenga MJ, Kostense S. Source: Journal of Clinical Microbiology. 2003 November; 41(11): 5046-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605137
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Quantitation of adenovirus DNA and virus particles with the PicoGreen fluorescent Dye. Author(s): Murakami P, McCaman MT. Source: Analytical Biochemistry. 1999 October 15; 274(2): 283-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10527527
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Quantitative analysis of adenovirus-specific CD4+ T-cell responses from healthy adults. Author(s): Olive M, Eisenlohr LC, Flomenberg P. Source: Viral Immunology. 2001; 14(4): 403-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11792069
152
Adenovirus
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Quantitative detection of serum adenovirus in a transplant recipient. Author(s): Teramura T, Naya M, Yoshihara T, Morimoto A, Imashuku S. Source: Lancet. 2002 June 1; 359(9321): 1945. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12057576
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Quantitative microscopy of fluorescent adenovirus entry. Author(s): Nakano MY, Greber UF. Source: Journal of Structural Biology. 2000 February; 129(1): 57-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10675297
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Questions about systemic adenovirus delivery. Author(s): Nasto B. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 June; 5(6): 652-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12027545
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Rapid and quantitative detection of human adenovirus DNA by real-time PCR. Author(s): Heim A, Ebnet C, Harste G, Pring-Akerblom P. Source: Journal of Medical Virology. 2003 June; 70(2): 228-39. Erratum In: J Med Virol. 2003 October; 71(2): 320. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12696109
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Ras-dependent oncolysis with an adenovirus VAI mutant. Author(s): Cascallo M, Capella G, Mazo A, Alemany R. Source: Cancer Research. 2003 September 1; 63(17): 5544-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14500393
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Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection. Author(s): Leruez-Ville M, Minard V, Lacaille F, Buzyn A, Abachin E, Blanche S, Freymuth F, Rouzioux C. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 January 1; 38(1): 45-52. Epub 2003 December 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679447
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Recombinant adenovirus-p53 gene transfer and cell-specific growth suppression of human cervical cancer cells in vitro and in vivo. Author(s): Ahn WS, Bae SM, Lee KH, Lee JM, Namkoong SE, Chun HJ, Kim CK, Kim YW. Source: Gynecologic Oncology. 2004 February; 92(2): 611-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766255
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153
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Reduction of natural adenovirus tropism to mouse liver by fiber-shaft exchange in combination with both CAR- and alphav integrin-binding ablation. Author(s): Koizumi N, Mizuguchi H, Sakurai F, Yamaguchi T, Watanabe Y, Hayakawa T. Source: Journal of Virology. 2003 December; 77(24): 13062-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645563
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Refractory adenovirus infection after simultaneous kidney-pancreas transplantation: successful treatment with intravenous ribavirin and pooled human intravenous immunoglobulin. Author(s): Emovon OE, Lin A, Howell DN, Afzal F, Baillie M, Rogers J, Baliga PK, Chavin K, Nickeleit V, Rajagapalan PR, Self S. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 November; 18(11): 2436-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551382
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Regulation of adenovirus alternative RNA splicing correlates with a reorganization of splicing factors in the nucleus. Author(s): Gama-Carvalho M, Condado I, Carmo-Fonseca M. Source: Experimental Cell Research. 2003 September 10; 289(1): 77-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12941606
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Replication of an E1B 55-kilodalton protein-deficient adenovirus (ONYX-015) is restored by gain-of-function rather than loss-of-function p53 mutants. Author(s): Hann B, Balmain A. Source: Journal of Virology. 2003 November; 77(21): 11588-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557644
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Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. Author(s): Vogels R, Zuijdgeest D, van Rijnsoever R, Hartkoorn E, Damen I, de Bethune MP, Kostense S, Penders G, Helmus N, Koudstaal W, Cecchini M, Wetterwald A, Sprangers M, Lemckert A, Ophorst O, Koel B, van Meerendonk M, Quax P, Panitti L, Grimbergen J, Bout A, Goudsmit J, Havenga M. Source: Journal of Virology. 2003 August; 77(15): 8263-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12857895
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Restoration of p53 tumor-suppressor activity in human tumor cells in vitro and in their xenografts in vivo by recombinant avian adenovirus CELO-p53. Author(s): Logunov DY, Ilyinskaya GV, Cherenova LV, Verhovskaya LV, Shmarov MM, Chumakov PM, Kopnin BP, Naroditsky BS. Source: Gene Therapy. 2004 January; 11(1): 79-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14681700
154
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Sequestration of p53 in the cytoplasm by adenovirus type 12 E1B 55-kilodalton oncoprotein is required for inhibition of p53-mediated apoptosis. Author(s): Zhao LY, Liao D. Source: Journal of Virology. 2003 December; 77(24): 13171-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645574
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Serological and genetic characterisation of a unique strain of adenovirus involved in an outbreak of epidemic keratoconjunctivitis. Author(s): Adhikary AK, Inada T, Banik U, Mukouyama A, Ikeda Y, Noda M, Ogino T, Suzuki E, Kaburaki T, Numaga J, Okabe N. Source: Journal of Clinical Pathology. 2004 April; 57(4): 411-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15047747
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Spacers increase the accessibility of peptide ligands linked to the carboxyl terminus of adenovirus minor capsid protein IX. Author(s): Vellinga J, Rabelink MJ, Cramer SJ, van den Wollenberg DJ, Van der Meulen H, Leppard KN, Fallaux FJ, Hoeben RC. Source: Journal of Virology. 2004 April; 78(7): 3470-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15016870
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Specific gene inhibition by adenovirus-mediated expression of small interfering RNA. Author(s): Zhao LJ, Jian H, Zhu H. Source: Gene. 2003; 316(Oct 16): 137-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14563560
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Specific oncolytic effect of a new hypoxia-inducible factor-dependent replicative adenovirus on von Hippel-Lindau-defective renal cell carcinomas. Author(s): Cuevas Y, Hernandez-Alcoceba R, Aragones J, Naranjo-Suarez S, Castellanos MC, Esteban MA, Martin-Puig S, Landazuri MO, del Peso L. Source: Cancer Research. 2003 October 15; 63(20): 6877-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583486
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Stable transduction of large DNA by high-capacity adeno-associated virus/adenovirus hybrid vectors. Author(s): Goncalves MA, van der Velde I, Knaan-Shanzer S, Valerio D, de Vries AA. Source: Virology. 2004 April 10; 321(2): 287-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051388
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Strategic attack on host cell gene expression during adenovirus infection. Author(s): Zhao H, Granberg F, Elfineh L, Pettersson U, Svensson C. Source: Journal of Virology. 2003 October; 77(20): 11006-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512549
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Structural and phylogenetic analysis of adenovirus hexons by use of high-resolution x-ray crystallographic, molecular modeling, and sequence-based methods. Author(s): Rux JJ, Kuser PR, Burnett RM. Source: Journal of Virology. 2003 September; 77(17): 9553-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915569
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Successful cidofovir treatment of adenovirus-associated hemorrhagic cystitis and renal dysfunction after allogenic bone marrow transplant. Author(s): Hatakeyama N, Suzuki N, Kudoh T, Hori T, Mizue N, Tsutsumi H. Source: The Pediatric Infectious Disease Journal. 2003 October; 22(10): 928-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579818
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Switch from capsid protein import to adenovirus assembly by cleavage of nuclear transport signals. Author(s): Wodrich H, Guan T, Cingolani G, Von Seggern D, Nemerow G, Gerace L. Source: The Embo Journal. 2003 December 1; 22(23): 6245-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633984
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Targeting of adenovirus to human renal cell carcinoma cells. Author(s): Jongmans W, van den Oudenalder K, Tiemessen DM, Molkenboer J, Willemsen R, Mulders PF, Oosterwijk E. Source: Urology. 2003 September; 62(3): 559-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12946777
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Targeting of adenovirus via genetic modification of the viral capsid combined with a protein bridge. Author(s): Korokhov N, Mikheeva G, Krendelshchikov A, Belousova N, Simonenko V, Krendelshchikova V, Pereboev A, Kotov A, Kotova O, Triozzi PL, Aldrich WA, Douglas JT, Lo KM, Banerjee PT, Gillies SD, Curiel DT, Krasnykh V. Source: Journal of Virology. 2003 December; 77(24): 12931-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645549
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Ternary complex formation between DNA-adenovirus core protein VII and TAFIbeta/SET, an acidic molecular chaperone. Author(s): Haruki H, Gyurcsik B, Okuwaki M, Nagata K. Source: Febs Letters. 2003 December 18; 555(3): 521-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675767
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The adenovirus E3-6.7K protein adopts diverse membrane topologies following posttranslational translocation. Author(s): Moise AR, Grant JR, Lippe R, Gabathuler R, Jefferies WA. Source: Journal of Virology. 2004 January; 78(1): 454-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671125
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The coxsackie-adenovirus receptor--a new receptor in the immunoglobulin family involved in cell adhesion. Author(s): Philipson L, Pettersson RF. Source: Curr Top Microbiol Immunol. 2004; 273: 87-111. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674599
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The effect of sequestration by nontarget tissues on anti-tumor efficacy of systemically applied, conditionally replicating adenovirus vectors. Author(s): Bernt KM, Ni S, Li ZY, Shayakhmetov DM, Lieber A. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 November; 8(5): 746-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599807
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Tight positive regulation of transgene expression by a single adenovirus vector containing the rtTA and tTS expression cassettes in separate genome regions. Author(s): Mizuguchi H, Xu ZL, Sakurai F, Mayumi T, Hayakawa T. Source: Human Gene Therapy. 2003 September 1; 14(13): 1265-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952598
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Transforming growth factor beta1 receptor II is downregulated by E1A in adenovirusinfected cells. Author(s): Tarakanova VL, Wold WS. Source: Journal of Virology. 2003 September; 77(17): 9324-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915548
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Tumor-suppressive activities by chemokines introduced into OV-HM cells using fiber-mutant adenovirus vectors. Author(s): Gao JQ, Alexandre LS, Tsuda Y, Katayama K, Eto Y, Sekiguchi F, Mizuguchi H, Hayakawa T, Nakayama T, Yoshie O, Tsutsumi Y, Mayumi T, Nakagawa S. Source: Pharmazie. 2004 March; 59(3): 238-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15074605
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Two distinct transport motifs in the adenovirus E3/10.4-14.5 proteins act in concert to down-modulate apoptosis receptors and the epidermal growth factor receptor. Author(s): Hilgendorf A, Lindberg J, Ruzsics Z, Honing S, Elsing A, Lofqvist M, Engelmann H, Burgert HG. Source: The Journal of Biological Chemistry. 2003 December 19; 278(51): 51872-84. Epub 2003 September 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506242
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Unusual properties of adenovirus E2E transcription by RNA polymerase III. Author(s): Huang W, Flint SJ. Source: Journal of Virology. 2003 April; 77(7): 4015-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634361
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Upregulation of the Golgi protein GP73 by adenovirus infection requires the E1A CtBP interaction domain. Author(s): Kladney RD, Tollefson AE, Wold WS, Fimmel CJ. Source: Virology. 2002 September 30; 301(2): 236-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12359426
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Use of a chimeric adenovirus vector enhances BMP2 production and bone formation. Author(s): Olmsted-Davis EA, Gugala Z, Gannon FH, Yotnda P, McAlhany RE, Lindsey RW, Davis AR. Source: Human Gene Therapy. 2002 July 20; 13(11): 1337-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162816
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Use of adenovirus proteins to enhance the transfection activity of synthetic gene delivery systems. Author(s): Carlisle RC. Source: Curr Opin Mol Ther. 2002 August; 4(4): 306-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12222868
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Use of adenovirus vectors expressing Epstein-Barr virus (EBV) immediate-early protein BZLF1 or BRLF1 to treat EBV-positive tumors. Author(s): Feng WH, Westphal E, Mauser A, Raab-Traub N, Gulley ML, Busson P, Kenney SC. Source: Journal of Virology. 2002 November; 76(21): 10951-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12368338
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Use of adenovirus vectors for functional gene analysis in the chicken chorioallantoic membrane. Author(s): Schughart K, Accart N. Source: Biotechniques. 2003 January; 34(1): 178-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12545557
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Use of multiply deleted adenovirus vectors to probe adenovirus vector performance and toxicities. Author(s): Amalfitano A. Source: Curr Opin Mol Ther. 2003 August; 5(4): 362-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14513678
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Use of polymerase chain reaction for diagnosis of disseminated adenovirus infection. Author(s): Rector A, Azzi N, Liesnard C, Zlateva K, Van Beers D, Snoeck R, Van Ranst M. Source: The Pediatric Infectious Disease Journal. 2002 December; 21(12): 1176-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12508794
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Use of recombinant adenovirus for gene transfer into the rat brain. Evaluation of gene transfer efficiency, toxicity, and inflammatory and immune reactions. Author(s): Hurtado-Lorenzo A, David A, Thomas C, Castro MG, Lowenstein PR. Source: Methods in Molecular Medicine. 2003; 76: 113-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12526161
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Use of replication-conditional adenovirus as a helper system to enhance delivery of P450 prodrug-activation genes for cancer therapy. Author(s): Jounaidi Y, Waxman DJ. Source: Cancer Research. 2004 January 1; 64(1): 292-303. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729637
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Validation of a high-performance liquid chromatographic assay for the quantification of adenovirus type 5 particles. Author(s): Transfiguracion J, Bernier A, Arcand N, Chahal P, Kamen A. Source: J Chromatogr B Biomed Sci Appl. 2001 September 25; 761(2): 187-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11587348
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Variability of adenovirus receptor density influences gene transfer efficiency and therapeutic response in head and neck cancer. Author(s): Li D, Duan L, Freimuth P, O'Malley BW Jr. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1999 December; 5(12): 4175-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10632357
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Variables affecting in vivo performance of high-capacity adenovirus vectors. Author(s): Schiedner G, Hertel S, Johnston M, Biermann V, Dries V, Kochanek S. Source: Journal of Virology. 2002 February; 76(4): 1600-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11799154
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Variation in adenovirus transgene expression between BALB/c and C57BL/6 mice is associated with differences in interleukin-12 and gamma interferon production and NK cell activation. Author(s): Peng Y, Falck-Pedersen E, Elkon KB. Source: Journal of Virology. 2001 May; 75(10): 4540-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11312324
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Vascular cell adhesion molecule-1 augments adenovirus-mediated gene transfer. Author(s): Chu Y, Heistad D, Cybulsky MI, Davidson BL. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 February; 21(2): 238-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11156859
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Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer. Author(s): Kim KN, Watanabe S, Ma Y, Thornton S, Giannini EH, Hirsch R. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 February 1; 164(3): 1576-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10640777
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Widespread distribution of adenovirus-transduced monkey amniotic epithelial cells after local intracerebral injection: implication for cell-mediated therapy for lysosome storage disorders. Author(s): Kosuga M, Takahashi S, Tanabe A, Fujino M, Li XK, Suzuki S, Yamada M, Kakishita K, Ono F, Sakuragawa N, Okuyama T. Source: Cell Transplantation. 2001; 10(4-5): 435-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11549068
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Wild-type adenovirus decreases tumor xenograft growth, but despite viral persistence complete tumor responses are rarely achieved--deletion of the viral E1b-19-kD gene increases the viral oncolytic effect. Author(s): Harrison D, Sauthoff H, Heitner S, Jagirdar J, Rom WN, Hay JG. Source: Human Gene Therapy. 2001 July 1; 12(10): 1323-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11440625
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Woodchuck hepatitis virus post-transcriptional regulation element enhances transgene expression from adenovirus vectors. Author(s): Xu ZL, Mizuguchi H, Mayumi T, Hayakawa T. Source: Biochimica Et Biophysica Acta. 2003 June 11; 1621(3): 266-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12787924
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YB-1 relocates to the nucleus in adenovirus-infected cells and facilitates viral replication by inducing E2 gene expression through the E2 late promoter. Author(s): Holm PS, Bergmann S, Jurchott K, Lage H, Brand K, Ladhoff A, Mantwill K, Curiel DT, Dobbelstein M, Dietel M, Gansbacher B, Royer HD. Source: The Journal of Biological Chemistry. 2002 March 22; 277(12): 10427-34. Epub 2002 January 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11788582
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Yeast recombinase FLP functions effectively in human cells for construction of adenovirus vectors. Author(s): Ng P, Cummings DT, Evelegh CM, Graham FL. Source: Biotechniques. 2000 September; 29(3): 524-6, 528. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10997266
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CHAPTER 2. NUTRITION AND ADENOVIRUS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and adenovirus.
Finding Nutrition Studies on Adenovirus The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “adenovirus” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “adenovirus” (or a synonym): •
A bcl-xS adenovirus selectively induces apoptosis in transformed cells compared to normal mammary cells. Author(s): Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109-0942, USA. Source: Sumantran, V N Lee, D S Woods Ignatoski, K M Ethier, S P Wicha, M S Neoplasia. 2000 May-June; 2(3): 251-60 1522-8002
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Activation of transcription factor IIIC by the adenovirus E1A protein. Author(s): Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, New York 10021. Source: Hoeffler, W K Kovelman, R Roeder, R G Cell. 1988 June 17; 53(6): 907-20 00928674
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Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism. Author(s): Departments of Cell Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. Source: Brader, K R Wolf, J K Hung, M C Yu, D Crispens, M A van Golen, K L Price, J E Clin-Cancer-Res. 1997 November; 3(11): 2017-24 1078-0432
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Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Author(s): Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri 63110. Source: Frisch, S M Reich, R Collier, I E Genrich, L T Martin, G Goldberg, G I Oncogene. 1990 January; 5(1): 75-83 0950-9232
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Adenovirus E3 14.7K protein functions in the absence of other adenovirus proteins to protect transfected cells from tumor necrosis factor cytolysis. Author(s): Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322. Source: Horton, T M Ranheim, T S Aquino, L Kusher, D I Saha, S K Ware, C F Wold, W S Gooding, L R J-Virol. 1991 May; 65(5): 2629-39 0022-538X
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Adenovirus E3-6.7K maintains calcium homeostasis and prevents apoptosis and arachidonic acid release. Author(s): Biotechnology Laboratory, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Source: Moise, Alexander R Grant, Jason R Vitalis, Timothy Z Jefferies, Wilfred A JVirol. 2002 February; 76(4): 1578-87 0022-538X
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Adenovirus endocytosis via alpha(v) integrins requires phosphoinositide-3-OH kinase. Author(s): Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. Source: Li, E Stupack, D Klemke, R Cheresh, D A Nemerow, G R J-Virol. 1998 March; 72(3): 2055-61 0022-538X
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Adenovirus late gene expression does not require a Rev-like nuclear RNA export pathway. Author(s): Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
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Source: Rabino, C Aspegren, A Corbin Lickfett, K Bridge, E J-Virol. 2000 July; 74(14): 6684-8 0022-538X •
Adenovirus type 37 uses sialic acid as a cellular receptor on Chang C cells. Author(s): Department of Virology, University of Umea, SE-901 85 Umea, Sweden.
[email protected] Source: Arnberg, Niklas Pring Akerblom, Patricia Wadell, Goran J-Virol. 2002 September; 76(17): 8834-41 0022-538X
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Adenovirus type 5 uptake by lung adenocarcinoma cells in culture correlates with Ad5 fibre binding is mediated by alpha(v)beta1 integrin and can be modulated by changes in beta1 integrin function. Author(s): Department of Respiratory Medicine & Allergy, The Guy's, King's College and St. Thomas' Hospitals School of Medicine, Guy's Hospital, London, UK. Source: Davison, E Kirby, I Whitehouse, J Hart, I Marshall, J F Santis, G J-Gene-Med. 2001 Nov-December; 3(6): 550-9 1099-498X
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Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2. Author(s): Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, 800 N. Research Pkwy., Oklahoma City, OK 73104, USA. Source: Alcorn, M J Booth, J L Coggeshall, K M Metcalf, J P J-Virol. 2001 July; 75(14): 6450-9 0022-538X
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Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16. Author(s): Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. Source: Zhou, R R Jia, S F Zhou, Z Wang, Y Bucana, C D Kleinerman, E S Cancer-GeneTher. 2002 May; 9(5): 407-13 0929-1903
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Adenovirus-mediated expression and packaging of tissue-type plasminogen activator in megakaryocytic cells. Author(s): Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Source: Chuang, J L Schleef, R R Thromb-Haemost. 2001 June; 85(6): 1079-85 0340-6245
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Analysis of antiviral resistance in the intestinal tracts of nude mice infected with a mouse adenovirus. Author(s): Department of Microbiology, School of Medicine, Tokai University. Source: Umehara, K Tazume, S Hashimoto, K Tokai-J-Exp-Clin-Med. 1987 May; 12(2): 125-34 0385-0005
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Analysis of DNA binding by the adenovirus type 5 E1A oncoprotein. Author(s): Department of Microbiology and Immunology, The University of Western Ontario, London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, Canada. Source: Avvakumov, Nikita Sahbegovic, Majdina Zhang, Zhiying Shuen, Michael Mymryk, Joe S J-Gen-Virol. 2002 March; 83(Pt 3): 517-24 0022-1317
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Butyrate-inducible and tumor-restricted gene expression by adenovirus vectors. Author(s): Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA. Source: Tang, D C Johnston, S A Carbone, D P Cancer-Gene-Ther. 1994 March; 1(1): 1520 0929-1903
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c-fos is a positive regulator of carcinogen enhancement of adenovirus transformation. Author(s): Department of Urology, Institute of Cancer Research, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. Source: Su, Z Z Yemul, S Stein, C A Fisher, P B Oncogene. 1995 May 18; 10(10): 2037-49 0950-9232
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Chemo- and immunotherapy of an adenovirus-induced transplantable sarcoma in hamsters. Source: Todorov, D K Silyanovska, K K Maneva, K M Ilarionova, M V Gantchev, G T Getov, C M Neoplasma. 1987; 34(3): 287-94 0028-2685
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Chemosensitization of HER-2/neu-overexpressing human breast cancer cells to paclitaxel (Taxol) by adenovirus type 5 E1A. Author(s): Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. Source: Ueno, N T Yu, D Hung, M C Oncogene. 1997 August 18; 15(8): 953-60 0950-9232
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Defective expression of adenovirus genes during early infection of undifferentiated OTF963 embryonal carcinoma cells. Author(s): Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra. Source: Nelson, C C Braithwaite, A W Silvestro, M Bellett, A J J-Virol. 1990 September; 64(9): 4329-37 0022-538X
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Differential regulation of JunB and JunD by adenovirus type 5 and 12 E1A proteins. Author(s): Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht. Source: de Groot, R P Meijer, I van den Brink, S Mummery, C Kruijer, W Oncogene. 1991 December; 6(12): 2357-61 0950-9232
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Distribution of viral RNA molecules during the adenovirus type 5 infectious cycle in HeLa cells. Author(s): Laboratoire de Biologie et Ultrastructure du Noyau de l'UPR272 CNRS, Villejuif, France. Source: Puvion Dutilleul, F Roussev, R Puvion, E J-Struct-Biol. 1992 May-June; 108(3): 209-20 1047-8477
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Efficient and cancer-selective gene transfer to hepatocellular carcinoma in a rat using adenovirus vector with iodized oil esters. Author(s): Department of Surgery, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
[email protected] Source: Shiba, H Okamoto, T Futagawa, Y Ohashi, T Eto, Y Cancer-Gene-Ther. 2001 October; 8(10): 713-8 0929-1903
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Efficient gene delivery into human dendritic cells by adenovirus polyethylenimine and mannose polyethylenimine transfection. Author(s): Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. Source: Diebold, S S Lehrmann, H Kursa, M Wagner, E Cotten, M Zenke, M Hum-GeneTher. 1999 March 20; 10(5): 775-86 1043-0342
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Endotoxins and prednisolone alter replication of type 5 adenovirus and its temperature sensitive mutants. Author(s): Institute of Microbiology, Semmelweis University Medical School, Budapest, Hungary. Source: Ongradi, J Bertok, L Farkas, J Nasz, I Bendinelli, M Acta-Microbiol-ImmunolHung. 1994; 41(4): 423-40 1217-8950
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Exchange of the cellular growth medium supplement from fetal bovine serum to Ultroser G increases the affinity of adenovirus for HeLa cells. Author(s): Department of Microbiology, University of Lund, Sweden. Source: Blixt, Y Arch-Virol. 1993; 129(1-4): 251-63 0304-8608
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Functional alterations in adult rat myocytes after overexpression of phospholamban with use of adenovirus. Author(s): Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London SW3 6LY, United Kingdom. Source: Davia, K Hajjar, R J Terracciano, C M Kent, N S Ranu, H K O'Gara, P Rosenzweig, A Harding, S E Physiol-Genomics. 1999 August 31; 1(2): 41-50 1094-8341
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General repression of enhanson activity by the adenovirus-2 E1A proteins. Author(s): Laboratoire de Genetique Moleculaire des Eucaryotes du Centre National de la Recherche Scientifique, Faculte de Medecine, Strasbourg, France. Source: Rochette Egly, C Fromental, C Chambon, P Genes-Devolume 1990 January; 4(1): 137-50 0890-9369
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Genes for fowl adenovirus CELO penton base and core polypeptides. Source: Akopian, T.A. Lazareva, S.E. Tikhomirov, E.E. Karpov, V.A. Naroditsky, B.S. Arch-virol. Wien, Austria : Springer-Verlag. 1996. volume 141 (2) page 357-365. 03048608
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Genetically modified adenovirus vector containing an RGD peptide in the HI loop of the fiber knob improves gene transfer to nonhuman primate isolated pancreatic islets. Author(s): Department of Medicine, University of Alabama at Birmingham 35294, USA. Source: Bilbao, G Contreras, J L Dmitriev, I Smyth, C A Jenkins, S Eckhoff, D Thomas, F Thomas, J Curiel, D T Am-J-Transplant. 2002 March; 2(3): 237-43 1600-6135
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Genomic location and nucleotide sequence of a porcine adenovirus penton base gene. Source: McCoy, R.J. Johnson, M.A. Studdert, M.J. Sheppard, M. Arch-virol. Wien, Austria : Springer-Verlag. 1996. volume 141 (7) page 1367-1375. 0304-8608
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Genomic mapping and sequence analysis of the fowl adenovirus serotype 10 hexon gene. Source: Sheppard, M. McCoy, R.J. Werner, W. J-gen-virol. Reading : Society for General Microbiology. October 1995. volume 76 (pt.10) page 2595-2600. 0022-1317
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Identification of two distinct regions within the adenovirus minimal origin of replication that are required for adenovirus type 4 DNA replication in vitro. Author(s): Department of Biochemistry and Microbiology, University of St. Andrews, Fife, Scotland. Source: Temperley, S M Burrow, C R Kelly, T J Hay, R T J-Virol. 1991 September; 65(9): 5037-44 0022-538X
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Identification, cloning and sequence analysis of the equine adenovirus 1 hexon gene. Source: Reubel, G.H. Studdert, M.J. Arch-virol. Wien, Austria : Springer-Verlag. 1997. volume 142 (6) page 1193-1212. 0304-8608
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Immune responses against replication-deficient adenovirus inhibit ovalbuminspecific allergic reactions in mice. Author(s): First Department of Internal Medicine, Yokohama City University School of Medicine, Kanazawa, Yokohama, Japan.
[email protected] Source: Suzuki, M Suzuki, S Yamamoto, N Komatsu, S Inoue, S Hashiba, T Nishikawa, M Ishigatsubo, Y Hum-Gene-Ther. 2000 April 10; 11(6): 827-38 1043-0342
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Induction of cyclo-oxygenase-2 in non-small cell lung cancer cells by infection with DeltaE1, DeltaE3 recombinant adenovirus vectors. Author(s): Division of Pulmonary and Critical Care Medicine, Lexington Veteran's Administration Medical Center, University of Kentucky, Chandler Medical Center, Lexington, KY 40536, USA. Source: Hirschowitz, E Hidalgo, G Doherty, D Gene-Ther. 2002 January; 9(1): 81-4 09697128
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Induction of polyploidy in adenovirus E1-transformed cells by the mitotic inhibitor colcemid. Author(s): Sylvius Laboratory, Department of Molecular Carcinogenesis, Leiden University, The Netherlands. Source: Kranenburg, O Van der Eb, A J Zantema, A Virus-Res. 1996 February; 40(2): 18590 0168-1702
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Interactions between the double-stranded RNA binding motif and RNA: definition of the binding site for the interferon-induced protein kinase DAI (PKR) on adenovirus VA RNA. Author(s): Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. Source: Clarke, P A Mathews, M B RNA. 1995 March; 1(1): 7-20 1355-8382
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Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Author(s): Palo Alto Veterans Administration Hospital and Stanford University Medical Center, CA, USA. Source: Reid, T Galanis, E Abbruzzese, J Sze, D Andrews, J Romel, L Hatfield, M Rubin, J Kirn, D Gene-Ther. 2001 November; 8(21): 1618-26 0969-7128
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Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Author(s): US Oncology, Dallas, TX 75246, USA. Source: Nemunaitis, J Cunningham, C Buchanan, A Blackburn, A Edelman, G Maples, P Netto, G Tong, A Randlev, B Olson, S Kirn, D Gene-Ther. 2001 May; 8(10): 746-59 09697128
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Involvement of cellular adhesion sequences in the attachment of adenovirus to the HeLa cell surface. Author(s): Laboratoire de Biochimie, Faculte de Medecine, Lille, France. Source: Belin, M T Boulanger, P J-Gen-Virol. 1993 August; 74 ( Pt 8)1485-97 0022-1317
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Involvement of topoisomerases in replication, transcription, and packaging of the linear adenovirus genome. Author(s): Department of Microbiology, Mount Sinai School of Medicine of City University of New York, New York 10029-6574. Source: Wong, M L Hsu, M T J-Virol. 1990 February; 64(2): 691-9 0022-538X
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Localization of adenovirus DNA by in situ hybridization electron microscopy. Author(s): Department of Biology, Peking University, Beijing, People's Republic of China. Source: Jiao, R Yu, W Ding, M Zhai, Z Microsc-Res-Tech. 1992 March 1; 21(1): 23-31 1059-910X
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Negative regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells via a retinoic acid response element. Author(s): Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104.
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Source: Kralli, A Ge, R Graeven, U Ricciardi, R P Weinmann, R J-Virol. 1992 December; 66(12): 6979-88 0022-538X •
Novel proteins associated with MHC class I antigens in cells expressing the adenovirus protein E3/19K. Author(s): Hans-Spemann-Laboratory, Max-Planck-Institute for Immunobiology, Freiburg, Germany. Source: Feuerbach, D Burgert, H G EMBO-J. 1993 August; 12(8): 3153-61 0261-4189
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O-linked GlcNAc in serotype-2 adenovirus fibre. Author(s): Unite de Virologie Moleculaire de l'Institut National de la Sante et de la Recherche Medicale, Lille, France. Source: Caillet Boudin, M L Strecker, G Michalski, J C Eur-J-Biochem. 1989 September 1; 184(1): 205-11 0014-2956
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Overexpression of the human vitamin D3 receptor in mammalian cells using recombinant adenovirus vectors. Author(s): Mineral Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892. Source: Smith, C L Hager, G L Pike, J W Marx, S J Mol-Endocrinol. 1991 June; 5(6): 86778 0888-8809
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Pathogenic avian adenovirus type II induces apoptosis in turkey spleen cells. Author(s): Department of Veterinary PathoBiology, University of Minnesota, St. Paul 55108, USA. Source: Rautenschlein, S Suresh, M Sharma, J M Arch-Virol. 2000; 145(8): 1671-83 03048608
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Phosphorylation of the adenovirus E1A-associated 300 kDa protein in response to retinoic acid and E1A during the differentiation of F9 cells. Author(s): Tsukuba Life Science Center, The Institute of Physical and Chemical Research Riken, Japan. Source: Kitabayashi, I Eckner, R Arany, Z Chiu, R Gachelin, G Livingston, D M Yokoyama, K K EMBO-J. 1995 July 17; 14(14): 3496-509 0261-4189
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Potentiation of gene transfer to the mouse lung by complexes of adenovirus vector and polycations improves therapeutic potential. Author(s): Genzyme Corporation, Framingham, MA 01701-9322, USA. Source: Kaplan, J M Pennington, S E St George, J A Woodworth, L A Fasbender, A Marshall, J Cheng, S H Wadsworth, S C Gregory, R J Smith, A E Hum-Gene-Ther. 1998 July 1; 9(10): 1469-79 1043-0342
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Pro-apoptotic treatment with an adenovirus encoding Bax enhances the effect of chemotherapy in ovarian cancer. Author(s): Gene Therapy Center, University of Alabama at Birmingham, 35233, USA. Source: Xiang, J Gomez Navarro, J Arafat, W Liu, B Barker, S D Alvarez, R D Siegal, G P Curiel, D T J-Gene-Med. 2000 Mar-April; 2(2): 97-106 1099-498X
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Processing of human cytomegalovirus glycoprotein B in recombinant adenovirusinfected cells. Author(s): Department of Pediatrics, University of Louisville School of Medicine, Kentucky 40292, USA. Source: Marshall, G S Fenger, D P Stout, G G Knights, M E Hunt, L A J-Gen-Virol. 1996 July; 77 ( Pt 7)1549-57 0022-1317
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Protocol of electron microscope in situ nucleic acid hybridization for the exclusive detection of double-stranded DNA sequences in cells containing large amounts of
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homologous single-stranded DNA and RNA sequences: application to adenovirus type 5 infected HeLa cells. Author(s): Laboratoire de Biologie et Ultrastructure du Noyau de l'UPR272 CNRS, Villejuif, France. Source: Puvion Dutilleul, F Microsc-Res-Tech. 1993 May 1; 25(1): 2-11 1059-910X •
Replication of adenovirus DNA in vitro is ATP-independent. Author(s): Laboratory for Physiological Chemistry, Utrecht University, The Netherlands. Source: Pronk, R Van Driel, W Van der Vliet, P C FEBS-Lett. 1994 January 3; 337(1): 33-8 0014-5793
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Sequence analysis of bovine adenovirus type 3 early region 3 and fibre protein genes. Source: Mittal, S.K. Prevec, L. Babiuk, L.A. Graham, F.L. J-Gen-Virol. Reading : Society for General Microbiology. December 1992. volume 73 (pt.12) page 3295-3300. 0022-1317
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Sequence of the avian adenovirus FAV 1 (CELO) DNA encoding the hexon-associated protein pVI and hexon. Source: Akopian, T.A. Doronin, K.K. Karpov, V.A. Naroditsky, B.S. Arch-virol. Wien, Austria : Springer-Verlag. 1996. volume 141 (9) page 1759-1765. 0304-8608
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Soluble coxsackievirus adenovirus receptor is a putative inhibitor of adenoviral gene transfer in the tumor milieu. Author(s): Department of Medicine, The University of California at Los Angeles (UCLA)/ Wadsworth Pulmonary Immunology and Gene Medicine Laboratory, Los Angeles, CA 90073, USA. Source: Bernal, R M Sharma, S Gardner, B K Douglas, J T Bergelson, J M Dubinett, S M Batra, R K Clin-Cancer-Res. 2002 June; 8(6): 1915-23 1078-0432
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Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide. Author(s): Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Source: Bouvet, M Fang, B Ekmekcioglu, S Ji, L Bucana, C D Hamada, K Grimm, E A Roth, J A Gene-Ther. 1998 February; 5(2): 189-95 0969-7128
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The adenovirus-5 12S E1a protein, but not the 13S induces expression of the endoA differentiation marker in F9 cells. Author(s): Department of Biochemistry, New York University School of Medicine, NY 10016. Source: Velcich, A Ziff, E B Oncogene. 1989 June; 4(6): 707-13 0950-9232
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The avian adenovirus penton: two fibres and one base. Source: Hess, M. Cuzange, A. Ruigrok, R.W.H. Chroboczek, J. Jacrot, B. J-mol-biol. London; New York : Academic Press, 1959-. Sept 29, 1995. volume 252 (4) page 379-385. 0022-2836
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The binding of in vitro synthesized adenovirus DNA binding protein to singlestranded DNA is stimulated by zinc ions. Author(s): Laboratory for Physiological Chemistry, State University of Utrecht, The Netherlands. Source: Vos, H L van der Lee, F M Sussenbach, J S FEBS-Lett. 1988 November 7; 239(2): 251-4 0014-5793
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The complete DNA sequence and genomic organization of the avian adenovirus CELO. Source: Chiocca, S. Kurzbauer, R. Schaffner, G. Baker, A. Mautner, V. Cotten, M. J-virol. Washington, D.C. : American Society for Microbiology. May 1996. volume 70 (5) page 2939-2949. 0022-538X
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The effect of cicloxolone sodium on the replication in cultured cells of adenovirus type 5, reovirus type 3, poliovirus type 1, two bunyaviruses and Semliki Forest virus. Author(s): MRC Virology Unit, University of Glasgow, U.K. Source: Dargan, D J Galt, C B Subak Sharpe, J H J-Gen-Virol. 1992 February; 73 ( Pt 2)407-11 0022-1317
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The effect of prostaglandins on the replication of adenovirus wild types and temperature-sensitive mutants. Author(s): Institute of Microbiology, Semmelweis University Medical School, Budapest, Hungary. Source: Ongradi, J Telekes, A Farkas, J Nasz, I Bendinelli, M Acta-Microbiol-ImmunolHung. 1994; 41(2): 173-88 1217-8950
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The fibre of bovine adenovirus type 3 is very long but bent. Source: Ruigrok, R.W.H. Barge, A. Mittal, S.K. Jacrot, B. J-gen-virol. Reading : Society for General Microbiology. August 1994. volume 75 (pt.8) page 2069-2073. 0022-1317
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The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. Author(s): Department of Medicine, University of Washington, Seattle 98195, USA. Source: Lieber, A He, C Y Meuse, L Schowalter, D Kirillova, I Winther, B Kay, M A JVirol. 1997 November; 71(11): 8798-807 0022-538X
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The role of the nuclear pore complex in adenovirus DNA entry. Author(s): University of Zurich, Department of Zoology, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Source: Greber, U F Suomalainen, M Stidwill, R P Boucke, K Ebersold, M W Helenius, A EMBO-J. 1997 October 1; 16(19): 5998-6007 0261-4189
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Topoisomerase I and II cleavage of adenovirus DNA in vivo: both topoisomerase activities appear to be required for adenovirus DNA replication. Author(s): Department of Biology, Howard Hughes Medical Institute, Princeton, New Jersey. Source: Schaack, J Schedl, P Shenk, T J-Virol. 1990 January; 64(1): 78-85 0022-538X
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Toxicity of human adenovirus E4orf4 protein in Saccharomyces cerevisiae results from interactions with the Cdc55 regulatory B subunit of PP2A. Author(s): Department of Biochemistry, McGill University, McIntyre Medical Building, Montreal, Quebec, Canada, H3G 1Y6. Source: Roopchand, D E Lee, J M Shahinian, S Paquette, D Bussey, H Branton, P E Oncogene. 2001 August 30; 20(38): 5279-90 0950-9232
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Tracing axons in the peripheral nerve using lacZ gene recombinant adenovirus and its application to regeneration of the peripheral nerve. Author(s): Department of Orthopedic Surgery, Niigata University School of Medicine, Japan. Source: Miwa, H Shibata, M Okado, H Hirano, S J-Neuropathol-Exp-Neurol. 2001 July; 60(7): 671-5 0022-3069
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Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo. Author(s): Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. Source: Gaetano, C Catalano, A Palumbo, R Illi, B Orlando, G Ventoruzzo, G Serino, F Capogrossi, M C Gene-Ther. 2000 October; 7(19): 1624-30 0969-7128
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Variation in adenovirus receptor expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle. Author(s): Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY, USA.
[email protected] Source: Seidman, M A Hogan, S M Wendland, R L Worgall, S Crystal, R G Leopold, P L Mol-Ther. 2001 July; 4(1): 13-21 1525-0016
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
Nutrition
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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CHAPTER 3. ALTERNATIVE MEDICINE AND ADENOVIRUS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to adenovirus. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to adenovirus and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “adenovirus” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to adenovirus: •
A bcl-xS adenovirus selectively induces apoptosis in transformed cells compared to normal mammary cells. Author(s): Sumantran VN, Lee DS, Woods Ignatoski KM, Ethier SP, Wicha MS. Source: Neoplasia (New York, N.Y.). 2000 May-June; 2(3): 251-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10935511
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A prodrug strategy using ONYX-015-based replicating adenoviruses to deliver rabbit carboxylesterase to tumor cells for conversion of CPT-11 to SN-38. Author(s): Stubdal H, Perin N, Lemmon M, Holman P, Bauzon M, Potter PM, Danks MK, Fattaey A, Dubensky T, Johnson L. Source: Cancer Research. 2003 October 15; 63(20): 6900-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583489
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A simple and efficient method for purification of infectious recombinant adenovirus. Author(s): Kanegae Y, Makimura M, Saito I.
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Source: Jpn J Med Sci Biol. 1994 June; 47(3): 157-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7823411 •
A virus-directed enzyme prodrug therapy approach to purging neuroblastoma cells from hematopoietic cells using adenovirus encoding rabbit carboxylesterase and CPT-11. Author(s): Meck MM, Wierdl M, Wagner LM, Burger RA, Guichard SM, Krull EJ, Harris LC, Potter PM, Danks MK. Source: Cancer Research. 2001 July 1; 61(13): 5083-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11431345
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Additive effect of adenovirus-mediated E2F-1 gene transfer and topoisomerase II inhibitors on apoptosis in human osteosarcoma cells. Author(s): Yang HL, Dong YB, Elliott MJ, Wong SL, McMasters KM. Source: Cancer Gene Therapy. 2001 April; 8(4): 241-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11393276
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Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism. Author(s): Brader KR, Wolf JK, Hung MC, Yu D, Crispens MA, van Golen KL, Price JE. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1997 November; 3(11): 2017-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9815592
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Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism. Author(s): Frisch SM, Dolter KE. Source: Cancer Research. 1995 December 1; 55(23): 5551-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7585633
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Adenovirus E3 protein causes constitutively internalized epidermal growth factor receptors to accumulate in a prelysosomal compartment, resulting in enhanced degradation. Author(s): Hoffman P, Carlin C. Source: Molecular and Cellular Biology. 1994 June; 14(6): 3695-706. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8196613
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Adenovirus infection enhances killing of melanoma cells by a mitotoxin. Author(s): Satyamoorthy K, Soballe PW, Soans F, Herlyn M. Source: Cancer Research. 1997 May 15; 57(10): 1873-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9157978
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Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2. Author(s): Alcorn MJ, Booth JL, Coggeshall KM, Metcalf JP. Source: Journal of Virology. 2001 July; 75(14): 6450-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11413312
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Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16. Author(s): Zhou RR, Jia SF, Zhou Z, Wang Y, Bucana CD, Kleinerman ES. Source: Cancer Gene Therapy. 2002 May; 9(5): 407-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11961663
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Adenovirus-mediated delivery of p16 to p16-deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel. Author(s): Grim J, D'Amico A, Frizelle S, Zhou J, Kratzke RA, Curiel DT. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1997 December; 3(12 Pt 1): 2415-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9815642
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Adenovirus-mediated E2F-1 gene transfer sensitizes melanoma cells to apoptosis induced by topoisomerase II inhibitors. Author(s): Dong YB, Yang HL, Elliott MJ, McMasters KM. Source: Cancer Research. 2002 March 15; 62(6): 1776-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11912154
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Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo. Author(s): Chester JD, Kennedy W, Hall GD, Selby PJ, Knowles MA. Source: Gene Therapy. 2003 January; 10(2): 172-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12571646
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Adenovirus-mediated human topoisomerase IIalpha gene transfer increases the sensitivity of etoposide-resistant human breast cancer cells. Author(s): Zhou Z, Zwelling LA, Kawakami Y, An T, Kobayashi K, Herzog C, Kleinerman ES. Source: Cancer Research. 1999 September 15; 59(18): 4618-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10493516
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Adenovirus-mediated inhibition of NF-kappaB confers chemo-sensitization and apoptosis in prostate cancer cells. Author(s): Flynn V Jr, Ramanitharan A, Moparty K, Davis R, Sikka S, Agrawal KC, Abdel-Mageed AB.
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Source: International Journal of Oncology. 2003 August; 23(2): 317-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851680 •
Adenovirus-mediated p16 gene transfer changes the sensitivity to taxanes and Vinca alkaloids of human ovarian cancer cells. Author(s): Kawakami Y, Hama S, Hiura M, Nogawa T, Chiba T, Yokoyama T, Takashima S, Tajiri H, Eguchi K, Nagai N, Shigemasa K, Ohama K, Kurisu K, Heike Y. Source: Anticancer Res. 2001 July-August; 21(4A): 2537-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724319
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Adenovirus-mediated p16 transfer to glioma cells induces G1 arrest and protects from paclitaxel and topotecan: implications for therapy. Author(s): Fueyo J, Gomez-Manzano C, Puduvalli VK, Martin-Duque P, Perez-Soler R, Levin VA, Yung WK, Kyritsis AP. Source: International Journal of Oncology. 1998 March; 12(3): 665-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9472109
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Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck, ovarian, prostate, and breast cancer. Author(s): Nielsen LL, Lipari P, Dell J, Gurnani M, Hajian G. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1998 April; 4(4): 835-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9563876
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Adenovirus-mediated p53 gene therapy: overview of preclinical studies and potential clinical applications. Author(s): Horowitz J. Source: Curr Opin Mol Ther. 1999 August; 1(4): 500-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11713766
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Adenovirus-mediated p53 gene transduction inhibits telomerase activity independent of its effects on cell cycle arrest and apoptosis in human pancreatic cancer cells. Author(s): Kusumoto M, Ogawa T, Mizumoto K, Ueno H, Niiyama H, Sato N, Nakamura M, Tanaka M. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1999 August; 5(8): 2140-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10473098
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Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. Author(s): Schuler M, Herrmann R, De Greve JL, Stewart AK, Gatzemeier U, Stewart DJ, Laufman L, Gralla R, Kuball J, Buhl R, Heussel CP, Kommoss F, Perruchoud AP, Shepherd FA, Fritz MA, Horowitz JA, Huber C, Rochlitz C.
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Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 March 15; 19(6): 1750-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11251006 •
Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells. Author(s): Osaki S, Nakanishi Y, Takayama K, Pei XH, Ueno H, Hara N. Source: Cancer Gene Therapy. 2000 February; 7(2): 300-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10770640
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Antibody assay for adenoviruses and mycoplasma pneumoniae by the platelet aggregation test. Author(s): Patscheke H, Breinl M, Schafer E. Source: Z Immunitatsforsch Immunobiol. 1976; 151(4): 341-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=820101
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Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Author(s): Yu DC, Chen Y, Dilley J, Li Y, Embry M, Zhang H, Nguyen N, Amin P, Oh J, Henderson DR. Source: Cancer Research. 2001 January 15; 61(2): 517-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11212244
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Apical localization of the coxsackie-adenovirus receptor by glycosylphosphatidylinositol modification is sufficient for adenovirus-mediated gene transfer through the apical surface of human airway epithelia. Author(s): Walters RW, van't Hof W, Yi SM, Schroth MK, Zabner J, Crystal RG, Welsh MJ. Source: Journal of Virology. 2001 August; 75(16): 7703-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11462042
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Association of p130CAS with phosphatidylinositol-3-OH kinase mediates adenovirus cell entry. Author(s): Li E, Stupack DG, Brown SL, Klemke R, Schlaepfer DD, Nemerow GR. Source: The Journal of Biological Chemistry. 2000 May 12; 275(19): 14729-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10799562
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ATP requirement for release of adenovirus mRNA from isolated nuclei. Author(s): Raskas HJ, Rho YC. Source: Nat New Biol. 1973 September 12; 245(141): 47-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4354009
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Camptothecin: mechanism of inhibition of adenovirus formation. Author(s): Horwitz MS, Brayton C. Source: Virology. 1972 June; 48(3): 690-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5031506
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Cancer gene therapy using a survivin mutant adenovirus. Author(s): Mesri M, Wall NR, Li J, Kim RW, Altieri DC. Source: The Journal of Clinical Investigation. 2001 October; 108(7): 981-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11581299
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Cellular and adenovirus dl312 DNA metabolism in cycling or mitotic human cultures exposed to supralethal gamma radiation. Author(s): Ross PM. Source: The Journal of Cell Biology. 1989 November; 109(5): 1993-2002. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2808517
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c-fos is a positive regulator of carcinogen enhancement of adenovirus transformation. Author(s): Su ZZ, Yemul S, Stein CA, Fisher PB. Source: Oncogene. 1995 May 18; 10(10): 2037-49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7761104
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Characterization of the pH 4.0 endonuclease from adenovirus-type-2-infected KB cells. Author(s): Reif U, Winterhoff U, Doerfler W. Source: European Journal of Biochemistry / Febs. 1977 March 1; 73(2): 327-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14826
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Chemosensitization of HER-2/neu-overexpressing human breast cancer cells to paclitaxel (Taxol) by adenovirus type 5 E1A. Author(s): Ueno NT, Yu D, Hung MC. Source: Oncogene. 1997 August 18; 15(8): 953-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9285690
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Chemotherapeutic response of tumor derived from human adenovirus 12--induced retinal tumor cell line in syngeneic CDF (F 344) rats. Author(s): Kobayashi M, Mukai N, Solish SP, Sawada T, Pomeroy ME. Source: Anticancer Res. 1983 March-April; 3(2): 101-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6847128
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Chromosomal damage induced by human adenovirus type 12 requires expression of the E1B 55-kilodalton viral protein. Author(s): Schramayr S, Caporossi D, Mak I, Jelinek T, Bacchetti S.
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Source: Journal of Virology. 1990 May; 64(5): 2090-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2325204 •
Combination effect of adenovirus-mediated pro-apoptotic bax gene transfer with cisplatin or paclitaxel treatment in ovarian cancer cell lines. Author(s): Tsuruta Y, Mandai M, Konishi I, Kuroda H, Kusakari T, Yura Y, Hamid AA, Tamura I, Kariya M, Fujii S. Source: European Journal of Cancer (Oxford, England : 1990). 2001 March; 37(4): 531-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11267864
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Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models. Author(s): Nielsen LL, Shi B, Hajian G, Yaremko B, Lipari P, Ferrari E, Gurnani M, Malkowski M, Chen J, Bishop WR, Liu M. Source: Cancer Research. 1999 December 1; 59(23): 5896-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10606231
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Cytotoxicity of gelonin conjugated to targeting molecules: effects of weak amines, monensin, adenovirus, and adenoviral capsid proteins penton, hexon, and fiber. Author(s): Goldmacher VS, Blattler WA, Lambert JM, McIntyre G, Stewart J. Source: Molecular Pharmacology. 1989 November; 36(5): 818-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2531272
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Differences in sequence content of nuclear and cytoplasmic polyribosomal RNA from adenovirus-infected cells. Author(s): Chatterjee NK, Tuchowski C, Eagan GE, Haley TM. Source: The Biochemical Journal. 1984 March 1; 218(2): 583-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6324758
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Early events in the interaction of adenoviruses with HeLa cells. IV. Association with microtubules and the nuclear pore complex during vectorial movement of the inoculum. Author(s): Dales S, Chardonnet Y. Source: Virology. 1973 December; 56(2): 465-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4271287
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Effects of adriamycin and etoposide on the replication of adenovirus 5 in sensitive and resistant human tumour cells. Author(s): Parsons PG, Lean J, Khoo SK, Lark J. Source: Biochemical Pharmacology. 1989 January 1; 38(1): 31-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2910307
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Efficient induction of apoptosis by ONYX-015 adenovirus in human colon cancer cell lines regardless of p53 status. Author(s): Petit T, Davidson KK, Cerna C, Lawrence RA, Von Hoff DD, Heise C, Kirn D, Izbicka E. Source: Anti-Cancer Drugs. 2002 January; 13(1): 47-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11914640
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Electron microscopy of adenovirus cores. Author(s): Nermut MV, Harpst JA, Russell WC. Source: The Journal of General Virology. 1975 July; 28(1): 49-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=808587
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Enhanced etoposide sensitivity following adenovirus-mediated human topoisomerase IIalpha gene transfer is independent of topoisomerase IIbeta. Author(s): Zhou Z, Zwelling LA, Ganapathi R, Kleinerman ES. Source: British Journal of Cancer. 2001 September 1; 85(5): 747-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531262
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Entry of adenovirus 2 into HeLa cells. Author(s): Svensson U, Persson R. Source: Journal of Virology. 1984 September; 51(3): 687-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6471167
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Enzyme-activated Prodrug Therapy Enhances Tumor-specific Replication of Adenovirus Vectors. Author(s): Bernt KM, Steinwaerder DS, Ni S, Li ZY, Roffler SR, Lieber A. Source: Cancer Research. 2002 November 1; 62(21): 6089-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414633
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Evaluation of E1B gene-attenuated replicating adenoviruses for cancer gene therapy. Author(s): Kim J, Cho JY, Kim JH, Jung KC, Yun CO. Source: Cancer Gene Therapy. 2002 September; 9(9): 725-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189522
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Generation of a new adenovirus type 12-inducible fragile site by insertion of an artificial U2 locus in the human genome. Author(s): Li YP, Tomanin R, Smiley JR, Bacchetti S. Source: Molecular and Cellular Biology. 1993 October; 13(10): 6064-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8413208
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Genetic background determines the response to adenovirus-mediated wild-type p53 expression in pancreatic tumor cells.
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Author(s): Cascallo M, Mercade E, Capella G, Lluis F, Fillat C, Gomez-Foix AM, Mazo A. Source: Cancer Gene Therapy. 1999 September-October; 6(5): 428-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10505853 •
Identification of human uroplakin II promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. Author(s): Zhang J, Ramesh N, Chen Y, Li Y, Dilley J, Working P, Yu DC. Source: Cancer Research. 2002 July 1; 62(13): 3743-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12097284
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Induction of cyclo-oxygenase-2 in non-small cell lung cancer cells by infection with DeltaE1, DeltaE3 recombinant adenovirus vectors. Author(s): Hirschowitz E, Hidalgo G, Doherty D. Source: Gene Therapy. 2002 January; 9(1): 81-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11850726
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Induction of polyploidy in adenovirus E1-transformed cells by the mitotic inhibitor colcemid. Author(s): Kranenburg O, Van der Eb AJ, Zantema A. Source: Virus Research. 1996 February; 40(2): 185-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8725114
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Inhibition of adenovirus infection and adenain by green tea catechins. Author(s): Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S. Source: Antiviral Research. 2003 April; 58(2): 167-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742577
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Interaction between the octamer-binding protein nuclear factor III and the adenovirus origin of DNA replication. Author(s): Pruijn GJ, van Miltenburg RT, Claessens JA, van der Vliet PC. Source: Journal of Virology. 1988 September; 62(9): 3092-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2841465
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Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Author(s): Sawadogo M, Roeder RG. Source: Cell. 1985 November; 43(1): 165-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4075392
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Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer.
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Author(s): Kieback DG, Fischer DC, Engehausen DG, Sauerbrei W, Oehler MK, Tong XW, Aguilar-Cordova E. Source: Cancer Gene Therapy. 2002 May; 9(5): 478-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11961671 •
Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Author(s): Nemunaitis J, Cunningham C, Buchanan A, Blackburn A, Edelman G, Maples P, Netto G, Tong A, Randlev B, Olson S, Kirn D. Source: Gene Therapy. 2001 May; 8(10): 746-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11420638
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Involvement of microtubules in cytopathic effects of animal viruses: early proteins of adenovirus and herpesvirus inhibit formation of microtubular paracrystals in HeLaS3 cells. Author(s): Ebina T, Satake M, Ishida N. Source: The Journal of General Virology. 1978 March; 38(3): 535-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=204735
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Involvement of topoisomerases in replication, transcription, and packaging of the linear adenovirus genome. Author(s): Wong ML, Hsu MT. Source: Journal of Virology. 1990 February; 64(2): 691-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2153235
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Isolated-organ perfusion for local gene delivery: efficient adenovirus-mediated gene transfer into the liver. Author(s): de Roos WK, Fallaux FJ, Marinelli AW, Lazaris-Karatzas A, von Geusau AB, van der Eb MM, Cramer SJ, Terpstra OT, Hoeben RC. Source: Gene Therapy. 1997 January; 4(1): 55-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9068796
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Localization of adenovirus DNA by in situ hybridization electron microscopy. Author(s): Jiao R, Yu W, Ding M, Zhai Z. Source: Microscopy Research and Technique. 1992 March 1; 21(1): 23-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1591411
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Microtubule-dependent plus- and minus end-directed motilities are competing processes for nuclear targeting of adenovirus. Author(s): Suomalainen M, Nakano MY, Keller S, Boucke K, Stidwill RP, Greber UF. Source: The Journal of Cell Biology. 1999 February 22; 144(4): 657-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10037788
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Molecular biological characterization of adenovirus DNA. Author(s): Berencsi G, Nasz I. Source: Acta Microbiol Immunol Hung. 1998; 45(3-4): 297-304. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9873935
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Multiple proteins bind to VA RNA genes of adenovirus type 2. Author(s): Van Dyke MW, Roeder RG. Source: Molecular and Cellular Biology. 1987 March; 7(3): 1021-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3561405
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Oncolysis of human gastric cancers by an E1B 55 kDa-deleted YKL-1 adenovirus. Author(s): Lee B, Choi J, Kim J, Kim JH, Joo CH, Cho YK, Kim YK, Lee H. Source: Cancer Letters. 2002 November 28; 185(2): 225-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169397
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ONYX-015, an E1B gene-defective adenovirus, induces cell death in human anaplastic thyroid carcinoma cell lines. Author(s): Portella G, Scala S, Vitagliano D, Vecchio G, Fusco A. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 June; 87(6): 2525-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12050209
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P21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients. Author(s): Boulay JL, Perruchoud AP, Reuter J, Bolliger C, Herrmann R, Rochlitz C. Source: Cancer Gene Therapy. 2000 September; 7(9): 1215-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11023193
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Phenotype correction in murine mucopolysaccharidosis type VII by transplantation of human amniotic epithelial cells after adenovirus-mediated gene transfer. Author(s): Kosuga M, Takahashi S, Sasaki K, Enosawa S, Li XK, Okuyama S, Fujino M, Suzuki S, Yamada M, Matsuo N, Sakuragawa N, Okuyama T. Source: Cell Transplantation. 2000 September-October; 9(5): 687-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11144966
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Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients. Author(s): Nemunaitis J, Cunningham C, Tong AW, Post L, Netto G, Paulson AS, Rich D, Blackburn A, Sands B, Gibson B, Randlev B, Freeman S. Source: Cancer Gene Therapy. 2003 May; 10(5): 341-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12719704
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Polyribosomes of cells abortively or productively infected with adenovirus, papovavirus, or their hybrid. Author(s): Rapp F, Guentzel MJ. Source: Arch Gesamte Virusforsch. 1969; 28(3): 255-68. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4318616
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Pro-apoptotic treatment with an adenovirus encoding Bax enhances the effect of chemotherapy in ovarian cancer. Author(s): Xiang J, Gomez-Navarro J, Arafat W, Liu B, Barker SD, Alvarez RD, Siegal GP, Curiel DT. Source: The Journal of Gene Medicine. 2000 March-April; 2(2): 97-106. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10809143
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Processing of human cytomegalovirus glycoprotein B in recombinant adenovirusinfected cells. Author(s): Marshall GS, Fenger DP, Stout GG, Knights ME, Hunt LA. Source: The Journal of General Virology. 1996 July; 77 ( Pt 7): 1549-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8757998
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Purification and partial characterization of a 33 000 molecular weight endonuclease associated with human adenovirus type 5. Author(s): Tsang LW, Marusyk RG. Source: Canadian Journal of Microbiology. 1980 October; 26(10): 1224-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6257357
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Relationship between adenovirus-mediated aquaporin 1 expression and fluid movement across epithelial cells. Author(s): Delporte C, Hoque AT, Kulakusky JA, Braddon VR, Goldsmith CM, Wellner RB, Baum BJ. Source: Biochemical and Biophysical Research Communications. 1998 May 29; 246(3): 584-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9618254
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Reversal of CPT-11 resistance of lung cancer cells by adenovirus-mediated gene transfer of the human carboxylesterase cDNA. Author(s): Kojima A, Hackett NR, Crystal RG. Source: Cancer Research. 1998 October 1; 58(19): 4368-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9766666
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Studies of hamster cells transformed by adenovirus 2 and the nondefective Ad2-SV40 hybrids. Author(s): Lewis AM Jr, Breeden JH, Wewerka YL, Schnipper LE, Levine AS.
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Source: Cold Spring Harb Symp Quant Biol. 1975; 39 Pt 1: 651-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=169097 •
Studies on inhibition of viral oncogenesis. 3. Effect of clam extracts and methotrexate on tumor formation in male and female hamsters induced by virulent and attenuated adenovirus-12. Author(s): Li CP, Tauraso NM, Eddy B, Prescott B, Martino EC. Source: Arch Gesamte Virusforsch. 1972; 36(3): 284-95. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5020679
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Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide. Author(s): Bouvet M, Fang B, Ekmekcioglu S, Ji L, Bucana CD, Hamada K, Grimm EA, Roth JA. Source: Gene Therapy. 1998 February; 5(2): 189-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9578838
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Synergistic inhibition of human lung cancer cell growth by adenovirus-mediated wild-type p53 gene transfer in combination with docetaxel and radiation therapeutics in vitro and in vivo. Author(s): Nishizaki M, Meyn RE, Levy LB, Atkinson EN, White RA, Roth JA, Ji L. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2001 September; 7(9): 2887-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11555607
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Temperature-sensitive mutants of human adenovirus type 12. Author(s): Hama S, Kimura G. Source: Jpn J Microbiol. 1972 July; 16(4): 337-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4631614
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The effect of infection with adenovirus 2 on the transcription of cellular RNA. Author(s): Dinowitz M, Green M. Source: Virology. 1972 December; 50(3): 619-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4629686
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The endoplasmic reticulum retention signal of the E3/19K protein of adenovirus-2 is microtubule binding. Author(s): Dahllof B, Wallin M, Kvist S. Source: The Journal of Biological Chemistry. 1991 January 25; 266(3): 1804-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1671043
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The survival of adenovirus in multidose bottles of topical fluorescein. Author(s): Kowalski RP, Romanowski EG, Waikhom B, Gordon YJ.
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Source: American Journal of Ophthalmology. 1998 December; 126(6): 835-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9860013 •
The use of laser scanning cytometry to assess depth of penetration of adenovirus p53 gene therapy in human xenograft biopsies. Author(s): Grace MJ, Xie L, Musco ML, Cui S, Gurnani M, DiGiacomo R, Chang A, Indelicato S, Syed J, Johnson R, Nielsen LL. Source: American Journal of Pathology. 1999 December; 155(6): 1869-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10595917
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There are two different species B adenovirus receptors: sBAR, common to species B1 and B2 adenoviruses, and sB2AR, exclusively used by species B2 adenoviruses. Author(s): Segerman A, Arnberg N, Erikson A, Lindman K, Wadell G. Source: Journal of Virology. 2003 January; 77(2): 1157-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502832
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Topoisomerase I and II cleavage of adenovirus DNA in vivo: both topoisomerase activities appear to be required for adenovirus DNA replication. Author(s): Schaack J, Schedl P, Shenk T. Source: Journal of Virology. 1990 January; 64(1): 78-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2152835
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Transcription of adenovirus and HeLa cell genes in the presence of drugs that inhibit topoisomerase I and II function. Author(s): Schaak J, Schedl P, Shenk T. Source: Nucleic Acids Research. 1990 March 25; 18(6): 1499-508. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2158079
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Tyrosine kinase-dependent release of an adenovirus preterminal protein complex from the nuclear matrix. Author(s): Angeletti PC, Engler JA. Source: Journal of Virology. 1996 May; 70(5): 3060-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8627784
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Variation in adenovirus receptor expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle. Author(s): Seidman MA, Hogan SM, Wendland RL, Worgall S, Crystal RG, Leopold PL. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2001 July; 4(1): 13-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11472101
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to adenovirus; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Herbs and Supplements Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON ADENOVIRUS Overview In this chapter, we will give you a bibliography on recent dissertations relating to adenovirus. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “adenovirus” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on adenovirus, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Adenovirus ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to adenovirus. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
Adenovirus infections in relation to tumor induction and the immune response by MacKay, John Sinclair; ADVDEG from University of Toronto (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK08798
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Biological and molecular studies of a low oncogenic mutant of human adenovirus type 12 by Ezoe, Hisanori; PhD from McMaster University (Canada), 1976 http://wwwlib.umi.com/dissertations/fullcit/NK29585
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CD46 (membrane cofactor protein) is a receptor for the rigid fiber proteins of adenoviruses associated with severe ocular infections by Wu, Eugene Y.; PhD from The Scripps Research Institute, 2003, 239 pages http://wwwlib.umi.com/dissertations/fullcit/3111400
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Cellular D N A metabolism after infection by adenovirus type 12 by Pater, Mary M; PhD from McMaster University (Canada), 1976 http://wwwlib.umi.com/dissertations/fullcit/NK29705
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Characterization and mapping of a DNA degradation function (CYT) in adenovirus by Lai Fatt, Richard Bernardo; PhD from McMaster University (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK65407
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Characterization of human adenovirus type 5 early region 1 protein using antipeptide antibodies by Yee, Siu-Pok; PhD from McMaster University (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL30553
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Characterization of the transforming proteins of adenovirus type 5 synthesized in infected human cells and transformed hamster cells by Rowe, David Thomas; PhD from McMaster University (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK65456
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Comparison of membrane and nuclear T antigen, a tumor antigen specified by the adenovirus 2-Simian virus hybrid, Ad2#1Bp+#1BsD2 by Ismail, Alnashir A; PhD from Mcgill University (Canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL20838
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Construction and characterization of insertion and deletion mutations in the transforming genes of human adenovirus type 5 by McKinnon, Randy D; PhD from McMaster University (Canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65477
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Development and characterization of a human adenovirus type 5 cloning vector by Haj-Ahmad, Yousef; PhD from McMaster University (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL30569
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Immunological and biochemical studies on inclusions produced in canine adenovirus infected cells by Shahrabadi, Mahmood Shamsi; PhD from University of Alberta (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK11168
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Isolation and characterization of novel insertional mutants in the early region 1A of adenovirus type 5 by Bautista, Diosdado S; PhD from McMaster University (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL57933
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Molecular characterization of early region 4 of porcine adenovirus type 3 by Li, Xiaoxin; PhD from The University of Saskatchewan (Canada), 2003, 142 pages http://wwwlib.umi.com/dissertations/fullcit/NQ83555
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Molecular fate of adenovirus type 5 DNA in eukaryotic cells by Ruben de Campione, Martha M; PhD from McMaster University (Canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65422
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Physical studies of the organization and transcription of the genome of human adenovirus type 12 by Smiley, James Richard; PhD from McMaster University (Canada), 1977 http://wwwlib.umi.com/dissertations/fullcit/NK36561
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Radiation enhanced reactivation of irradiated human adenovirus type 2 in human cells by Jeeves, William Patrick; PhD from McMaster University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK52247
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Regulation of human adenovirus proteinase activity by its cofactors: A structure function analysis by Baniecki, Mary Lynn; PhD from State University of New York at Stony Brook, 2003, 149 pages http://wwwlib.umi.com/dissertations/fullcit/3098809
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Regulation of inflammatory and fibrotic mediators by adenovirus E1A in guinea pig lung cells by Behzad, Ali Reza; PhD from The University of British Columbia (Canada), 2003, 206 pages http://wwwlib.umi.com/dissertations/fullcit/NQ85424
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Regulation of the adenovirus E3 transcription unit in human T cells by Mahr, Jeffrey Andrew; PhD from Emory University, 2003, 200 pages http://wwwlib.umi.com/dissertations/fullcit/3080339
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Sequences in adenovirus 5 E1A gene that are required for transcriptional activation, enhancer repression, and oncogenic transformation by Jelsma, Anthony Norman; PhD from McMaster University (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL50277
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Structure-function studies of adenovirus type 5 fiber protein and its receptor CAR: Implications for adenovirus cell entry mechanism and gene delivery by Chen, Xinhua; PhD from University of Southern California, 2003, 69 pages http://wwwlib.umi.com/dissertations/fullcit/3103873
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Studies on some early polypeptides encoded by adenovirus type 5 by Downey, James Frederick; PhD from McMaster University (Canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65464
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Studies on the replication and biochemical analysis of an oncogenic avian adenovirus CELO virus by Okubo, Case K; ADVDEG from University of Guelph (Canada), 1969 http://wwwlib.umi.com/dissertations/fullcit/NK06560
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Studies on the replication of adenovirus-2 DNA by Raptis, Leda Helen; PhD from Universite De Sherbrooke (Canada), 1979 http://wwwlib.umi.com/dissertations/fullcit/NK43312
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Studies on tumor antigens of adenovirus type 5 by Lassam, Norman John Errington; PhD from McMaster University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK52260
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Terminal stages of the cytoplasmic trafficking of adenovirus by Bailey, Christopher James; PhD from Cornell University Medical College, 2003, 173 pages http://wwwlib.umi.com/dissertations/fullcit/3099960
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The interaction of the adenovirus E1B-55K protein with a histone deacetylase complex: Its importance in regulation ofp53 protein functions by Punga, Tanel; PhD from Uppsala Universitet (Sweden), 2004, 62 pages http://wwwlib.umi.com/dissertations/fullcit/f2433
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The nature of the DNA associates with incomplete particles of adenovirus type 2 by Khittoo, Govindranathsing; PhD from Universite De Sherbrooke (Canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK47273
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UV enhanced mutagenesis of adenovirus in human fibroblasts by Bennett, Craig; PhD from McMaster University (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL30556
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON ADENOVIRUS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “adenovirus” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on adenovirus, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Adenovirus By performing a patent search focusing on adenovirus, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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Adenovirus
example of the type of information that you can expect to obtain from a patent search on adenovirus: •
Adenoviral vector with a deletion in the E1A coding region expressing a hetorologous protein Inventor(s): Ballay; Annick (Orgeval, FR), Levredo; Massimo (Roma, FR), Perricaudet; Michel (Paris, FR), Tiollais; Pierre (Paris, FR) Assignee(s): Centre National DE LA Recherche Scientifique (paris, Fr), Institut National DE LA Sante ET DE LA Recherche Medicale (paris, Fr), Institut Pasteur (paris, Fr) Patent Number: 6,696,420 Date filed: July 20, 1993 Abstract: Recombinant DNA modified by a nucleotide sequence coding for a specific polypeptide sequence whose expression is sought, this recombinant DNA being appropriate to the transformation of eucaryotic cell lines, notably human or animal, the endogenous polymerases of which are susceptible of recognizing the adenovirus promoters. The DNA according to the invention is more particularly characterized by the fact that the said insertion nucleotide sequence is placed under the direct control of the early promoter of the E1A region of the genome of adenovirus. Excerpt(s): The invention concerns a recombinant DNA including a nucleotide sequence coding for a specific polypeptide under the control of an adenovirus promoter, the vectors containing this recombinant DNA, the eucaryotic cells transformed by this recombinant DNA, the excretion products of these transformed cells and their applications, notably to the constitution of vaccines. The genetic organization of type 2 or 5 human adenovirus (Ad2, Ad5) is sufficiently well known that their genome may be manipulated in vitro and its use as a vector for the expression of a foreign gene in an animal cell in culture has already been envisaged. Indeed it is known that the E3 region, which represents 6% of the genome, is not essential in vitro and may therefore be substituted in its entirety. The size of the foreign DNA fragment which it is possible to insert into the genome of these viruses, is large. In fact, the virus may encapsulate a genome whose length exceeds by 5% that of the wild genome. Different vectors derived from adenoviruses of type 2 or 5 have therefore been constructed. In these recombinants, the foreign gene was expressed under the control of the major late promoter. This has permitted the obtaining in certain cases of a synthesis of the protein coded by a foreign gene at a level comparable to that of the late viral proteins. This being the case, it results from the preceding that the expression of the foreign gene under the control of the late promoter can only manifest itself in the late phase of the viral cycle. Web site: http://www.delphion.com/details?pn=US06696420__
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Adenoviral vectors with tandem fiber proteins Inventor(s): Falck-Pedersen; Erik S. (Dobbs Ferry, NY) Assignee(s): Cornell Research Foundation, Inc. (ithaca, Ny) Patent Number: 6,599,737 Date filed: October 30, 2000
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Abstract: The present invention provides an adenoviral gene transfer vector comprising a first fiber gene and a second fiber gene, wherein the fiber genes are different. The present invention also provides related recombinant adenoviral gene transfer vectors and methods of propagating an adenovirus with a fiber protein that does not bind to a native adenoviral fiber receptor. Excerpt(s): The present invention relates to adenoviral gene transfer vectors, as well as methods of making and using the same. The 49 serotypes of human adenovirus are divided into six serogroups, A-F. All human adenoviruses have a capsid that contains 12 fiber proteins and other capsid proteins, such as penton base protein and hexon protein. The 12 fiber proteins extend from the surface of the capsid protein and bind with a native receptor that is expressed on the surface of cells that adenoviruses efficiently infect. This initial binding step is usually followed by a second virus-host cell interaction in which the penton base protein binds to an integrin. The binding of penton base protein to the cell is necessary for integrin mediated endocytosis of the virus. However, it is the binding characteristics of the fiber protein that are normally dominant (e.g., in non-recombinant adenoviruses) in selecting which cell types are infected by an adenovirus. Of the 49 different serotypes of human adenoviruses, the subgroup F viruses (Ad40 and Ad41) are unique. They are the only serotypes that contain two distinct fiber genes (one short and one long) in the major late transcription unit. Both of these fiber genes are expressed and form homotrimers in equimolar ratios on the surface of group F adenoviruses. However, group F viruses are extremely fastidious (i.e., have complex requirements for viral propagation), and, in general, do not grow well in cell types normally used to grow adenoviruses, such as A549 cells, HeLa cells, and HEK-293 cells. For these and other reasons, it has not been desirable to use group F adenoviruses to make adenoviral vectors that comprise and direct the expression (in target cells) of heterologous genes (i.e., as gene transfer vectors). Web site: http://www.delphion.com/details?pn=US06599737__ •
Adenovirus E1B-55K single amino acid mutants and methods of use Inventor(s): Hermiston; Terry (Corte Madera, CA), Nye; Julie (Berkeley, CA), Shen; Yuqiao (Richmond, CA) Assignee(s): Onyx Pharmaceuticals, Inc. (richmond, Ca) Patent Number: 6,635,244 Date filed: July 30, 2001 Abstract: Adenoviral mutants are described that have single amino acid mutations in the E1B-55K protein which mutations effect the p53 binding/inactivation and the late functions of the E1B-55K protein in a manner that enhances the efficacy of such viruses for treating cancer when compared to adenoviral mutants that have the E1B-55K region deleted. Excerpt(s): The invention is in the field of cancer therapy and provides compositions of recombinant cytopathic adenoviruses that express mutant E1B-55K protein, and methods of using such adenoviruses for treating neoplastic disease. From the early part of this century, viruses have been used to treat cancer. The approach has been two-fold; first, to isolate or generate oncolytic viruses that selectively replicate in and kill neoplastic cells, while sparing normal cells. Investigators initially used wild type viruses, and this approach met with some, albeit, limited success. While oncolysis and slowing of tumor growth occurred with little or no damage to normal tissue, there was
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no significant alteration in the course of the disease. See, Smith et al., Cancer 9: 12111218 (1956), Cassel, W. A. et al., Cancer 18: 863-868 (1965), Webb, H. E. et al., Lancet 1: 1206-1209 (1966). See, also, Kenney, S and Pagano, J. J. Natl. Cancer Inst., vol. 86, no. 16, p.1185 (1994). More recently, and because of the reoccurrence of disease associated with the limited efficacy of the use of wild type viruses, investigators have resorted to using recombinant viruses that can be delivered at high doses, and that are replication competent in neoplastic but not normal cells. Such viruses are effective oncolytic agents in their own right, and further, can be engineered to carry and express a transgene that enhances the anti neoplastic activity of the virus. An example of this class of viruses is an adenovirus that is mutant in the E1B region of the viral genome. See, U.S. Pat. No. 5,677,178, and Bischoff, J. R., D. H. Kirn, A. Williams, C. Heise, S. Horn, M. Muna, L. Ng, J. A. Nye, A. Sampson-Johannes, A. Fattaey, and F. McCormick. 1996, Science. 274:373-6. Web site: http://www.delphion.com/details?pn=US06635244__ •
Adenovirus E4 proteins for inducing cell death Inventor(s): Branton; Philip E. (Lambert, CA), Lavoie; Josee N. (Montreal, CA), Marcelius; Richard C. (Montreal, CA), Shore; Gordon C. (Montreal, CA), Teodoro; Jose G. (Worchester, MA) Assignee(s): Mcgill University (montreal, Ca) Patent Number: 6,730,662 Date filed: June 7, 1999 Abstract: The invention features E4orf4-encoding nucleic acids, pharmaceutical compositions and expression vectors containing the same, and methods for their use. E4orf4-encoding nucleic acids include (i) nucleic acids capable of hybridizing at high stringency to the complement of the nucleic acid encoding Ad2E4orf4, and (ii) nucleic acids having 50% or greater nucleotide sequence identity to the nucleotide sequence of Ad2E4orf4, so long as the nucleic acids encode a polypeptide capable of inducing apoptosis. Excerpt(s): The invention relates to a pharmaceutical agent(s) to induce cell death for use in treating conditions which involve inappropriate cell survival. Replication of human adenoviruses in terminally differentiated epithelial cells requires an efficient mechanism to induce cellular DNA synthesis. This induction permits replication of viral DNA and production of progeny virus. Human adenoviruses infect and kill epithelial cells very efficiently. Cell death occurs by apoptosis and virus spread occurs through endocytosis by surrounding cells. Considerable evidence indicates that a major function of E1B proteins in lytic infection and cell transformation is to suppress cytotoxic effects and apoptosis induced by expression of E1A. Without E1B, the toxicity of E1A products results in the death of E1A-transformed cells and a reduction in the yield of progeny due to the early demise of productively infected cells. E1A proteins can cause apoptosis by a process mediated by the tumor suppressor p53, which controls growth arrest and programmed cell death pathways (Teodoro, J. G. et al., 1995, Oncogene 11: 467-474). Expression of E1A products results in the elevation of p53 levels. The 55 kDa E1B protein binds to p53 and blocks both p53-mediated activation of gene expression and apoptosis (Teodoro, J. G. et al., 1994, J. Virol. 68: 776-786). The 19 kDa E1B protein appears to suppress apoptosis by a mechanism that is functionally analogous to that of the cellular proto-oncogene product Bcl-2 (Nguyen, M. et al., 1994, J. Biol. Chem. 269: 16521-16524). Cells infected with adenovirus mutants which fail to express the 19 kDa protein display enhanced cytotoxicity and extensive degradation of both cellular and
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viral DNA into nucleosome sized fragments (McLorie, W. et al., supra; Teodoro, J. G. et al., 1995, Oncogene 11: 467-474). At later times, even in the presence of E1B proteins, infected cells suffer apoptotic death and viral progeny spread to neighboring cells through endocytosis of cell fragments. In addition to the induction of DNA synthesis and cell transformation, the large 289-residue (289R) E1A protein also transactivates expression of all early viral genes, including early regions 1A, 1B, 2, 3 and 4 (reviewed in Teodoro, J. G. et al., 1995, Oncogene 11: 467-474). Web site: http://www.delphion.com/details?pn=US06730662__ •
Adenovirus vectors generated from helper viruses and helper-dependent vectors Inventor(s): Chen; Liane (Hamilton, CA), Graham; Frank L. (Hamilton, CA), Parks; Robin (Hamilton, CA) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,566,128 Date filed: November 15, 1999 Abstract: The present invention provides an improved helper-dependent vector system for production of high capacity adenoviral cloning vectors. The invention makes use of the DNA size packaging constraints imposed on a pIX-defective Ad virion that prevent such virions from packaging DNA larger than approximately 35 kb. This constraint can be used to develop helper viruses that do not package their DNA. In one embodiment, the invention combines this methodology with the Cre-loxP helper-dependent system to decrease the quantity of contaminating helper virus in vector preparations. In another embodiment the invention is used for vector growth. Excerpt(s): The present invention relates to the construction of adenovirus vectors that have increased safety and stability for gene transfer in mammalian cells. The vector system described herein is an improvement and modification of the helper-dependent system, described in copending patent application Ser. No. 08/473,168. Adenoviruses (Ads) are a family of DNA viruses characterized by icosahedral, non-enveloped capsids containing a linear DNA genome. The human adenovirus type 5 (Ad5) has a linear, double-stranded genome of approximately 36 kb, divided into early and late viral functions (see Berkner 1992, Curr. Topics Micro. Immunol. 158:39-66). A representative Adenovirus 5 ("Ad5") genome for use with the embodiments of the present invention is a 36 kB linear duplex. Its sequence has been published. (Chroboczek, J., Bieber, F., and Jacrot, B. (1992) The Sequence of the Genome of Adenovirus Type 5 and Its Comparison with the Genome of Adenovirus Type 2, Virology 186, 280-285; hereby incorporated by reference). Web site: http://www.delphion.com/details?pn=US06566128__
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Adenovirus vectors specific for cells expressing alpha-fetoprotein and methods of use thereof Inventor(s): Henderson; Daniel R. (Palo Alto, CA), Lamparski; Henry (San Mateo, CA), Little; Andrew S. (Los Altos, CA), Schuur; Eric R. (Palo Alto, CA) Assignee(s): Cell Genesys, Inc. (foster City, Ca) Patent Number: 6,585,968 Date filed: July 2, 2001 Abstract: Adenovirus vectors replication specific for cells expressing.alpha.-fetoprotein (AFP) and their methods of use are provided. By providing for a transcriptional initiating regulation dependent upon AFP expression, virus replication is restricted to target cells expressing AFP, particularly hepatocellular carcinoma cells. The adenovirus vectors can be used to detect and monitor samples for the presence of AFP-producing cells as well as to kill selectively malignant cells producing AFP. Excerpt(s): This invention relates to cell transfection using adenoviral vectors. More specifically, it relates to cell-specific replication of adenovirus vectors in cells expressing alpha-fetoprotein, particularly hepatoma cells. In spite of extensive medical research and numerous advances, cancer remains the second leading cause of death in the United States. Hepatocellular carcinoma (HCC or malignant hepatoma) is one of the most common cancers in the world, and is especially problematic in Asia. Treatment prospects for patients with hepatocellular carcinoma are dim. Even with improvements in therapy and availability of liver transplant, only a minority of patients are cured by removal of the tumor either by resection or transplantation. For the majority of patients, the current treatments remain unsatisfactory, and the prognosis is poor. Web site: http://www.delphion.com/details?pn=US06585968__
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Adenovirus-mediated gene therapy Inventor(s): Loimas; Sami (Kuopio, FI), Sandmair; Anu-Maaria (Kuopio, FI), Vapalahti; Matti (Kuopio, FI), Yla-Herttuala; Seppo (Kuopio, FI) Assignee(s): Ark Therapeutics, Ltd. (gb) Patent Number: 6,579,855 Date filed: June 25, 2001 Abstract: An adenovirus having a functional thymidine kinase gene is useful in the treatment of brain tumors. Excerpt(s): This invention relates to the treatment of brain tumours using gene therapy. The treatment of malignant glioma continues to challenge physicians and scientists. Thymidine kinase gene therapy, using the Herpes Simplex virus thymidine kinase (HSVtk) gene, is one of the most promising treatment modalities, in attempts to change the survival of malignant glioma patients. HSVtk gene therapy is based on the ability of thymidine kinase to catalyze the phosphorylation of ganciclovir (GCV). Phosphorylated GCV acts as a toxic nucleotide analogue, leading to the death of the target cells. This phenomenon is further enhanced by a bystander effect, where neighbouring cells are also destroyed even without transfection. This effect is thought to be due to the release of toxic nucleotide analogues from the transfected cells to neighbouring cells via gap junctions. Retroviruses and adenoviruses have been used as vectors for gene therapy. Both vectors have certain advantages and limitations. Brain tumours are especially
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suitable for retrovirus-mediated gene transfer, since retroviruses can only infect proliferating cells while normal, non-dividing brain tissue remains intact. The gene transfer efficiency of retroviruses is relatively low, but could be improved by using retrovirus packaging cells instead of isolated viruses. The transduction time can theoretically be prolonged and the number of transfected cells increased. With retroviruses, the transfected gene incorporates into the genome of the target cell and therefore long-term gene expression can be achieved. Web site: http://www.delphion.com/details?pn=US06579855__ •
Adenovirus-mediated intratumoral delivery of an angiogenesis antagonist for the treatment of tumors Inventor(s): Griscelli; Frank (Paris, FR), Legrand; Yves (Paris, FR), Li; Hong (Epinay sur Seine, FR), Lu; He (Epinay sur Seine, FR), Mabilat; Christelle (Corbeil Essonnes, FR), Opolon; Paule (Paris, FR), Perricaudet; Michel (Ecrosnes, FR), Ragot; Thierry (Meudon, FR), Soria; Claudine (Taverny, FR), Soria; Jeannette (Taverny, FR), Yeh; Patrice (Gif sur Yvette, FR) Assignee(s): Gencell Sas (vitry Sur Seine, Fr) Patent Number: 6,638,502 Date filed: June 29, 2000 Abstract: The present invention relates to gene therapy for the treatment of tumors. The invention more particularly relates to introduction of a gene encoding an antiangiogenic factor into cells of a tumor, for example with a defective adenovirus vector, to inhibit growth or metastasis, or both, of the tumor. In a specific embodiment, delivery of a defective adenovirus that expresses the amino terminal fragment of urokinase (ATF) inhibited growth and metastasis of tumors. These effects were correlated with a remarkable inhibition of neovascularization within, and at the immediate vicinity of, the injection site. Delivery of a defective adenovirus vector that expresses kringles 1 to 3 of angiostatin inhibited tumor growth and tumorigenicity, and induced apoptosis of tumor cells. The invention further provides viral vectors for use in the methods of the invention. Excerpt(s): The present invention relates to gene therapy for the treatment of tumors. The invention more particularly relates to introduction of a gene encoding an antiangiogenic factor into cells of a tumor, for example with an adenovirus vector, to inhibit growth or metastasis, or both, of the tumor. Cell migration is a coordinated process that bridges cellular activation and adhesion whereas the equilibrium between pericellular proteolysis and its inhibition (e.g., triggered by plasminogen activator inhibitors and tissue inhibitors of metalloproteinases) is disrupted (1-3). Urokinase plasminogen activator (uPA) is a pivotal player in this process because it initiates a proteolytic cascade at the surface of migrating cells by binding to its cell surface receptor (uPAR) (4, 5). Binding of uPA to its receptor greatly potentiates plasminogen/plasmin conversion at the cell surface (6). Plasmin is a broadly specific serine protease which can directly degrade components of the extracellular matrix such as fibronectin, vitronectin or laminin. Plasmin also indirectly promotes a localized degradation of the stroma by converting inactive zymogens into active metalloproteinases (7). The selective distribution of uPAR at the leading edge of migrating cells (invadopodes) apparently concentrates uPA secreted by themselves or by neighboring stroma cells (8). uPAR is also directly involved in cellular adhesion to the extracellular matrix as illustrated by its uPA-dependent binding to vitronectin (9), and because uPAR modulates the binding
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properties of several integrin molecules (10). Finally, uPA and plasmin are somehow involved in cell morphogenesis by activating or inducing the release of morphogenic factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factors (FGFs) and transforming growth factor.beta. (TGF.beta.) (11, 12). Taken together, these observations indicate that the uPA/uPAR system controls cell migration by coordinating cellular activation, adhesion and motility. This statement is supported by clinical observations that correlate the presence of enhanced uPA activity at the invasive edge of the tumors (13, 14). That melanoma induced by DMBA and croton oil do not progress to a malignant stage in uPA-deficient mice also support a role of uPA in tumor establishment and progression (15). Web site: http://www.delphion.com/details?pn=US06638502__ •
Cell-specific adenovirus vectors comprising an internal ribosome entry site Inventor(s): Henderson; Daniel R. (Palo Alto, CA), Li; Yuanhao (Palo Alto, CA), Little; Andrew S. (Santa Ana, CA), Yu; De-Chao (Foster City, CA) Assignee(s): Cell Genesys, Inc. (south San Francisco, Ca) Patent Number: 6,692,736 Date filed: March 21, 2001 Abstract: Disclosed herein are replication-competent adenovirus vectors comprising cotranscribed first and second genes under transcriptional control of a heterologous, target cell-specific transcriptional regulatory element (TRE), wherein the second gene is under translational control of an internal ribosome entry site. Methods for the preparation and use of such vectors are also provided. The vectors provide target cell-specific virus replication in applications such as cancer therapy and gene therapy. Excerpt(s): This invention relates to new replication competent adenovirus vectors comprising an internal ribosome entry site which replicate preferentially in target cells. The present invention also relates to cell transduction using adenovirus vectors comprising an internal ribosome entry site. Diseases involving altered cell proliferation, particularly hyperproliferation, constitute an important health problem. For example, despite numerous advances in medical research, cancer remains the second leading cause of death in the United States. In the industrialized nations, roughly one in five persons will die of cancer. Traditional modes of clinical care, such as surgical resection, radiotherapy and chemotherapy, have a significant failure rate, especially for solid tumors. Neoplasia resulting in benign tumors can usually be completely cured by surgical removal of the tumor mass. If a tumor becomes malignant, as manifested by invasion of surrounding tissue, it becomes much more difficult to eradicate. Once a malignant tumor metastasizes, it is much less likely to be eradicated. Excluding basal cell carcinoma, there are over one million new cases of cancer per year in the United States alone, and cancer accounts for over one half million deaths per year in this country. In the world as a whole, the five most common cancers are those of lung, stomach, breast, colon/rectum, and uterine cervix, and the total number of new cases per year is over 6 million. Web site: http://www.delphion.com/details?pn=US06692736__
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Chimeric adenovirus fiber protein Inventor(s): Bruder; Joseph T. (New Market, MD), Falck-Pedersen; Erik (Dobbs Ferry, NY), Gall; Jason (New York, NY), Kovesdi; Imre (Rockville, MD), Roelvink; Petrus W. (Gaithersburg, MD), Wickham; Thomas J. (Bethesda, MD) Assignee(s): Cornell Research Foundation, Inc. (ithaca, Ny), Genvec, Inc. (gaithersburg, Md) Patent Number: 6,576,456 Date filed: June 4, 1999 Abstract: The invention provides a chimeric adenovirus fiber protein including a nonnative amino acid sequence, and a chimeric adenovirus fiber protein lacking a native amino acid receptor-binding sequence. The chimeric protein trimerizes when produced in a mammalian cell. Excerpt(s): The present invention relates to a recombinant adenovirus comprising a chimeric adenoviral fiber protein and the use of a recombinant adenovirus comprising a chimeric adenoviral fiber protein in gene therapy. Adenoviruses belong to the family Adenoviridae, which is divided into two genera, namely Mastadenovirus and Aviadenovirus. Adenoviruses are nonenveloped, regular icosahedrons 65-80 nm in diameter (Home et al., J. Mol. Biol., 1, 84-86 (1959)). The capsid is composed of 252 capsomeres of which 240 are hexons and 12 are pentons (Ginsberg et al., Virology, 28, 782-783 (1966)). The hexons and pentons are derived from three different viral polypeptides (Maizel et al., Virology, 36, 115-125 (1968); Weber et al, Virology, 76, 709724 (1977)). The hexon comprises three identical polypeptides of 967 amino acids each, namely polypeptide II (Roberts et al., Science, 232, 1148-1151 (1986)). The penton contains a penton base, which is bound to the capsid, and a fiber, which is noncovalently bound to and projects from the penton base. The fiber protein comprises three identical polypeptides of 582 amino acids each, namely polypeptide IV. The adenovirus serotype 2 (Ad2) penton base protein is an 8.times.9 nm ring-shaped complex composed of five identical protein subunits of 571 amino acids each, namely polypeptide III (Boudin et al., Virology, 92, 125-138 (1979)). Proteins IX, VI, and IIIa are also present in the adenoviral coat and are thought to stabilize the viral capsid (Stewart et al., Cell, 67, 145-154 (1991); Stewart et al., EMBO J., 12(7), 2589-2599 (1993)). Once an adenovirus attaches to a cell, it undergoes receptor-mediated internalization into clathrin-coated endocytic vesicles of the cell (Svensson et al., J. Virol., 51, 687-694 (1984); Chardonnet et al., Virology, 40, 462-477 (1970)). Virions entering the cell undergo a stepwise disassembly in which many of the viral structural proteins are shed (Greber et al, Cell, 75, 477-486 (1993)). During the uncoating process, the viral particles cause disruption of the cell endosome by a pH-dependent mechanism (Fitzgerald et al., Cell, 32, 607-617 (1983)), which is still poorly understood. The viral particles are then transported to the nuclear pore complex of the cell (Dales et al., Virology, 56, 465-483 (1973)), where the viral genome enters the nucleus, thus initiating infection. Web site: http://www.delphion.com/details?pn=US06576456__
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Controlling immune response to specific antigens Inventor(s): Curiel; David T. (Birmingham, AL), Mountz; John D. (Birmingham, AL), Zhang; Huang-Ge (Birmingham, AL) Assignee(s): Uab Research Foundation (birmingham, Al) Patent Number: 6,689,605 Date filed: January 2, 2000 Abstract: One major problem with adenovirus gene therapy has been the T-cell mediated immune response elicited by inoculation of adenovirus, which leads to rapid clearance of the virus and loss of transgene expression. In the instant invention, the immune response to a virus is prevented by pre-treatment with adenovirus, adenoassociated virus or herpes virus infected antigen-presenting cell (APC) expressing Fas ligand with induced T-cell tolerance. Administration of AdCMVLacZ after tolerance resulted in prolonged expression of LacZ in tolerized animals compared to control treated animals. In control, but not tolerized animals, there was proliferation of CD3.sup.+ T-cell in the spleen in response to AdCMVLacZ treatment. Tolerance induction is also indicated by decreased production of interferon-.gamma. and IL-2 by peripheral T-cells isolated from treated animals after stimulation with the adenovirus infected APCs. T-cell tolerance is specific for the virus as the T-cell responses to an irrelative virus, mouse cytomegalovirus (MCMV) remained unimpaired. The instant invention utilizes virus specific T-cell tolerance, which is induced by APCs that coexpress Fas ligand and virus antigens. The instant invention involves novel vectors and methods to induce tolerance to a viral vector gene therapy and prolong expression of a transgene in a viral host. Excerpt(s): This invention relates generally to gene therapy. More specifically, the invention relates to suppressing immune system response to antigens expressed on an infected host cell. The proper function of the immune system of an organism is to attack and neutralize materials which are perceived as being foreign to that organism. T-cells are one component of the immune system. T-cells can become activated to specific antigens, and function to directly destroy materials which display that antigen, and they also function to sensitize other components of the immune system to the presence of that antigen. While a properly functioning immune system is vital to the health of an organism, in some instances there is a need for the selective inhibition of an immune response to particular materials. For example, viral vectors, such as adenovirus, are employed in genetic therapies to introduce genetic material and products into an organism. One problem encountered with the use of such viral vectors is that they can provoke an immune response in the organism. This immune response can destroy the viral vector, and those host cells which are intentionally infected by the vector, as well as therapeutic gene products produced by the action of the vector. Furthermore, immune system "memory" provides a lasting response to this vector; hence, readministration of the material will be ineffective. Therefore, there is a need for a method whereby the immune response to a selected viral vector may be blocked or destroyed. Suppression of immune response is also desirable in the instances of autoimmune disease. As is known, such disease results when the immune system of an organism inappropriately recognizes an organ or tissue of that organism as being foreign, and commences an immune response against it. If this immune response can be blocked, the autoimmune disease can be controlled. Immune suppression is also needed in those instances where organs are transplanted. Immune system suppressing drugs are sometimes employed in the foregoing situations; however, such drugs produce a generalized suppression of the immune system, which leaves a patient open to a number of infections. It would
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therefore be advantageous if immune response to a specific antigen could be suppressed and/or an immune suppressed zone of tissue created within an organism. Web site: http://www.delphion.com/details?pn=US06689605__ •
Defective adenoviruses including a therapeutic gene and an immunoprotectove gene Inventor(s): Lee; Martin (Paris, FR), Perricaudet; Michel (Ecrosnes, FR) Assignee(s): Aventis Pharma S.a. (antony Cedex, Fr) Patent Number: 6,669,942 Date filed: April 15, 1997 Abstract: Novel adenovirus-derived viral vectors, the preparation thereof, and the use of such vectors in gene therapy, are disclosed. In particular, defective adenoviruses having a genome that includes a first recombinant DNA containing a therapeutic gene and a second recombinant DNA containing an immunoprotective gene, are disclosed. Excerpt(s): The present invention relates to new viral vectors, to their preparation and to their use in gene therapy. It also relates to pharmaceutical compositions containing the said viral vectors. More especially, the present invention relates to recombinant adenoviruses as vectors for gene therapy. Gene therapy consists in correcting a deficiency or an abnormality (mutation, aberrant expression, and the like) by introducing genetic information into the cell or organ affected. This genetic information may be introduced either in vitro into a cell extracted from the organ, the modified cell then being reintroduced into the body, or directly in vivo into the appropriate tissue. In this second case, different techniques exist, including various techniques of transfection involving complexes of DNA and DEAE-dextran (Pagano et al., J.Virol. 1 (1967) 891), of DNA and nuclear proteins (Kaneda et al., Science 243 (1989) 375) and of DNA and lipids (Felgner et al., PNAS 84 (1987) 7413), the use of liposomes (Fraley et al., J.Biol.Chem. 255 (1980) 10431), and the like. More recently, the use of viruses as vectors for gene transfer has been seen to be a promising alternative to these physical transfection techniques. In this connection, different viruses have been tested for their capacity to infect certain cell populations. This applies especially to retroviruses (RSV, HMS, MMS, and the like), the HSV virus, adeno-associated viruses and adenoviruses. In view of the properties of adenoviruses, mentioned above, the latter have already been used for in vivo gene transfer. To this end, different vectors derived from adenoviruses have been prepared, incorporating different genes (.beta.-gal, OTC,.alpha.-1AT, cytokines, and the like). In each of these constructions the adenovirus has been modified so as to render it incapable of replication in the infected cell. Thus, the constructions described in the prior art are adenoviruses from which the E1 (E1a and/or E1b) and, where appropriate, E3 regions have been deleted, in which regions a heterologous DNA sequence is inserted(Levrero et al., Gene 101 (1991) 195; Gosh-Choudhury et al., Gene 50 (1986) 161). Web site: http://www.delphion.com/details?pn=US06669942__
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Efficient generation of adenovirus-based libraries by positive selection of adenoviral recombinants through ectopic expression of the adenovirus protease Inventor(s): Elahi; Seyyed Mehdy (Montreal, CA), Massie; Bernard (Laval, CA), Oualikene; Wahiba (Montrouge, FR) Assignee(s): National Research Council of Canada (ottawa, Ca) Patent Number: 6,642,052 Date filed: April 30, 2001 Abstract: Disclosed is a new system for generating recombinant adenovirus vectors and adenovirus-based expression libraries, by positive selection of recombinants deleted for the endogenous protease gene, which gene is expressibly cloned into another region of the adenoviral genome. In a preferred embodiment, the invention allows positive selection of E1-deleted, protease-deleted recombinant adenovirus vectors comprising an exogenous gene or an expressible piece of exogenous DNA, by providing an expression cassette comprising the protease gene and the exogenous DNA inserted in place of E1 region in a shuttle vector. In vivo recombination of the shuttle vector with a proteasedeleted adenoviral genome in suitable non-complementing cells generates viable recombinants only when rescuing the protease cloned in E1 region. Non-recombinant viral genomes are not able to grow due to the deletion of the protease gene, ensuring that only recombinant viral plaques are generated. This positive selection can be used for the generation of a large number of high purity recombinant adenovirus vectors and allows generation of adenovirus-based libraries with diversity exceeding 10.sup.6 clones. Excerpt(s): The present invention relates to a method of generation of adenovirus recombinant vectors and adenovirus-based expression libraries, in particular to a method of generation of adenovirus recombinant vectors and adenovirus-based expression libraries by positive selection of adenovirus recombinant vectors through ectopic expression of the adenovirus protease. The term "gene therapy" is usually understood to mean the process in which a gene is introduced into the somatic cells of an individual with the aim of being expressed in the cells, to produce some therapeutic effect. Initially this principle was applied to cases where an additional normal copy of a defective gene was provided to restore the synthesis of a missing protein, such as an enzyme. The concept of gene therapy has since been broadened to include several other approaches. In particular, the transferred gene (transgene) may code for a protein that is not necessarily missing but that may be of therapeutic benefit and difficult to administer exogenously, for example IL-2 or antitumor cytokines. This form of gene therapy aims to enhance in vivo production of potentially therapeutic proteins. This approach is similar to gene vaccination, where the transferred gene is introduced into the cells to express a protein acting as an antigen inducing a protective immune response of the host's immune system. Another form of gene therapy involves transferring into cells nonphysiological sequences which have antiviral activity, such as antisense oligonucleotides or sequences. Finally, so-called suicide genes can be transferred into undesirable cells (cancer cells or infected cells), to sensitize them to specific substances. When these substances are administered subsequently, they trigger selective destruction of the targeted cells. Gene delivery systems which transfer the desired gene into the target cells are based either on physico-chemical or on biological methods. In each case the desired gene can be transferred into cells either in vitro, by extracting cells from an organ and reintroducing the cells transfected in vitro into the same organ or organism, or in vivo, i.e., directly into an appropriate tissue. Known physico-chemical methods of transfection include, for example, gene gun (biolistics), in situ naked DNA injections, complexes of
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DNA with DEAE-dextran or with nucleic proteins, liposomal DNA preparations, etc. Biological methods, considered to be a more reliable alternative to physico-chemical methods, rely on infectious agents as gene transfer vectors. In this group of methods, viruses have become infectious agents of choice, due to their inherent capability of infecting various cells. The transfer of a foreign gene by a viral vector is known as transduction of the gene. Web site: http://www.delphion.com/details?pn=US06642052__ •
Enhanced first generation adenovirus vaccines expressing codon optimized HIV1gag, pol, nef and modifications Inventor(s): Bett; Andrew J. (Landsdale, PA), Casimiro; Danilo R. (Harleysville, PA), Chen; Ling (Blue Bell, PA), Emini; Emilio A. (Wayne, PA), Kaslow; David C. (Bryn Mawr, PA), Shiver; John W. (Doylestown, PA), Toner; Timothy J. (Marlton, NJ), Youil; Rima (North Wales, PA) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,733,993 Date filed: September 14, 2001 Abstract: First generation adenoviral vectors and associated recombinant adenovirusbased HIV vaccines which show enhanced stability and growth properties and greater cellular-mediated immunity are described within this specification. These adenoviral vectors are utilized to generate and produce through cell culture various adenoviralbased HIV-1 vaccines which contain HIV-1 gag, HIV-1 pol and/or HIV-1 nef polynucleotide pharmaceutical products, and biologically relevant modifications thereof. These adenovirus vaccines, when directly introduced into living vertebrate tissue, preferably a mammalian host such as a human or a non-human mammal of commercial or domestic veterinary importance, express the HIV1-Gag, Pol and/or Nef protein or biologically modification thereof, inducing a cellular immune response which specifically recognizes HIV-1. The exemplified polynucleotides of the present invention are synthetic DNA molecules encoding HIV-1 Gag, encoding codon optimized HIV-1 Pol, derivatives of optimized HIV-1 Pol (including constructs wherein protease, reverse transcriptase, RNAse H and integrase activity of HIV-1 Pol is inactivated), HIV-1 Nef and derivatives of optimized HIV-1 Nef, including nef mutants which effect wild type characteristics of Nef, such as myristylation and down regulation of host CD4. The adenoviral vaccines of the present invention, when administered alone or in a combined modality regime, will offer a prophylactic advantage to previously uninfected individuals and/or provide a therapeutic effect by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV-1 infection. Excerpt(s): The present invention relates to recombinant, replication-deficient first generation adenovirus vaccines found to exhibit enhanced growth properties and greater cellular-mediated immunity as compared to other replication-deficient vectors. The invention also relates to the associated first generation adenoviral vectors described herein, which, through the incorporation of additional 5' adenovirus sequence, enhance large scale production efficiency of the recombinant, replication-defective adenovirus described herein. Another aspect of the instant invention is the surprising discovery that the intron A portion of the human cytomegalovirus (hCMV) promoter constitutes a region of instability in adenoviral vector constructs. Removal of this region from adenoviral expression constructs results in greatly improved vector stability. Therefore, improved vectors expressing a transgene under the control of an intron A-deleted CMV
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promoter constitute a further aspect of this invention. These adenoviral vectors are useful for generating recombinant adenovirus vaccines against human immunodeficiency virus (HIV). In particular, the first generation adenovirus vectors disclosed herein are utilized to construct and generate adenovirus-based HIV-1 vaccines which contain HIV-1 Gag, HIV-1 Pol and/or HIV-1 Nef polynucleotide pharmaceutical products, and biologically active modifications thereof. Host administration of the recombinant, replication-deficient adenovirus vaccines described herein results in expression of HIV-1 Gag, HIV-1-Pol and/or Nef protein or immunologically relevant modifications thereof, inducing a cellular immune response which specifically recognizes HIV-1. The exemplified polynucleotides of the present invention are synthetic DNA molecules encoding codon optimized HIV-1 Gag, HIV-1 Pol, derivatives of optimized HIV-1 Pol (including constructs wherein protease, reverse transcriptase, RNAse H and integrase activity of HIV-1 Pol is inactivated), HIV-1 Nef, and derivatives of optimized HIV-1 Nef, including nef mutants which effect wild type characteristics of Nef, such as myristylation and down regulation of host CD4. The HIV adenovirus vaccines of the present invention, when administered alone or in a combined modality and/or prime/boost regimen, will offer a prophylactic advantage to previously uninfected individuals and/or provide a therapeutic effect by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV-1 infection. Human Immunodeficiency Virus-1 (HIV-1) is the etiological agent of acquired human immune deficiency syndrome (AIDS) and related disorders. HIV-1 is an RNA virus of the Retroviridae family and exhibits the 5' LTR-gag-pol-env-LTR 3' organization of all retroviruses. The integrated form of HIV-1, known as the provirus, is approximately 9.8 Kb in length. Each end of the viral genome contains flanking sequences known as long terminal repeats (LTRs). The HIV genes encode at least nine proteins and are divided into three classes; the major structural proteins (Gag, Pol, and Env), the regulatory proteins (Tat and Rev); and the accessory proteins (Vpu, Vpr, Vif and Nef). The gag gene encodes a 55-kilodalton (kDa) precursor protein (p55) which is expressed from the unspliced viral mRNA and is proteolytically processed by the HIV protease, a product of the pol gene. The mature p55 protein products are p17 (matrix), p24 (capsid), p9 (nucleocapsid) and p6. Web site: http://www.delphion.com/details?pn=US06733993__ •
Fiber receptor-independent system for the propagation of adenoviral vectors Inventor(s): Curiel; David T. (Birmingham, AL), Dmitriev; Igor (Homewood, AL), Douglas; Joanne T. (Huntsville, AL), Krasnykh; Victor N. (Birmingham, AL) Assignee(s): Uab Research Foundation (birmingham, Al) Patent Number: 6,649,396 Date filed: February 3, 2000 Abstract: The present invention provides a means for the propagation of adenovirus lacking the native tropism by using genetic methods to modify the fiber protein by addition of a C-terminal tag. The modified virus is then propagated in a cell line transfected with a sequence encoding an artificial receptor for the C-terminal tag on the modified fiber protein. Excerpt(s): The present invention relates generally to the fields of virology and gene therapy. More specifically, the present invention relates to the production of recombinant adenoviral vectors with modified fibers for the purpose of cell-specific targeting with the additional advantage of concomitant elimination of endogenous
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tropism. Recombinant adenovirus vectors are used in a number of gene therapy applications principally because of the high levels of gene transfer achievable with this approach both in vitro and in vivo. In addition, recombinant adenovirus vectors are distinguished from other available systems by their unique ability to accomplish in situ gene delivery to differentiated target cells in a variety of organ contexts. Recombinant human adenovirus vectors of serotypes 2 (Ad2) and 5 (Ad5) have the ability to transfer genes to a range of cell types in vivo efficiently and have therefore been employed in a number of gene therapy approaches. However, it is not currently possible to exploit the full potential of adenovirus as a gene delivery vehicle exhibiting systemic stability following intravenous administration. Adenovirus-mediated delivery of a therapeutic gene selectively to target disease cells is precluded by the widespread distribution of primary cellular receptors for Ad2 and Ad5. In addition, it has recently been reported that a number of tissues which represent important targets for gene therapy, including the airway epithelium and primary tumors, express only low levels of primary adenovirus receptors and are thus poorly transduced by adenovirus vectors (1-4). Therefore, strategies are being developed to alter the tropism of the adenovirus vector to permit efficiently targeted gene delivery to specific cell types. Web site: http://www.delphion.com/details?pn=US06649396__ •
Formulation of adenovirus for gene therapy Inventor(s): Wu; Zheng (Sugar Land, TX), Zhang; Shuyuan (Media, PA) Assignee(s): Introgen Therapeutics, Inc. (houston, Tx) Patent Number: 6,689,600 Date filed: November 16, 1999 Abstract: The present invention addresses the need to improve the long-term storage stability (i.e. infectivity) of vector formulations. In particular, it has been demonstrated that for adenovirus, the use of bulking agents, cryoprotectants and lyoprotectants imparts desired properties that allow both lyophilized and liquid adenovirus formulations to be stored at 4.degree. C. for up to 6 months and retain an infectivity between 60-100% of the starting infectivity. Excerpt(s): The present invention relates generally to the fields of molecular biology, virus production and gene therapy. More particularly, it concerns methods for the formulation of highly purified lyophilized and liquid adenovirus particles stable for long-term storage. An important embodiment of the present invention is the use of such long-term storage virus preparations for gene therapy treatments of viral disease, genetic disease and malignancies. Viruses are highly efficient at nucleic acid delivery to specific cell types, while often avoiding detection by the infected hosts immune system. These features make certain viruses attractive candidates as gene-delivery vehicles for use in gene therapies (Robbins and Ghivizzani; 1998; Cristiano et al., 1998). Retrovirus, adenovirus, adeno-associated virus (AAV), and herpes simplex virus are examples of commonly used viruses in gene therapies. Each of the aforementioned viruses has its advantages and limitations, and must therefore be selected according to suitability of a given gene therapy (Robbins and Ghivizzani; 1998). A variety of cancer and genetic diseases currently are being addressed by gene therapy. Cardiovascular disease (Morishita et al., 1998), colorectal cancer (Fujiwara and Tanaka, 1998), lung cancer (Roth et al., 1998), brain tumors (Badie et al., 1998), and thyroid carcinoma (Braiden et al., 1998) are examples of gene therapy treatments currently under investigation. Further,
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the use of viral vectors in combination with other cancer treatments also is an avenue of current research (Jounaidi et al., 1998). Web site: http://www.delphion.com/details?pn=US06689600__ •
Ligands added to adenovirus fiber Inventor(s): Curiel; David T. (Birmingham, AL), Engler; Jeffrey A. (Birmingham, AL) Assignee(s): Uab Research Foundation (birmingham, Al) Patent Number: 6,683,170 Date filed: July 13, 2001 Abstract: The fiber protein of adenovirus has been genetically altered via attachment at the carboxyl end of a peptide linker, preferably up to 26 amino acids in length which forms a random coil, which can be used to attach a non-adenovirus ligand altering the binding specificity of the fiber protein. Examples of ligands include peptides which are selectively bound by a targeted cell so that the modified fiber protein is internalized by receptor-mediated endocytosis, and peptides which can act as an universal coupling agent, for example, biotin or strepavidin. The linker is designed to not interfere with normal trimerization of fiber protein, to avoid steric hindrance of binding of the fiber protein to a targeted cell, and to serve as a site to introduce new peptide sequence. Excerpt(s): The present invention generally relates to modification of the adenovirus fiber protein and methods for use thereof to modify cellular attachment by the fiber protein. In general, receptors are involved in pathways of endocytosis, either constitutive or ligand induced. These receptors cluster in clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through an acidified endosome in which the receptors are sorted, and then either recycle to the cell surface, become stored intracellularly, or are degraded in lysosomes. The internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor-level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis is reviewed by Brown and Greene, DNA and Cell Biology 1991 10:6, 399-409. A number of viruses infect cells via a receptor-ligand interaction. Adenovirus is an example of a virus that utilizes receptor-mediated endocytosis to internalize infectious virus. Gene therapy requires transfer of recombinant nucleic acid constructs into cells. Although a number of different methods for gene transfer have been proposed, one of the most promising remains by utilizing recombinant viruses. The development of recombinant adenoviruses for this purpose has had a number of applications, based upon the unique advantages of this system. Web site: http://www.delphion.com/details?pn=US06683170__
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Method of preparing recombinant adeno-associated virus compositions Inventor(s): Byrne; Barry J. (Gainesville, FL), Muzyczka; Nicholas (Gainesville, FL), Zolotukhin; Sergei (Gainesville, FL) Assignee(s): University of Florida Research Foundation (gainesville, Fl) Patent Number: 6,660,514 Date filed: July 21, 2000 Abstract: Disclosed are methods for the isolation and purification of high-titer recombinant adeno-associated virus (rAAV) compositions. Also disclosed are methods for reducing or eliminating the concentration of helper adenovirus in rAAV samples. Methods are disclosed that provide highly-purified rAAV stocks having titers up to about 10.sup.13 particles/ml at particle-to-infectivity ratios of less than 100 in processes that are accomplished about 24 hours or less. Excerpt(s): The present invention relates generally to the field of virology, and in particular, to methods for preparing highly-purified, high-titer recombinant adenoassociated virus compositions. In certain embodiments, the invention concerns the use of equilibrium density centrifugation techniques, affinity chromatographic media, and in certain embodiments anion- and cation-exchange resins, to remove rAAV particles from solution and to prepare highly purified viral stocks for use in a variety of investigative, diagnostic and therapeutic regimens. Methods are also provided for purifying rAAVs from solution and for reducing the concentration of adenovirus in rAAV stocks. Adeno-associated virus-2 (AAV) is a human parvovirus which can be propagated both as a lytic virus and as a provirus (Cukor et al., 1984; Hoggan et al., 1972). The viral genome consists of linear single-stranded DNA (Rose et al., 1969), 4679 bases long (Srivastava et al., 1983), flanked by inverted terminal repeats of 145 bases (Lusby et al., 1982). For lytic growth AAV requires co-infection with a helper virus. Either adenovirus (Ad; Atchinson et al., 1965; Hoggan, 1965; Parks et al., 1967) or herpes simplex virus (HSV; Buller et al., 1981) can supply helper function. Without helper, there is no evidence of AAV-specific replication or gene expression (Rose et al., 1972; Carter et al., 1983; Carter et al., 1983). When no helper is available, AAV can persist as an integrated provirus (Hoggan, 1965; Berns et al., 1975; Handa et al., 1977; Cheung et al., 1980; Berns et al., 1982). Integration apparently involves recombination between AAV termini and host sequences and most of the AAV sequences remain intact in the provirus. The ability of AAV to integrate into host DNA is apparently an inherent strategy for insuring the survival of AAV sequences in the absence of the helper virus. When cells carrying an AAV provirus are subsequently superinfected with a helper, the integrated AAV genome is rescued and a productive lytic cycle occurs (Hoggan, 1965). Web site: http://www.delphion.com/details?pn=US06660514__
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Methods and compositions for the large scale production of recombinant adenoassociated virus Inventor(s): Dong; Jianyun (Birmingham, AL), Frizzell; Raymond A. (Birmingham, AL) Assignee(s): Uab Research Foundation (birmingham, Al) Patent Number: 6,686,200 Date filed: August 31, 1993
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Abstract: This invention provides novel methods and compositions for use in the efficient and large-scale production of recombinant adeno-associated virus (AAV). Described herein are new producer cell lines, recombinant adenovirus or herpes virus vectors and AAV constructs. Also disclosed are particularly advantageous methods of using such materials to produce recombinant AAV virions using only the efficient process of viral infection, without requiring transfection steps. The AAV produced may be used in a variety of embodiments including, for example, for transferring exogenous genes into human cell lines and for use in human gene therapy regimens. Excerpt(s): The present invention relates generally to the fields of molecular biology and gene transfer and particularly concerns recombinant adeno-associated virus (AAV). The invention provides novel methods and compositions, including cell lines, recombinant AAV and adenovirus or herpes virus vectors, for use in the efficient and large-scale production of adeno-associated virus. The AAV production methods described herein do not require a transfection step. The resultant AAV may be used in a variety of embodiments including, for example, for transferring exogenous genes into human cell lines and for use in human gene therapy regimens. There are currently more than 4,000 known genetic disorders which lack fully effective therapies. In recent years the prospect of using gene therapy to treat such diseases has become to be viewed as a realistic goal. The ultimate form of gene therapy requires the integration of a wild-type gene able to correct the genetic disorder into the host genome, where it can co-exist and replicate with the host DNA. The expression of the gene should be regulated at a level that can best compensate for the defective gene. In the most ideal circumstances, the disease would be cured for life by one or a few treatments, with no serious side effects. There have been several experimental approaches to gene therapy proposed to date, but each suffer from their particular drawbacks (Mulligan, 1993). Firstly, there are basic transfection methods in which DNA containing the gene of interest is introduced into cells non-biologically, for example, by permeabilizing the cell membrane physically or chemically. This approach is limited to cells that can be temporarily removed from the body and can tolerate the cytotoxicity of the treatment, i.e. lymphocytes. Furthermore, the efficiency of gene integration is very low, on the order of one integration event per 1,000 to 100,000 cells, and expression of transfected genes is often limited to days in proliferating cells or weeks in non proliferating cells. Web site: http://www.delphion.com/details?pn=US06686200__ •
Methods for generating high titer helper-free preparations of released recombinant AAV vectors Inventor(s): Aranha; Ian L. (Seattle, WA), Atkinson; Edward M. (Seattle, WA), Takeya; Ryan K. (Lynnwood, WA) Assignee(s): Targeted Genetics Corporation (seattle, Wa) Patent Number: 6,566,118 Date filed: March 15, 2000 Abstract: This invention provides methods and compositions for producing high titer, substantially purified preparations of recombinant adeno-associated virus (AAV) that can be used as vectors for gene delivery. At the onset of vector production, AAV producer cells of this invention typically comprise one or more AAV packaging genes, an AAV vector comprising a heterologous (i.e. non-AAV) transgene of interest, and a helper virus such as an adenovirus. The AAV vector preparations produced are generally replication incompetent but are capable of mediating delivery of a transgene
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of interest (such as a therapeutic gene) to any of a wide variety of tissues and cells. The AAV vector preparations produced according to this invention are also substantially free of helper virus as well as helper viral and cellular proteins and other contaminants. The invention described herein provides methods of producing rAAV particles by culturing producer cells under conditions, such as temperature and pH, that promote release of virus. Also provided is a quantitative, high-throughput assay useful in the assessment of viral infectivity and replication, as well as in the screening of agent that affect viral infectivity and/or replication. Excerpt(s): The present invention relates generally to the field of-recombinant adenoassociated virus (AAV) vectors and preparations thereof that can be used for gene transfer. More specifically, it relates to methods for generating high titer preparations of recombinant AAV vectors that are substantially free of helper virus (e.g. adenovirus) as well as cellular proteins. Adeno-associated viruses (AAV) have unique features that make them attractive as vectors for gene therapy. Adeno-associated viruses infect a wide range of cell types. However, they are non-transforming, and are not implicated in the etiology of any human disease. Introduction of DNA to recipient host cells generally leads to long-term persistence and expression of the DNA without disturbing the normal metabolism of the cell. There are at least three desirable features of a recombinant AAV vector preparation for use in gene transfer, especially in human gene therapy. First, it is preferred that the vector should be generated at titers sufficiently high to transduce an effective proportion of cells in the target tissue. Gene therapy in vivo typically requires a high number of vector particles. For example, some treatments may require in excess of 10.sup.8 particles, and treatment of cystic fibrosis by direct delivery to the airway may require in excess of 1.sup.10 particles. Second, it is preferred that the vector preparations should be essentially free of replication-competent AAV (i.e. phenotypically wild-type AAV which can be replicated in the presence of helper virus or helper virus functions). Third, it is preferred that the rAAV vector preparation as a whole be essentially free of other viruses (such as a helper virus used in AAV production) as well as helper virus and cellular proteins, and other components such as lipids and carbohydrates, so as to minimize or eliminate any risk of generating an immune response in the context of gene therapy. This latter point is especially significant in the context of AAV because AAV is a "helper-dependent" virus that requires co-infection with a helper virus (typically adenovirus) or other provision of helper virus functions in order to be effectively replicated and packaged during the process of AAV production; and, moreover, adenovirus has been observed to generate a host immune response in the context of gene therapy applications (see, e.g., Byrnes et al., Neuroscience 66:1015, 1995; McCoy et al., Human Gene Therapy 6:1553, 1995; and Barr et al., Gene Therapy 2:151, 1995). The methods of the present invention address these and other desirable features of rAAV vector preparations, as described and illustrated in detail below. Web site: http://www.delphion.com/details?pn=US06566118__
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Methods of treating chronic pain Inventor(s): Caudle; Robert M. (Gainesville, FL), Finegold; Alan A. (Bethesda, MD), Iadarola; Michael J. (Washington, DC), Mannes; Andrew J. (Chevy Chase, MD), Olah; Zoltan (Kensington, MD) Assignee(s): The United States of America AS Represented by the Department of Health and (washington, Dc) Patent Number: 6,596,269 Date filed: August 24, 2001 Abstract: This invention pertains to the surprising discovery of novel compositions and methods which selectively treat chronic pain while not significantly affecting basal nociceptive, acute pain, responses. The invention provides for compositions and methods of treating chronic pain by administering beta-endorphin-expressing recombinant expression systems such as adenovirus or adeno-associated virus into a subarachnoid or epidural space. The recombinant virus infects the pia mater connectve tissue cells and the infected cells express the fusion protein, wherein the fusion protein is secreted into the spinal cord parenchymal tissue in an amount effective to treat the chronic pain but not significantly affecting basal nociceptive responses. Excerpt(s): This invention generally pertains to the field of medicine and pain control. In particular, this invention pertains to the surprising discovery that pia mater cells transformed to secrete beta-endorphin will selectively control chronic pain while not significantly affecting basal nociceptive, acute pain, responses. This invention is the surprising discovery of a method of using beta endorphin through genetic engineering to treat chronic pain, while at the same time not significantly affecting the ability to react to acutely painful, potentially dangerous, stimuli. As will be explained below, prior to this invention, there was a great amount of academic debate as to whether betaendorphin can be used to treat or control chronic pain. Thus, the discovery of betaendorphin's selective control of chronic pain when secreted by transformed pia mater cells was unpredictable and therapeutically advantageous. Current analgesic therapies often fall short of therapeutic goals and typically have unacceptable side effects. In many chronic pain syndromes, such as those subsequent to neuropathic injury, pain is not well controlled by any currently available method. Furthermore, most chronic pain treatment regimes affect the patient's ability to perceive acute pain, thus blunting or abrogating necessary protective basal nociceptive responses. Web site: http://www.delphion.com/details?pn=US06596269__
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Molecular chemotherapy enhancement of radiotherapy Inventor(s): Buchsbaum; Donald J. (South Birmingham, AL), Garyer, Jr.; Robert J. (Hoover, AL), Gillespie; G. Yancey (Birmingham, AL), Miller; C. Ryan (Homewood, AL) Assignee(s): Uab Research Foundation (birmingham, Al) Patent Number: 6,703,375 Date filed: November 26, 2002 Abstract: The present invention provides a new approach for cancer treatment by utilizing gene therapy combined with radiation therapy to enhance cytotoxicity in malignant cells. Specifically, the present invention demonstrates that molecular chemotherapy with the cytosine deaminase gene and 5-fluorocytosine is an effective
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radiosensitizing strategy which may lead to substantial improvement in tumor control, with less normal tissue toxicity than conventional systemic administration of 5fluorouracil, that would translate into improved cure rates and better survival. A noninvasive method is described for continuous in vivo monitoring of 5-fluorouracil production via magnetic resonance spectroscopy An adenovirus encoding cytosine deaminase gene which selectively replicates in tumor cells with a defective p53 pathway was constructed. Also provided is an adenovirus which encodes a fusion protein of cytosine deaminase and uracil phosphoribosyltransferase. Excerpt(s): The present invention relates generally to the fields of molecular biology, radiation oncology and cancer therapy. More specifically, the present invention relates to the finding that a combination of molecular chemotherapy and radiation therapy enhances therapeutic effects against cancer. Clinical applications of cancer gene therapy have had limited success due to a variety of factors, including ineffective therapeutic gene delivery in situ. The physiologic milieu of the target tumor may have deleterious effects on the delivery of therapeutic genes. This limitation may be disease specific, and variable depending on the specific tumor type and tumor location. Most clinical gene therapy trials thus far have utilized compartmental models of malignant disease (1, 2). In this regard, thoracic malignancies and intra-abdominal carcinomatosis represent common body compartmentalized diseases that have been explored in an experimental therapeutic context. Attempts to address the issue of achieving viral vector delivery to cancer cells in the face of a physiologic infection medium of pleural fluid or abdominal ascites have been examined (3, 4). Yang et al. demonstrated retroviral transduction of pancreatic cancer cells in the presence of human ascites, similar to the results obtained in culture medium (3). Batra et al. reported significant inhibition of retroviral transduction of mesothelioma cells in the presence of malignant pleural fluid, specifically the chondroitin sulfate proteoglycan fraction (4). Radiotherapy combined with the radiosensitizing chemotherapeutic drug 5-fluorouracil (5-FU) has been studied as a therapeutic modality in many human tumor types (5). Systemic toxicity limits the amount of 5-FU that can be administered for many clinical anti-cancer applications (6, 7). Radiation therapy and gene therapy have the potential to be combined to enhance effectiveness of cancer therapy without enhancing dose limiting toxicity. To this end, reports have investigated this interaction (8). These include: TNF_ under the control of a radiation inducible promoter (9, 10), conversion of prodrugs to toxic metabolites that are also radiosensitizers (11-15), p53 mediated radiosensitization (16, 17) and the genetic induction of membrane receptors that can be targeted with radiolabeled peptides (1821). Web site: http://www.delphion.com/details?pn=US06703375__ •
Noninvasive genetic immunization, expression products therefrom, and uses thereof Inventor(s): Curiel; David T. (Birmingham, AL), Marks; Donald H. (Rockaway, NJ), Shi; Zhongkai (Birmingham, AL), Tang; De-chu C. (Birmingham, AL) Assignee(s): The Uab Research Foundation (birmingham, Al) Patent Number: 6,716,823 Date filed: March 23, 2000 Abstract: Disclosed and claimed are methods of non-invasive genetic immunization in an animal and/or methods of inducing a systemic immune or therapeutic response in an animal, products therefrom and uses for the methods and products therefrom. The methods can include contacting skin of the animal with a vector in an amount effective
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to induce the systemic immune or therapeutic response in the animal. The vector can include and express an exogenous nucleic acid molecule encoding an epitope or gene product of interest. The systemic immune response can be to or from the epitope or gene product. The nucleic acid molecule can encode an epitope of interest and/or an antigen of interest and/or a nucleic acid molecule that stimulates and/or modulates an immunological response and/or stimulates and/or modulates expression, e.g., transcription and/or translation, such as transcription and/or translation of an endogenous and/or exogenous nucleic acid molecule; e.g., one or more of influenza hemagglutinin, influenza nuclear protein, influenza M2, tetanus toxin C-fragment, anthrax protective antigen, anthrax lethal factor, rabies glycoprotein, HBV surface antigen, HIV gp 120, HIV gp 160, human carcinoembryonic antigen, malaria CSP, malaria SSP, malaria MSP, malaria pfg, and mycobacterium tuberculosis HSP; and/or a therapeutic, an immunomodulatory gene, such as co-stimulatory gene and/or a cytokine gene. The immune response can be induced by the vector expressing the nucleic acid molecule in the animal's cells. The animal's cells can be epidermal cells. The immune response can be against a pathogen or a neoplasm. A prophylactic vaccine or a therapeutic vaccine or an immunological composition can include the vector. The animal can be a vertebrate, e.g., a mammal, such as human, a cow, a horse, a dog, a cat, a goat, a sheep or a pig; or fowl such as turkey, chicken or duck. The vector can be one or more of a viral vector, including viral coat, e.g., with some or all viral genes deleted therefrom, bacterial, protozoan, transposon, retrotransposon, and DNA vector, e.g., a recombinant vector; for instance, an adenovirus, such as an adenovirus defective in its E1 and/or E3 and/or E4 region(s). The method can encompass applying a delivery device including the vector to the skin of the animal, as well as such a method further including disposing the vector in and/or on the delivery device. The vector can have all viral genes deleted therefrom. The vector can induce a therapeutic and/or an anti-tumor effect in the animal, e.g., by expressing an oncogene, a tumor-suppressor gene, or a tumor-associated gene. Immunological products generated by the expression, e.g., antibodies, cells from the methods, and the expression products, are likewise useful in in vitro and ex vivo applications, and such immunological and expression products and cells and applications are disclosed and claimed. Methods for expressing a gene product in vivo and products therefor and therefrom including mucosal and/or intranasal administration of an adenovirus, advantageously an E1 and/or E3 and/or E4 defective or deleted adenovirus, such as a human adenovirus or canine adenovirus, are also disclosed and claimed. Excerpt(s): The present invention relates generally to the fields of immunology and vaccine technology. The present invention also relates to techniques of skin-targeted non-invasive gene delivery to elicit immune responses and uses thereof. The invention further relates to methods of non-invasive genetic immunization in an animal and/or methods of inducing an immunological, e.g., systemic immune response or a therapeutic, e.g., a systemic therapeutic response, in an animal, products therefrom and uses for the methods and products therefrom. The invention yet further relates to such methods comprising contacting skin of the animal with a vector in an amount effective to induce the response, e.g., systemic immune response, in the animal. Even further, the invention relates to such methods wherein the vector comprises and express an exogenous nucleic acid molecule encoding an epitope or gene product of interest, e.g., an antigen or therapeutic. Still further, the invention relates to such methods wherein the response, e.g., systemic immune or therapeutic response, can be to or from the epitope or gene product. The invention yet further still relates to such methods wherein the nucleic acid molecule can encode an epitope of interest and/or an antigen of interest and/or a nucleic acid molecule that stimulates and/or modulates an immunological
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response and/or stimulates and/or modulates expression, e.g., transcription and/or translation, such as transcription and/or translation of an endogenous and/or exogenous nucleic acid molecule. The invention additionally relates to such methods wherein the nucleic acid molecule can be exogenous to the vector. The invention also relates to such methods wherein the exogenous nucleic acid molecule encodes one or more of an antigen or portion thereof, e.g., one or more of an epitope of interest from a pathogen, e.g., an epitope, antigen or gene product which modifies allergic response, an epitope antigen or gene product which modifies physiological function, influenza hemagglutinin, influenza nuclear protein, influenza M2, tetanus toxin C-fragment, anthrax protective antigen, anthrax lethal factor, rabies glycoprotein, HBV surface antigen, HIV gp 120, HIV gp 160, human carcinoembryonic antigen, malaria CSP, malaria SSP, malaria MSP, malaria pfg, and mycobacterium tuberculosis HSP; and/or a therapeutic or an immunomodulatory gene, a co-stimulatory gene and/or a cytokine gene. Even further, the invention relates to such methods wherein the immune response can be induced by the vector expressing the nucleic acid molecule in the animal's cells, e.g., epidermal cells. The invention still further relates to such methods wherein the immune response can be against a pathogen or a neoplasm. Web site: http://www.delphion.com/details?pn=US06716823__ •
Packaging systems for human recombinant adenovirus to be used in gene therapy Inventor(s): Bout; Abraham (Moerkapelle, NL), Fallaux; Frits Jacobus (Leiderdorp, NL), Hoeben; Robert Cornelis (Leiden, NL), Valerio; Domenico (Leiden, NL), Van Der Eb; Alex Jan (Oegstgeest, NL) Assignee(s): Introgene B.v. (leiden, Nl) Patent Number: 6,602,706 Date filed: February 17, 2000 Abstract: Presented are ways to address the problem of replication competent adenovirus in adenoviral production for use with, for example, gene therapy. Packaging cells having no overlapping sequences with a selected vector and are suited for large scale production of recombinant adenoviruses. A system for use with the invention produces adenovirus incapable of replicating. The system includes a primary cell containing a nucleic acid based on or derived from adenovirus and an isolated recombinant nucleic acid molecule for transfer into the primary cell. The isolated recombinant nucleic acid molecule is based on or derived from an adenovirus, and further has at least one functional encapsidating signal, and at least one functional Inverted Terminal Repeat. The isolated recombinant nucleic acid molecule lacks overlapping sequences with the nucleic acid of the cell. Otherwise, the overlapping sequences would enable homologous recombination leading to replication competent adenovirus in the primary cell into which the isolated recombinant nucleic acid molecule is to be transferred. Excerpt(s): The invention relates to the field of recombinant DNA technology, more in particular to the field of gene therapy. In particular the invention relates to gene therapy using materials derived from adenovirus, specifically human recombinant adenovirus. It especially relates to novel virus derived vectors and novel packaging cell lines for vectors based on adenoviruses. Gene therapy is a recently developed concept for which a wide range of applications can be and have been envisioned. In gene therapy a molecule carrying genetic information is introduced into some or all cells of a host, as a result of which the genetic information is added to the host in a functional format. The
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genetic information added may be a gene or a derivative of a gene, such as a cDNA, which encodes a protein. This is a functional format in that the protein can be expressed by the machinery of the host cell. Web site: http://www.delphion.com/details?pn=US06602706__ •
Packaging systems for human recombinant adenovirus to be used in gene therapy Inventor(s): Bout; Abraham (Moerkapelle, NL), Vogels; Ronald (Linschoten, NL) Assignee(s): Crucell Holland B.v. (leiden, Nl) Patent Number: 6,670,188 Date filed: April 24, 1998 Abstract: The invention provides improved methods and products based on adenoviral materials which can advantageously be used in for instance gene therapy. In one aspect an adenoviral vector is provided which has no overlap with a suitable packaging cell line which is another aspect of the invention. This combination excludes the possibility of homologous recombination, thereby excluding the possibility of the formation of replication competent adenovirus. In another aspect an adenovirus based helper construct which by its size is incapable of being encapsidated. This helper virus can be transferred into any suitable host cell making it a packaging cell. Further, a number of useful mutations to adenoviral based materials and combinations of such mutations are disclosed, which all have in common the safety of the methods and the products, in particular avoiding the production of replication competent adenovirus and/or interference with the immune system. Further, a method of intracellular amplification is provided. Excerpt(s): The invention relates to the field of recombinant DNA technology, more in particular to the field of gene therapy. In particular the invention relates to gene therapy using materials derived from adenovirus, in particular human recombinant adenovirus. It especially relates to novel virus derived vectors and novel packaging cell lines for vectors based on adenoviruses. Gene therapy is a recently developed concept for which a wide range of applications can be and have been envisaged. In gene therapy a molecule carrying genetic information is introduced into some or all cells of a host, as a result of which the genetic information is added to the host in a functional format. Included is the treatment of genetic disorders by providing the genetic information for supplementing a protein or other substance which is, through said genetic disorder, not present or at least present in insufficient amounts in the host, the treatment of tumors and (other) acquired disease such as (auto) immune diseases or infections, or other processes. The genetic information added may be a gene or a derivative of a gene, such as a cDNA, which encodes a protein. In this case the functional format means that the protein can be expressed by the machinery of the host cell. The genetic information can also be a sequence of nucleotides complementary to a sequence of nucleotides (be it DNA or RNA) present in the host cell. The functional format in this case is that the added DNA (nucleic acid) molecule or copies made thereof in situ are capable of base pairing with the complementary sequence present in the host cell. Thus, there are basically three different approaches in gene therapy, one directed towards compensating a deficiency present in a (mammalian) host; the second directed towards the removal or elimination of unwanted substances (organisms or cells) and the third directed towards application of a recombinant vaccine (tumors or foreign microorganisms).
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Web site: http://www.delphion.com/details?pn=US06670188__ •
Packaging systems for human recombinant adenovirus to be used in gene therapy Inventor(s): Bout; Abraham (Moerkapelle, NL), Fallaux; Frits J. (Leiderdorp, NL), Hoeben; Robert C. (Leiden, NL), Valerio; Domenico (Oegstgeest, NL), van der Eb; Alex J. (Oegstgeest, NL) Assignee(s): Crucell Holland B.v. (leiden, Nl) Patent Number: 6,692,966 Date filed: July 23, 2001 Abstract: The problem of replication-competent adenovirus in virus production is solved in that we have developed packaging cells that have no overlapping sequences with a new basic vector and thus, are suited for safe large scale production of recombinant adenoviruses. One of the additional problems associated with the use of recombinant adenovirus vectors is the host-defense reaction against treatment with adenovirus. Another aspect of the invention involves screening recombinant adenovirus vector lots, especially those intended for clinical use, for the presence of adenovirus E1 sequences, as this will reveal replication-competent adenovirus, as well as revertant E1 adenoviruses. It is also an aspect of the present invention to molecularly characterize the revertants that are generated in the newer helper/vector combinations. Excerpt(s): The present invention relates to the field of recombinant DNA technology, more in particular to the field of gene therapy. Specifically, the present invention relates to gene therapy using materials derived from adenovirus, in particular human recombinant adenovirus, and relates to novel virus-derived vectors and novel packaging cell lines for vectors based on adenoviruses. Furthermore, this invention also pertains to the screening of replication-competent and revertant E1 adenoviruses from recombinant adenoviruses used in gene therapy. Gene therapy is a recently developed concept for which a wide range of applications can be and have been envisaged. In gene therapy, a molecule carrying specific genetic information is introduced into some or all cells of a host. This results in the specific genetic information being padded to the host in a functional format. The specific genetic information added may be a gene or a derivative of a gene, such as a cDNA (which encodes a protein), or the like. In the case where cDNA is added, the encoded protein can be expressed by the machinery of the host cell. The genetic information can also be a sequence of nucleotides complementary to a sequence of nucleotides (be it DNA or RNA) present in the host cell. With this functional format, the added DNA molecule or copies made thereof in situ are capable of base pairing with the complementary sequence present in the host cell. Web site: http://www.delphion.com/details?pn=US06692966__
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Permanent amniocytic cell line, its production and use for the production of gene transfer vectors Inventor(s): Kochanek; Stefan (Werthmann Str. 24, D-50935 Koln, DE), Schiedner; Gudrun (Nelken Str. 16, D-50733 Koln, DE) Assignee(s): None Reported Patent Number: 6,558,948 Date filed: November 16, 2000
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Abstract: The invention relates to a permanent amniocytic cell line comprising at least one nucleic acid which brings about expression of the gene products of the adenovirus E1A and E1B regions. The present invention further relates to the production of a permanent amniocytic cell line and to its use for producing gene transfer vectors and/or adenovirus mutants. Further aspects are the use of amniocytes and of the adenoviral gene products of the E1A and E1B regions for producing permanent amniocytic cell lines. Excerpt(s): The present invention relates to a permanent amniocytic cell line comprising at least one nucleic acid which brings about expression of the gene products of the adenovirus E1A and E1B regions. The present invention further relates to the production of a permanent amniocytic cell line and to its use for producing gene transfer vectors and/or adenovirus mutants. Further aspects are the use of amniocytes and of the adenoviral gene products of the E1A and E1B regions for producing permanent amniocytic cell lines. Adenoviruses are a relatively homogeneous group of viruses characterized by an icosahedral capsid which consists mainly of the virally encoded hexon, penton and fiber proteins, and of a linear, double-stranded DNA genome with a size of about 36 kilobases (kb). The viral genome contains at the ends the inverted terminal repeat sequences (ITRs) which comprise the viral origin of replication. There is furthermore at the left-hand end of the genome the packaging signal which is necessary for packaging of the viral genome into the virus capsids during an infection cycle. Adenoviruses have been isolated from many species. There are more than 40 different human serotypes based on parameters which discriminate between the various serotypes, such as hemagglutination, tumorigenicity and DNA sequence homology (Wigand et al., in: Adenovirus DNA, Doerfler ed., Martinus Nijoff Publishing, Boston, pp. 408-441, 1986). Adenoviral vectors to date are usually derived from serotypes 2 (Ad2) and 5 (Ad5). Infections by Ad2 and Ad5 are endemic in humans. Ad2 and Ad5 are not oncogenic in humans and have good safety documentation because vaccinations have been performed on military personnel successfully and without complications in the USA (Pierce et al., Am. J. Epidemiol. 87, 237-246, 1968). The biology of adenoviruses is relatively well understood because adenoviruses have played an essential part in molecular biology as experimental tool for elucidating various fundamental biological principles such as DNA replication, transcription, RNA splicing and cellular transformation. Adenoviral particles enter the cell during an infection through receptormediated endocytosis in which, according to the current view, interaction of the knob domain of the fiber protein with the coxsackie adenovirus receptor (CAR) mediates adhesion of the virus particle to the cell surface (Bergelson et al., Science 275, 1320-1323, 1997). In a second step there is internalization of the virus particle, for which interaction of the penton base with integrins plays an essential part (Wickham et al., Cell 73, 309319, 1993). After the particle has entered the cell, the viral genome gets into the cell nucleus as DNA-protein complex. The adenoviral infection cycle is divided into an early and a late phase which are separated by the start of adenoviral replication (Shenk, in: Virology, Fields ed., Lippincott-Raven Publishing, Philadelphia, pp. 2111-2148, 1996). In the early phase there is expression of the early viral functions E1, E2, E3 and E4. The late phase is characterized by transcription of late genes which are responsible for the expression of viral structural proteins and for the production of new viral particles. E1A is the first viral gene to be expressed by the viral chromosome after the cell nucleus is reached. The E1A gene codes for the 12S and 13S proteins which are formed by alternative splicing of the E1A RNA. The E1A proteins activate the transcription of a number of cellular and viral genes by interacting with transcription factors. The main functions of E1A are a) activation of the other early viral functions E1B, E2, E3 and E4
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and b) inducing resting cells to enter the S phase of the cell cycle. Expression of E1A on its own leads to programmed cell death (apoptosis). Web site: http://www.delphion.com/details?pn=US06558948__ •
Rapid methods and kits for detection and semi-quantitation of anti-adenovirus antibody Inventor(s): Charlton; David (Redwood City, CA), Henderson; Daniel R. (Palo Alto, CA) Assignee(s): Cell Genesys, Inc. (san Francisco, Ca) Patent Number: 6,673,614 Date filed: June 27, 2001 Abstract: Methods for rapid detection and/or semi-quantitation of anti-adenovirus antibody are disclosed. Anti-adenovirus antibody is detected using a device comprising a membrane with adsorbed antigen which specifically binds anti-adenovirus antibody and an absorbent pad which is contacted with the membrane. By consolidating detection reactions in a confined location and eliminating the need to manually remove input reagents, detection and semi-quantitation is achieved rapidly and conveniently. The invention also provides kits and devices for detection and/or semi-quantitation of anti-adenovirus antibodies. Excerpt(s): This invention relates to the field of antibody detection, particularly rapid methods, devices and kits for detection and semi-quantitation of anti-adenovirus antibody. The ability to detect antibodies to viruses such as adenovirus in a patient sample is increasingly becoming a prerequisite for optimal utilization of many modern health care technologies. This is especially relevant in two broad areas of health care: detection of infections based on presence of pathogen-specific antibodies, and "prepping" of patients for therapeutic agent administration. The pathogenesis of the ubiquitous adenovirus is well-documented. Many relatively minor illnesses are associated with adenovirus infections, including acute febrile pharyngitis, pharyngoconjunctival fever, acute respiratory disease, pneumonia, epidemic keratoconjunctivitis, pertussis-like syndrome, acute hemorrhagic cystitis, gastroenteritis, hepatitis and persistence of virus in urinary tract. Fields, et al., Fields' VIROLOGY, Vol. 2, p. 2155 (3rd Ed.). A vaccine for the most severe of these diseases has been developed using a wild-type unattenuated replicating polyvalent vaccine comprised of adenovirus types 4 and 7. Web site: http://www.delphion.com/details?pn=US06673614__
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Recombinant adenoviral vectors Inventor(s): Rooke; Ronald (Illkirch, FR) Assignee(s): Transgene S.a. (strasbourg, Fr) Patent Number: 6,692,956 Date filed: October 4, 2001 Abstract: The present invention concerns a recombinant adenoviral vector derived from an adenovirus genome in which at least a part of the E3 region is deleted or is non functional, wherein said adenoviral vector retains E3 sequences encoding a functional 14.7K protein, a functional 14.5K protein, and/or a functional 10.4K protein. The present
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invention further relates to the use of a polynucleotide comprising at least one or more gene(s) of an E3 region of an adenovirus, taken individually or in combination, to protect from an inflammatory reaction in a host cell, tissue or organism. The present invention additionally concerns a viral particle, a host cell and a composition comprising said recombinant adenoviral vector or said polynucleotide, as well as their use for therapeutic or prophylactic purpose. Excerpt(s): Gene therapy can be defined as the transfer of genetic material into a cell or an organism. The possibility of treating human disorders by gene therapy has changed in the last few years from the stage of theoretical considerations to that of clinical applications. The first protocol applied to man was initiated in the USA in September 1990 on a patient suffering from adenine deaminase (ADA) deficiency. This first encouraging experiment has been followed by numerous new applications and promising clinical trials based on gene therapy are currently ongoing. The large majority of the current protocols employ vectors to carry the therapeutic gene to the cells to be treated. There are two main types of gene-delivery vectors, viral and non-viral. Viral vectors are derived from naturally-occuring viruses and use the diverse and highly sophisticated mechanisms that wild-type viruses have developed to cross the cellular membrane, escape from lysosomal degradation and deliver their genome to the nucleus. Many different viruses are being adapted as vectors, but the most advanced are retrovirus, adenovirus and adeno-associated virus (AAV) (Robbins et al., 1998, Trends Biotechnol. 16, 35-40; Miller, 1997, Human Gene Therapy 8, 803-815; Montain et al., 2000, Tibtech 18, 119-128). Substantial effort has also gone into developing poxviruses (especially vaccinia) and herpes simplex virus (HPV). Non-viral approaches include naked DNA (i.e., plasmidic DNA; Wolff et al., 1990, Science 247, 1465-1468), DNA complexed with cationic lipids (for a review, see for example Rolland, 1998, Critical reviews in Therapeutic Drug Carrier Systems 15, 143-198) and particles comprising DNA condensed with cationic polymers (Wagner et al., 1990, Proc. Natl. Acad. Sci. USA 87, 3410-3414 and Gottschalk et al., 1996, Gene Ther. 3, 448-457). At the present stage of development, the viral vectors generally give the most efficient transfection but their main disadvantages include their limited cloning capacity, their tendency to elicit immune and inflammatory responses and their manufacturing difficulties. Non-viral vectors achieve less efficient transfection but have no insert-size limitation, are less immunogenic and easier to manufacture. Web site: http://www.delphion.com/details?pn=US06692956__ •
Recombinant adenovirus vectors that are replication-competent in tert-expressing cells Inventor(s): Doronin; Konstantin (Moscow, RU), Kuppuswamy; Mohan (Ballwin, MO), Tollefson; Ann E. (St. Louis, MO), Toth; Karoly (St. Louis, MO), Wold; William S. M. (Chesterfield, MO) Assignee(s): Saint Louis University (saint Louis, Mo) Patent Number: 6,627,190 Date filed: September 19, 2001 Abstract: Novel adenovirus vectors which overexpress an adenovirus death protein and which are replication-competent in and, preferably, replication-restricted to cells expressing telomerase. One embodiment provides for efficient destruction and removal of viral-infected host cells expressing telomerase. Still further, another embodiment provides for additional restriction and safety by disrupting E1A's ability to bind p300
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and/or members of the Rb family members. Compositions of the novel vectors and methods for promoting death of cells expressing telomerase with these vectors are also disclosed. Excerpt(s): This invention relates generally to recombinant adenovirus vectors which overexpress adenovirus death proteins (ADP) and which are replication-restricted to cells expressing telomerase. Cancer is a leading cause of death in the United States and elsewhere. Depending on the type of cancer, it is typically treated with surgery, chemotherapy, and/or radiation. These treatments often fail: surgery may not remove all the cancer; some cancers are resistant to chemotherapy and radiation therapy; and chemotherapy-resistant tumors frequently develop. New therapies are necessary, to be used alone or in combination with classical techniques. One potential therapy under active investigation is treating tumors with recombinant viral vectors expressing anticancer therapeutic proteins. Adenovirus-based vectors contain several characteristics that make them conceptually appealing for use in treating cancer, as well as for therapy of genetic disorders. Adenoviruses (hereinafter used interchangeably with "Ads") can easily be grown in culture to high titer stocks that are stable. They have a broad host range, replicating in most human cancer cell types. Their genome can be manipulated by site-directed mutation and insertion of foreign genes expressed from foreign promoters. Web site: http://www.delphion.com/details?pn=US06627190__ •
Recombinant virus Inventor(s): Jacobs; Susan C (Salisbury, GB) Assignee(s): The Secretary of State for Defence in Her Britannic Majesty's Government of (hampshire, Gb) Patent Number: 6,565,853 Date filed: October 23, 2000 Abstract: An adenovirus which encodes a polypeptide which produces a protective immune response against an alpha-virus such as a Venezuelan Equine Encephalitis Virus, in a mammal to which it is administered, said nucleic acid lacking a competant nuclear targeting signal in the capsid gene. Excerpt(s): The present invention relates to the production of vectors which express alpha-virus genes, such as recombinant viral vectors like adenovirus. The invention further relates to prophylactic and therapeutic vaccines which are protective against these alpha-viruses, such Venezuelan Equine Encephalitis Virus (VEEV), as well as nucleic acids which are used in the vectors, and methods of treatment using the vaccines. capsid-E3-E2-6K-E1. The capsid protein is also known as the "core" and both terms are used herein. Web site: http://www.delphion.com/details?pn=US06565853__
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Structure of adenovirus bound to cellular receptor car Inventor(s): Freimuth; Paul I. (East Setauket, NY) Assignee(s): Brookhaven Science Associates, Lcc (upton, Ny) Patent Number: 6,737,234 Date filed: September 3, 1999
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Abstract: Disclosed is a mutant adenovirus which has a genome comprising one or more mutations in sequences which encode the fiber protein knob domain wherein the mutation causes the encoded viral particle to have significantly weakened binding affinity for CARD1 relative to wild-type adenovirus. Such mutations may be in sequences which encode either the AB loop, or the HI loop of the fiber protein knob domain. Specific residues and mutations are described. Also disclosed is a method for generating a mutant adenovirus which is characterized by a receptor binding affinity or specificity which differs substantially from wild type. In the method, residues of the adenovirus fiber protein knob domain which are predicted to alter D1 binding when mutated, are identified from the crystal structure coordinates of the AD12knob:CAR-D1 complex. A mutation which alters one or more of the identified residues is introduced into the genome of the adenovirus to generate a mutant adenovirus. Whether or not the mutant produced exhibits altered adenovirus-CAR binding properties is then determined. Excerpt(s): Characterization of the molecular basis for virus attachment to cells has importance both for understanding virus tropism and for developing agents that inhibit virus binding or alter the specificity of binding. Recently, a cellular receptor for adenovirus type 2 and other closely related serotypes was identified. This receptor, encoded by a single gene on human chromosome 21 (Mayr et al., J. Virol. 71: 412-8 (1997)), is a 46 kD glycoprotein which also serves as a receptor for group B coxsackieviruses (CBV) and thus was termed CAR. CAR mRNA is present in many human tissues. A broad tissue distribution of CAR protein expression correlates with the broad tropism of CBV, but subgroup C adenoviruses that are known to bind CAR have a much more restricted tropism limited. primarily to the upper respiratory tract. Thus, other factors in addition to receptor availability clearly have important roles in determining adenovirus tropism. Although adenovirus binds to CAR with high affinity (Mayr et al., J. Virol. 71: 412-8 (1997); Wickham et al., Cell. 73: 309-19 (1993)), virus titers are significantly reduced on cells with down-regulated CAR expression (Freimuth, P., J. Virol. 70: 4081-5 (1996)). These results suggest that adenovirus infection in vivo may be restricted to cells which express CAR at levels above a minimum threshold concentration. CAR protein levels are relatively low on the apical surface of differentiated (ciliated) respiratory epithelial cell cultures, which may account for the poor efficiency of adenoviral gene transfer to human lung tissue in vivo. Adenovirus binding to CAR results from an interaction between rod-shaped proteins located at the capsid vertices, called viral fibers, and the extracellular region of CAR. The monomers of this homotrimeric fiber protein range in size from 30 to 65 kDa depending on the serotype (Huang et al., J. Virol. 73: 2798-2802 (1999)). They are composed of a conserved amino terminal tail that mediates their interaction with the Ad penton base, a variablelength elongated (shaft) domain, and a carboxyl-terminal globular domain, termed the knob, which mediates the high-affinity interaction with its cellular receptor. The knob domain of adenovirus type 5 (Ad5) was expressed in E. coli as a soluble, trimeric, biologically active protein, and its 3-dimensional structure was determined by x-ray crystallography (Xia et al., Structure 2: 1259-70 (1994)). The predicted amino acid sequence of CAR suggests a structure consisting of two extracellular domains related to the immunoglobulin IgV and IgC2 domain folds (Bork et al., J. Mol Biol. 242: 309-20 (1994); Bergelson et al., Science 275: 1320-3 (1997); Tomko et al., Proc. Natl. Acad. Sci. USA 94: 3352-6 (1997)), a single membrane-spanning region, and one carboxy-terminal cytoplasmic domain. Regions of CAR necessary for binding the fiber knob domain have not yet been determined. Web site: http://www.delphion.com/details?pn=US06737234__
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Targeting adenovirus with use of constrained peptide motifs Inventor(s): Kovesdi; Imre (Rockville, MD), Roelvink; Petrus W. (Germantown, MD), Wickham; Thomas J. (Germantown, MD) Assignee(s): Genvec, Inc. (gaithersburg, Md) Patent Number: 6,649,407 Date filed: October 1, 2001 Abstract: The present invention provides a chimeric adenovirus fiber protein, which differs from the wild-type coat protein by the introduction of a nonnative amino acid sequence in a conformationally-restrained manner. Such a chimeric adenovirus fiber protein according to the invention is able to direct entry into cells of a vector comprising the chimeric fiber protein that is more efficient than entry into cells of a vector that is identical except for comprising a wild-type adenovirus fiber protein rather than the chimeric adenovirus fiber protein. The nonnative amino acid sequences encodes a peptide motif that comprises an epitope for an antibody, or a ligand for a cell surface receptor, that can be employed in cell targeting. The present invention also pertains to vectors comprising such a chimeric adenovirus fiber protein, and to methods of using such vectors. Excerpt(s): The present invention pertains to a chimeric adenovirus fiber protein comprising a constrained nonnative amino acid sequence. Despite their prior poor reputation as major pathogenic agents that lead to numerous infectious diseases, adenoviruses (and particularly, replication-deficient adenoviruses) have more recently attracted considerable recognition as highly effective viral vectors for gene therapy. Adenoviral vectors offer exciting possibilities in this new realm of therapeutics based on their high efficiency of gene transfer, substantial carrying capacity, and ability to infect a wide range of cell types (Crystal, Science, 270, 404-410 (1995); Curiel et al., Human Gene Therapy, 3, 147-154 (1992); International Patent Application WO 95/21259). Due to these desirable properties of adenoviruses, recombinant adenoviral vectors have been used for the cell-targeted transfer of one or more recombinant genes to diseased cells or tissue in need of treatment. In terms of the general structure of an adenovirus, under the electron microscope, an adenovirus particle resembles a space capsule having protruding antennae (Xia et al., Structure, 2, 1259-1270 (1994)). The viral capsid comprises at least six different polypeptides, including 240 copies of the trimeric hexon (i.e., polypeptide II) and 12 copies each of the pentameric penton (polypeptide III) base and trimeric fiber (Xia et al., supra). Web site: http://www.delphion.com/details?pn=US06649407__
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Temperature-sensitive regulation of viral vector production Inventor(s): Abernathy; Corinne (Gainesville, FL), Gavin; Denise (Silver Spring, MD), Muzyczka; Nicholas (Gainesville, FL), Pereira; Daniel (Alexandria, VA), Samulski; Richard Jude (Chapel Hill, NC) Assignee(s): University of North Carolina at Chapel Hill (chapel Hill, Nc) Patent Number: 6,627,617 Date filed: September 29, 2000 Abstract: The present invention provides temperature-sensitive (ts) adeno-associated virus (AAV) Rep78 and Rep68 proteins. In preferred embodiments, the ts AAV Rep78
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and Rep68 proteins have missense mutations at amino acid positions 40, 42 and 44 that confer a temperature-sensitive phenotype. Also provided are nucleotide sequences and vectors encoding the inventive ts Rep proteins. In preferred embodiments, a hybrid adenovirus vector is provided that stably comprises a nucleotide sequence encoding a ts AAV Rep protein according to the invention. The present invention also provides methods of packaging AAV vectors and methods of ex vivo gene delivery using the ts Rep proteins of the invention. Further provided are cells containing the ts AAV Rep proteins, preferably stably integrated into the genome of the cell. Excerpt(s): The present invention pertains to reagents and methods for producing virus vectors, in particular, reagents and methods for producing adeno-associated virus vectors. Adeno-associated virus (AAV) type 2 is a nonpathogenic human parvovirus that generally depends on coinfection with a helper virus (adenovirus or herpesvirus) for efficient replication (reviewed in Berns (1996). Parvoviridae: The viruses and their replication, p. 2173-2197, in B. N. Fields (ed.), Fields Virology, 3.sup.rd ed., vol. 2, Raven, Philadelphia). The linear, single-stranded DNA genome of AAV encodes two open reading frames (rep and cap) flanked by 145 bp inverted terminal repeats (ITR) (Srivastava et al., (1983) J. Virol. 45:555). Replication of the AAV genome requires two viral components, the ITR that serves as the origin of replication (Hauswirth et al., (1977) Virology 78:488; Straus et al., (1976) Proc. Natl. Acad. Sci. USA 73:742; Samulski et al., (1983) Cell 33:135; Senepathy et al., (1984) J. Mol. Biol. 179:1) and the rep gene products (Senepathy et al., (1984) J. Mol. Biol. 179:1, Hermonat et al., (1984) J. Virology 51:329; Tratschin et al., (1984) J. Virology 51:611). The rep gene encodes four multifunctional proteins (Hermonat et al., (1984) J. Virology 51:329; Tratschin et al., (1984) J. Virology 51:611; Mendelson et al., (1986) J. Virology 60:823; Trempe et al., (1987) Virology 161:18) that are expressed from two promoters at map units 5 (p5) and 19 (p19). The larger Rep proteins transcribed from the p5 promoter (Rep78 and Rep68), are essentially identical except for unique carboxy termini generated from unspliced (Rep78) and spliced (Rep68) transcripts, respectively (Srivastava et al, (9183) J. Virol. 45:555). Two smaller rep proteins (Rep52, Rep40), transcribed from the p19 promoter are amino terminal truncations of Rep78 and Rep68, respectively. Several biochemical activities of Rep78 and Rep68 have been characterized as necessary for AAV replication. These include specific binding to the AAV ITR (Ashktorab et al., (1989) J. Virology 63:3034; Im et al., 1989) J. Virology 63:3095; Snyder et al., (1993) J. Virology 67:6096) and site-specific endonuclease cleavage at the terminal resolution site (trs) (Im et al., (1990) J. Virology 63:447; Im et al., (1992) J. Virology 66:1119; Snyder et al., (1990) Cell 60:105; Snyder et al., (1990) J. Virology 64:6204). Rep78/68 also possess ATP dependent DNA-DNA helicase ((Im et al., (1990) J. Virology 63:447; Im et al., (1992) J. Virology 66:1119) and DNA-RNA helicase as well as ATPase activities (Wonderling et al., (1995) J. Virology 69:3542). In addition to these activities required for replication, Rep78/68 also regulate transcription from the viral promoters (Beaton et al., (1989) J. Virology 63:4450; Labow et al., (1986) J. Virology 60:251; Tratschin et al., (1986) Mol. Cellular Biol. 6:2884; Kyostio et al., (1994) J. Virology 68:2947; Pereira et al., (1997) J. Virology 71:1079), and have been shown to mediate viral targeted integration (Xiao, W., (1996), "Characterization of cis and trans elements essential for the targeted integration of recombinant adeno-associated virus plasmid vectors", Ph.D. Dissertation, University of North Carolina-Chapel Hill; Balague et al., (1997) J. Virology 71:3299; LaMartina et al., (1998) J. Virology 72:7653; Pieroni et al., (1998) Virology 249:249). Web site: http://www.delphion.com/details?pn=US06627617__
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Tissue specific adenoviral vectors Inventor(s): Henderson; Daniel R. (Palo Alto, CA), Schuur; Eric R. (Palo Alto, CA) Assignee(s): Cell Genesys, Inc. (south San Francisco, Ca) Patent Number: 6,676,935 Date filed: September 10, 1998 Abstract: Host cell specific adenovirus vehicles are provided for transfecting target host cells. By providing for transcriptional initiating regulation dependent upon transcription factors that are only active in specific, limited cell types, virus replication will be restricted to the target cells. The modified adenovirus may be used as a vehicle for introducing new genetic capability, particularly associated with cytotoxicity for treating neoplasia. Excerpt(s): The field of this invention is cell transfection, particularly by adenoviral vectors. The ability to change the genotype and phenotype of cells in vitro and in vivo has many applications. For studying physiologic processes, particularly with dedicated cells, there is substantial interest in being able to modify the phenotype to affect a particular process. By enhancing or depressing the amount of a member of the physiological pathway, by inhibiting the activity of a member of the pathway, by providing an allele or mutated analog of the naturally occurring member, one may be able to unravel the role of the various members in the pathway, the order in which the members participate, the presence of alternative pathways and the like. Also, one can use the cells for producing proteins. Adenovirus does not require cell proliferation for efficient transduction of cells. Adenovirus modified by introduction of a transgene provides for transient expression of proteins. Adenovirus can be rendered incompetent by inactivating one or more essential genes and then be packaged in a helper cell line for use in transfection. Thus, adenovirus affords a convenient vehicle for modifying cellular traits or killing cells, as appropriate. Web site: http://www.delphion.com/details?pn=US06676935__
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Tissue-vectors specific replication and gene expression Inventor(s): Chang; Yung-Nien (Cockeysville, MD), Hallenbeck; Paul L. (Gaithersburg, MD), Hay; Carl M. (Damascus, MD), Stewart; David A. (Eldersburg, MD) Assignee(s): Genetic Therapy, Inc. (gaithersburg, Md) Patent Number: 6,638,762 Date filed: November 19, 1997 Abstract: The invention generally relates to cell-specific expression vectors. It particularly relates to targeted gene therapy using recombinant expression vectors and particularly adenovirus vectors. The invention specifically relates to replicationconditional expression vectors and methods for using them. Such vectors are able to selectively replicate in a target cell or tissue to provide a therapeutic benefit in a tissue from the presence of the vector per se or from one or more heterologous gene products expressed from the vector and distributed throughout the tissue. In such vectors, a gene essential for replication is placed under the control of a heterologous tissue-specific transcriptional regulatory sequence. Thus, replication is conditioned on the presence of a factor(s) that induces transcription or the absence of a factor(s) that inhibits
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transcription of the gene by means of the transcriptional regulatory sequence with this vector; therefore, a target tissue can be selectively treated. Excerpt(s): The invention generally relates to cell-specific expression vectors. It particularly relates to targeted gene therapy using recombinant expression vectors and particularly adenovirus vectors. The invention specifically relates to modulatable replication-conditional expression vectors and methods for using them. Such vectors are able to selectively replicate in a target cell or tissue to provide a therapeutic benefit in a tissue from the presence of the vector per se or from one or more heterologous gene products expressed from the vector and distributed throughout the tissue, and which vectors are designed so that replication and gene expression from the vector can be modulated. In such vectors, a gene essential for replication is placed under the control of a heterologous tissue-specific transcriptional regulatory sequence. Thus, replication is conditioned on the presence of a factor(s) that induces transcription or the absence of a factor(s) that inhibits transcription of the gene by means of the transcriptional regulatory sequence. Preferred vectors contain a heterologous gene that produces a product that increases or inhibits viral replication. Such genes are useful for modulating viral replication and thus also for modulating expression of genes in the vector. With these vectors, therefore, the vector can be expressed in a desirable cell, target tissue can be selectively treated, and replication and expression modulated. Web site: http://www.delphion.com/details?pn=US06638762__ •
Utilization of osteocalcin promoter to deliver therapeutic genes to tumors Inventor(s): Cheon; Jun (Anam-Dong, KR), Chung; Leland W. K. (Lovingston, VA), Kao; Chinghai (Charlottesville, VA), Ko; Song-Chu (Charlottesville, VA), Sikes; Robert A. (Charlottesville, VA) Assignee(s): The University of Virginia Patent Foundation (charlottesville, Va) Patent Number: 6,596,534 Date filed: March 23, 2000 Abstract: A therapeutic agent based on a recombinant adenovirus which employs an osteocalcin promoter for the expression of thymidine kinase can be administered intravascularly to treat metastatic cancer, including osteosarcoma, breast cancer, prostate cancer, ocular melanoma or brain cancer. Systemic administration of this agent provides a preferred route over previous disclosure of local direct administration. The same therapeutic agent can be effectively employed in the treatment of benign conditions, including benign prostatic hypertrophy and arteriosclerosis. Excerpt(s): This invention pertains to the systemic administration of an active agent, a recombinant gene comprising an adenovirus (Ad) which contains an osteocalcin promoter (OC) which drives the expression of thymidine kinase (TK). The agent itself is fully disclosed in the parent application. This invention pertains to the discovery that Ad-OC-TK may be administered systemically, both to treat tumors, and to treat certain benign conditions such as benign prostatic hypertrophy and certain forms of arteriosclerosis. Toxic gene therapy for the treatment of cancer continues to gain prominence in basic research, but remains limited in clinical application because of an inability to deliver the toxic gene to the tumor cells with specificity. Many vectors (e.g. retroviruses, retroviral producing cells, adenoviruses, liposomes, and others) can deliver genes (therapeutic or toxic) to target cells. Localized delivery and restricted gene expression to the primary tumor have been accomplished via direct injection of
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therapeutic viruses in animal models.sup.1-4 and clinical trails.sup.5,6 This approach is not feasible for the treatment of metastatic disease because of the presence of multiple lesions that would each require separate injection and manipulation. Therefore, alternative approaches to the treatment of metastatic disease with gene therapy must be developed. Systemic delivery of therapeutic genes is attractive for targeting metastatic disease, pulmonary metastases in particular. Because the pulmonary vascular system would be the first encountered, the adenovirus would be trapped in the lung parenchyma, allowing for higher infectivity. Lesoon-Wood et al,.sup.7 reported the systemic delivery of wild type p53 complexed with liposomes, targeting the p53 mutated breast cancer cell line (MDA-MB435), inhibiting primary tumor growth by 60%, and decreasing pulmonary metastases in nude mice. Vile et al.sup.8 demonstrated inhibition of B-16 melanoma pulmonary metastases in syngeneic immunocompetent mice by a systemic delivery of retrovirus using a tyrosinase promoter to drive the expression of the toxic gene thymidine kinase (TK) gene. Web site: http://www.delphion.com/details?pn=US06596534__ •
Viral expression vectors comprising a ribosomal promoter sequence Inventor(s): Askari; Frederick K. (Ann Arbor, MI) Assignee(s): Regents of the University of Michigan (ann Arbor, Mi) Patent Number: 6,599,744 Date filed: May 1, 2000 Abstract: The present invention provides improved vectors, including viral vectors such as adenovirus vectors. The vectors comprise ribosomal promoters in operable combination with a gene of interest. The improved vectors are useful for a wide variety of gene therapy applications. Excerpt(s): The invention relates to improved vectors, and more specifically, improved adenovirus vectors useful for gene therapy. Adenoviruses (Ad) are double-stranded DNA viruses. The genome of adenoviruses (.about.36 kb) is complex and contains over 50 open reading frames (ORFs). These ORFs are overlapping and genes encoding one protein are often embedded within genes coding for other Ad proteins. Expression of Ad genes is divided into an early and a late phase. Early genes are those transcribed prior to replication of the genome while late genes are transcribed after replication. The early genes comprise E1a, E1b, E2a, E2b, E3 and E4. The E1a gene products are involved in transcriptional regulation; the E1b gene products are involved in the shut-off of host cell functions and MRNA transport. E2a encodes the a DNA-binding protein (DBP); E2b encodes the viral DNA polymerase and preterminal protein (pTP). The E3 gene products are not essential for viral growth in cell culture. The E4 region encodes regulatory protein involved in transcriptional and post-transcriptional regulation of viral gene expression; a subset of the E4 proteins are essential for viral growth. The products of the late genes (e.g., L1-5) are predominantly components of the virion as well as proteins involved in the assembly of virions. The VA genes produce VA RNAs which block the host cell from shutting down viral protein synthesis. Adenoviruses or Ad vectors have been exploited for the delivery of foreign genes to cells for a number of reasons including the fact that Ad vectors have been shown to be highly effective for the transfer of genes into a wide variety of tissues in vivo and the fact that Ad infects both dividing and non-dividing cells; a number of tissues which are targets for gene therapy comprise largely non-dividing cells.
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Web site: http://www.delphion.com/details?pn=US06599744__
Patent Applications on Adenovirus As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to adenovirus: •
Acetylation of prb by p300 assay method for compounds which modulate this process Inventor(s): Chan, Ho Man; (Boston, MA), la Thangue, Nicholas Barrie; (Abingdon, GB) Correspondence: Harness Dickey & Pierce; Suite 400; 7700 Bonhomme; ST Louis; MO; 63105; US Patent Application Number: 20040048242 Date filed: August 5, 2003 Abstract: The present invention is based upon the finding that the protein p300 has acetylation activity which is directed to the retinoblastoma tumour suppressor protein pRb by the presence in the cell of the adenovirus E1A protein. This represents a target for modulators of the cell cycle, to which end the invention provides an assay for a modulator of acetylation of pRb by p300, which comprises: a) bringing into contact a p300 protein a pRb protein and a putative modulator compound under conditions where the p300 protein, in the absence of said modulator is capable of acetylating the pRb protein; b) providing conditions for acetylation of said pRb protein; and c) measuring the degree of inhibition of acetylation caused by said modulator compound. Excerpt(s): The present invention relates to the finding of a novel interaction between the proteins p300 and pRb, assays based upon this interaction and novel compounds obtainable by such assay methods. The product of the retinoblastoma tumour suppressor gene, pRb, mediates control of the G1 to S phase transition by interacting with growth-regulating transcription factors, such as the E2F family [1, 2]. The Rb gene is frequently mutated in tumour cells, and can be inactivated through the physical association with viral oncoproteins such as adenovirus E1A [3]. Post-translational phosphorylation control of pRb by G1 cyclin-dependent kinases plays an important role in regulating pRb activity [4]. The p300/CBP transcriptional co-activator proteins are endowed with histone acetyltransferase (HAT), which is involved in regulating chromatin [6]. We have identified acetylation as a new level of control in the regulation of pRb. Adenovirus E1A, which sequesters p300/CBP proteins through an N-terminal transformation-sensitive domain3, stimulates the acetylation of pRb by the E1Adependent recruitment of p300 and pRb into a ternary protein complex. Our data indicate that the acetylation of pRb is specific to the p300/CBP histone acetyl transferases and not a feature of other HATs such as pCAF. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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This has been a common practice outside the United States prior to December 2000.
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Adenoviral vectors for gene delivery in skeletal muscle cells or myoblasts Inventor(s): Bout, Abraham; (Moerkapelle, NL), Havenga, Menzo Jans Emco; (Rijn, NL) Correspondence: Allen C Turner; Traskbritt; P O Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20040071660 Date filed: August 13, 2003 Abstract: The invention provides means and methods for transduction of a skeletal muscle cell and/or a muscle cell specific precursor thereof. Provided is the use of a gene delivery vehicle derived from an adenovirus, having a tropism for said cells, for the preparation of a medicament. In a preferred aspect of the invention, said gene delivery vehicle comprises at least a tropism determining part of an adenoviral fiber protein of subgroup B and/or F. More preferably, said gene delivery vehicle comprises at least part of a fiber protein of an adenovirus of stereotype (11, 16, 35, 40 and/or 51) or a functional part, derivative and/or analogue thereof. Excerpt(s): The invention relates to the field of molecular genetics and medicine. More in particular the invention relates to adenoviral vectors for targeting to skeletal muscle and/or myoblast cells. The technology of delivering genetic material to cells is currently wide spread and finds many applications. With the technology at hand, it is possible to transfer a wide variety of nucleic acids into a wide variety of different cell types. Some of the more classical technologies include calcium phosphate precipitation, liposome mediated transfer, viral vector mediated transfer, particle bombardment and electroporation. However, there is no ideal system for the transfer of nucleic acid into cells. All of the transfer systems of the art have their advantages and disadvantages. For instance, the calcium phosphate technology has been shown to be very effective in the transfection of many in vitro growing immortalized cell lines, however, transfer of nucleic acid into many primary cells both in vitro and in vivo has proven to be very difficult. In fact, efficient transfer of nucleic acid in primary cells has only become broadly applicable with the development of systems that use viral elements. Such viral vector systems utilize the very efficient mechanisms that viruses have developed to introduce their genetic information into the target cell. One of the best-studied viral vector systems is the adenovirus vector system. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Adenoviral vectors for modulating the cellular activities associated to PODs Inventor(s): Calatrava, Manuel Rosa; (Strasbourg, FR) Correspondence: Burns Doane Swecker & Mathis L L P; Post Office Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030219410 Date filed: January 31, 2003 Abstract: The present invention concerns a method of modulating one or more cellular activities dependent on a POD nuclear structure in a host cell through the action of a molecule of adenoviral origin, wherein said molecule of adenoviral origin is capable of interacting with the cellular function of said POD nuclear structure. In a first aspect, the present invention provides a method, a replication-defective adenoviral vector and a composition intended to reduce or inhibit one or more POD-dependent cellular activities by introducing said adenoviral molecule in the host cell. The invention also
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relates to the use of such replication-defective adenoviral vector or molecule to provide a reduction or an inhibition of the antiviral or apoptosis cellular activities as well as to provide a reduction of the toxicity induced by a replication-defective adenovirus vector or to enhance transgene expression driven from said replication-defective adenovirus vector. In a second aspect, the present invention provides a replication-competent adenoviral vector having native pIX or E4orf3 gene non-functional or deleted, as well as a viral particle, a host cell and a composition comprising such a replication-competent adenoviral vector and a method of treatment using such a replication-competent adenoviral vector. The present invention also concerns a method of enhancing apoptosis in a host cell using such a replication-competent adenoviral vector. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119 of EP 02/36 0050.5, filed Feb. 1, 2002, and of provisional application Serial No. 60/353,226, filed Feb. 4, 2002, both hereby expressly incorporated by reference. The application is also a continuation of said '226 provisional. Gene therapy can be defined as the transfer of genetic material into a cell or an organism. The possibility of treating human disorders by gene therapy has changed in the last few years from the stage of theoretical considerations to that of clinical applications. The first protocol applied to man was initiated in the USA in September 1990 on a patient suffering from adenine deaminase (ADA) deficiency. This first encouraging experiment has been followed by numerous new applications and promising clinical trials based on gene therapy are currently ongoing (see for example clinical trials listed at http://cnetdb.nci.nih.gov/trialsrch.shtml or http://www.wiley.co.uk/genetherapy/clinical/). The large majority of the current protocols employ vectors to carry the therapeutic gene to the cells to be treated. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Adenoviral vectors having nucleic acids encoding immunomodulatory molecules Inventor(s): Scaria, Abraham; (Framingham, MA), Wadsworth, Samuel; (Shrewsbury, MA) Correspondence: Genzyme Corporation; Legal Department; 15 Pleasant ST Connector; Framingham; MA; 01701-9322; US Patent Application Number: 20040023389 Date filed: November 12, 2002 Abstract: The invention relates to recombinant adenoviral vectors for use in delivering a nucleic acid(s) encoding an immunomodulatory molecule(s) to the cells of an individual that allows the vector to reduce or evade the host immune response from the cells of said individual. These vectors could be used to induce tolerance to an adenovirus antigen or transgenic products by transduction of antigen-presenting cells of an individual and/or increase the half-life of antigen-presenting cells in order to enhance immune response against tumor antigens.The invention further relates to recombinant adenoviral vectors for use in delivering desired therapeutic transgenes to cells in patients, said vectors containing at least one nucleic acid encoding an immunomodulatory molecule that allow the vectors containing said nucleic acid(s) to reduce or evade the host antiviral immune response to the adenovirus and one or more transgenes. These vectors are capable of increased persistence in the individual to whom they are administered, thereby facilitating longer term administration of transgenes and reduced immunologic response upon administration. The invention also relates to methods for the use of such vectors in delivering transgenes to patients for therapeutic uses.
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Excerpt(s): The invention relates to recombinant adenoviral vectors that can be used to deliver a nucleic acid encoding an immunomodulatory molecule(s) to the cells of an individual. The nucleic acid encoding the immunomodulatory molecule allows the vector to reduce or evade an immune response to the vector or the cells harboring the vector. The vectors may be used to induce tolerance to an adenovirus antigen and/or biologically active transgene product in antigen-presenting cells of an individual to whom they are administered, increase the half-life of cells in the body that have taken up the vector and expressed the antigen and/or transgene product, e.g. antigenpresenting cells. The invention further relates to recombinant adenoviral vectors that can be used to deliver a desired transgene to cells of an individual, said vectors containing at least one nucleic acid encoding an immunomodulatory molecule that allow such vectors to reduce or evade the host antiviral immune response to the adenovirus and/or the transgene. These vectors can provide increased persistence in the individual to whom they are administered, thereby reducing the need for multiple readministration, as well as reduced immunologic response upon administration or readministration. The invention also relates to methods for the use of such vectors in delivering genes to cells of an individual for expression therein. The ability to deliver a transgene to a target cell or tissue and have it expressed therein to produce a desired phenotypic effect depends on the development of gene transfer vehicles that can safely and efficiently deliver an exogenous nucleic acid (transgene) to the recipient cell. To this end, most efforts have focused on the use of virus-derived vectors in order to exploit the natural ability of a virus to deliver its genetic content to a target cell. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Adenovirus carrying gag gene HIV vaccine Inventor(s): Bett, Andrew J.; (Lansdale, PA), Casimiro, Danilo R.; (Harleysville, PA), Caulfield, Michael J.; (Fort Washington, PA), Chastain, Michael A.; (Glenside, PA), Chen, Ling; (Blue Bell, PA), Emini, Emilio A.; (Strafford, PA), Shiver, John W.; (Doylestown, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030228329 Date filed: June 13, 2003 Abstract: An adenoviral vector is described which carries a codon-optimized gag gene, along with a heterologous promoter and transcription terminator. This viral vaccine can effectively prevent HIV infection when administered to humans either alone or as part of a prime and boost regime also with a vaccine plasmid. Excerpt(s): This application is a continuation-in-part of PCT International Application No. PCT/US00/18332, filed Jul. 3, 2000, which designates the U.S., which claims the benefit, under 35 U.S.C.sctn.119(e), of U.S. Provisional Application Serial No. 60/148,981, filed Aug. 13, 1999 and U.S. Provisional Application Serial No. 60/142,631, filed Jul. 6, 1999. This invention relates to replication deficient adenovirus vectors comprising an optimized human immunodeficiency virus (HIV) gag gene under the control of a strong promoter, which are suitable for vaccines against HIV. Human Immunodeficiency Virus-1 (HIV-1) is the etiological agent of acquired human immune deficiency syndrome (AIDS) and related disorders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Adenovirus formulations Inventor(s): Evans, Robert K; (Souderton, PA), Volkin, David B; (Doylestown, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20040033239 Date filed: August 20, 2002 Abstract: The invention relates to viral formulations and related pharmaceutical products for use in gene therapy and/or vaccine applications. Especially preferred viral formulations disclosed herein are liquid adenovirus formulations, which show improved stability when stored in about the 2-8.degree. C. range while also being compatible with parenteral administration. These formulations comprise a buffer, a sugar, a salt, a divalent cation, a non-ionic detergent, as well as a free radical scavenger and/or a chelating agent to inhibit free radical oxidation. Excerpt(s): This application claims benefit, under 35 U.S.C.sctn.119(e), to U.S. provisional application serial No. 60/187,440, filed Mar. 7, 2000. The present invention relates to viral formulations and related pharmaceutical products for use in gene therapy and/or vaccine applications. Especially preferred viral formulations disclosed herein are liquid adenovirus formulations, which show improved stability when stored in about the 2-8.degree. C. range while also being compatible with parenteral administration. These formulations may comprise a buffer, a sugar, a salt, a divalent cation, a non-ionic detergent, as well as a free radical scavenger and/or chelating agent to inhibit free radical oxidation. An especially preferred stabilized virus formulation disclosed herein is a formulation based on inclusion of one or a combination of excipients that inhibit free radical oxidation, which are shown herein to increase stability of adenovirus formulations over commercially acceptable periods of time in about the 28.degree. C. range. An ongoing challenge in the field of gene therapy and vaccine research is to generate liquid virus formulations which are stable for longer periods of time within a useful temperature range, such as from about 2.degree. C. to about 8.degree. C. Adenovirus vectors are currently considered one of the leading approaches for gene delivery/therapy. Because of the great potential for adenoviruses in the field of gene therapy, there remains a need for virus formulations that are suitable for human parenteral use, and have a 1-2 year shelf-life at 2-8.degree. C. Although the U.S. military has developed live adenovirus vaccines for human use, they were lyophilized formulations delivered as oral dosage forms in enteric coated capsules (Chanock, et al., 1966, J. Am. Med. Assoc. 195: 151-158; Griffin, et al., 1970, Arch. Intern. Med. 125: 981986; Top, et al., 1971, J. Infect. Dis. 124: 148-154). The excipients used in these early lyophilized formulations (gelatin, skim milk, human serum albumin) make these lyophilized formulations very unattractive for human parenteral administration. Despite reports on the structure and characterization of adenoviruses, there has been little published on the development of stabilization and formulation of adenovirus for parenteral administration in humans. Furthermore, most of the formulation work concerns lyophilized rather than aqueous formulations, presumably because the prospects for a stable liquid formulation seemed rather poor. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Adenovirus serotype 30 (Ad30) Inventor(s): Davidson, Beverly L.; (North Liberty, IA), Law, Lane K.; (Iowa City, IA) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20040038924 Date filed: July 15, 2003 Abstract: The present invention provides an adenovirus serotype 30 (Ad30) fiber amino acid sequence. The present invention also provides polynucleotides and expression vectors encoding an Ad30 fiber and viral particles and cells containing such expression vectors. The present invention further provides methods of treating genetic diseases or cancers in a mammal using the polynucleotides, polypeptides, expression vectors, viral particles and cells of the present invention. Excerpt(s): This is a divisional application of U.S. application Ser. No. 09/758,008 filed Jan. 9, 2001, which application is incorporated herein by reference. Gene transfer for the correction of inborn errors of metabolism and neurodegenerative diseases of the central nervous system (CNS), and for the treatment of cancer has been accomplished with recombinant adenoviral vectors. High particle doses, however, are required for efficacy in mice and rats, and for the infection of large numbers of cells in monkeys. The delivery of such high particle loads has the negative side effect of inducing an immune response in vivo. Thus, gene transfer to brain tissues with adenovirus type 2 (Ad2) or Ad5 vectors is inefficient, which is also true for endothelia, smooth muscle, and differentiated airway epithelia. Methods that improve the efficiency of adenovirus-mediated gene transfer to cells of the CNS, or other target cells such as tumor cells, could reduce the particle load required to achieve sufficient levels of transduction. Improved efficiency could then reduce toxicity and increase the therapeutic index. There is a continuing need for vehicles and methods for efficient adenovirus-mediated gene transfer of nucleic acids or proteins to cells, such as cells of the CNS or tumor cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Aryl phosphate derivatives of d4T with selective activity against adenovirus and HIV Inventor(s): Uckun, Fatih M.; (White Bear Lake, MN) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030236218 Date filed: October 25, 2002 Abstract: Methods and compositions for treating ADV infections and HIV/ADV coinfections by administering an aryl phosphate derivative of d4T having an electron withdrawing substituent on the aryl group and an amino acid substituent on the phosphate group are described. Preferred aryl phosphate derivatives of d4T are d4T-5'[p-bromophenyl methoxyalaninyl phosphate] and d4T-5'-[p-chlorophenyl methoxyalaninyl phosphate]. Excerpt(s): 60/388,470 "PHENYL ACTIVITY
This application claims priority to U.S. Provisional Application No. filed on Jun. 12, 2002 and U.S. Provisional Application No. ______, entitled PHOSPHATE DERIVATIVES OF STAVUDINE WITH SELECTIVE AGAINST ADENOVIRUS AND HIV" filed on Oct. 21, 2002. Adenovirus
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(ADV) infection results in significant morbidity and mortality in both immunocompetent and immunosuppressed hosts. Adenoviruses have been recovered from human immunodeficiency virus (HIV) positive patients since the beginning of the AIDS epidemic (Khoo et al. J. Infect. Dis., 1996, 172:629-637). In immunocompromised hosts, such as HIV infected individuals, adenoviruses are responsible for a broad range of clinical diseases that may be associated with high mortality, including pneumonia, hepatitis, encephalitis, hemorrhagic cystitis, nephritis, and gastroenteritis in immunocompromised patients. (Bhanthumkosol, J. C., J Med. Assoc. Thai., 1998, 81:214222; Carrigan et al., Am. J Med., 1997, 102:71-74; De Jong et al., J Clin. Microbiol., 1999, 37:3940-0945; Dombrowski et al., Virchows Arch, 1997, 431:469-472; Ghez et al., Am. J Hematol., 2000, 63:32-34; Green et al., Clin. Infect. Dis., 1994, 172:629-637; Khoo et al., J. Infect. Dis., 1995, 172:629-637; Maslo et al., Am. J. Respir. Crit. CareMed., 1997, 156:12631264). Adenovirus colitis is a common cause of diarrhea in HIV-infected patients and may facilitate enteric infection with cytomegalovirus (CMV) (Thomas et al., HIV Med., 1999, 1:19-24). Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease (Sabin et al., J. Med. Virol., 1999, 58:280-285). The median survival of HIVinfected patients with adenovirus-positive diarrhea is 1 year compared with 2.4 years for those without adenoviruses (Sabin et al., J. Med. Virol., 1999, 58:280-285). This difference remains significant after accounting for differences in CD4 counts between the groups, suggesting that adenoviruses may contribute to mortality in this population (Sabin et al., J. Med. Virol., 1999, 58:280-285). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Bipartite T-cell factor (Tcf)-responsive promoter Inventor(s): Hung, Mien-Chie; (Houston, TX), Kwong, Ka Yin; (Rockville, MD), Zou, Yiyu; (Bronx, NY) Correspondence: Fulbright & Jaworski, Llp; 1301 Mckinney; Suite 5100; Houston; TX; 77010-3095; US Patent Application Number: 20030228285 Date filed: May 5, 2003 Abstract: The present invention is directed to methods and compositions for cancer therapy, particularly cancers resulting from a defective Wnt/.beta.-catenin signaling pathway. In specific embodiments, a T-cell factor (Tcf)-responsive promoter regulating expression of a therapeutic gene is administered to an individual having the cancer. In a specific embodiment, the Tcf-responsive promoter comprises a minimal CMV promoter and is present on an adenovirus vector. The promoter regulates expression of a therapeutic gene. Excerpt(s): The present invention claims priority to U.S. Provisional Patent Application 60/377,672, filed May 3, 2002, which is incorporated by reference herein in its entirety. The present invention is directed to the fields of cancer therapy and cell biology. Specifically, the present invention regards compositions and methods for cancers related to activation of the Wnt/.beta.-catenin pathway. Specifically, the present invention regards a vector having a bipartite T-cell factor (Tcf)-responsive promoter regulating a therapeutic gene for cancer therapy. Cancer is a serious health issue for millions of individuals. Colon cancer affects over 100,000 persons in the United States each year and an estimated 50,000 die of the disease during the same period (Landis et al., 1998; Landis et al., 1999). Mutation in the adenomatous polyposis coli gene (APC) or other components of the Wnt/.beta.-catenin signaling pathway is believed to be a critical step
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in colon tumorigenesis. Loss of functional APC protein or constitutively stable.beta.catenin mutants in cancer cells prevents degradation of the.beta.-catenin protein through the ubiqutin/proteosome pathway. As a result,.beta.-catenin protein is accumulated in the cytoplasm and nucleus of the cancer cells, leading to hyperactivation of downstream target promoters of the Wnt/.beta.-catenin signaling pathway (also referred to as the APC/.beta.-catenin pathway or the.beta.-catenin/Tcf pathway. The.beta.-catenin protein does not bind DNA by itself; rather, it forms a bipartite complex with the T-cell factor family transcription factors and activates.beta.catenin/Tcf-resp- onsive promoters. Many transcription targets of the Wnt/.beta.catenin signaling pathway have been identified, including genes that are involved in tumorigenesis, such as CyclinD-1 (Tetsu and McCormick, 1999; Shtutman, et al., 1999; Lin SY, et al., 2000), c-myc (He et al., 1998a), and metalloprotease (Crawford et al., 1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Capsid-modified recombinant adenovirus and methods of use Inventor(s): Curiel, David T.; (Birmingham, AL) Correspondence: Benjamin Aaron Adler; Adler & Associates; 8011 Candle Lane; Houston; TX; 77071; US Patent Application Number: 20040081637 Date filed: September 23, 2003 Abstract: The present invention describes recombinant adenoviral vectors modified by incorporating targeting ligands or label into viral capsid or structural proteins. In one embodiment, single-chain antibody was introduced into the minor capsid proteins pIIIa or pIX so that the adenoviral vector can be targeted to a particular cell type. In another embodiment, there is provided a noninvasive imaging strategy useful for monitoring the replication and spread of conditionally replicative adenoviral vectors. Viral structural proteins such as pIX capsid protein, core proteins mu, V and VII were expressed as fusion protein with a fluorescent label. Once incorporated into the virions, detection of the structural fusion protein label would indicate the localization of the disseminated viral progeny. The detected fluorescent signals also closely correlate with the level of viral replication and progeny production. Excerpt(s): This continuation-in-part application claims the benefit of priority of application Ser. No. 10/424,409, filed Apr. 28, 2003, which is a divisional application of U.S. Pat. No. 6,555,368, which claims the benefit of priority of application 60/156,104, filed Sep. 24, 1999, now abandoned. The present invention relates generally to modification of adenoviral gene therapy vectors and uses thereof. In one embodiment, the present invention discloses modified adenoviral vectors that have altered tropism. In another embodiment, there is provided fluorescently labeled adenoviral vectors useful for monitoring viral vector distribution. Adenoviral vectors (Ad) have proven to be of enormous utility for a variety of gene therapy applications. This usefulness is derived largely from the unparalleled delivery efficiency of these vectors for in vitro and in vivo applications. Despite this property, however, the full benefit of these vectors is undermined currently by the lack of cell-specific gene delivery capability. Specifically, the promiscuous tropism of the adenovirus hinders gene delivery in a targeted, cellspecific manner. Thus, for the many gene therapy applications where such cell-specific transduction is required, current adenoviral vectors have limited utility. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Complementing cell lines Inventor(s): Havenga, Menzo; (Alphen aan den Rijn, NL), Mehtali, Majid; (Plobseim, FR), Vogels, Ronald; (Linschoten, NL) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20030171336 Date filed: June 4, 2002 Abstract: A packaging cell line capable of complementing recombinant adenoviruses based on serotypes from subgroup B, preferably adenovirus type 35. The cell line is preferably derived from primary, diploid human cells transformed by adenovirus E1 sequences either operatively linked on one or two DNA molecules, the sequences operatively linked to regulatory sequences enabling transcription and translation of encoded proteins. Also, a cell line derived from PER.C6 that expresses functional Ad35 E1B sequences. The Ad35-E1B sequences are driven by the E1B promoter and terminated by a heterologous poly-adenylation signal. The new cell lines are useful for producing recombinant adenoviruses. The cell lines can be used to produce human recombinant therapeutic proteins such as human antibodies. In addition, the cell lines are useful for producing human viruses other than adenovirus such as influenza, herpes simplex, rotavirus, and measles. Excerpt(s): This application is a divisional of application Ser. No. 09/713,678, filed Nov. 15, 2000, pending (the contents of the entirety of which are incorporated by this reference), now U.S. Pat. No. ______, which is a continuation-in-part of application Ser. No. 09/573,740, filed May 18, 2000, pending, which claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/134,764, filed May 18, 1999. The invention relates to the field of biotechnology generally, and more specifically to adenoviral-based complementing cell lines. Typically, vector and packaging cells are adapted to one another so that they have all the necessary elements, but they do not have overlapping elements which lead to replication competent virus by recombination. Therefore, the sequences necessary for proper transcription of the packaging construct may be heterologous regulatory sequences derived from, for example, other human adenovirus ("Ad") serotypes, non-human adenoviruses, other viruses including, but not limited to, SV40, hepatitis B virus ("HBV"), Rous Sarcoma Virus ("RSV"), cytomegalovirus ("CMV"), etc. or from higher eukaryotes such as mammals. In general, these sequences include a promoter, enhancer and polyadenylation sequences. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Composition and method for stimulating immune response to pathogen using complex adenoviral vector Inventor(s): Wang, Danher; (Mt. Pleasant, SC) Correspondence: Wilson Sonsini Goodrich & Rosati; 650 Page Mill Road; Palo Alto; CA; 943041050 Patent Application Number: 20040028652 Date filed: December 19, 2002 Abstract: Genetic vaccines and methods are provided for enhancing the immunity of a host such as a human to one or more pathogens. In one aspect, a method of enhancing the immunity of a host to a pathogen is provided. The method comprises administering
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to the host a recombinant virus comprising an antigen sequence that is heterologous to a native progenitor of the recombinant adenovirus and encodes a viral antigen from a pathogenic virus, expression of which is under the transcriptional control of a first promoter; and a cytokine sequence that is heterologous to the native progenitor of the recombinant adenovirus and encodes a cytokine, expression of which is under the transcriptional control of a second promoter. Expression of the antigen and cytokine sequences elicits an immune response directed against the viral antigen upon infection of the host by the recombinant virus. The method can be used for immunizing a host against a wide variety of pathogen viruses, such as HIV, Ebola virus, Marburg virus, hepatitis B virus, hepatitis C virus, influenza virus, human simplex virus, human papilloma virus and respiratory syncytial virus. Excerpt(s): This application is a divisional application of U.S. Patent Application entitled "GENETIC VACCINE THAT MIMICS NATURAL VIRAL INFECTION AND INDUCES LONG-LASTING IMMUNITY TO PATHOGEN", application Ser. No.: 09/585,599, Filed: Jun. 2, 2000, which is incorporated herein by reference. This invention relates to vaccines for stimulating immune responses in human and other hosts, and, in particular, relates to recombinant viruses that express heterologous antigens of pathogenic viruses, such as Ebola, HIV, hepatitis, and influenza viruses. Current techniques for developing vaccines are largely based on the concept of using denatured virus or purified viral proteins made from bacteria. These types of vaccines may be effective for only a limited number of infectious agents, and the protection rates are limited. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compositions and methods for viral delivery Inventor(s): Evans, Lawrence; (Seattle, WA), Mossman, Sally; (Seattle, WA), Swanson, Ryan M.; (Seattle, WA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030228279 Date filed: October 29, 2002 Abstract: Compositions and methods comprising a recombinant virus and an immunostimulant are provided for enhancing the immune response to a polypeptide expressed from the recombinant virus. Preferably this is done without also enhancing the neutralizing antibody response to the recombinant virus. Illustrative compositions comprise an adenovirus and an adjuvant such as, for example, monophosphoryl lipid A, an alkyl glucosaminide phosphate, a saponin, or a combination thereof. The disclosed compositions and methods are useful, for example, in the treatment of diseases such as cancer or infectious disease. Excerpt(s): This application claims the priority of U.S. Provisional Application Serial No. 60/335,512, filed Oct. 31, 2002, and No. 60/369,715, filed Apr. 3, 2002, the disclosures of which are hereby incorporated herein in their entirety. The present invention relates generally to compositions and methods for viral delivery and, more specifically, to compositions and methods comprising combinations of recombinant viruses and immunostimulants, such as adjuvants, having improved immunological properties. Conventional compositions and methodologies employing recombinant viruses in combination with immunostimulants such as, for example, Seppic adjuvant ISA206 for delivery and protein expression of therapeutic polynucleotides are frequently hampered
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by the in vivo induction of neutralizing antibody responses that effectively blocks viral efficacy. See, e.g., Adam et al., Veterinary Microbiology 42:205-215 (1994). Thus, there remains a need in the art for improved compositions and methods that permit immunization regimens employing reduced recombinant viral titers while maintaining strong immune responses. As described in further detail herein, the compositions and methods of the present invention fulfill this need and further provide other related advantages. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Coxsackievirus vectors and their use in prevention and treatment of disease Inventor(s): Chapman, Nora M.; (Omaha, NE), Tracy, Steven M.; (Omaha, NE) Correspondence: Janet E. Reed, ESQ.; Woodcock Washburn Llp; 46th Floor; One Liberty Place; Philadelphia; PA; 19103; US Patent Application Number: 20030190329 Date filed: March 26, 2001 Abstract: The present invention is drawn to the use of attenuated coxsackievirus cardiotropic virus vectors as efficient gene transfer vectors to deliver immunomodulatory or other biologically active proteins and/or antigenic epitopes in transient infections to aid in preventing, ameliorating, and/or ablating infectious viral heart disease and reducing, or ablating entirely, heart transplant rejection. Specifically disclosed are univalent and multivalent vaccines for certain viruses, including adenovirus and coxsackieviruses. Also disclosed are compositions and methods for suppressing onset of type 1 diabetes, using vectors of the invention that express immunomodulatory proteins, specifically IL-4. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/403,672, having a filing date of Mar. 27, 2000 and claiming priority under 35 U.S.C.sctn.371 to International Application No. PCT/US98/04291, which itself claims priority under 35 U.S.C.sctn.120 to U.S. application Ser. No. 08/812,121, filed Mar. 5, 1997, now U.S. Pat. No. 6,071,742, issued Jun. 6, 2000. The entireties of each of the abovelisted applications are incorporated by reference herein. The present invention relates generally to the fields of molecular biology and virology. More specifically, the present invention relates to an attenuated Coxsackievirus, its use as a delivery vehicle for nucleic acids encoding antigenic or biologically active proteins, and treatment or prevention of viral infection or type 1 diabetes. Various scientific articles, scholarly publications and patent documents are referred to herein to describe the state of the art to which the invention pertains. Each of these documents is incorporated by reference herein in its entirety. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Efficient purification of adenovirus Inventor(s): Carrion, Miguel E.; (New Market, MD), Kovesdi, Imre; (Rockville, MD), Menger, Marilyn; (Germantown, MD) Correspondence: Leydig Voit & Mayer, Ltd; Two Prudential Plaza, Suite 4900; 180 North Stetson Avenue; Chicago; IL; 60601-6780; US Patent Application Number: 20030203469 Date filed: May 5, 2003 Abstract: A method of enriching a solution for an adenovirus comprising contacting a solution containing an adenovirus with an anion exchange chromatography resin comprising an acrylate or sulphonamide linker such that the adenovirus binds to the chromatography resin and eluting the adenovirus from the resin with an eluant to obtain an enriched solution of adenovirus. Excerpt(s): This patent application is a divisional of copending U.S. patent application Ser. No. 09/997,909, filed Nov. 30, 2001, which is a continuation of U.S. patent application Ser. No. 09/296,962, filed Apr. 22, 1999, now U.S. Pat. No. 6,383,795, which claims the benefit of U.S. Provisional Patent Application No. 06/082,628, filed Apr. 22, 1998. The present invention relates to the efficient purification of adenovirus. Traditionally, adenoviral particles have been isolated through the use of density gradient purification protocols, such as through the use of cesium chloride (CsCl) gradients. While suitable for small-scale preparations, density gradient purification is tedious and time consuming and cannot be easily scaled-up. Accordingly, the process is frequently considered commercially undesirable. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Enhancement of drug cytotoxicity in tumor cells containing mutant Rb gene Inventor(s): Lowe, Scott W.; (Cold Spring Harbor, NY) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20040048821 Date filed: March 26, 2003 Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/103,953, filed Jun. 24, 1998, which claims the benefit of U.S. Provisional Application No. 60/051,086, filed Jun. 27, 1997. The entire teachings of the above application(s) are incorporated herein by reference. Cancer therapy is an area of medicine in which there is an ongoing need for more effective treatment, particularly drugs and protocols which have enhanced cytotoxicity toward tumor cells. Described herein are mutant forms of the adenovirus E1A oncoprotein which are unable to bind and inactivate retinoblastoma (Rb) protein and are defective in promoting apoptosis and chemosensitivity in normal (non-tumorigenic or nonmalignant) cells, but enhance apoptosis and sensitivity to toxic agents (e.g., chemotherapeutic agents, radiation) in Rb protein deficient mutant cells. Such E1A mutant oncoproteins are useful to enhance apoptosis and sensitivity to toxic agents in Rb protein deficient mammalian cells. Rb protein mutant or deficient cells include mammalian cells which lack a Rb gene or contain a mutant Rb gene and in which, as a result, Rb gene product is not produced or is produced to a lesser extent than in corresponding cells which contain a normal Rb gene and mammalian cells in
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which Rb gene product is produced but is inactivated, directly or indirectly. Rb protein mutant or deficient cells also include mammalian cells in which there are mutations or alterations in the pathway through which Rb acts, rendering Rb defective or inactive. Rb mutant cells are also referred to herein as Rb protein deficient cells; the two terms are used interchangeably. Also described is a method of enhancing drug cytotoxicity specifically in tumor cells which are Rb mutant cells. This method is useful in specifically enhancing the cytotoxicity of toxic agents, such as irradiation or chemotherapeutic agents (e.g., adriamycin), toward tumor cells and, thus, in the treatment of individuals receiving anti-cancer therapy. A particular advantage of the method is that Rb protein deficient cells (e.g., tumor cells) are killed to a greater extent than are normal cells and less drug is needed to kill tumor (Rb protein deficient) cells than is necessary using conventional methods of treatment. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Large-scale recombinant adeno-associated virus (rAAV) production and purification Inventor(s): Qu, Quang; (Alameda, CA), Wright, John Fraser; (Mill Valley, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030207439 Date filed: May 19, 2003 Abstract: Methods are provided for large-scale purification of recombinant AAV (rAAV) virions that were produced in the absence of infectious adenovirus. Preferably, the rAAV is produced in a host cell line via triple-transfection with an accessory function vector, an AAV vector, and an AAV helper vector. The methods include preparing a lysate from the host cell line and passing that lysate over various combination of ion exchange chromatography media and/or affinity chromatography media. The affinity chromatography medium is an AAV receptor or an antibody with binding affinity for AAV, e.g., heparin sulfate. A variety of cation exchange and anion exchange media are contemplated by the present invention. In certain embodiment, optional purification steps may be included, such as filtering the lysate through one or more filters, or treating the lysate with a nuclease. Excerpt(s): The present application is a continuation patent application of U.S. patent application Ser. No. 09/633,834, entitled Large-Scale Recombinant Adeno-Associated Virus (rAAV) Production and Purification, which was filed Aug. 7, 2000 on behalf of John Fraser Wright and Quang Qu. The invention relates to methods for producing and purifying recombinant adeno-associated virus (rAAV). More particularly, it relates to methods for producing commercial grade rAAV at large scale where rAAV was generated in the absence of infectious helper virus. The methods employ a plurality of column purification steps that yield purified rAAV. One embodiment of the invention is a two-column purification system comprising purification over an anion exchange column and over an affinity column. In another embodiment, a cation exchange column purification step is included. Gene delivery is a promising method for the treatment of acquired and inherited diseases. A number of viral-based systems for gene transfer purposes have been described, including adeno-associated virus (AAV)-based systems. AAV is a helper-dependent DNA parvovirus that belongs to the genus Dependovirus. AAV requires coinfection with an unrelated helper virus, e.g., adenovirus, herpes virus, or vaccinia, in order for a productive infection to occur. In the absence of a helper virus, AAV establishes a latent state by inserting its genome into a host cell chromosome.
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Subsequent infection by a helper virus rescues the integrated viral genome, which can then replicate to produce infectious viral progeny. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for direct rescue and amplification of integrated viruses from cellular DNA of tissues Inventor(s): Alvira, Mauricio R.; (Philadelphia, PA), Gao, Guangping; (Rosemont, PA), Wilson, James M.; (Gladwyne, PA) Correspondence: Howson And Howson; One Spring House Corporation Center; Box 457; 321 Norristown Road; Spring House; PA; 19477; US Patent Application Number: 20030207259 Date filed: April 22, 2003 Abstract: A method for isolating AAV viruses from cellular DNA of non-human primate (NHP) tissues by transfecting the DNA of NHP into 293 cells, rescuing the virus and amplifying it through serial passages in the presence of adenovirus helper functions is provided. Also provided are kits useful for performing this method. Excerpt(s): This is a non-provisional of U.S. patent application Ser. No. 60/376,469, filed Apr. 29, 2002. Adeno-associated virus (AAV), a member of the Parvovirus family, is a small nonenveloped, icosahedral virus with single-stranded linear DNA genomes of 4.7 to 6 kb (Mr. 1.5-2.0.times.10.sup.6). AAV is assigned to the genus, Dependovirus, because the virus was discovered as a contaminant in purified adenovirus stocks. AAV's life cycle includes a latent phase at which AAV genomes, after infection, are site specifically integrated into host chromosomes and a lytic or production phase in which, following either adenovirus or herpes simplex virus super-infection, the integrated genomes are subsequently rescued, replicated, and packaged into infectious viruses. The properties of simple genomic structure, non-pathogenicity, broad host range of infectivity, including non-dividing cells, and potential site-specific chromosomal integration make AAV an attractive tool for gene transfer. Recent studies suggest that AAV vectors may be the preferred vehicle for achieving stable gene expression. To date, six different serotypes of AAV (AAV1-6) have been isolated from human or non-human primates (NHP), well characterized and vectored for gene transfer applications. All of them have been isolated as infectious viruses from either contaminated adenovirus preparations or tissues specimen of primate and non-human primate origin. Among them, AAV1 and AAV4 were isolated from non-human primates; AAV2, 3 and 5 were derived from humans, and AAV6 was a contaminant of a human adenovirus preparation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for the purification and production of oncolytic adenoviruses Inventor(s): Pennathur-Das, Rukmini; (Los Altos, CA), Wypych, Joseph; (Tracy, CA), Yu, De Chao; (Foster City, CA) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20030175688 Date filed: March 15, 2002 Abstract: A process is provided for the production of substantially pure replication competent adenovirus. Virus infected cells are lysed with detergent. An initial purification step utilizes a pass through a high throughput ion exchange filter. The eluant is treated with nuclease, then refiltered on a high throughput ion exchange filter. The virus suspension is optionally sterile filtered and formulated for use. Excerpt(s): The technical field of the invention is methods of producing and purifying replication competent adenoviral vectors. The use of viruses as a cancer therapy was first explored after observations of occasional tumor regressions in cancer patients suffering from virus infections or receiving vaccinations. Although these early clinical trials were abandoned, the idea was revived after the development of genetic engineering techniques, which held the promise of enhanced efficacy and decreased toxicity. As a result of increasing knowledge of adenoviral interactions with cell cycle regulatory proteins and the experience gained from its use as a gene delivery vehicle, adenovirus has emerged as a virus that can be engineered with oncotropic properties. Adenoviruses generally undergo an effective lytic replication cycle following infection of a host cell. In addition to lysing the infected cell, the replicative process of adenovirus blocks the transport and translation host cell mRNA, thus inhibiting protein synthesis of the infected cell. For a review of adenoviruses and adenovirus replication, see Shenk and Horwitz, Virology, third edition, Fields et al., eds., Raven Press Limited, New York (1996), Chapters 67 and 68, respectively. In addition, replication-competent adenoviruses can sensitize tumor cells to chemotherapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method of obtaining a non-human mammal susceptible to adenovirus-mediated gene delivery, a method for such delivery, and a non-human mammal susceptible to such delivery Inventor(s): Pettersson, Sven; (Tullinge, SE), Philipson, Lennart; (Stockholm, SE), Tallone, Tiziano; (Fribourg, CH) Correspondence: Michael R Ward; Morrison & Foerster; 425 Market Street; San Francisco; CA; 94105-2482; US Patent Application Number: 20040016009 Date filed: July 14, 2003 Abstract: A method of obtaining a non-human mammal susceptible to adenovirusmediated gene delivery, a method for such delivery, and a transgenic non-human mammal susceptible to adenovirus-mediated gene delivery, and more specifically a trans-genic mouse that expresses a cytoplasmically truncated human Coxsackievirus and Adenovirus Receptor (hCAR) in essentially all tissues thereof. The mammal allows for efficient infections at low multiplicity of infection (MOI) into cells that are normally
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resistant or not very susceptible to adenovirus-mediated gene delivery, such as spleenocytes and dendritic cells (DC). The hCAR transgenic mammal is highly susceptible to adenovirus-mediated gene transfer and will be a useful tool to probe gene function in development and to elucidate molecular pathways, dynamic properties and differentiation mechanisms in non-transformed cells. Excerpt(s): The present invention relates to a method of obtaining a non-human mammal susceptible to adenovirus-mediated gene delivery, a method for such delivery, and a transgenic non-human mammal susceptible to adenovirus-mediated gene delivery, and more specifically a transgenic mouse that expresses a cytoplasmically truncated human Coxsackievirus and Adenovirus Receptor (hCAR) protein in essentially all tissues thereof. The mouse allows for efficient infections at low multiplicity of infection (MOI) into cells that are normally resistant or not very susceptible to adenovirus-mediated gene delivery, such as, for example, spleenocytes and dendritic cells PC). The hCAR transgenic mice of the present invention are therefore highly susceptible to adenovirus-mediated gene transfer and will be a useful tool to probe gene function in development and to elucidate molecular pathways, dynamic properties and differentiation mechanisms in non-transformed cells. The elucidation of biological pathways is often derived from the experimental observations following introduction or deletion of nucleic acids. Such experiments with mammalian organisms or cells can be complex and time-consuming. For example, the engineering of in vivo chromosomal alterations usually takes about two years before phenotypes can be assessed, whilst at the same time many primary eukaryotic cells remain recalcitrant to transfection. The use of recombinant viruses is currently one of the most powerful ways to introduce foreign genes into mammalian cells in vivo and in vitro. Adenoviruses (Ads) have received considerable attention as gene delivery vectors because of i) their relatively large cloning capacity, ii) ease of genetic manipulation and growth to high virus titers, iii) the structural stability of the virus particle and iv) their ability to infect proliferating and quiescent cells. Despite the fact that Ad can infect a wide range of cell types, some tissues and cells, such as lymphocytes, are refractory to adenovirus infection. The CAR is a 46 kDa transmembrane protein that belongs to the immunglobulin surperfamily and possesses the highest structural similarity to CTX and human A33-antigen. Its cellular function has not yet been completely elucidated, but recent data suggest that CAR may function as an adhesion molecule. The expression pattern of CAR varies, not only between different developmental stages and tissues but also between species. While CAR is abundantly expressed in the majority of the mouse epithelial cells during embryogenesis, its expression in adult mouse is restricted to a few epithelial cells (Tomko, R. P. et al., Exp. Cell Res. 255, 47-55 (2000) and Fechner, H. et al., Gene Ther. 6, 1520-1535 (1999)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of separating viral particles Inventor(s): Barbot, Anne; (Verrieres-les-Buisson, FR), Blanche, Francis; (Paris, FR), Cameron, Beatrice; (Paris, FR) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20030170710 Date filed: February 25, 2003
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Abstract: The invention concerns a novel method for purifying and quantifying viral particles. More particularly, the invention concerns a method for purifying and quantifying adenovirus by ion-exchange chromatography. The invention also concerns a method for identifying different adenovirus serotypes. Excerpt(s): The present invention relates to a new method for the purification and quantification of viral particles. More particularly, the invention relates to a method of purifying and quantifying adenoviruses by ion-exchange chromatography. The invention also relates to a method of identifying various adenovirus serotypes. Gene therapy is currently undergoing a remarkable development and various clinical studies in humans have been in progress since the first trials conducted in 1990. Among the methods commonly used for the transfer of genes, viral vectors have proved particularly promising, and adenoviruses occupy a key position among them. The development of adenovirus vectors in gene therapy requires access to two types of technologies which are nowadays limiting for the production of viral stocks: the first is to have a method which is rapid, is highly sensitive and is very selective for the quantification of viral particles in samples obtained from the steps of constructing and amplifying the virus considered; this point is particularly important for the optimization of the method of producing viral stocks; the second-is to have a method of purification which is reliable, reproducible, simple and can be easily extrapolated on the industrial scale for the purification of virus particles. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of treating allergic disease and asthma by recombinant adenovirus- and adeno-associated virus- mediated IFN-gamma gene transfer Inventor(s): Behera, Aruna; (Boston, MA), Kumar, Mukesh; (Norwood, MA), Mohapatra, Shyam S.; (Tampa, FL) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20030198624 Date filed: March 3, 2003 Abstract: The subject invention concerns an effective therapy for asthma, including allergic disease, using cytokine gene expression therapy. The subject invention further pertains to the use of adenovirus-medicated IFN-.gamma.(Ad-IFN-.gamma.)gene transfer to prevent or treat allergic disease and asthma, including associated conditions such as allergen-induced airway inflammation and airway hyperresponsiveness. The subject invention includes a method for effectively attenuating allergen-induced airway inflammation and airway hyperresponsiveness by administering to the respiratory tract Ad-IFN-.gamma., to affect IL-12 and Stat-4 levels. The subject invention also provides compositions for gene therapy for asthma by the transfer of IFN-.gamma. Excerpt(s): This application claims the benefit of U.S. Provisional application Serial No. 60/360,841, filed Mar. 1, 2002. The subject invention pertains to the field of asthma and allergen treatment, more particularly to the use of adenovirus as a transfer vector to facilitate such treatment. Allergic asthma is a chronic inflammatory disorder often characterized by airway inflammation and airway hyperreactivity (AHR). It is a leading cause of morbidity and mortality in children, adults, and the elderly. Current therapy for asthma includes treatment with bronchodilators, inhaled steroids, and leukotriene modifiers. Antigen specific immune therapy has also been used to desensitize patients to
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specific allergens; however, it can be ineffective for many allergic asthmatics sensitive to multiple antigens. Similarly, inhaled corticosteriods have severe adverse effects along with suppression of Th1 and Th2 cytokine responses. Also, even with currently available therapies, the incidence of asthma has continued to increase over the last two decades. Thus, an allergic asthmatic therapy is needed that induces long term effects against a broad array of antigens while providing fewer adverse effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods and compositions for the diagnosis and treatment of cancer Inventor(s): Clayman, Gary L.; (Houston, TX) Correspondence: Steven L. Highlander, ESQ.; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20030166603 Date filed: March 24, 2003 Abstract: Methods for the treatment of squamous cell carcinoma using a p53-expressing viral vector are disclosed. In particular embodiments, the vector is a replication-deficient adenovirus. In addition, there are provided methods for examining the development and treatment of microscopic residual disease in the context of post-surgical environments and in body cavities. Excerpt(s): The present invention is related generally to the field of cancer biology. In particular, the invention relates to compositions and methods of treatment for squamous cell carcinoma. Also provided is an animal model for the examination of microscopic residual tumors and tumor seeding into body cavities, as well as methods for treatment thereof. Balancing rates of cell proliferation and cell death is important in maintaining normal tissue homeostasis. Disruption of this balance may be a major factor in the multistep process of tumorigenesis, and inhibition of apoptosis, or programmed cell death, is one cause of this disruption. The effects of such defects are catastrophic, causing over half a million deaths annually in the United States alone. There is considerable evidence implicating mutations of the p53 gene, a tumor suppressor, in the etiology of many human cancers. Reports have demonstrated that growth of several different human cancer cell lines, including representatives of colon cancer, glioblastoma, breast cancer, osteosarcoma and lung cancer can be functionally suppressed by viral-mediated transfer of a wild-type p53 gene. Induction of exogenous p53 expression of wild-type p53 has been shown to induce apoptosis in colon cancer cell lines and in human lung cancer spheroids, suggesting a role for p53 in programmed cell death. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods and compositions useful for targeting activated vitronectin receptor alphavbeta3 Inventor(s): Hato, Takaaki; (Imabari, JP), Nemerow, Glen R.; (Encinitas, CA), Pampori, Nisar A.; (Frederick, MD), Shattil, Sanford J.; (La Jolla, CA), Stupack, Dwayne G.; (San Diego, CA) Correspondence: The Scripps Research Institute; Office OF Patent Counsel, Tpc-8; 10550 North Torrey Pines Road; LA Jolla; CA; 92037; US Patent Application Number: 20040005550 Date filed: June 3, 2003 Abstract: The present invention provides ligands which can selectively bind to activated.alpha.sub.v.beta.sub.3 integrin. A novel monovalent ligand-mimetic (WOW-1 Fab) which includes a single.alpha.sub.v integrin-binding domain from multivalent adenovirus penton base is provided. Further, the present invention describes particular compositions of activated.alpha.sub.v.beta.sub.3-specific ligands, such as an antibody which immunoreacts preferentially with activated.alpha.sub.v.beta.sub.3 integrin. The invention also describes methods using an activated.alpha.sub.v.beta.sub.3-specific ligand for diagnostic detection of activated.alpha.sub.v.beta.sub.3 integrin in tissues and for the targeted delivery of therapeutic agents to tissues containing activated.alpha.sub.v.beta.sub.3 integrin. Excerpt(s): The invention relates to ligands which bind to activated vitronectin receptor.alpha.sub.v.beta.sub.3. The invention also relates to methods using these ligands for diagnostic detection of activated.alpha.sub.v.beta.sub.3 and for targeted delivery of therapeutic agents to activated.alpha.sub.v.beta.sub.3 and to tissues containing activated.alpha.sub.v.beta.sub.3. The integrin known as the vitronectin receptor.alpha.sub.v.beta.sub.3 is well characterized and known to play a role in a variety of biological processes including proliferation of endothelial cells, osteoclasts and arterial smooth muscle cells. Further, it is involved in the biological processes of angiogenesis, arterial restenosis, bone remodeling, osteoporosis and tumor progression. It is further known in the art that integrins mediate cell adhesion and signaling during many developmental, physiological and pathological processes. However, the role of activation of.alpha.sub.v.beta.sub.3 in biological processes is not well understood at present. The.beta.sub.3 integrin family includes.alpha.sub.IIb.beta.sub.3, often referred to as the fibrinogen receptor, and.alpha.sub.v.beta.sub.3, the vitronectin receptor.alpha.sub.IIb.beta.sub.3 is confined to megakaryocytes and platelets and is required for platelet aggregation through interactions with Arg-Gly-Asp (RGD)containing adhesive ligands, including fibrinogen and von Willebrand factor. The vitronectin receptor (.alpha.sub.v.beta.sub.3 integrin) is more widely expressed in proliferating endothelial cells, arterial smooth muscle cells, osteoclasts, platelets and certain subpopulations of leukocytes and tumor cells. The list of cognate ligands for.alpha.sub.v.beta.sub.3 overlaps that of.alpha.sub.IIb.beta.sub.3 but includes others, such as osteopontin, matrix metalloproteinase-2, and adenovirus penton base, which do not interact with the fibrinogen receptor.alpha.sub.IIb.beta.sub.3. One fundamental function of integrins is ligand binding, which in many cases is rapidly regulated by a process variously referred to as "integrin activation", "inside-out signaling" or "affinity/avidity modulation". Integrin activation encompasses at least two events: 1) modulation of receptor affinity through conformational changes in the.alpha.beta. heterodimer; and 2) modulation of receptor avidity through facilitation of lateral diffusion and/or clustering of heterodimers. Studies of.alpha.sub.IIb.beta.sub.3 activation have been facilitated by the use of soluble ligands, most notably a
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multivalent, ligand-mimetic antibody called PAC1, and its monovalent Fab fragment, which contain an RG/YD tract in H-CDR3 (complementarity determining region no. 3 of the heavy chain) (Shattil, S. J., Kashiwagi, H., and Pampori, N. (1998) Blood 91, 26452657; Abrams, C., Deng, J., Steiner, B., and Sihattil, S. J. (1994) J. Biol. Chem. 269, 1878118788). The significance of inside-out signaling, and in particular affinity modulation, for.alpha.sub.v.beta.sub.3 has been less certain. The ligand binding function of.alpha.sub.v.beta.sub.3 has usually been assessed by cell adhesion assays, and these have clearly shown that activation of certain cells leads to.alpha.sub.v.beta.sub.3mediated adhesion. However, adhesion assays can be strongly influenced by postligand binding events, including changes in cell shape, that can obscure the precise contributions of affinity or avidity modulation to the overall response. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods for modulation of cholesterol transport Inventor(s): Kozarsky, Karen; (Philadelphia, PA), Krieger, Monty; (Needham, MA), Rigotti, Attilio; (Malden, MA) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20030167475 Date filed: June 24, 2002 Abstract: Methods for regulation of lipid and cholesterol uptake are described which are based on regulation of the expression or function of the SR-BI HDL receptor. The examples demonstrate that estrogen dramatically downregulates SR-BI under conditions of tremendous upregulation of the LDL-receptor. The examples also demonstrate the upregulation of SR-BI in rat adrenal membranes and other nonplacental steroidogenic tissues from animals treated with estrogen, but not in other nonplacental non-steroidogenic tissues, including lung, liver, and skin. Examples further demonstrate the uptake of fluorescently labeled HDL into the liver cells of animal, which does not occur when the animals are treated with estrogen. Examples also demonstrate the in vivo effects of SR-BI expression on HDL metabolism, in mice transiently overexpressing hepatic SR-BI following recombinant adenovirus infection. overexpression of the SR-BI in the hepatic tissue caused a dramatic decrease in cholesterol blood levels. These results demonstrate that modulation of SR-BI levels, either directly or indirectly, can be used to modulate levels of cholesterol in the blood. Excerpt(s): The present invention is generally in the area of modulation of cholesterol transport via the SR-BI scavenger receptor. All members of the LDL receptor gene family consist of the same basic structural motifs. Ligand-binding (complement-type) cysteine-rich repeats of approximately 40 amino acids are arranged in clusters (ligandbinding domains) that contain between two and eleven repeats. Ligand-binding domains are always followed by EGF-precursor homologous domains. In these domains, two EGF-like repeats are separated from a third EGF-repeat by a spacer region containing the YWTD motif. In LRP and gp330, EGF-precursor homologous domains are either followed by another ligand-binding domain or by a spacer region. The EGFprecursor homology domain, which precedes the plasma membrane, is separated from the single membrane-spanning segment either by an O-linked sugar domain (in the LDL receptor and VLDL receptor) or by one (in C. elegans and gp330) or six EGF-repeats (in LRP). The cytoplasmic tails contain between one and three "NPXY" internalization signals required for clustering of the receptors in coated pits. In a later compartment of
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the secretory pathway, LRP is cleaved within the eighth EGF-precursor homology domain. The two subunits LRP-515 and LRP-85 (indicated by the brackets) remain tightly and non-covalently associated. Only partial amino acid sequence of the vitellogenin receptor and of gp330 are available. LDL receptors and most other mammalian cell-surface receptors that mediate binding and, in some cases, the endocytosis, adhesion, or signaling exhibit two common ligand-binding characteristics: high affinity and narrow specificity. However, two additional lipoprotein receptors have been identified which are characterized by high affinity and broad specificity: the macrophage scavenger receptors type I and type II. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods for the identification of antiviral compounds Inventor(s): Brus, Ronald H.P.; (Voorschoten, NL), Schouten, Govert Johan; (Leiderdorp, NL), UytdeHaag, Alphonsus G.C.M.; (Utrecht, NL) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20040086850 Date filed: October 30, 2003 Abstract: The present invention provides novel methods for determining whether a compound influences a phase in the life cycle of a virus comprising providing a cell with the compound and with at least a fragment of the virus sufficient for performing the phase and determining whether the phase is influenced in the cell, the cell comprising a nucleic acid encoding an adenovirus early protein or a functional part, derivative and/or analogue of the adenovirus early protein. In another aspect, the invention provides the use of a cell, the cell comprising nucleic acid encoding an adenovirus early protein, for screening a library of compounds for the presence of a compound capable of influencing a phase in the life cycle of a virus capable of entering the cell. The invention also provides novel methods for identifying a compound with antiviral activity comprising providing a cell with at least a fragment of a virus, the fragment capable of performing a step in the life cycle of the virus, providing the cell with a compound and determining whether the compound is capable of influencing the step in the life cycle of the virus, wherein the cell comprises a nucleic acid encoding an adenovirus early protein or a functional part, derivative and/or analogue of the adenovirus early protein. Excerpt(s): This application is a continuation of PCT International Patent Application No. PCT/NL02/00296, filed on May 6, 2002 and published, in English, on Nov. 14, 2002 as PCT International Publication No. WO 02/090982, the contents of the entirety of which are incorporated by this reference. This application also claims the benefit under 35 U.S.C.sctn. 119(e) to U.S. provisional patent application 60/289,541. The invention relates generally to the field of biotechnology and microbiology. In particular, the invention relates to the field of identification of antiviral compounds. Several procedures are known for treating virus-related diseases and for preventing disorders that arise as a consequence of viral infections. Prophylactic vaccination is probably one of the most effective measures against potential fatal infectious diseases, since an individual can become fully or partly protected against new infections. The immune system makes sure that the virus that has entered the body or cell is prevented from replicating in the individual, and in most cases the virus disappears completely from the system. Therapeutic vaccination refers to the treatment of infected individuals intentionally to prevent the virus from replicating further and consequently to halt disease progression or to cure the disease by eliminating the virus from the body.
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Modified adenoviral fiber and target adenoviruses Inventor(s): Boulanger, Pierre; (Montpellier, FR), Legrand, Valerie; (Strasbourg, FR), Mehtali, Majid; (Illkirch Graffenstaden, FR) Correspondence: Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030175243 Date filed: April 1, 2003 Abstract: The invention relates to an adenovirus fiber modified by the mutation of one or more residues. The residues are directed towards the natural cell receptor in the three-dimensional structure of said adenovirus. The invention further relates to a DNA fragment, and expression vector, and a cell line expressing said fiber, and also concerns an adenovirus, the process for producing this type of adenovirus, and a infectable host cell, as well as their therapeutic application and a corresponding pharmaceutical composition. Excerpt(s): The subject of the present invention is an adenoviral fiber mutated in the regions involved in the recognition and the binding of the natural cell receptor for adenoviruses. It also relates to the recombinant viruses carrying at their surface such a fiber and a ligand which confers on them a modified or targeted host specificity towards a particular cell type, the cells containing these adenoviruses as well as a method for preparing infectious viral particles thereof intended for therapeutic use. The invention is most particularly of interest for gene therapy perspectives, in particular in humans. By virtue of their particular properties, adenoviruses are used in an increasing number of applications in gene therapy. Having been identified in numerous animal species, they are not very pathogenic, are nonintegrative and replicate both in dividing and quiescent cells. Furthermore, they exhibit a broad host spectrum and are capable of infecting a very large number of cell types such as epithelial cells, endothelial cells, myocytes, hepatocytes, nerve cells and synoviocytes (Bramson et al., 1995, Curr. Op. Biotech. 6, 590-595). However, this absence of specificity of infection could constitute a limit to the use of recombinant adenoviruses, on the one hand, from a safety point of view since there may be dissemination of the recombinant gene in the host organism and, on the other hand, from the efficiency point of view since the virus does not infect specifically the cell type which it is desired to treat. In general, the adenoviral genome consists of a double-stranded linear DNA molecule of about 36 kb containing the genes encoding the viral proteins and, at its ends two inverted repeats (designated ITR for Inverted Terminal Repeat) involved in the replication and the encapsidation region. The early genes are distributed in 4 regions dispersed in the adenoviral genome (E1 to E4; E for early), containing 6 transcriptional units equipped with their own promoters. The late genes (L1 to L5; L for late) partly cover the early transcription units and are, for the most part, transcribed from the major late promoter MLP. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Neuroprotective and neurogenerative effects of the long-term expression of TNF alpha in the substantia nigra and a new animal model for Parkinson's disease Inventor(s): Eisel, Ulrich Lothar Maria; (Waiblingen, DE), Pitossi, Fernando Juan; (Buenos Aires, AR) Correspondence: Bruce Londa; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20030228276 Date filed: April 9, 2003 Abstract: Methods for treating a neurodegenerative disease in a mammal, specifically methods for treating Parkinson's disease. The treatment is based on administering an effective amount of a TNF-related molecules and/or TNF down regulating molecules, acting preferably in the substantia nigra. The effects of TNF over the substantia nigra are disclosed. Low concentration of TNF provides a neuroprotective activity and high concentration of TNF provides a neurodegenerative effect on the mammal. The method is based on a treatment with TNF wherein the concentration of TNF in the patients affected by the Parkinson's disease is regulated. In addition, a treatment in which molecules activate a survival signal into neurons via TNFR 2 receptors is provided. A new animal model for Parkinson's disease studies is also provided, wherein the adenovirus vector, the CRE/loxP and transgenic knock-in mice are combined. The transgenic knock in mouse has a transgene comprising a DNA sequence that encodes mTNF in operable linkage with the endogenous engrailed-1 promoter; and a loxP interference cassette downstream of the transgene, wherein the mTNF coding sequence is expressed at low levels in the substantia nigra, and mimics Parkinson's pathological conditions. Excerpt(s): This is a nonprovisional of U.S. Ser. No. 60/370974, filed Apr. 9, 2002. The invention relates to methods of treating neurodegenerative diseases in mammals, more particularly in human beings, in need of such treatment, wherein the treatment is based in the regulation of the TNF activity in the patient. More particularly, the treatment comprises administering to the patient an effective amount of TNF signal transduction pathway compounds and/or TNF down regulating molecules. We disclose the effects of TNF over the substantia nigra, wherein such effects depend on the concentration of TNF in the substantia nigra. A low concentration of TNF provides a neuroprotective activity and a high concentration of TNF provides a neurodegenerative effect on the mammal. More specifically, the invention relates to a method of treating a patient affected by Parkinson's disease. A treatment with TNF is provided by the invention wherein the activity of TNF in patients affected by the Parkinson's disease is regulated. In addition, treatments in which molecules activate a survival signal into neurons via TNF receptor type 2 (TNFR 2) or inhibit a death signal from the TNF receptor type I is also provided. The invention also relates to a new animal model for use in the studying of the Parkinson's disease, wherein the adenovirus vector, the CRE/loxP and transgenic knock-in mice are combined. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Non-viral vesicle vector for cardiac specific gene delivery Inventor(s): Chien, Kenneth; (La Jolla, CA), Hoshijima, Masahiko; (La Jolla, CA) Correspondence: Brown, Martin, Haller & Mcclain Llp; 1660 Union Street; San Diego; CA; 92101-2926; US Patent Application Number: 20030166593 Date filed: April 30, 2002 Abstract: The invention is a non-viral vesicle vector for the delivery of nucleic acid to various cardiac cell types. The vesicle vector contains the hepatitis B envelope protein wherein at least part of the liver targeting sequence is deleted and replaced with a specific cardiac cell targeting sequence. The targeting sequence may be derived from viruses that have the natural tropism desired (e.g. adenovirus type 5 knob protein for cardiomyocyte delivery) or mammalian sequences (e.g. endothelin-1 for vascular endothelial cell delivery). The vesicle vector contains an expression construct for the expression of therapeutic genes in cardiac tissues. Excerpt(s): This application claims the benefit of priority of U.S. provisional application Serial No. 60/287,423 filed Apr. 30, 2001 which is incorporated herein by reference in its entirety. A sequence listing is submitted herewith under 35 C.F.R.sctn.1.821 and is incorporated herein by reference. The utility of gene delivery vectors for gene therapy is limited by the nonselective nature in which the vectors, either non-viral or viral, interact with the cell surface, resulting in transduction of numerous cell types in addition to the target cells. Much effort has been devoted to understand the mechanisms of viral targeting to different cell types. The information derived from these studies is now being exploited to select viruses that have the desired natural tropism or to modify viral targeting signals to redirect viruses to the cell type of choice. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel fluorescence dyes and their applications for whole-cell fluorescence screening assays for caspases, peptidases, proteases and other enzymes and the use thereof Inventor(s): Cai, Sui Xiong; (San Diego, CA), Drewe, John A.; (Carlsbad, CA), Yang, Wu; (Irvine, CA), Zhang, Han-Zhong; (San Diego, CA) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W.; Washington; DC; 20005; US Patent Application Number: 20030208037 Date filed: May 6, 2002 Abstract: The present invention relates to novel fluorescent dyes, novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of caspases and other enzymes involved in apoptosis in whole cells, cell lines and tissue samples derived from any living organism or organ. The reporter molecules and assay processes can be used in drug screening procedures to identify compounds which act as inhibitors or inducers of the caspase cascade in whole cells or tissues. The reagents and assays described herein are also useful for determining the chemosensitivity of human cancer cells to treatment with chemotherapeutic drugs. The present invention also relates to novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of type 2
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methionine aminopeptidase, HIV protease, adenovirus protease, HSV-1 protease, HCMV protease and HCV protease. Excerpt(s): This invention is in the field of intracellular detection of enzymes using fluorogenic or fluorescent probes. The invention relates to novel fluorescent dyes and application of these dyes for the preparation of novel fluorogenic or fluorescent peptide or amino acid derivatives which are substrates of proteases and peptidases. In particular, the invention relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of enzymes involved in apoptosis, such as caspases and the lymphocyte-derived serine protease Granzyme B. The invention also relates to a process for measuring the activity of caspases and other enzymes involved in apoptosis in living or dead whole cells, cell lines or tissue samples derived from any healthy, diseased, infected or cancerous organ or tissue. The invention also relates to the use of the fluorogenic or fluorescent substrates in a novel assay system for discovering or detecting inhibitors or inducers of apoptosis in compound collections or compound libraries. Furthermore, the invention relates to the use of the fluorogenic or fluorescent substrates in determining the sensitivity of cancer cells to treatment with chemotherapeutic drugs. The invention also relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of exopeptidases such as aminopeptidase A and N, methionine aminopeptidase and dipeptidyl-peptidase IV, endopetidases such as calpain, proteases such as HIV proteases, HCMV protease, HSV protease, HCV protease and adenovirus protease. Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis et al., Dev. 112:591-603 (1991); Vaux et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721). There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel recombinant adenovirus vector with relieved side effects Inventor(s): Komiya, Kazuo; (Hyogo, JP), Murata, Masashi; (Osaka, JP), Nakai, Michio; (Osaka, JP), Saito, Izumu; (Tokyo, JP), Tohdoh, Naoki; (Hyogo, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Suite 800; Washington; DC; 20037; US Patent Application Number: 20040091456 Date filed: November 26, 2002 Abstract: The present invention provides a novel adenovirus vector for which inflammation during the in vivo administration thereof is alleviated by inhibiting the induction of expression of an adenovirus gene by a foreign promoter inserted into the adenovirus genome, and a method for producing the vector, a cell line for use in the
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production of said recombinant adenovirus vector, or a gene therapy method using said recombinant adenovirus vector. Excerpt(s): The present invention relates to a recombinant adenovirus vector for gene therapy and a method for producing the vector. Specifically, the present invention relates to a novel recombinant adenovirus vector for which inflammation after in vivo administration thereof is alleviated by inhibiting the induction of the gene expression of adenovirus by a foreign promoter inserted into the adenovirus genome, and a method for producing the vector, a cell line for use in the production of said recombinant adenovirus vector, or a gene therapy method using said recombinant adenovirus vector. Adenovirus vectors are an excellent gene transfer vector for animal cells because of the high efficiency of gene transfer, the ability of allowing a gene to be transferred into nondividing cells, the ease of preparing a high titer virus stock, and the like, and clinical applications thereof have been attempted as a vector for use in gene therapy. Adenovirus vectors that are widely used currently are replication-defective vectors in which the E1 gene essential for the replication of adenovirus and the expression of all adenovirus proteins has been deleted, and the vectors are termed as the first generation adenovirus vectors (some of them are further comprise the deletion of the E3 gene). It was thought that since the first generation adenovirus vectors lack the E1 gene, none of adenovirus proteins could be expressed in normal cells such as human cells that are not expressing the E1 gene. However, recent studies have demonstrated that when a gene was transferred using a first generation adenovirus vector in vivo, expression of the transgene has been transient, and an inflammatory response occurs at the site of gene transfer (Yang Y. et al., Proc. Natl. Acad. Sci. USA 91: 4407-4411 (1994), and Wilmott R. W. et al., Hum. Gene Ther., 7: 301-318 (1996)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Recombinant adenoviral vector and methods of use Inventor(s): Gregory, Richard J.; (Carlsbad, CA), Maneval, Daniel C.; (San Diego, CA), Wills, Ken N.; (Encinitas, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040038404 Date filed: May 19, 2003 Abstract: This invention provides a recombinant adenovirus expression vector characterized by the partial or total deletion of the adenoviral protein IX DNA and having a gene encoding a foreign protein or a functional fragment or mutant thereof. Transformed host cells and a method of producing recombinant proteins and gene therapy also are included within the scope of this invention.Thus, for example, the adenoviral vector of this invention can contain a foreign gene for the expression of a protein effective in regulating the cell cycle, such as p53, Rb, or mitosin, or in inducing cell death, such as the conditional suicide gene thymidine kinase. (The latter must be used in conjunction with a thymidine kinase metabolite in order to be effective). Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 08/233,777, filed May 19, 1994, which is a continuation-in-part of U.S. Ser. No. 08/142,669 filed Oct. 25, 1993, the contents of which are hereby incorporated by reference into the present disclosure. Throughout this application, various publications are referred to by citations within parentheses and in the bibliographic description, immediately preceding the
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claims. The disclosures of these publications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains. Production of recombinant adenoviruses useful for gene therapy requires the use of a cell line capable of supplying in trans the gene products of the viral E1 region which are deleted in these recombinant viruses. At present the only useful cell line available is the 293 cell line originally described by Graham et al. in 1977. 293 cells contain approximately the left hand 12% (4.3 kb) of the adenovirus type 5 genome (Aiello (1979) and Spector (1983)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Somatic gene therapy to suppress secondary cataract formation following eye surgery Inventor(s): Munier, Francis; (Gandvaux, CH), Sahli, Roland; (Lausanne, CH), Shaw, Phillip Herbert; (Lausanne, CH), Sickenberg, Michel; (Lausanne, CH) Correspondence: Mintz, Levin, Cohn, Ferris, Glovsky; And Popeo, P.C.; One Financial Center; Boston; MA; 02111; US Patent Application Number: 20030219412 Date filed: March 11, 2003 Abstract: Disclosed is a replication-recombinant virus, preferably an adenovirus that lacks E1a, E1b and E4 ORF 6, capable of infecting an eye and comprising a lens epithelial cell specific promoter driving an ORF encoding at least one protein, which when expressed in lens epithelial cells of an eye suppresses, at the level of the germinative epithelium of the lens of the eye, cellular proliferation which is stimulated by eye surgery and which would otherwise result in secondary cataract formation in the eye. Also disclosed is the use of the recombinant virus for the treatment of an eye, undergoing eye (e.g. cataract) surgery, in order to reduce the incidence of cellular proliferation in the eye following the surgery and thereby to prevent the formation of secondary cataracts. Excerpt(s): This application is a continuation of U.S. Ser. No. 09/710,035, filed Mar. 10, 2000, which is a continuation application of U.S. Ser. No. 08/867,902, filed Jun. 3, 1997, which was issued as patent number U.S. Pat. No. 6,200,799 B1 on Mar. 13, 2001, each of which is incorporated herein by reference in its entirety. This invention relates to materials and methods for the construction of recombinant viral, particularly adenoviral, delivery systems that provide lens epithelial cell type specific regulation of expression of proteins which inhibit cellular proliferation. This invention also relates to the use of these recombinant viral delivery systems for inhibiting or preventing the formation of secondary cataracts following surgical intervention on the eye. Cataract operations are the second most frequent operation in the western world. The cataract is an affliction characterized by an opacification of the crystalline lens of the eye which reduces the visual acuity of the patient. The surgical technique currently utilized for removing cataracts consists of removing the crystalline with a small aspirator. Access to the interior of the crystalline capsule is achieved by a circular opening at the anterior face of the lens capsule. This permits the surgeon to insert a new lens, which will restore the eye's ability to focus incoming light on the surface of the retina. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Stabilized formulations of adenovirus Inventor(s): Lehmberg, Elisabeth; (Kelseyville, CA), Pungor, Erno; (Millbrae, CA) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030232018 Date filed: January 15, 2003 Abstract: A method is disclosed to stabilize compositions comprising airborne viruses, particularly Adenoviruses; and more particularly recombinant Adenoviruses, by adding to the compositions a non-ionic detergent which comprises an alkyl moiety and a polyethylene glycol (PEG). Pharmaceutical and other compositions of Adenoviruses, particularly recombinant Adenoviruses suitable for methods of gene therapy, which comprise such detergents are also disclosed. Excerpt(s): This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/349,222 filed Jan. 18, 2002. wherein X is 5-15, preferably 7-10, ring A is phenylene or cyclohexylene, and R' is R as above, or combinations thereof. in Formula IV, R' is (CH.sub.3).sub.3C.CH.sub.2C(CH.sub.3).sub.2--, A is phenylene, and X is 9-10 (Triton X-100, NP40), or R' is (CH.sub.3).sub.3C.CH.sub.2C(CH.sub.3).sub.2--, A is cyclohexylene, and X is 9-10 (reduced Triton X-100). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Substituted heterocyclic compounds and methods of use Inventor(s): Dominguez, Celia; (Thousand Oaks, CA), Zhang, Dawei; (Thousand Oaks, CA) Correspondence: Amgen Incorporated; Mail Stop 27-4-A; One Amgen Center Drive; Thousand Oaks; CA; 91320-1799; US Patent Application Number: 20040058918 Date filed: September 8, 2003 Abstract: The present invention relates to compounds having the general formula 1or a pharmaceutically acceptable salt thereof. Also included is a method of prophylaxis or treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic.beta. cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount a compound as described above. Excerpt(s): The present invention comprises a new class of compounds useful in treating diseases, such as TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving
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inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds. Interleukin-1 (IL-1) and Tumor Necrosis Factor.alpha. (TNF-.alpha.) are proinflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharide--LPS) or external cellular stress (e.g., osmotic shock and peroxide). Elevated levels of TNF-.alpha.and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic 13 cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-.alpha. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
System for production of helper dependent adenovirus vectors based on use of endonucleases Inventor(s): Anglana, Mauro; (Paris Cedex, FR), Bacchetti, Silvia; (Hamilton, CA), Graham, Frank L.; (Hamilton, CA), Ng, Philip; (Caledonia, CA), Parks, Robin; (Ottawa, CA) Correspondence: Van Dyke & Associates, P.A.; 7200 Lake Ellenor Drive, Suite 252; Orlando; FL; 32809; US Patent Application Number: 20030228280 Date filed: January 31, 2003 Abstract: The present invention relates to methods for efficient and reliable construction of adenovirus vectors which contain and express foreign DNA and are useful for gene transfer into mammalian cells, for vaccines and for gene therapy. The invention provides for the growth and purification of adenovirus vectors (helper dependent vectors or HDVs) from which all or most of the viral genes have been removed. The vector system described herein is a new method designed to eliminate helper viruses from the final HDV preparation by cleavage of the helper virus DNA with an endonuclease, alone or in combination with other methods known to limit the level of helper virus contamination of helper dependent vector preparations. The disclosed methods and compositions also provide for regulated control of gene expression. Excerpt(s): This application is a continuation of application Ser. No. 09/883,649, filed on Jun. 19, 2001, pending, which is a continuation of application Ser. No. 09/475,813, filed on Dec. 30, 1999, abandoned, which is a continuation-in-part of application Ser. No. 09/250,929, filed on Feb. 18, 1999, abandoned, which was a continuation-in-part of application Ser. No. 08/473,168, filed Jun. 7, 1995, now U.S. Pat. No. 5,919,676, which was a continuation-in-part of application Ser. No. 08/250,885, filed on May 31, 1994, pending, which was a continuation-in-part of application Ser. No. 08/080,727, filed on Jun. 24, 1993, abandoned. Priority of each of these applications is claimed herein, and the disclosure of each of these applications is hereby incorporated by reference. The invention is a new method of producing helper adenoviruses and helper-dependent
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adenovirus vectors (HDVs) in which helper virus is eliminated from HDV preparations by cleavage of the helper virus DNA with an endonuclease. The invention can be used independently of Cre/lox, or other helper virus containment systems, or in combination with Cre/lox, or other helper virus containment systems, to minimize the level of helper virus contamination of HDV preparations. In U.S. patent application Ser. No. 08/473,168, (the '168 application), published as WO96/40955, now U.S. Pat. No. 5,919,676, hereby incorporated by reference, a system for making helper-dependent adenovirus vectors and helper andenoviruses was disclosed. That system employed a recombinase, such as Cre, expressed by a cell into which a helper virus, comprising loxP sites flanking the adenovirus packaging signal, was introduced, (i.e. the packaging sequence was "floxed"). By virtue of the recombinase expressed by the host cell, the helper adenovirus packaging signal was excised, thereby restricting the packaging of the helper virus. Co-introduction of a helper-dependent, recombinant adenovirus vector (HDV) containing a packaging signal permitted isolation of efficiently packaged helperdependent virus. However, as may be appreciated by those skilled in the art, any "leakage" of that system results in the contamination of helper-dependent adenovirus vector preparations with helper virus. The present invention is directed to methods and helper virus constructs, which result in production of HDV preparations wherein the level of packaged helper virus contamination is reduced by an endonuclease. The constructs and techniques taught herein may be employed independently from the CreloxP system described according to the WO96/40955 publication, or the techniques taught herein may be used to augment the effectiveness of that system. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Targeted recombinant viral vectors Inventor(s): Keller, Jonathan R.; (Frederick, MD), Smith, Jeffrey S.; (Bethesda, MD), Spence, Sally E.; (Frederick, MD) Correspondence: National Institute OF Health; C/o Needle & Rosenberg, P.C.; Suite 1000; 999 Peachtree Street; Atlanta; GA; 30303; US Patent Application Number: 20030175973 Date filed: March 20, 2003 Abstract: The present invention provides methods and a composition for targeted delivery of a nucleic acid to a cell comprising a biotinylated recombinant encapsidated virus, particularly adenovirus, wherein the recombinant adenovirus comprises the nucleic acid, and wherein the biotinylated recombinant virus is linked via streptavidin to a biotinylated targeting moiety. Excerpt(s): The present invention is in the field of targeted gene delivery. Specifically, the invention relates to recombinant viral vectors for targeted delivery to selected cells, wherein the recombinant virus is a small, encapsidated virus, such as adenovirus or adeno-associated virus. Recent attempts to target gene transfer to human cells have focused on the use of retroviral and adenoviral vectors. However, the most promising current vectors have resulted in limited success, due in part to the inability to target specific cell types such as hematopoietic stem cells, and the need to culture target cells in vitro to promote cell cycling which can result in the loss of stem cell function. The ability to target gene transfer to specific cell types in situ would greatly enhance current approaches to gene therapy. Several approaches have been taken to target viral and non viral vectors that include using ligands, antibodies or peptides in the vector construction thereby redirecting virus infection through antigens or receptors expressed on specific
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cell types. Early experiments designed to redirect the host range of retroviruses by molecular modification of ecotropic envelopes to recognize cellular receptors through antigen binding, ligand or peptide sequences were unsuccessful. It has subsequently been shown that efficient uncoating of the virus requires a conformational change in a subunit of the envelope protein which is only induced upon interaction of the retrovirus particle with its cognate receptor; thus retroviruses directed to alternate receptors do not yield high frequencies of infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Vaccine and drug delivery by topical application of vectors and vector extracts Inventor(s): Shi, Zhongkai; (Birmingham, AL), Tang, De-chu C.; (Birmingham, AL), van Kampen, Kent Rigby; (Hoover, AL) Correspondence: Frommer Lawrence & Haug; 745 Fifth Avenue- 10th FL.; New York; NY; 10151; US Patent Application Number: 20040009936 Date filed: January 16, 2003 Abstract: Disclosed and claimed are methods of non-invasive immunization and drug delivery in an animal and/or methods of inducing a systemic immune or therapeutic response in an animal following topical application of non-replicative vectors, products therefrom and uses for the methods and products therefrom. Also disclosed and claimed are methods of non-invasive immunization and drug delivery in an animal and/or a method of inducing a systemic immune response or systemic therapeutic response to a gene product comprising contacting skin of the animal with cell-free extracts in an amount effective to induce the response, wherein the extracts are prepared by filtration of disrupted cells, wherein the cell comprises and expresses a nucleic acid molecule. Preferably, the cell is temporarily disrupted by sonication, remaining intact and viable after the sonication. Also, methods are disclosed and claimed for enhancing the immunogenicity and efficacy of an epicutaneous vaccine for inducing a systemic immune response to an antigen, in an animal comprising contacting skin of the animal with vaccines admixed with heat-shock protein 27, in an amount effective to induce the response. The methods include contacting skin of the animal with a vector in an amount effective to induce the systemic immune or therapeutic response. The vector can include and express an exogenous nucleic acid molecule encoding an epitope or gene product of interest. The systemic immune response can be to or from the epitope or gene product. The nucleic acid molecule can encode an epitope or antigen of interest and/or a nucleic acid molecule that stimulates and/or modulates an immunological response and/or stimulates and/or modulates expression, e.g., transcription and/or translation, such as transcription and/or translation of an endogenous and/or exogenous nucleic acid molecule; e.g., one or more of influenza hemagglutinin, influenza nuclear protein, influenza M2, tetanus toxin C-fragment, anthrax protective antigen, anthrax lethal factor, anthrax germination factors, rabies glycoprotein, HBV surface antigen, HIV gp120, HIV gp160, human carcinoembryonic antigen, malaria CSP, malaria SSP, malaria MSP, malaria pfg, botulinum toxin A, and mycobacterium tuberculosis HSP; and/or a therapeutic, an immunomodulatory gene, such as co- stimulatory gene and/or a cytokine gene. The immune response can be induced by the vector expressing the nucleic acid molecule in the animal's cells including epidermal cells. The immune response can also be induced by antigens expressed from the nucleic acid molecule within the vector. The immune response can be against a pathogen or a neoplasm. A
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prophylactic vaccine or a therapeutic vaccine or an immunological composition can include the vector. The animal can be a vertebrate, e.g., a mammal, such as human, a cow, a horse, a dog, a cat, a goat, a sheep or a pig; or fowl such as turkey, chicken or duck. The vector can be one or more of a viral vector, including viral coat, e.g., with some or all viral genes deleted therefrom, bacterial, protozoan, transposon, retrotransposon, and DNA vector, e.g., a recombinant vector; for instance, an adenovirus, such as an adenovirus defective in its E1 and/or E3 and/or E4 region(s) and/or all adenoviral genes. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 10/116,963, filed Apr. 5, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 10/052,323, filed Jan. 18, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 09/563,826, filed May 3, 2000 (issued Feb. 19, 2002 as Patent No. 6,348,450), which claims priority from U.S. Provisional Application No. 60/132,216, filed May 3, 1999, and is also a continuation-in-part of U.S. patent application Ser. No. 09/533,149, filed Mar. 23, 2000, which in turn is a continuation of U.S. patent application Ser. No. 09/402,527, filed on Aug. 13, 2000. Each of these applications and each of the documents cited in each of these applications ("application cited documents"), and each document referenced or cited in the application cited documents, either in the text or during the prosecution of those applications, as well as all arguments in support of patentability advanced during such prosecution, are hereby incorporated herein by reference. Various documents are also cited in this text ("application cited documents"). Each of the application cited documents, and each document cited or referenced in the application cited documents, is hereby incorporated herein by reference. The present invention relates generally to the fields of immunology and vaccine technology. The present invention also relates to techniques of skin-targeted non-invasive delivery of to elicit immune responses and uses thereof. The invention further relates to methods of non-invasive immunization in an animal and/or methods of inducing an immunological, e.g., systemic immune response or a therapeutic, e.g., a systemic therapeutic response, in an animal, products therefrom and uses for the methods and products therefrom. The invention yet further relates to such methods comprising contacting skin of the animal with a vector in an amount effective to induce the response, e.g., systemic immune response, in the animal. Even further, the invention relates to such methods wherein the vector comprises and expresses an exogenous nucleic acid molecule encoding an epitope or gene product of interest, e.g., an antigen or therapeutic. Still further, the invention relates to such methods wherein the response, e.g., systemic immune or therapeutic response, can be to or from the epitope or gene product. Even further still, the invention relates to such methods wherein the vector is non-replicative. The invention yet further relates to such methods wherein the response is induced by contacting the skin of an animal with cell-free extracts in an amount effective to induce the response, wherein the extracts are prepared by filtration of disrupted cells chosen from the group consisting of bacterium, fungus, cultured animal cells, and cultured plant cells, wherein the cell comprises and expresses a nucleic acid molecule encoding the gene product. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Vector Inventor(s): Bundell, Kenneth Robert; (Macclesfield Cheshire, GB), Winkler, Johann; (Macclesfield Cheshire, GB) Correspondence: Janis K Fraser; Fish & Richardson; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20040048381 Date filed: May 8, 2003 Abstract: The invention provides a two component system for in vitro cloning of a heterologous polynucleotide into adenoviral DNA. The first component is an insert donor comprising a heterologous polynucleotide encoding a heterologous polypeptide. The second component is a vector donor comprising an adenovirus genome and an expression cassette. The insert donor and vector donor are adapted for site specific recombination using recombination sites from phage lambda for insertion of the heterologous polynucleotide into the expression cassette capable of forming an adenoviral expression clone in vitro in the presence of a suitable recombination mediator protein or proteins. The invention also provides a method of making recombinant adenovirus and use of the first and second components in such a method. Excerpt(s): Adenoviruses are a group of DNA viruses which can cause generally mild infections in humans respiratory illness, conjunctivitis and infantile gastroenteritis. Easily grown in cell culture, adenoviruses have been widely studied for many years (e.g. RNA splicing was first described in adenovirus infected cell). The ability of adenoviruses to infect human cells at up to 100% efficiency has led to its use as a vector for introducing foreign (recombinant) DNA in both cell culture and in humans (gene therapy). Recombinant adenoviruses generally have certain regions of DNA deleted (e.g. E1 region necessary for replication, E3 required for evading host immunity). The purpose of this is twofold. First, the removal of non-necessary regions of DNA allows space for the introduction of foreign DNA which can then be packaged as adenovirus DNA and subsequently introduced into human cells (there is also some leeway for insertion of extra DNA into the genome without affecting infectivity). Second, the removal of the E1 region determines that the recombinant virus can infect human cells but not replicate; this is an important safety consideration. To generate and replicate recombinant adenovirus, DNA is transfected into a cell line (e.g. HEK 293) which has the E1 region engineered into its genome i.e. the cell line provides the replicative machinery lacking in the recombinant adenovirus. Recombinant adenovirus technology is often based around human adenovirus type 5. The genome for Ad5 is 35.935 kb. This whole sequence can be cloned into a plasmid vector and replicated in E. coli. However, because of the length of adenovirus sequence, there are very few suitable restriction enzyme sites available which would allow direct cloning into such a vector. To circumvent this problem, a two vector approach has been adopted. One vector contains the complete adenovirus sequence minus E1 and E3 sequence. The second vector contains a eukaryotic promoter (e.g. CMV) upstream of a cloning site (for insertion of foreign DNA), and polyadenylation sequences necessary for stability of transcribed RNA. Flanking this expression cassette are two regions of adenovirus DNA which are common with adenovirus sequences in the first vector. Thus, the expression cassette from the second vector can be introduced into the adenovirus sequence in the first vector by a process of homologous recombination. This tedious, exacting and timeconsuming process has traditionally been performed in HEK 293 cells. Viruses produced have to be plaque purified, propagated and tested to ensure that the desired recombinant DNA has been introduced. A recent advance in recombinant adenovirus
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generation, the `AdEasy.TM.` system (He, T-G et al, PNAS, 95, 1998, 2509-2514), simplifies the procedure by carrying out the plasmid recombination step in E. coli strain BJ 5183 which allows limited recombination. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Vectors for tissue-specific replication and gene expression Inventor(s): Chang, Yung-Nien; (Cockysville, MD), Hallenbeck, Paul L.; (Gaithersburg, MD), Hay, Carl M.; (Damascus, MD), Stewart, David A.; (Eldersburg, MD) Correspondence: Thomas Hoxie; Novartis, Corporate Intellectual Property; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20040009588 Date filed: June 24, 2003 Abstract: The invention generally relates to cell-specific expression vectors. It particularly relates to targeted gene therapy using recombinant expression vectors and particularly adenovirus vectors. The invention specifically relates to replicationconditional expression vectors and methods for using them. Such vectors are able to selectively replicate in a target cell or tissue to provide a therapeutic benefit in a tissue from the presence of the vector per se or from one or more heterologous gene products expressed from the vector and distributed throughout the tissue. In such vectors, a gene essential for replication is placed under the control of a heterologous tissue-specific transcriptional regulatory sequence. Thus, replication is conditioned on the presence of a factor(s) that induces transcription or the absence of a factor(s) that inhibits transcription of the gene by means of the transcriptional regulatory sequence with this vector; therefore, a target tissue can be selectively treated. Excerpt(s): This application is a division of U.S. application Ser. No. 08/974,391, filed Nov. 19, 1997, which is a continuation-in-part of U.S. application Ser. No. 08/487,992, filed Jun. 7, 1995 (abandoned), which is a continuation-in-part of U.S. application Ser. No. 08/348,258, filed Nov. 28, 1994 (abandoned). Said U.S. application Ser. No. 08/974,391, filed Nov. 19, 1997, is also a continuation-in-part of U.S. application Ser. No. 08/849,117, filed Jul. 1, 1997 (U.S. Pat. No. 5,998,205), which is a.sctn.371 of PCT/US95/15455, which has an international filing date under the PCT of Nov. 28, 1995, and which entered the United States national phase on May 28, 1997, which is a continuation-in-part of U.S. application Ser. No. 08/487,992, filed Jun. 7, 1995 (abandoned), which is a continuation-in-part of U.S. application Ser. No. 08/348,258, filed Nov. 28, 1994 (abandoned), all incorporated herein in their entirety by reference. The invention generally relates to cell-specific expression vectors. It particularly relates to targeted gene therapy using recombinant expression vectors and particularly adenovirus vectors. The invention specifically relates to modulatable replicationconditional expression vectors and methods for using them. Such vectors are able to selectively replicate in a target cell or tissue to provide a therapeutic benefit in a tissue from the presence of the vector per se or from one or more heterologous gene products expressed from the vector and distributed throughout the tissue, and which vectors are designed so that replication and gene expression from the vector can be modulated. In such vectors, a gene essential for replication is placed under the control of a heterologous tissue-specific transcriptional regulatory sequence. Thus, replication is conditioned on the presence of a factor(s) that induces transcription or the absence of a factor(s) that inhibits transcription of the gene by means of the transcriptional regulatory sequence.
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Viral vectors having tissue tropism for T-lymphocytes, B- and mast cells Inventor(s): Havenga, Menzo Jans Emko; (Alphen a/d Rijn, NL), Ma, Libin; (Oegstgeest, NL), van Es, Helmuth Hendrikus Gerardus; (Hoofddorp, NL), van Zutphen, Marlijn; (Leiderdorp, NL) Correspondence: Synnestvedt & Lechner Llp; Aramark Tower, Suite 2600; 1101 Market Street; Philadelphia; PA; 19107; US Patent Application Number: 20030180258 Date filed: September 25, 2001 Abstract: The present invention relates to a method of introducing an expressible nonviral nucleic acid sequence into a cell having a common non-universal binding receptor and selected from T lymphocytes, B-, and mast cells, comprising contacting said cell with a viral vector comprising a recombinant nucleic acid sequence containing sequence for said expressible non-viral nucleic acid and comprising a modified viral coat consisting of native viral coat proteins and modified coat protein containing adenoviral amino acid sequence from an adenoviral serotype 35 or 51 fibre protein, wherein said adenoviral sequence of said modified protein is a ligand for said binding receptor. Alternatively said vector comprises a sequence coding for a viral capsid consisting of native adenoviral capsid proteins and modified capsid protein containing amino acid sequence from an adenoviral serotype other than the serotype of said native capsid proteins, wherein said modified protein is a ligand for said binding receptor. The present invention also relates to a method for transducing a cell, said cell selected from the group consisting of T lymphocytes, B cells, and mast cells comprising contacting said cells with an adenovirus particle comprising a non-adenovirus nucleic acid sequence and a chimeric capsid protein comprising amino acid sequence derived from at least two adenovirus serotypes, wherein said particle has a greater tropism for said cells relative to at least one of the adenovirus serotypes comprising said chimeric capsid protein. The present invention further relates to transduced cells, arrays of subpopulations of cells, a method for ex vivo transduction of a population of cells comprising and a method of administering to a human or other mammalian animal subject a population of cells genetically modified ex vivo. The present invention further relates to a method for identifying the function of a first nucleic acid in hematopoietic cells. Excerpt(s): The invention relates to the field of molecular genetics and medicine. In particular the present invention relates to the field of functional genomics and gene therapy, in particular, methods useful in ex vivo gene therapy and functional genomics using adenovirus vectors. In functional genomics, genetic information with unknown function but somehow pre-selected for, is usually delivered to a host cell in order to either correct (supplement) a genetic deficiency in said cell, or to inhibit an undesired function in said cell or to otherwise induce a phenotype. Of course the genetic information can also be intended to provide the host cell with a desired function, e.g. to supply a secreted protein or express a transcription factor. Many different methods have been developed to introduce new genetic information into cells. Although many different systems may work on cell-lines cultured in vitro, only the group of viral vector mediated gene delivery methods seems to be able to meet the required efficiency of gene transfer in vivo. Thus for gene therapy purposes most of the attention is directed towards the development of suitable viral vectors. Today, most of the attention for the
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development of suitable viral vectors is directed towards those vectors that are based on adenoviruses. Studies in clinical trials have provided valuable information on the use of these vectors in patients. Moreover adenoviral vectors are relatively easy to concentrate and purify. For functional genomics adenoviral vectors are also ideally suited. They can be used to build gene expression libraries that can be used with specific cell based assays to search for genes or antagonists of those genes that give a desired phenotype. They can also be used to validate genes further that have been isolated using other gene selection techniques such as comparative expression profiling and subtraction techniques. Validation using adenoviral vectors can be done in vitro as well as in vivo using either in situ or in vitro cell or tissue based assays or appropriate animal models. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Viruses for the treatment of cellular proliferative disorders Inventor(s): Coffey, Matthew C.; (Calgary, CA), Thompson, Bradley G.; (Calgary, CA) Correspondence: Burns Doane Swecker & Mathis L L P; Post Office Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20040057929 Date filed: April 18, 2003 Abstract: Methods for treating cell proliferative disorders by administering virus to proliferating cells having an activated Ras-pathway are disclosed. The virus is administered so that it ultimately directly contacts proliferating cells having an activated Ras-pathway. Proliferative disorders include but are not limited to neoplasms. The virus is selected from modified adenovirus, modified HSV, modified vaccinia virus and modified parapoxvirus orf virus. Also disclosed are methods for treating cell proliferative disorders by further administering a immunosuppressive agent. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/164,878, filed Nov. 12, 1999, which is incorporated by reference in its entirety. The present invention pertains to methods for treating cellular proliferative disorders in a mammal that are mediated by Ras-activation using mutant viruses. All of the above publications, patent applications and patents are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or patent was specifically and individually indicated to be incorporated by reference in its entirety. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with adenovirus, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “adenovirus” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on adenovirus.
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You can also use this procedure to view pending patent applications concerning adenovirus. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON ADENOVIRUS Overview This chapter provides bibliographic book references relating to adenovirus. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on adenovirus include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “adenovirus” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on adenovirus: •
Clinical Management -- Infections I. III International Conference on Acquired Immunodeficiency Syndrome (AIDS); Washington, D.C., June 1-5, 1987 Contact: InfoMedix, 12800 Garden Grove Blvd, Ste F, Garden Grove, CA, 92643, (714) 530-3454. Summary: This sound recording of proceedings from the III International Conference on AIDS, held June 1-5, 1987, in Washington, D.C., deals with the clinical management of opportunistic infections in persons with Human immunodeficiency virus (HIV) infection or Acquired immunodeficiency syndrome (AIDS). The first speaker discusses cytomegalovirus retinitis, its diagnosis, and its treatment. Several case studies are included. Adenovirus as the cause of infections is also discussed. Several types of infections caused by members of the herpes virus group are also described. The use of Acyclovir to treat them is explained. Case studies are analyzed. Means of diagnosing and treating toxoplasmic encephalitis are examined.
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Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “adenovirus” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “adenovirus” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “adenovirus” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Adenovirus DNA: The Viral Genome and Its Expression (Developments in Molecular Virology) by Walter Doerfler (Editor); ISBN: 0898387582; http://www.amazon.com/exec/obidos/ASIN/0898387582/icongroupinterna
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Adenovirus Methods and Protocols (Methods in Molecular Medicine , Vol 21) by William S. M. Wold (Editor); ISBN: 0896035514; http://www.amazon.com/exec/obidos/ASIN/0896035514/icongroupinterna
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Adenovirus, kletka, organizm; ISBN: 5120002447; http://www.amazon.com/exec/obidos/ASIN/5120002447/icongroupinterna
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Characterisation of Ctbp: A Co-Repressor of Transcription That Interacts With the Adenovirus E1a Protein by Anders Sundqvist; ISBN: 9155451446; http://www.amazon.com/exec/obidos/ASIN/9155451446/icongroupinterna
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Nuclear Organization of Gene Expression in Adenovirus Infected Cells by Anders Aspegren; ISBN: 9155450954; http://www.amazon.com/exec/obidos/ASIN/9155450954/icongroupinterna
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Regulation of Adenovirus Alternative Pre-Mrna Splicing: Functional Characterization of Exotic and Intronic Splicing Enhancer Elements by Bai-Gong Yue; ISBN: 9155447120; http://www.amazon.com/exec/obidos/ASIN/9155447120/icongroupinterna
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The Molecular Biology of Adenoviruses Two: Thirty Years of Adenovirus Research 1953-1983: Current Topics in Microbiology and Immunology by Walter Doerfler (Editor); ISBN: 0387131272; http://www.amazon.com/exec/obidos/ASIN/0387131272/icongroupinterna
Chapters on Adenovirus In order to find chapters that specifically relate to adenovirus, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and adenovirus using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “adenovirus” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on adenovirus:
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Viral Arthritis Source: in Maddison, P.J.; et al., Eds. Oxford Textbook of Rheumatology. Volume 2. New York, NY: Oxford University Press, Inc. 1993. p. 552-560. Contact: Available from Oxford University Press, Inc., New York, NY. Summary: This chapter for health professionals focuses on viral causes of arthritis. Virus-host interactions are examined. The viral pathogenesis of arthritis is explained. The structure, epidemiology, clinical and rheumatic manifestations, pathogenesis, diagnosis, treatment, and outcome of various viruses or virus vaccines are discussed. These viruses or vaccines include rubella and the rubella vaccine, human parvovirus B19, hepatitis B and hepatitis B vaccine, mumps, and arboviruses. In addition, enteroviruses, variola and vaccinia viruses, adenovirus, varicella-zoster, Epstein-Barr virus, herpes simplex virus, and cytomegalovirus are described. 45 references.
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Small Intestine: Infections with Common Bacterial and Viral Pathogens Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 1530-1560. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: This chapter on infections of the small intestine is from a lengthy, twovolume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. In this chapter, the authors focus on the major bacterial and viral pathogens that infect the small intestine. Whether by toxin-mediated effects or direct destruction of intestinal epithelial cells, these microbial pathogens have devised ways to disrupt the normal fluid handling capabilities of the intestinal tract and cause diarrhea. In general, the diarrhea caused by infection with a small bowel pathogen is characterized by high-volume, less frequent bowel movements, whereas lower-volume and more frequent bowel movements are associated with colonic diarrhea. Topics covered include food poisoning and common source outbreaks, traveler's diarrhea, bacterial infection, viral pathogens, and therapeutic considerations. Specific organisms discussed include Clostridium perfringens, Listeria monocytogenes, Escherichia coli, Salmonella, Yersinia, Vibrio (including Vibrio cholera), Aeromonas, Plesiomonas, Edwardsiella, rotavirus, Norwalk and Norwalk-like caliciviruses, astrovirus, and enteric adenovirus. Treatment options discussed include oral rehydration therapy (ORT), antimicrobial therapy, antidiarrheal drugs, and enteric vaccines. 5 tables. 368 references.
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Chapter 12-B: Infectious Disorders: Viral Arthritis Source: in Klippel, J.H., et al., eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation. 2001. p. 265-269. Contact: Available from Arthritis Foundation. P.O. Box 1616, Alpharetta, GA 300091616. (800) 207-8633. Fax (credit card orders only) (770) 442-9742. Website: www.arthritis.org. PRICE: $69.95 plus shipping and handling. ISBN: 0912423293. Summary: This section of a chapter on infectious disorders provides health professionals with information on the viruses causing arthralgia or arthritis. Infection with human parvovirus, designated B19, may be responsible for up to 12 percent of the cases of recent onset polyarthralgia or polyarthritis. Although only a small percentage of
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children with B19 infection may experience arthralgias or arthritis, as many as 78 percent of infected, symptomatic adults develop joint symptoms. Serologic diagnosis is possible only during a brief period because anti-B19 immunoglobulin M antibodies may be elevated for just 2 months following an acute infection. Hepatitis B virus infection may cause an immune complex mediated arthritis that occurs suddenly and is often severe. The joints of the hand and knee are most often affected. Rubella infection causes more joint complaints in adults, particularly women. Arthralgias are more common than frank arthritis. The joints of the hands, knees, wrists, ankles, and elbows are most frequently involved. Postvaccine arthralgia, myalgia, arthritis, and paresthesia have been associated with all rubella vaccine preparations. Several musculoskeletal syndromes, including Reiter's syndrome and psoriatic arthritis, have been detected in people infected with HIV. The alphavirus genus of the Togaviridae family includes various arthritogenic viruses that are mosquito borne. The known major viral pathogens of this genus include Sindbis virus, Chikungunya fever virus, O'nyong-nyong virus, Ross River virus, Barmah Forest virus, and Mayaro virus. Joint involvement is occasionally found in various commonly encountered viral syndromes, including varicella, mumps, adenovirus, and coxsackievirus A9, B2, B3, B4, and B6 infection. 1 figure and 18 references.
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CHAPTER 7. PERIODICALS AND NEWS ON ADENOVIRUS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover adenovirus.
News Services and Press Releases One of the simplest ways of tracking press releases on adenovirus is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “adenovirus” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to adenovirus. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “adenovirus” (or synonyms). The following was recently listed in this archive for adenovirus: •
Engineered adenovirus selectively targets tumor cells Source: Reuters Medical News Date: June 09, 2003
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Engineered adenovirus may be useful in colorectal cancer therapy Source: Reuters Medical News Date: May 20, 2003
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Modified adenovirus shows promise against glioma cells Source: Reuters Industry Breifing Date: May 06, 2003
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Adenovirus expressing modified apoptotic molecule thwarts HCV infection in mice Source: Reuters Industry Breifing Date: May 01, 2003
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Efficacy of chimp-vector HIV vaccine unaffected by human adenovirus antibodies Source: Reuters Industry Breifing Date: February 21, 2003
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Attenuated adenovirus mouthwash may prevent progression of oral dysplasia Source: Reuters Industry Breifing Date: November 22, 2002
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Modified adenovirus halts colorectal liver metastases, but trials on hold Source: Reuters Industry Breifing Date: April 08, 2002
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Cancer gene therapy using survivin mutant adenovirus effective in animal model Source: Reuters Industry Breifing Date: October 22, 2001
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Barr to develop adenovirus vaccines for Department of Defense Source: Reuters Industry Breifing Date: September 28, 2001
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Intensified effort needed in US to reestablish adenovirus vaccine production Source: Reuters Industry Breifing Date: July 05, 2001
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Adenovirus in myocardium predicts heart transplant loss in children Source: Reuters Medical News Date: May 16, 2001
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Adenovirus an important pathogen in adult BMT patients Source: Reuters Medical News Date: March 29, 2001
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Adenovirus implicated in gene therapy death Source: Reuters Medical News Date: January 26, 2001
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Working group will set adenovirus vectors standard for gene therapies by late 2001 Source: Reuters Industry Breifing Date: December 18, 2000
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Adenovirus linked to steroid resistance in allergic lung inflammation Source: Reuters Medical News Date: December 15, 2000
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Humoral response to unusual adenovirus strains impaired in HIV-infected patients Source: Reuters Medical News Date: November 15, 2000
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p53-expressing adenovirus gene therapy causes lymphoma regression in mice Source: Reuters Industry Breifing Date: July 17, 2000
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Modified, replication-competent adenovirus targets tumors in mice Source: Reuters Medical News Date: June 26, 2000 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “adenovirus” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “adenovirus” (or synonyms). If you know the name of a company that is relevant to adenovirus, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “adenovirus” (or synonyms).
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Academic Periodicals covering Adenovirus Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to adenovirus. In addition to these sources, you can search for articles covering adenovirus that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
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These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11 Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “adenovirus” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 28052 112 223 128 156 28671
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “adenovirus” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on adenovirus can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to adenovirus. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to adenovirus. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “adenovirus”:
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Gastroenteritis http://www.nlm.nih.gov/medlineplus/gastroenteritis.html Genes and Gene Therapy http://www.nlm.nih.gov/medlineplus/genesandgenetherapy.html Infectious Mononucleosis http://www.nlm.nih.gov/medlineplus/infectiousmononucleosis.html Influenza http://www.nlm.nih.gov/medlineplus/influenza.html Viral Infections http://www.nlm.nih.gov/medlineplus/viralinfections.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to adenovirus. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMDHealth: http://my.webmd.com/health_topics
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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to adenovirus. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with adenovirus. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about adenovirus. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “adenovirus” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “adenovirus”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “adenovirus” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.
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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “adenovirus” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
Finding Medical Libraries
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Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
•
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
Finding Medical Libraries
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
293
ADENOVIRUS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In
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dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenomatous Polyposis Coli: An autosomal dominant polyposis syndrome in which the colon contains few to thousands of adenomatous polyps, often occurring by age 15 to 25. [NIH]
Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU]
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Agrin: A protein component of the synaptic basal lamina. It has been shown to induce clustering of acetylcholine receptors on the surface of muscle fibers and other synaptic molecules in both synapse regeneration and development. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] AK: Enzyme of the biosynthetic pathway. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alphavirus: A genus of Togaviridae, also known as Group A arboviruses, serologically related to each other but not to other Togaviridae. The viruses are transmitted by mosquitoes. The type species is the sindbis virus. [NIH]
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Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminopeptidases: A subclass of exopeptidases that act on the free N terminus end of a polypeptide liberating a single amino acid residue. EC 3.4.11. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The
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term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]
Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anthrax: An acute bacterial infection caused by ingestion of bacillus organisms. Carnivores may become infected from ingestion of infected carcasses. It is transmitted to humans by contact with infected animals or contaminated animal products. The most common form in humans is cutaneous anthrax. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the
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lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antimitotic: Inhibiting or preventing mitosis. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as
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presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthralgia: Pain in the joint. [NIH] Articular: Of or pertaining to a joint. [EU] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly
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contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Astrovirus: A genus of small, circular RNA viruses in the family Astroviridae. They cause gastroenteritis and are found in the stools of several vertebrates including humans. Transmission is by the fecal-oral route. There are at least seven human serotypes and the type species is human astrovirus 1. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Avian: A plasmodial infection in birds. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Back Pain: Acute or chronic pain located in the posterior regions of the trunk, including the thoracic, lumbar, sacral, or adjacent regions. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of
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cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacteriophage lambda: A temperate inducible phage and type species of the genus lambdalike Phages, in the family Siphoviridae. Its natural host is E. coli K12. Its virion contains linear double-stranded DNA, except for 12 complementary bases at the 5'-termini of the polynucleotide chains. The DNA circularizes on infection. [NIH] Bacteriophages: Viruses whose host is a bacterial cell. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal cell carcinoma: A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Pairing: Pairing of purine and pyrimidine bases by hydrogen bonding in doublestranded DNA or RNA. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basilar Artery: The artery formed by the union of the right and left vertebral arteries; it runs from the lower to the upper border of the pons, where it bifurcates into the two posterior cerebral arteries. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH] Beta-Endorphin: A peptide consisting of amino acid sequence 61-91 of the endogenous pituitary hormone beta-lipotropin. The first four amino acids show a common tetrapeptide sequence with methionine- and leucine enkephalin. The compound shows opiate-like activity. Injection of beta-endorphin induces a profound analgesia of the whole body for
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several hours. This action is reversed after administration of naloxone. [NIH] Beta-Galactosidase: A group of enzymes that catalyzes the hydrolysis of terminal, nonreducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause gangliodisosis GM1. EC 3.2.1.23. [NIH] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biolistics: Techniques where DNA is delivered directly into organelles at high speed using projectiles coated with nucleic acid, shot from a helium-powered gun (gene gun). One of these techniques involves immunization by DNA vaccines, which delivers DNA-coated gold beads to the epidermis. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived
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constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of bacteria, viruses, or toxins against people, animals, or plants. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Bladder: The organ that stores urine. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first,
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an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bulking Agents: Laxatives that make bowel movements soft and easy to pass. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in
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many enzymatic processes. [NIH] Calicivirus: A genus in the family Caliciviridae containing many species including feline calicivirus , vesicular exanthema of swine virus, and San Miguel sea lion viruses. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]
Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carboxy: Cannabinoid. [NIH] Carboxypeptidases: Enzymes that act at a free C-terminus of a polypeptide to liberate a single amino acid residue. They are further divided based on their catalytic mechanism into serine-type carboxypeptidases EC 3.4.16; metallocarboxypeptidases, EC 3.4.17; and cysteinetype carboxypeptidases, EC 3.4.18. EC 3.4.-. [NIH] Carboxy-terminal: The end of any polypeptide or protein that bears a free carboxyl group. [NIH]
Carcinoembryonic Antigen: A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the respone to colon cancer treatment. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Carcinoma in Situ: A malignant tumor that has not yet invaded the basement membrane of the epithelial cell of origin and has not spread to other tissues. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high
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blood pressure). [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cauda Equina: The lower part of the spinal cord consisting of the lumbar, sacral, and coccygeal nerve roots. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Celiac Artery: The arterial trunk that arises from the abdominal aorta and after a short course divides into the left gastric, common hepatic and splenic arteries. [NIH] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH]
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Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell motility: The ability of a cell to move. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellular adhesion: The close adherence (bonding) to adjoining cell surfaces. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Cesium: A member of the alkali metals. It has an atomic symbol Cs, atomic number 50, and atomic weight 132.91. Cesium has many industrial applications, including the construction of atomic clocks based on its atomic vibrational frequency. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and
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activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [NIH] Cholecystokinin: A 33-amino acid peptide secreted by the upper intestinal mucosa and also found in the central nervous system. It causes gallbladder contraction, release of pancreatic exocrine (or digestive) enzymes, and affects other gastrointestinal functions. Cholecystokinin may be the mediator of satiety. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]
Chorioallantoic membrane: The membrane in hen's eggs that helps chicken embryos get enough oxygen and calcium for development. The calcium comes from the egg shell. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Choroideremia: An X-chromosome-linked abnormality characterized by atrophy of the choroid and degeneration of the retinal pigment epithelium causing night blindness. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH]
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Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cidofovir: A drug used to treat infection caused by viruses. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clathrin-Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles is covered with a lattice-like network of the protein clathrin. Shortly after formation, however, the clathrin coat is removed and the vesicles are referred to as endosomes. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used
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as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Coiled Bodies: A distinct subnuclear domain enriched in splicesomal snRNPs (ribonucleoproteins, small nuclear) and p80-coilin. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes
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immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH]
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Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Contact dermatitis: Inflammation of the skin with varying degrees of erythema, edema and vesinculation resulting from cutaneous contact with a foreign substance or other exposure. [NIH]
Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneal Stroma: The lamellated connective tissue constituting the thickest layer of the cornea between the Bowman and Descemet membranes. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronavirus: A genus of the family Coronaviridae which causes respiratory or gastrointestinal disease in a variety of vertebrates. [NIH]
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Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Coxsackie virus: Group of viruses that is a common source of infection in kids. It is transmitted primarily by touch. The most common symptoms children experience are simply fever, feeling rundown, and a rash. [NIH] Coxsackieviruses: A heterogeneous group of the genus enterovirus found in association with various diseases in man and other animals. Two groups (A and B) have been identified with a number of serotypes in each. The name is derived from a village in New York State where the virus was first identified. [NIH] Coxsackieviruses A: One of the two groups of coxsackieviruses. Coxsackie A viruses are divided into 24 serotypes and are associated with or implicated in herpangina, aseptic meningitis, paralytic disease, encephalitis, ataxia, and cardiac diseases. Coxsackie A24 variant can cause acute hemorrhagic conjunctivitis. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniosynostoses: Premature closure of one or more sutures of the skull. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Croton Oil: Viscous, nauseating oil obtained from the shrub Croton tiglium (Euphorbaceae). It is a vesicant and skin irritant used as pharmacologic standard for skin inflammation and allergy and causes skin cancer. It was formerly used as an emetic and cathartic with frequent mortality. [NIH] Cryptosporidium: A genus of coccidian parasites of the family Cryptosporidiidae, found in the intestinal epithelium of many vertebrates including humans. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH]
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Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]
Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclospora: A genus of coccidian parasites in the family Eimeriidae. Cyclospora cayetanensis is pathogenic in humans, probably transmitted via the fecal-oral route, and causes nausea and diarrhea. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cystitis: Inflammation of the urinary bladder. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytomegalovirus Retinitis: Infection of the retina by cytomegalovirus characterized by retinal necrosis, hemorrhage, vessel sheathing, and retinal edema. Cytomegalovirus retinitis is a major opportunistic infection in AIDS patients and can cause blindness. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH]
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Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]
De novo: In cancer, the first occurrence of cancer in the body. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Dendritic cell vaccine: A vaccine made of antigens and dendritic antigen-presenting cells (APCs). [NIH] Dengue Virus: A species of the genus Flavivirus which causes an acute febrile and sometimes hemorrhagic disease in man. Dengue is mosquito-borne and four serotypes are known. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermatitis: Any inflammation of the skin. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Foot: Ulcers of the foot as a complication of diabetes. Diabetic foot, often with
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infection, is a common serious complication of diabetes and may require hospitalization and disfiguring surgery. The foot ulcers are probably secondary to neuropathies and vascular problems. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]
Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dipeptidases: Exopeptidases that specifically act on dipeptides. EC 3.4.13. [NIH] Dipeptidyl Peptidases: Enzymes which cleave dipeptides from the amino terminal of a polypeptide. Dipeptidyl peptidase I, II, III, IV are known. They hydrolyze the betanaphthylamides of glycine-arginine, lysine-alanine, arginine-arginine and glycine-proline, respectively. Dipeptidyl peptidase I is cathepsin C. EC 3.4.14.-. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU]
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Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Distemper: A name for several highly contagious viral diseases of animals, especially canine distemper. In dogs, it is caused by the canine distemper virus (distemper virus, canine). It is characterized by a diphasic fever, leukopenia, gastrointestinal and respiratory inflammation and sometimes, neurologic complications. In cats it is known as feline panleukopenia. [NIH] Distemper Virus, Canine: A species of morbillivirus causing distemper in dogs, wolves, foxes, raccoons, and ferrets. [NIH] Distention: The state of being distended or enlarged; the act of distending. [EU] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]
Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended
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effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysentery: Any of various disorders marked by inflammation of the intestines, especially of the colon, and attended by pain in the abdomen, tenesmus, and frequent stools containing blood and mucus. Causes include chemical irritants, bacteria, protozoa, or parasitic worms. [EU]
Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electron microscope: A microscope (device used to magnify small objects) that uses electrons (instead of light) to produce an enlarged image. An electron microscopes shows tiny details better than any other type of microscope. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH]
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Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emetic: An agent that causes vomiting. [EU] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometrium: The layer of tissue that lines the uterus. [NIH] Endonucleases: Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-. [NIH] Endorphin: Opioid peptides derived from beta-lipotropin. Endorphin is the most potent naturally occurring analgesic agent. It is present in pituitary, brain, and peripheral tissues. [NIH]
Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [NIH] Endostatin: A drug that is being studied for its ability to prevent the growth of new blood vessels into a solid tumor. Endostatin belongs to the family of drugs called angiogenesis
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inhibitors. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Enterovirus: A genus of the family Picornaviridae whose members preferentially inhabit the intestinal tract of a variety of hosts. The genus contains many species. Newly described members of human enteroviruses are assigned continuous numbers with the species designated "human enterovirus". [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH]
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Ependyma: A thin membrane that lines the ventricles of the brain and the central canal of the spinal cord. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermal growth factor receptor: EGFR. The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also known as ErbB1 or HER1. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. [NIH] Epidural Space: Space between the dura mater and the walls of the vertebral canal. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks
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containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Europium: An element of the rare earth family of metals. It has the atomic symbol Eu, atomic number 63, and atomic weight 152. Europium is used in the form of its salts as coatings for cathode ray tubes and in the form of its organic derivatives as shift reagents in NMR spectroscopy. [NIH] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Exopeptidases: A sub-subclass of peptide hydrolases that act only near the ends of polypeptide chains. Exopeptidases are further divided into aminopeptidases, EC 3.4.11; dipeptidases, EC 3.4.13; dipeptidyl peptidases & tripeptidyl peptidases, EC 3.4.14; peptidyldipeptidases, EC 3.4.15; carboxypeptidases, EC 3.4.16 - EC 3.4.18, and omega peptidases, EC 3.4.19. EC 3.4.-. [NIH] Expectorant: 1. Promoting the ejection, by spitting, of mucus or other fluids from the lungs
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and trachea. 2. An agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). [EU]
Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]
External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatal Outcome: Death resulting from the presence of a disease in an individual, as shown by a single case report or a limited number of patients. This should be differentiated from death, the physiological cessation of life and from mortality, an epidemiological or statistical concept. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Feline Panleukopenia: A highly contagious DNA virus infection of the cat family and of mink, characterized by fever, enteritis and bone marrow changes. It is also called feline
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ataxia, feline agranulocytosis, feline infectious enteritis, cat fever, cat plague, show fever. [NIH]
Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU]
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Flatus: Gas passed through the rectum. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Antibody Technique: Test for tissue antigen using either a direct method by conjugation of antibody with fluorescent dye or an indirect method by formation of antigenantibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody. The tissue is then examined by fluorescence microscopy. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluoroimmunoassay: The use of fluorescence spectrometry to obtain quantitative results for the fluorescent antibody technique. One advantage over the other methods (e.g., radioimmunoassay) is its extreme sensitivity, with a detection limit on the order of tenths of microgram/liter. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of
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shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single
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cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, Viral: The hereditary material of viruses, consisting in all DNA and some RNA viruses of a single molecule of nucleic acid, and in some RNA viruses of several separate pieces of RNA. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Giardia: A genus of flagellate intestinal protozoa parasitic in various vertebrates, including humans. Characteristics include the presence of four pairs of flagella arising from a complicated system of axonemes and cysts that are ellipsoidal to ovoidal in shape. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental
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glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose-6-Phosphatase: An enzyme that catalyzes the conversion of D-glucose 6-phosphate and water to D-glucose and orthophosphate. EC 3.1.3.9. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonadal: Pertaining to a gonad. [EU]
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Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Growth Plate: The area between the epiphysis and the diaphysis within which bone growth occurs. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]
Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage;
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craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematogenous: Originating in the blood or spread through the bloodstream. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematuria: Presence of blood in the urine. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatic Artery: A branch of the celiac artery that distributes to the stomach, pancreas, duodenum, liver, gallbladder, and greater omentum. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hepatoma: A liver tumor. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one
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generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see
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also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]
Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperaemia: An excess of blood in a part; engorgement. [EU] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypothalamic: Of or involving the hypothalamus. [EU]
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Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hysterectomy: Excision of the uterus. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Ileostomy: Surgical creation of an external opening into the ileum for fecal diversion or drainage. Loop or tube procedures are most often employed. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]
Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]
Immunodominant Epitopes: Subunits of the antigenic determinant that are most easily recognized by the immune system and thus most influence the specificity of the induced antibody. [NIH] Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH]
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Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a
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specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inoculum: The spores or tissues of a pathogen that serve to initiate disease in a plant. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which
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occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Integrase: An enzyme that inserts DNA into the host genome. It is encoded by the pol gene of retroviruses and also by temperate bacteriophages, the best known being bacteriophage lambda. EC 2.7.7.-. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]
Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper
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cells. It is an initiator of cell-mediated immunity. [NIH] Interleukin-13: T-lymphocyte-derived cytokine that produces proliferation, immunoglobulin isotype switching, and immunoglobulin production by immature Blymphocytes. It appears to play a role in regulating inflammatory and immune responses. [NIH]
Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervertebral: Situated between two contiguous vertebrae. [EU] Intervertebral Disk Displacement: An intervertebral disk in which the nucleus pulposus has protruded through surrounding fibrocartilage. This occurs most frequently in the lower lumbar region. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intravesical: Within the bladder. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Intussusception: A rare disorder. A part of the intestines folds into another part of the
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intestines, causing blockage. Most common in infants. Can be treated with an operation. [NIH]
Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Job Satisfaction: Personal satisfaction relative to the work situation. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA
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fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]
Kilobase: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kinetic: Pertaining to or producing motion. [EU] Kringles: Triple-looped protein domains linked by disulfide bonds. These common structural domains, so-named for their resemblance to Danish pastries known as kringlers, play a role in binding membranes, proteins, and phospholipids as well as in regulating proteolysis. Kringles are also present in coagulation-related and fibrinolytic proteins and other plasma proteinases. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lacrimal: Pertaining to the tears. [EU] Lacrimal gland: The small almond-shaped structure that produces tears; located just above the outer corner of the eye. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]
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Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Left ventricular assist device: A mechanical device used to increase the heart's pumping ability. [NIH] Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissues, probably arising from the smooth muscle of small blood vessels in these tissues. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukemia: Cancer of blood-forming tissue. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC
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3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]
Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]
Liver metastases: Cancer that has spread from the original (primary) tumor to the liver. [NIH]
Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locoregional: The characteristic of a disease-producing organism to transfer itself, but typically to the same region of the body (a leg, the lungs, .) [EU] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low Back Pain: Acute or chronic pain in the lumbar or sacral regions, which may be associated with musculo-ligamentous sprains and strains; intervertebral disk displacement; and other conditions. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH]
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Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysosome: A sac-like compartment inside a cell that has enzymes that can break down cellular components that need to be destroyed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic
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moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant mesothelioma: A rare type of cancer in which malignant cells are found in the sac lining the chest or abdomen. Exposure to airborne asbestos particles increases one's risk of developing malignant mesothelioma. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Measles Virus: The type species of morbillivirus and the cause of the highly infectious
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human disease measles, which affects mostly children. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Oncology: A subspecialty of internal medicine concerned with the study of neoplasms. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Meningoencephalitis: An inflammatory process involving the brain (encephalitis) and meninges (meningitis), most often produced by pathogenic organisms which invade the central nervous system, and occasionally by toxins, autoimmune disorders, and other conditions. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menorrhagia: Excessive menstrual flow. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU]
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Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesothelial: It lines the peritonealla and pleural cavities. [NIH] Mesothelioma: A benign (noncancerous) or malignant (cancerous) tumor affecting the lining of the chest or abdomen. Exposure to asbestos particles in the air increases the risk of developing malignant mesothelioma. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH]
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Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]
Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monensin: An antiprotozoal agent produced by Streptomyces cinnamonensis. It exerts its effect during the development of first-generation trophozoites into first-generation schizonts within the intestinal epithelial cells. It does not interfere with hosts' development of acquired immunity to the majority of coccidial species. Monensin is a sodium and proton selective ionophore and is widely used as such in biochemical studies. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH]
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Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Monocyte Chemoattractant Protein-1: A chemokine that is a chemoattractant for human monocytes and may also cause cellular activation of specific functions related to host defense. It is produced by leukocytes of both monocyte and lymphocyte lineage and by fibroblasts during tissue injury. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morbillivirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have hemagglutinin but not neuraminidase activity. All members produce both cytoplasmic and intranuclear inclusion bodies. MEASLES VIRUS is the type species. [NIH]
Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multidose: Occurring in, or using multiple doses. [EU] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH]
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Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]
Mycobacterium tuberculosis: A species of gram-positive, aerobic bacteria that produces tuberculosis in man, other primates, dogs, and some animals which have contact with man. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation. [NIH] Mycoplasma: A genus of gram-negative, facultatively anaerobic bacteria bounded by a plasma membrane only. Its organisms are parasites and pathogens, found on the mucous membranes of humans, animals, and birds. [NIH] Mycoplasma pneumoniae: Short filamentous organism of the genus Mycoplasma, which binds firmly to the cells of the respiratory epithelium. It is one of the etiologic agents of nonviral primary atypical pneumonia in man. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]
Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH]
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Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myometrium: The smooth muscle coat of the uterus, which forms the main mass of the organ. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Necrotizing Enterocolitis: A condition in which part of the tissue in the intestines is destroyed. Occurs mainly in under-weight newborn babies. A temporary ileostomy may be necessary. [NIH] Neomycin: Antibiotic complex produced by Streptomyces fradiae. It is composed of neomycins A, B, and C. It acts by inhibiting translation during protein synthesis. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephropathy: Disease of the kidneys. [EU] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube
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defects have difficulty walking and with bladder and bowel control. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neurotrophins: A nerve growth factor. [NIH] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Night Blindness: Anomaly of vision in which there is a pronounced inadequacy or complete absence of dark-adaptation. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by
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volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nonmalignant: Not cancerous. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Matrix: The fibrogranular network of residual structural elements within which are immersed both chromatin and ribonucleoproteins. It extends throughout the nuclear interior from the nucleolus to the nuclear pore complexes along the nuclear periphery. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleocapsid: A protein-nucleic acid complex which forms part or all of a virion. It consists of a capsid plus enclosed nucleic acid. Depending on the virus, the nucleocapsid may correspond to a naked core or be surrounded by a membranous envelope. [NIH] Nucleoprotein: Chromosomes consist largely of nuclei acids and proteins, joined here as complexes called nucleoproteins. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nursing Care: Care given to patients by nursing service personnel. [NIH] Octamer: Eight molecules of histone. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU]
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Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Omentum: A fold of the peritoneum (the thin tissue that lines the abdomen) that surrounds the stomach and other organs in the abdomen. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Orf: A specific disease of sheep and goats caused by a pox-virus that is transmissible to man and characterized by vesiculation and ulceration of the lips. [NIH] Orf Virus: The type species of Parapoxvirus which causes a skin infection in natural hosts, usually young sheep. Humans may contract local skin lesions by contact. The virus apparently persists in soil. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Oropharynx: Oral part of the pharynx. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a
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solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteocalcin: Vitamin K-dependent calcium-binding protein synthesized by osteoblasts and found primarily in bone. Serum osteocalcin measurements provide a noninvasive specific marker of bone metabolism. The protein contains three residues of the amino acid gammacarboxyglutamic acid (GLA), which, in the presence of calcium, promotes binding to hydroxyapatite and subsequent accumulation in bone matrix. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH]
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Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreas Transplant: A surgical procedure that involves replacing the pancreas of a person who has diabetes with a healthy pancreas that can make insulin. The healthy pancreas comes from a donor who has just died or from a living relative. A person can donate half a pancreas and still live normally. [NIH] Pancreas Transplantation: The transference of a pancreas from one human or animal to another. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Papilla: A small nipple-shaped elevation. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Parapoxvirus: A genus of the family Poxviridae, subfamily Chordopoxvirinae, which infect ungulates and may infect humans. Orf virus is the type species. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresthesia: Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU]
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Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH]
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Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharyngitis: Inflammation of the throat. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule,
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releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photophobia: Abnormal sensitivity to light. This may occur as a manifestation of eye diseases; migraine; subarachnoid hemorrhage; meningitis; and other disorders. Photophobia may also occur in association with depression and other mental disorders. [NIH] Phylogeny: The relationships of groups of organisms as reflected by their evolutionary history. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plaque Assay: Method for measuring viral infectivity and multiplication in cultured cells. Clear lysed areas or plaques develop as the viral particles are released from the infected cells during incubation. With some viruses, the cells are killed by a cytopathic effect; with others, the infected cells are not killed but can be detected by their hemadsorptive ability. Sometimes the plaque cells contain viral antigens which can be measured by immunofluorescence. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU]
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Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]
Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarthritis: An inflammation of several joints together. [EU] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polylysine: A peptide which is a homopolymer of lysine. [NIH]
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Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyploidy: The chromosomal constitution of a cell containing multiples of the normal number of chromosomes; includes triploidy (symbol: 3N), tetraploidy (symbol: 4N), etc. [NIH]
Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyvalent: Having more than one valence. [EU] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer.
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Also called premalignant. [NIH] Precipitation: The act or process of precipitating. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary tumor: The original tumor. [NIH] Primary vaccination: First or principal vaccination ( = introduction of a vaccine into the body for the purpose of inducing immunity). [EU] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent
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mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatectomy: Complete or partial surgical removal of the prostate. Three primary approaches are commonly employed: suprapubic - removal through an incision above the pubis and through the urinary bladder; retropubic - as for suprapubic but without entering the urinary bladder; and transurethral (transurethral resection of prostate). [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]
Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH]
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Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Provirus: Virus that is integrated into the chromosome of a host cell and is transmitted in that form from one host cell generation to another without leading to the lysis of the host cells. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulposus: Prolapse of the nucleus pulposus into the body of the vertebra; necrobacillosis of rabbits. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Pupil: The aperture in the iris through which light passes. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are
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known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Rabies: A highly fatal viral infection of the nervous system which affects all warm-blooded animal species. It is one of the most important of the zoonoses because of the inevitably fatal outcome for the infected human. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation Oncology: A subspecialty of medical oncology and radiology concerned with the radiotherapy of cancer. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radiculopathy: Disease involving a spinal nerve root (see spinal nerve roots) which may result from compression related to intervertebral disk displacement; spinal cord injuries; spinal diseases; and other conditions. Clinical manifestations include radicular pain, weakness, and sensory loss referable to structures innervated by the involved nerve root. [NIH]
Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in
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the diagnosis and treatment of disease. [NIH] Radiosensitization: The use of a drug that makes tumor cells more sensitive to radiation therapy. [NIH] Radiosensitizers: Drugs that make tumor cells more sensitive to radiation. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reading Frames: The sequence of codons by which translation may occur. A segment of mRNA 5'AUCCGA3' could be translated in three reading frames, 5'AUC. or 5'UCC. or 5'CCG., depending on the location of the start codon. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Refractory cancer: Cancer that has not responded to treatment. [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Rehydration Solutions: Fluids restored to the body in order to maintain normal waterelectrolyte balance. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH]
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Renal cell carcinoma: A type of kidney cancer. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual disease: Cancer cells that remain after attempts have been made to remove the cancer. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory syncytial virus: RSV. A virus that causes respiratory infections with cold-like symptoms. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]
Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin
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by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Neovascularization: Formation of new blood vessels originating from the retinal veins and extending along the inner (vitreal) surface of the retina. [NIH] Retinal Vein: Central retinal vein and its tributaries. It runs a short course within the optic nerve and then leaves and empties into the superior ophthalmic vein or cavernous sinus. [NIH]
Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoblastoma Protein: Product of the retinoblastoma tumor suppressor gene. It is a nuclear phosphoprotein hypothesized to normally act as an inhibitor of cell proliferation. Rb protein is absent in retinoblastoma cell lines. It also has been shown to form complexes with the adenovirus E1A protein, the SV40 T antigen, and the human papilloma virus E7 protein. [NIH]
Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retropubic: A potential space between the urinary bladder and the symphisis and body of the pubis. [NIH] Retrotransposons: DNA sequence which is a copy of a RNA virus into a host's DNA and which can reinsert itself elsewhere in the genome. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhinovirus: A genus of Picornaviridae inhabiting primarily the respiratory tract of mammalian hosts. It includes the human strains associated with common colds. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series
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of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Ribonucleoproteins: Proteins conjugated with ribonucleic acids (RNA) or specific RNA. Many viruses are ribonucleoproteins. [NIH] Ribonucleoproteins, Small Nuclear: Highly conserved nuclear RNA-protein complexes that function in RNA processing in the nucleus, including pre-mRNA splicing and pre-mRNA 3'end processing in the nucleoplasm, and pre-rRNA processing in the nucleolus. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rotavirus: A genus of Reoviridae, causing acute gastroenteritis in birds and mammals, including humans. Transmission is horizontal and by environmental contamination. [NIH] Rubella: An acute, usually benign, infectious disease caused by a togavirus and most often affecting children and nonimmune young adults, in which the virus enters the respiratory tract via droplet nuclei and spreads to the lymphatic system. It is characterized by a slight cold, sore throat, and fever, followed by enlargement of the postauricular, suboccipital, and cervical lymph nodes, and the appearances of a fine pink rash that begins on the head and spreads to become generalized. Called also German measles, roetln, röteln, and three-day measles, and rubeola in French and Spanish. [EU] Rubella Virus: The type (and only) species of Rubivirus causing acute infection in humans, primarily children and young adults. Humans are the only natural host. A live, attenuated vaccine is available for prophylaxis. [NIH] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Sagittal: The line of direction passing through the body from back to front, or any vertical plane parallel to the medial plane of the body and inclusive of that plane; often restricted to the medial plane, the plane of the sagittal suture. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salmonella: A genus of gram-negative, facultatively anaerobic, rod-shaped bacteria that utilizes citrate as a sole carbon source. It is pathogenic for humans, causing enteric fevers, gastroenteritis, and bacteremia. Food poisoning is the most common clinical manifestation. Organisms within this genus are separated on the basis of antigenic characteristics, sugar fermentation patterns, and bacteriophage susceptibility. [NIH] Saponin: A substance found in soybeans and many other plants. Saponins may help lower cholesterol and may have anticancer effects. [NIH] Sarcolemma: The plasma membrane of a smooth, striated, or cardiac muscle fiber. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH]
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Sarcoplasmic Reticulum: A network of tubules and sacs in the cytoplasm of skeletal muscles that assist with muscle contraction and relaxation by releasing and storing calcium ions. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sciatica: A condition characterized by pain radiating from the back into the buttock and posterior/lateral aspects of the leg. Sciatica may be a manifestation of sciatic neuropathy; radiculopathy (involving the L4, L5, S1 or S2 spinal nerve roots; often associated with intervertebral disk displacement); or lesions of the cauda equina. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Secretory Vesicles: Vesicles derived from the golgi apparatus containing material to be released at the cell surface. [NIH] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH]
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Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serial Passage: Inoculation of a series of animals or in vitro tissue with an infectious bacterium or virus, as in virulence studies and the development of vaccines. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [NIH] Shigella: A genus of gram-negative, facultatively anaerobic, rod-shaped bacteria that ferments sugar without gas production. Its organisms are intestinal pathogens of man and
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other primates and cause bacillary dysentery. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Sindbis Virus: The type species of alphavirus normally transmitted to birds by Culex mosquitoes in Egypt, South Africa, India, Malaya, the Philippines, and Australia. It may be associated with fever in humans. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for
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oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Iodide: Sodium iodide (NaI). A compound forming white, odorless deliquescent crystals and used as iodine supplement, expectorant or in its radioactive (I-131) form as an diagnostic aid, particularly for thyroid function determinants. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Spasmodic: Of the nature of a spasm. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatogenesis: Process of formation and development of spermatozoa, including spermatocytogenesis and spermiogenesis. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Nerve Roots: The paired bundles of nerve fibers entering and leaving the spinal cord at each segment. The dorsal and ventral nerve roots join to form the mixed segmental spinal nerves. The dorsal roots are generally afferent, formed by the central projections of the spinal (dorsal root) ganglia sensory cells, and the ventral roots efferent, comprising the
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axons of spinal motor and autonomic preganglionic neurons. There are, however, some exceptions to this afferent/efferent rule. [NIH] Spinal Stenosis: Narrowing of the spinal canal. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spondylitis: Inflammation of the vertebrae. [EU] Spondylolisthesis: Forward displacement of one vertebra over another. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Sprains and Strains: A collective term for muscle and ligament injuries without dislocation or fracture. A sprain is a joint injury in which some of the fibers of a supporting ligament are ruptured but the continuity of the ligament remains intact. A strain is an overstretching or overexertion of some part of the musculature. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Stabilization: The creation of a stable state. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH]
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Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]
Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptavidin: A 60kD extracellular protein of Streptomyces avidinii with four high-affinity biotin binding sites. Unlike AVIDIN, streptavidin has a near neutral isoelectric point and is free of carbohydrate side chains. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stringency: Experimental conditions (e. g. temperature, salt concentration) used during the hybridization of nucleic acids. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Subtraction Technique: Combination or superimposition of two images for demonstrating differences between them (e.g., radiograph with contrast vs. one without, radionuclide images using different radionuclides, radiograph vs. radionuclide image) and in the preparation of audiovisual materials (e.g., offsetting identical images, coloring of vessels in angiograms). [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH]
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Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superinfection: A frequent complication of drug therapy for microbial infection. It may result from opportunistic colonization following immunosuppression by the primary pathogen and can be influenced by the time interval between infections, microbial physiology, or host resistance. Experimental challenge and in vitro models are sometimes used in virulence and infectivity studies. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in
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mammary and uterine. [NIH] Taxanes: Anticancer drugs that inhibit cancer cell growth by stopping cell division. Also called antimitotic or antimicrotubule agents or mitotic inhibitors. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminal Repeat Sequences: Nucleotide sequences repeated on both the 5' and 3' ends of a sequence under consideration. For example, the hallmarks of a transposon are that it is flanked by inverted repeats on each end and the inverted repeats are flanked by direct repeats. The Delta element of Ty retrotransposons and LTRs (long terminal repeats) are examples of this concept. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Tetanus Toxin: The toxin elaborated by Clostridium tetani. It is a protein with a molecular weight of about 150,000, probably consisting of two fragments, tetanolysin being the hemolytic and tetanospasmin the neurotoxic principle. The toxin causes disruption of the inhibitory mechanisms of the CNS, thus permitting uncontrolled nervous activity, leading to fatal convulsions. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Tetravalent: Pertaining to a group of 4 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active
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form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerase. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances
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usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]
Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]
Transitional cell carcinoma: A type of cancer that develops in the lining of the bladder, ureter, or renal pelvis. [NIH] Translating: Conversion from one language to another language. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH]
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Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trans-Splicing: The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing. [NIH] Transurethral: Performed through the urethra. [EU] Transurethral resection: Surgery performed with a special instrument inserted through the urethra. Also called TUR. [NIH] Transurethral Resection of Prostate: Resection of the prostate using a cystoscope passed through the urethra. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other
Dictionary 379
mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]
Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]
Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]
Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Urothelium: The epithelial lining of the urinary tract. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH]
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Uteroglobin: A protein fraction of pregnant uterine fluid which can induce and regulate blastocystic development. Blastokinin is thought to be similar or identical to uteroglobin. Presence in uterine fluid regulated by progesterone. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Varicella: Chicken pox. [EU] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary
Dictionary 381
artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vesicular Exanthema of Swine: A calicivirus infection of swine characterized by hydropic degeneration of the oral and cutaneous epithelia. [NIH] Vesicular Exanthema of Swine Virus: The type species of the genus Calicivirus, an RNA virus infecting pigs. The resulting infection is an acute febrile disease which is clinically indistinguishable from foot and mouth disease. Transmission is by contaminated food. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vial: A small bottle. [EU] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Villous: Of a surface, covered with villi. [NIH] Vimentin: An intermediate filament protein found in most differentiating cells, in cells grown in tissue culture, and in certain fully differentiated cells. Its insolubility suggests that it serves a structural function in the cytoplasm. MW 52,000. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viral Proteins: Proteins found in any species of virus. [NIH] Viral Regulatory Proteins: Proteins which regulate the rate of transcription of viral structural genes. [NIH] Viral Structural Proteins: Viral proteins that do not regulate transcription. They are coded by viral structural genes and include nucleocapsid core proteins (gag proteins), enzymes (pol proteins), and membrane components (env proteins). Transcription of viral structural genes is regulated by viral regulatory proteins. [NIH] Viral Vaccines: Suspensions of attenuated or killed viruses administered for the prevention or treatment of infectious viral disease. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or
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viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Virus Replication: The process of intracellular viral multiplication, consisting of the synthesis of proteins, nucleic acids, and sometimes lipids, and their assembly into a new infectious particle. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral fat: One of the three compartments of abdominal fat. Retroperitoneal and subcutaneous are the other two compartments. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Vitellogenin: A serum and yolk protein which has been characterized as a calcium-binding glycolipophosphoprotein. It is induced by estrogen or juvenile hormone and is essential for yolk formation in various insect species. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU]
Dictionary 383
Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
385
INDEX 3 3-dimensional, 222, 293, 361 A Abdomen, 293, 304, 318, 321, 337, 341, 343, 345, 352, 354, 355, 372, 373, 382 Abdominal, 4, 213, 293, 306, 316, 326, 354, 355, 356, 379, 382 Abdominal fat, 293, 382 Abdominal Pain, 293, 326, 379 Aberrant, 203, 293 Ablate, 25, 293 Ablation, 53, 102, 153, 293 Acceptor, 293, 353, 376, 377 Acetylcholine, 16, 69, 293, 295, 350 Acetylcysteine, 146, 293 Acute myelogenous leukemia, 60, 293 Acute myeloid leukemia, 293 Acute nonlymphocytic leukemia, 293 Adaptability, 293, 306, 307 Adaptation, 56, 293, 350 Adenine, 220, 230, 294, 363 Adenocarcinoma, 24, 163, 294, 330, 351 Adenomatous Polyposis Coli, 234, 294 Adjustment, 293, 294 Adjuvant, 43, 75, 140, 237, 294 Adrenergic, 64, 294, 317, 321 Adverse Effect, 63, 245, 294, 370 Aerobic, 294, 346, 348 Aerosol, 27, 294 Affinity Chromatography, 70, 240, 294 Agar, 58, 294, 313, 333, 357 Age Groups, 80, 294 Aged, 80 and Over, 294 Agonist, 294, 317, 349, 374 Agrin, 70, 295 Airway, 27, 28, 34, 50, 177, 207, 211, 233, 244, 295 AK, 73, 80, 85, 116, 118, 119, 123, 131, 132, 133, 154, 176, 295 Albumin, 295, 353, 357 Algorithms, 295, 303 Alimentary, 295, 354 Alkaline, 295, 296, 304 Alkaloid, 295, 367 Alkylating Agents, 295, 379 Alkylation, 59, 295 Allergen, 244, 295, 315, 369 Allergic Rhinitis, 255, 256, 295, 329
Allogeneic, 22, 30, 121, 135, 145, 295, 329 Allogeneic bone marrow transplantation, 145, 295 Alpha Particles, 295, 363 Alpha-1, 20, 295, 356 Alpha-fetoprotein, 198, 295, 324 Alphavirus, 268, 295, 370 Alternative medicine, 271, 296 Alternative Splicing, 218, 296, 361 Ameliorating, 238, 296 Amino Acid Sequence, 74, 201, 222, 223, 233, 248, 262, 296, 297, 301, 322, 327 Amino Acid Substitution, 42, 296 Aminopeptidases, 296, 322 Amino-terminal, 108, 109, 296 Ammonia, 296, 328 Amplification, 31, 216, 241, 296 Anaerobic, 296, 348, 367, 369 Anaesthesia, 296, 335 Anal, 30, 296, 321, 324 Analgesic, 212, 296, 319 Analog, 225, 296, 325, 326 Analogous, 49, 196, 296, 377 Analytes, 296, 374 Anaphylatoxins, 297, 311 Anaphylaxis, 255, 256, 297 Anaplastic, 148, 183, 297 Anatomical, 297, 300, 308, 312, 334, 345, 354, 368 Anemia, 297, 343, 347 Anesthesia, 295, 297, 319 Angiogenesis inhibitor, 297, 320 Angioplasty, 49, 297, 348 Anions, 295, 297, 338, 369 Annealing, 297, 359 Anorexia, 297, 326, 379 Anthrax, 8, 214, 215, 258, 297 Antibacterial, 56, 297, 371 Antibiotic, 56, 297, 315, 317, 322, 349, 371, 375 Anticoagulant, 298, 361 Antigen-Antibody Complex, 298, 311, 325 Antigen-presenting cell, 202, 230, 231, 298, 315 Anti-inflammatory, 62, 298, 313, 328 Antimetabolite, 298, 325, 345, 367 Antimicrobial, 126, 267, 298, 315, 317 Antimitotic, 298, 375
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Adenovirus
Antineoplastic, 144, 295, 298, 303, 313, 314, 317, 325, 345, 353, 358, 376 Antiserum, 298, 300 Antiviral, 28, 34, 75, 123, 144, 163, 181, 204, 230, 231, 248, 293, 298, 336, 355, 367 Anus, 296, 298, 304, 310 Aorta, 14, 298, 306, 381 Apolipoproteins, 298, 341 Apoptosis, 25, 39, 49, 51, 54, 55, 65, 77, 79, 80, 89, 92, 93, 107, 109, 116, 119, 121, 124, 132, 134, 154, 156, 162, 167, 173, 174, 175, 176, 180, 196, 199, 219, 230, 239, 245, 251, 252, 298, 306 Applicability, 25, 298 Aqueous, 29, 232, 299, 301, 314, 319, 340, 341 Arachidonic Acid, 107, 162, 299, 340, 360 Archaea, 299, 345 Arginine, 96, 297, 299, 316, 331, 350, 378 Arterial, 14, 134, 166, 246, 299, 306, 308, 332, 361, 374 Arteries, 78, 298, 299, 301, 303, 306, 307, 312, 341, 348, 362, 376 Arterioles, 299, 303, 305, 345 Arteriolosclerosis, 299 Arteriosclerosis, 159, 226, 299 Arteriovenous, 299, 345 Artery, 9, 31, 40, 49, 70, 297, 299, 301, 312, 319, 348, 362, 365 Arthralgia, 267, 299 Articular, 299, 353 Asbestos, 299, 343, 345 Ascites, 65, 213, 299 Aseptic, 299, 313, 352, 372 Aspiration, 299, 324 Assay, 17, 24, 61, 85, 101, 105, 123, 158, 177, 211, 228, 251, 252, 299, 333, 363 Astrocytes, 142, 299, 300, 345 Astrocytoma, 300, 327 Astrovirus, 150, 267, 300 Asymptomatic, 205, 206, 300, 354 Ataxia, 300, 313, 324 Atrium, 300, 380 Atrophy, 300, 308, 350 Attenuated, 180, 185, 238, 270, 300, 367, 381 Atypical, 6, 300, 348 Autoantibodies, 143, 300 Autoantigens, 300 Autodigestion, 300, 354 Autoimmune disease, 6, 202, 300, 347 Autologous, 65, 300
Avian, 6, 48, 84, 97, 99, 105, 106, 108, 110, 112, 153, 167, 168, 169, 191, 300 Avidity, 246, 300 Axons, 169, 300, 352, 372 B Bacillus, 297, 300, 304 Back Pain, 6, 300 Bacteremia, 300, 367 Bacterial Infections, 5, 10, 56, 301 Bacterial Physiology, 294, 301 Bacteriophage lambda, 301, 336 Bacteriophages, 301, 336 Bacteriostatic, 301, 322 Bacterium, 259, 301, 330, 369 Basal cell carcinoma, 200, 301 Basal cells, 301 Basal Ganglia, 300, 301, 326, 327 Base Pairing, 216, 217, 301 Basement Membrane, 301, 305, 323, 339 Basilar Artery, 16, 301 Basophils, 301, 329 Benign, 3, 30, 200, 226, 299, 301, 324, 326, 329, 340, 345, 349, 354, 364, 367, 382 Benign tumor, 200, 301, 340 Beta-Endorphin, 212, 301 Beta-Galactosidase, 35, 302 Beta-Thromboglobulin, 302, 337 Bile, 302, 325, 331, 341, 372 Biliary, 302, 354 Biliary Tract, 302, 354 Binding agent, 59, 302 Binding Sites, 11, 37, 48, 102, 302, 373 Biochemical, 12, 17, 41, 69, 139, 179, 184, 190, 191, 224, 298, 302, 328, 340, 346, 353, 369 Biogenesis, 39, 51, 302 Biolistics, 204, 302 Biological response modifier, 302, 336 Biological therapy, 302, 329 Biological Transport, 302, 316 Biomarkers, 66, 302 Biomolecular, 37, 120, 302, 374 Biopsy, 4, 302, 355 Biosynthesis, 103, 299, 302, 369 Biotechnology, 28, 71, 113, 143, 144, 162, 236, 248, 271, 277, 302 Bioterrorism, 8, 303 Biotin, 208, 303, 373 Bleomycin, 62, 303 Blood Coagulation, 303, 304, 376 Blood Platelets, 303, 344, 358, 369 Blood pressure, 303, 306, 332, 346, 362, 371
387
Blood-Brain Barrier, 121, 303 Blot, 59, 105, 303 Body Fluids, 302, 303, 304, 318, 371, 378 Bolus, 23, 303 Bolus infusion, 303 Bone Marrow Cells, 57, 303, 344 Bone Marrow Transplantation, 57, 130, 303 Bone Remodeling, 246, 303 Bone Resorption, 255, 256, 304 Bowel, 4, 267, 296, 304, 335, 337, 339, 350, 356, 373, 379 Bowel Movement, 267, 304, 373 Brachytherapy, 304, 337, 338, 363, 383 Bradykinin, 304, 350, 357 Bronchial, 304 Bronchiseptica, 304, 356 Bronchitis, 304, 309 Bronchopulmonary, 62, 136, 304 Bronchopulmonary Dysplasia, 62, 136, 304 Buccal, 304, 342, 373 Bulking Agents, 207, 304 Bypass, 103, 153, 304, 348 C Cachexia, 255, 256, 304 Calcification, 299, 304 Calcium, 162, 229, 299, 304, 305, 308, 311, 343, 348, 353, 368, 370, 382 Calicivirus, 5, 119, 305, 381 Callus, 305, 319 Calpain, 252, 305 Capillary, 67, 304, 305, 381 Capsules, 232, 305, 317 Carbohydrate, 305, 313, 328, 359, 369, 373 Carboxy, 72, 100, 222, 224, 305 Carboxypeptidases, 305, 322 Carboxy-terminal, 72, 222, 305 Carcinoembryonic Antigen, 214, 215, 258, 305 Carcinogen, 164, 178, 305 Carcinogenesis, 58, 166, 305 Carcinogenic, 295, 305, 335, 352, 360, 372, 379 Carcinoma, 66, 136, 139, 148, 164, 166, 183, 198, 207, 305, 351 Carcinoma in Situ, 66, 305 Cardiac, 9, 30, 41, 64, 122, 165, 251, 305, 313, 321, 322, 348, 349, 367, 372 Cardiomyopathy, 305 Cardiovascular, 26, 117, 123, 207, 305, 340, 369
Cardiovascular disease, 26, 207, 305 Carotene, 306, 365 Case report, 3, 130, 140, 306, 323 Caspase, 54, 118, 251, 306 Cataract, 254, 306 Catecholamines, 64, 306, 317 Catheterization, 297, 306, 348 Catheters, 117, 306, 334, 337 Cathode, 306, 318, 322 Cations, 306, 338 Cauda Equina, 306, 368 Caudal, 306, 333, 359 Causal, 306, 321, 369, 375 Cause of Death, 65, 198, 200, 221, 306 Celiac Artery, 306, 330 Celiac Disease, 4, 306 Cell Adhesion, 67, 156, 159, 246, 306, 336 Cell Death, 37, 54, 57, 65, 109, 148, 183, 196, 219, 245, 252, 253, 298, 306, 322, 349 Cell Differentiation, 38, 62, 307, 370 Cell Division, 301, 306, 307, 322, 329, 344, 345, 346, 357, 360, 368, 375 Cell membrane, 210, 302, 307, 315, 318, 326, 356 Cell motility, 307, 330 Cell proliferation, 25, 49, 52, 58, 65, 138, 200, 225, 245, 299, 307, 337, 366, 370 Cell Respiration, 307, 346, 365 Cell Survival, 65, 196, 307, 329 Cell Transplantation, 22, 114, 135, 141, 159, 183, 307 Cellular adhesion, 166, 199, 307 Centrifugation, 118, 209, 307, 346 Cerebral, 68, 255, 256, 300, 301, 303, 307, 312, 321, 327, 343 Cerebral Arteries, 301, 307 Cerebral hemispheres, 301, 307, 327 Cerebrovascular, 305, 307 Cerebrum, 307 Cervical, 30, 71, 152, 307, 367 Cervix, 71, 200, 307 Cesium, 239, 307 Character, 142, 307, 315, 328 Chemokines, 30, 156, 307 Chemotactic Factors, 308, 311 Chemotherapeutic agent, 67, 239, 308 Chemotherapy, 65, 67, 126, 130, 167, 176, 183, 184, 200, 212, 213, 221, 242, 308 Chimera, 76, 308 Chin, 308, 344 Chlorophyll, 308, 325 Chloroplasts, 308, 378
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Cholecystokinin, 16, 308 Cholera, 267, 308, 369, 381 Cholesterol, 39, 57, 119, 247, 302, 308, 309, 312, 332, 341, 367, 372, 374 Cholesterol Esters, 308, 341 Chondrocytes, 308, 324 Chondroitin sulfate, 213, 308 Chorioallantoic membrane, 157, 308 Choroid, 308, 365, 366, 380 Choroideremia, 131, 308 Chromatin, 42, 52, 228, 252, 298, 308, 320, 342, 351, 371 Chromosomal, 54, 82, 178, 241, 243, 296, 308, 331, 358, 359, 366, 375 Chromosome, 218, 222, 240, 308, 340, 362, 368, 375, 378, 379 Chronic Disease, 12, 100, 304, 309 Chronic granulocytic leukemia, 309 Chronic myelogenous leukemia, 255, 256, 309 Chronic Obstructive Pulmonary Disease, 35, 309 Chylomicrons, 309, 341 Cidofovir, 155, 309 Circulatory system, 41, 309 CIS, 65, 96, 144, 224, 309, 365, 378 Cisplatin, 67, 175, 179, 309 Clathrin, 10, 201, 208, 309, 310, 319 Clathrin-Coated Vesicles, 208, 309 Clear cell carcinoma, 309, 315 Clinical Medicine, 309, 360 Clinical Protocols, 44, 309 Cloning, 135, 165, 190, 197, 220, 243, 260, 303, 309, 336 Clot Retraction, 309, 358 Coagulation, 303, 310, 330, 339, 357 Coated Vesicles, 309, 310, 319 Codon, 54, 205, 206, 231, 310, 327, 364 Cofactor, 121, 189, 310, 361, 376 Cohort Studies, 310, 321 Coiled Bodies, 108, 310 Colitis, 234, 310 Collagen, 14, 36, 159, 301, 310, 323, 324, 343, 358, 360 Collapse, 297, 310 Colloidal, 295, 310, 369 Colon, 180, 200, 234, 245, 294, 305, 310, 318, 335, 339, 379 Colorectal, 12, 31, 166, 207, 269, 270, 310 Colorectal Cancer, 31, 207, 269, 310 Combination Therapy, 36, 310 Combinatorial, 34, 310
Complement, 14, 19, 28, 69, 196, 247, 297, 310, 311, 327, 336, 343, 357, 369 Complementary and alternative medicine, 173, 187, 311 Complementary medicine, 173, 311 Complementation, 9, 56, 89, 95, 311 Computational Biology, 277, 311 Concomitant, 206, 311 Cones, 311, 366 Conjugated, 59, 179, 311, 325, 351, 367 Conjunctiva, 10, 311, 335, 339 Conjunctivitis, 32, 80, 83, 90, 94, 147, 260, 311, 313, 329 Connective Tissue, 303, 310, 311, 312, 324, 326, 342, 345, 361, 367, 373, 374 Connexins, 312, 326 Consciousness, 296, 312, 316, 317, 362 Constitutional, 4, 312, 366 Constriction, 312, 338, 380 Constriction, Pathologic, 312, 380 Contact dermatitis, 255, 256, 312 Contamination, 9, 256, 257, 312, 330, 367 Continuous infusion, 23, 312 Contraindications, ii, 312 Contralateral, 55, 312 Control group, 6, 312 Convulsions, 312, 375 Coordination, 312, 347 Cornea, 10, 32, 312, 328, 339, 368, 373, 380, 383 Corneal Stroma, 32, 312 Coronary, 40, 41, 49, 305, 312, 348 Coronary heart disease, 305, 312 Coronary Thrombosis, 312, 348 Coronavirus, 111, 312 Corticosteroid, 313, 360 Cowpox, 313, 380 Cowpox Virus, 313, 380 Coxsackie virus, 5, 313 Coxsackieviruses, 11, 26, 222, 238, 313 Coxsackieviruses A, 11, 26, 313 Cranial, 36, 313, 329, 352, 355 Craniosynostoses, 37, 313 Crossing-over, 313, 364 Cross-Sectional Studies, 313, 321 Croton Oil, 200, 313 Cryptosporidium, 5, 313 Culture Media, 294, 313 Cultured cells, 169, 314, 357 Curative, 314, 375 Cutaneous, 297, 312, 314, 342, 354, 380, 381
389
Cyclic, 121, 305, 314, 329, 350 Cyclin, 102, 138, 228, 314 Cyclin-Dependent Kinases, 228, 314 Cyclophosphamide, 314, 333 Cyclospora, 5, 314 Cysteine, 247, 293, 305, 308, 314, 374 Cystine, 314 Cystitis, 3, 99, 120, 155, 219, 234, 314 Cytokine, 7, 29, 68, 129, 214, 215, 237, 244, 245, 258, 314, 336, 337 Cytomegalovirus Infections, 136, 314, 326 Cytomegalovirus Retinitis, 265, 314 Cytoplasm, 10, 33, 76, 154, 235, 252, 298, 301, 307, 314, 320, 342, 349, 351, 367, 368, 381 Cytosine, 43, 116, 140, 212, 314, 363 Cytoskeletal Proteins, 305, 309, 314 Cytoskeleton, 75, 314, 336, 346 Cytotoxic chemotherapy, 119, 315 Cytotoxicity, 74, 179, 196, 210, 212, 225, 239, 309, 315, 339 D Daunorubicin, 315, 317 De novo, 129, 315 Defense Mechanisms, 315, 336 Degenerative, 6, 8, 315, 330, 353, 366 Dehydration, 308, 315 Deletion, 31, 39, 78, 84, 159, 190, 194, 204, 243, 253, 298, 315, 326 Denaturation, 315, 359 Dendrites, 315, 350 Dendritic, 7, 78, 79, 85, 115, 122, 137, 164, 243, 315, 344 Dendritic cell, 7, 79, 115, 122, 137, 164, 243, 315 Dendritic cell vaccine, 137, 315 Dengue Virus, 8, 315 Dentists, 5, 315 Depolarization, 40, 57, 315, 370 Dermatitis, 315 DES, 17, 165, 297, 315 Desensitization, 315, 334 Detergents, 255, 315 Diabetes Mellitus, 315, 327 Diabetic Foot, 36, 315 Diagnostic procedure, 193, 271, 316 Diaphragm, 316, 358 Diarrhea, 4, 5, 77, 87, 234, 267, 314, 316 Diarrhoea, 316, 326 Diastolic, 316, 332 Dietary Fats, 316, 340 Diffusion, 246, 302, 316, 333, 335
Digestion, 295, 302, 304, 316, 337, 340, 341, 373, 380 Digestive tract, 316, 370, 372 Dihydrotestosterone, 316, 364 Dilated cardiomyopathy, 136, 316 Dimerization, 108, 316 Dipeptidases, 316, 322 Dipeptidyl Peptidases, 316, 322 Diploid, 73, 236, 311, 316, 357 Discrete, 98, 304, 316, 383 Disease Progression, 248, 316, 381 Dissociation, 208, 294, 316, 338 Dissociative Disorders, 316, 317 Distal, 64, 317, 362 Distemper, 6, 317 Distemper Virus, Canine, 317 Distention, 4, 317 Docetaxel, 177, 181, 185, 317 Dominance, 51, 317 Dopamine, 317, 350, 356 Dorsal, 317, 359, 371 Dosage Forms, 232, 317 Dose-limiting, 66, 317 Doxorubicin, 67, 317 Doxycycline, 14, 29, 57, 142, 317 Drive, ii, vi, 4, 5, 20, 26, 53, 64, 67, 161, 227, 317 Drug Interactions, 317 Drug Tolerance, 317, 376 Duct, 306, 318, 322, 342, 367 Duodenum, 302, 318, 330, 373 Dura mater, 37, 318, 321, 344 Dyes, 251, 252, 301, 318, 325 Dysentery, 318, 370 Dysplasia, 270, 318 E Ectopic, 204, 318 Edema, 312, 314, 318, 348, 379 Effector, 22, 293, 311, 318, 339 Efficacy, 9, 12, 13, 18, 19, 21, 23, 25, 29, 35, 42, 50, 53, 56, 60, 61, 67, 71, 116, 128, 129, 140, 156, 176, 195, 196, 233, 238, 242, 258, 270, 318 Elastic, 318, 328, 374 Elasticity, 299, 318 Elastin, 310, 318, 323 Electrolyte, 313, 318, 364, 371, 379 Electron microscope, 167, 223, 318 Electrons, 301, 306, 318, 338, 343, 353, 363, 364, 374 Electroporation, 229, 318 Elementary Particles, 318, 343, 350, 361
390
Adenovirus
Emboli, 67, 319 Embryo, 307, 319, 335, 353 Embryogenesis, 243, 319 Emetic, 313, 319 Emphysema, 309, 319 Emulsions, 294, 319 Encapsulated, 319, 341 Encephalitis, 221, 234, 265, 313, 319, 344 Encephalitis, Viral, 319 Endarterectomy, 297, 319 Endemic, 218, 308, 319, 343, 372 Endocytosis, 10, 12, 41, 75, 101, 119, 162, 195, 196, 208, 218, 248, 319 Endometrial, 26, 319 Endometrium, 319 Endonucleases, 80, 256, 319 Endorphin, 212, 301, 319 Endosomes, 309, 319 Endostatin, 23, 319 Endothelial cell, 15, 49, 146, 246, 249, 251, 303, 320, 324, 337, 376 Endothelium, 41, 320, 350, 358 Endothelium, Lymphatic, 320 Endothelium, Vascular, 320 Endothelium-derived, 320, 350 Endotoxic, 320, 341 Endotoxin, 62, 320, 379 Enhancer, 52, 166, 191, 236, 266, 320, 365 Enkephalin, 60, 301, 320 Enteropeptidase, 320, 378 Enterovirus, 313, 320 Environmental Exposure, 320, 352 Environmental Health, 276, 278, 320 Enzymatic, 305, 306, 311, 314, 320, 324, 359, 365 Enzyme-Linked Immunosorbent Assay, 97, 320 Eosinophils, 320, 329 Ependyma, 117, 321 Epidemic, 32, 38, 76, 82, 97, 118, 141, 147, 154, 219, 234, 321, 372 Epidemiologic Studies, 6, 321 Epidemiological, 40, 96, 141, 321, 323 Epidermal, 85, 86, 107, 123, 156, 174, 214, 215, 258, 321, 339, 344, 382 Epidermal Growth Factor, 85, 86, 107, 123, 156, 174, 321 Epidermal growth factor receptor, 107, 123, 156, 174, 321 Epidermis, 301, 302, 321, 339 Epidermoid carcinoma, 321, 372 Epidural, 212, 321
Epidural Space, 212, 321 Epigastric, 321, 354 Epinephrine, 294, 317, 321, 350, 351, 379 Epithelium, 26, 28, 34, 111, 207, 254, 301, 308, 313, 320, 321, 338, 348, 354, 383 Epitope, 39, 58, 62, 82, 88, 214, 223, 258, 259, 321 Erythema, 312, 321, 379 Erythrocytes, 297, 303, 305, 321, 364, 369 Erythromycin, 56, 322 Escalation, 23, 322 Esophageal, 24, 139, 322 Esophagus, 316, 322, 356, 373 Estrogen, 25, 247, 322, 368, 374, 382 Estrogen receptor, 25, 322 Etoposide, 168, 175, 179, 180, 185, 322 Eukaryotic Cells, 190, 243, 314, 322, 334, 352, 379 Europium, 110, 322 Excipients, 232, 322 Excitability, 40, 322 Excitation, 40, 125, 322, 350 Exhaustion, 322, 343 Exocrine, 16, 308, 322, 354 Exogenous, 122, 139, 204, 210, 214, 231, 245, 258, 259, 319, 322, 326, 361 Exon, 134, 296, 322 Exopeptidases, 252, 296, 316, 322, 355 Expectorant, 322, 371 Extensor, 323, 362 External-beam radiation, 323, 338, 363, 383 Extracellular Matrix, 12, 37, 49, 53, 70, 199, 311, 312, 323, 324, 336, 343, 353 Extracellular Matrix Proteins, 12, 323, 343 Extracellular Space, 323 Extraction, 17, 323 Eye Infections, 294, 323 F Failure to Thrive, 4, 323 Family Planning, 277, 323 Farnesyl, 179, 323 Fat, 6, 38, 293, 299, 303, 306, 312, 313, 319, 323, 341, 347, 371, 374 Fatal Outcome, 135, 323, 363 Fatigue, 323, 330 Fatty acids, 295, 323, 360, 376 Febrile, 219, 315, 323, 343, 381 Feces, 305, 323, 373 Feline Panleukopenia, 317, 323 Fermentation, 324, 367 Fetoprotein, 198, 324
391
Fetus, 295, 324, 380 Fibrin, 303, 309, 324, 358, 376 Fibrinogen, 246, 324, 357, 376 Fibrinolytic, 324, 339 Fibroblast Growth Factor, 36, 115, 200, 324 Fibroblasts, 32, 58, 61, 66, 97, 120, 125, 191, 324, 337, 347 Fibroid, 324, 340 Fibronectin, 70, 199, 324 Fibrosis, 34, 50, 211, 324, 368 Filtration, 258, 259, 324 Fixation, 324, 369 Flatus, 325, 326 Fludarabine, 128, 130, 325 Fluorescence, 10, 53, 64, 105, 251, 325 Fluorescent Antibody Technique, 325 Fluorescent Dyes, 251, 252, 325 Fluoroimmunoassay, 83, 110, 325 Fluorouracil, 213, 325 Fold, 21, 27, 48, 60, 121, 195, 325, 352 Foot Ulcer, 36, 316, 325 Foramen, 308, 325, 356 Fractionation, 10, 325 Free Radicals, 316, 325, 348 Fungus, 259, 325 G Galactosides, 302, 325 Gallbladder, 125, 293, 302, 308, 325, 330 Gamma Rays, 325, 363, 364 Ganciclovir, 31, 43, 115, 198, 326 Ganglia, 293, 326, 349, 355, 371 Ganglion, 326, 352, 383 Gangrenous, 326, 369 Gap Junctions, 198, 312, 326 Gas, 14, 54, 58, 296, 316, 325, 326, 332, 350, 369, 373, 380 Gastric, 145, 148, 183, 300, 306, 317, 321, 326 Gastrin, 326, 331 Gastroenteritis, 92, 93, 95, 99, 106, 111, 150, 219, 234, 260, 282, 300, 326, 367 Gastrointestinal tract, 24, 305, 324, 326, 340, 369, 378 Gene Deletion, 78, 326 Gene Targeting, 61, 326 Genes, Viral, 244, 327 Genetic Code, 327, 351 Genetic Engineering, 212, 242, 303, 309, 327 Genetic testing, 327, 359 Genetics, 4, 7, 8, 15, 27, 30, 37, 162, 210, 229, 262, 317, 327, 346
Genital, 30, 77, 309, 327, 379 Genitourinary, 327, 379 Genomics, 27, 165, 262, 327 Genotype, 66, 225, 327, 356 Germ Cells, 327, 344, 353, 371, 375 Giardia, 5, 327 Gland, 10, 327, 342, 343, 354, 357, 361, 368, 372, 373, 376 Glioblastoma, 63, 245, 327 Glioma, 19, 113, 116, 132, 148, 149, 176, 198, 270, 327 Glomerular, 52, 327 Glomeruli, 52, 327 Glomerulonephritis, 52, 327 Glomerulosclerosis, 13, 327 Glomerulus, 327, 328, 349 Glottis, 328, 356 Glucocorticoid, 60, 328, 360 Glucose, 131, 315, 328, 336, 357 Glucose-6-Phosphatase, 131, 328 Glucuronic Acid, 328, 330 Glutamic Acid, 328, 350, 360 Glutamine, 143, 328 Gluten, 4, 306, 328 Glycine, 316, 328, 350, 369 Glycogen, 20, 328, 356 Glycoprotein, 125, 140, 167, 184, 214, 215, 222, 258, 305, 324, 328, 329, 339, 347, 376, 378 Glycosaminoglycan, 308, 328 Glycoside, 328, 332 Glycosylation, 127, 328 Goats, 328, 352 Gonadal, 328, 372 Governing Board, 329, 359 Gp120, 11, 258, 329, 355 Grade, 45, 66, 240, 329 Graft, 30, 151, 255, 256, 329, 334, 348 Graft Rejection, 329, 334 Grafting, 329, 334 Gram-negative, 304, 320, 329, 348, 367, 369, 381 Gram-positive, 329, 348 Granule, 16, 329, 367 Granulocyte, 28, 329 Growth factors, 36, 37, 70, 329, 345 Growth Plate, 36, 329 Guanine, 59, 329, 363 Guanylate Cyclase, 49, 329, 350 H Habitat, 329, 348 Habitual, 307, 329
392
Adenovirus
Half-Life, 23, 230, 231, 329 Haptens, 294, 329, 363 Hay Fever, 295, 329 Headache, 329, 335 Heart attack, 305, 330 Heart failure, 64, 330 Hematogenous, 67, 330 Hematopoiesis, 29, 330 Hematopoietic Stem Cells, 257, 330 Hematuria, 4, 330 Hemoglobinopathies, 327, 330 Hemolytic, 330, 375 Hemorrhage, 314, 329, 330, 348, 357, 373 Hemostasis, 330, 336, 369 Heparin, 134, 240, 330, 358 Hepatic, 22, 31, 97, 130, 131, 134, 247, 295, 306, 330 Hepatic Artery, 31, 330 Hepatitis, 5, 6, 102, 130, 135, 159, 219, 234, 236, 237, 251, 267, 268, 330 Hepatitis A, 219, 330 Hepatocellular, 126, 135, 164, 198, 330 Hepatocellular carcinoma, 126, 135, 164, 198, 330 Hepatocyte, 22, 200, 330 Hepatocyte Growth Factor, 200, 330 Hepatoma, 139, 198, 330 Hepatovirus, 330 Hereditary, 327, 330, 350, 366 Heredity, 326, 327, 331 Herpes virus, 5, 202, 210, 240, 255, 256, 265, 331 Herpes Zoster, 255, 256, 331 Heterodimer, 49, 246, 331 Heterogeneity, 89, 97, 104, 294, 331 Heterozygotes, 317, 331 Histology, 45, 331 Histone Deacetylase, 191, 331 Histones, 308, 331 Homeostasis, 14, 29, 162, 245, 252, 304, 331 Homodimer, 331, 377 Homogeneous, 218, 299, 331, 356 Homologous, 72, 168, 215, 216, 247, 260, 312, 313, 326, 331, 347, 368, 369, 374, 375, 378 Homozygotes, 317, 331 Hormonal, 53, 300, 313, 331 Horseradish Peroxidase, 320, 331 Human papillomavirus, 30, 71, 99, 109, 137, 151, 331 Humoral, 8, 99, 142, 270, 329, 331 Humour, 331
Hybrid, 23, 53, 72, 73, 85, 106, 121, 131, 154, 184, 190, 224, 331, 332 Hybridization, 83, 84, 86, 105, 332, 346, 373 Hybridomas, 318, 332 Hydration, 4, 332 Hydrogen, 293, 301, 305, 315, 323, 332, 346, 350, 351, 353, 361 Hydrogen Bonding, 301, 332, 351 Hydrolases, 10, 332, 356 Hydrolysis, 302, 309, 319, 332, 355, 356, 359, 361, 378 Hydrophilic, 315, 332 Hydrophobic, 62, 315, 332, 341 Hydroxylysine, 310, 332 Hydroxyproline, 310, 332 Hyperaemia, 311, 332 Hypercholesterolemia, 143, 332 Hyperplasia, 78, 332 Hyperreflexia, 332, 375 Hypersensitivity, 295, 297, 315, 332, 340, 366, 369 Hypertension, 35, 299, 305, 330, 332, 379 Hypertrophy, 226, 332 Hypoplasia, 36, 332 Hypothalamic, 7, 332 Hypothalamus, 320, 332, 333, 357 Hypoxia, 35, 60, 113, 154, 252, 333 Hysterectomy, 25, 333 I Ifosfamide, 67, 333 Ileostomy, 333, 349 Imidazole, 303, 333 Immune response, 7, 8, 9, 13, 18, 21, 25, 32, 33, 44, 50, 104, 111, 118, 165, 168, 185, 189, 202, 204, 205, 206, 211, 214, 221, 230, 231, 233, 236, 237, 238, 258, 259, 294, 298, 300, 313, 329, 333, 334, 337, 343, 369, 373, 380, 381, 382 Immune Sera, 333 Immunization, 8, 39, 138, 143, 213, 214, 238, 258, 259, 302, 333, 334, 369 Immunoassay, 83, 87, 92, 100, 120, 320, 333 Immunocompromised, 3, 5, 22, 78, 128, 234, 333 Immunocompromised Host, 78, 234, 333 Immunodeficiency, 56, 78, 82, 99, 112, 113, 115, 206, 231, 234, 265, 333 Immunodeficiency syndrome, 265, 333 Immunodiffusion, 294, 333 Immunodominant Epitopes, 80, 333
393
Immunoelectrophoresis, 294, 333 Immunofluorescence, 55, 86, 334, 357 Immunogenic, 18, 220, 334, 341, 363 Immunohistochemistry, 30, 45, 334 Immunologic, 30, 33, 134, 230, 231, 308, 333, 334, 342, 364 Immunosuppressant, 295, 325, 334, 345 Immunosuppression, 95, 334, 342, 352, 374 Immunosuppressive, 263, 314, 328, 333, 334 Immunosuppressive Agents, 334 Immunosuppressive therapy, 334 Immunotherapy, 5, 39, 88, 128, 140, 164, 302, 315, 334 Impairment, 10, 300, 323, 334, 345 Implant radiation, 334, 337, 338, 363, 383 Implantation, 45, 64, 334 In situ, 16, 23, 81, 166, 167, 182, 204, 207, 213, 216, 217, 257, 263, 334 In Situ Hybridization, 81, 166, 182, 334 Incision, 334, 338, 361 Incubation, 37, 334, 340, 356, 357 Incubation period, 334, 340, 356 Infancy, 335 Infant, Newborn, 294, 335 Infantile, 260, 335 Infarction, 335, 365 Infertility, 25, 335 Infiltration, 327, 335, 383 Inflammatory bowel disease, 255, 256, 335 Influenza, 5, 122, 214, 215, 236, 237, 255, 256, 258, 282, 335 Informed Consent, 47, 335 Infusion, 10, 22, 110, 134, 166, 169, 182, 183, 335, 348 Ingestion, 297, 335, 358 Inhalation, 14, 294, 299, 335, 358 Initiation, 31, 37, 59, 78, 79, 108, 109, 335, 360, 377 Initiator, 109, 335, 337 Inoculum, 179, 335 Inorganic, 309, 335, 347 Inotropic, 64, 317, 335 Insertional, 190, 335 Insight, 7, 16, 32, 35, 336 Insulator, 336, 347 Insulin, 28, 336, 354 Insulin-dependent diabetes mellitus, 336 Integrase, 205, 206, 336 Integrins, 10, 11, 19, 21, 28, 30, 56, 74, 75, 94, 97, 104, 136, 162, 218, 246, 336
Intensive Care, 35, 336 Intensive Care Units, 35, 336 Interferon, 75, 79, 91, 94, 103, 112, 158, 166, 202, 336 Interferon-alpha, 336 Interleukin-1, 63, 103, 112, 126, 149, 158, 256, 336, 337 Interleukin-12, 103, 112, 126, 149, 158, 336 Interleukin-13, 63, 337 Interleukin-2, 336, 337 Interleukin-8, 32, 77, 114, 163, 175, 337 Interleukins, 68, 334, 337 Intermittent, 337, 341 Internal radiation, 337, 338, 363, 383 Interstitial, 62, 304, 323, 337, 338, 349, 383 Intervertebral, 337, 341, 363, 368 Intervertebral Disk Displacement, 337, 341, 363, 368 Intestinal, 58, 130, 139, 163, 267, 306, 308, 313, 320, 327, 337, 343, 346, 369 Intestinal Mucosa, 306, 308, 337 Intestine, 16, 267, 304, 310, 337, 339 Intoxication, 337, 382 Intracellular Membranes, 337, 344 Intrahepatic, 22, 337 Intramuscular, 9, 337, 354 Intravascular, 35, 337 Intravenous, 31, 48, 153, 166, 182, 183, 207, 335, 337, 354 Intravesical, 54, 117, 337 Intrinsic, 29, 58, 294, 301, 337 Introns, 337, 378 Intussusception, 139, 337 Invasive, 24, 31, 48, 50, 59, 65, 66, 200, 213, 214, 258, 259, 333, 338, 342 Invertebrates, 338, 378 Involuntary, 338, 348, 370 Iodine, 338, 371 Ion Channels, 40, 126, 300, 338 Ion Exchange, 240, 242, 338 Ionization, 17, 338 Ionizing, 295, 320, 338, 364 Ions, 168, 301, 316, 318, 332, 338, 346, 368 Iris, 312, 338, 362, 380 Irradiation, 45, 240, 338, 365, 383 Ischemia, 68, 117, 252, 255, 256, 300, 338, 348, 365 Isoelectric, 338, 373 Isoelectric Point, 338, 373 J Job Satisfaction, 6, 338
394
Adenovirus
K Kb, 32, 197, 206, 218, 227, 241, 249, 254, 260, 276, 338, 339 Keratin, 339 Keratinocytes, 30, 73, 137, 337, 339 Keratoconjunctivitis, 32, 76, 82, 91, 118, 147, 154, 219, 339 Kidney Disease, 14, 167, 276, 339 Killer Cells, 339 Kilobase, 82, 90, 339 Kinetic, 12, 42, 338, 339 Kringles, 131, 199, 339 L Labile, 310, 339 Laceration, 339, 375 Lacrimal, 10, 339 Lacrimal gland, 10, 339 Laminin, 199, 301, 323, 339 Large Intestine, 310, 316, 337, 339, 364, 370 Larynx, 65, 328, 339, 377 Latent, 141, 240, 241, 339 Laxative, 294, 339 Lectin, 4, 340, 344 Left ventricular assist device, 64, 340 Leiomyoma, 25, 324, 340 Lens, 254, 306, 340, 382 Lentivirus, 23, 340 Leprosy, 325, 340 Lesion, 57, 325, 340, 341 Lethal, 8, 17, 22, 67, 141, 214, 215, 258, 340 Leucine, 301, 340 Leucocyte, 295, 340 Leukemia, 15, 65, 128, 130, 133, 138, 309, 317, 327, 340 Leukopenia, 317, 340 Leukotrienes, 299, 340 Life cycle, 24, 241, 248, 340 Ligament, 340, 361, 372 Ligands, 12, 15, 21, 34, 55, 56, 69, 96, 133, 154, 208, 235, 246, 257, 336, 340, 374 Ligation, 10, 59, 340 Linkage, 16, 250, 340 Lipase, 144, 340 Lipid, 39, 132, 144, 237, 247, 298, 299, 319, 336, 341, 347 Lipid A, 40, 132, 247, 341 Lipopolysaccharide, 16, 256, 329, 341 Lipoprotein, 40, 248, 329, 341, 381 Liposomal, 205, 341 Liposome, 120, 229, 341 Liver cancer, 55, 150, 295, 341 Liver metastases, 270, 341
Localization, 26, 35, 59, 64, 86, 95, 98, 146, 147, 166, 177, 182, 235, 334, 341 Localized, 67, 69, 199, 226, 319, 324, 335, 339, 341, 357, 375, 379 Locoregional, 68, 341 Long-Term Care, 14, 341 Loop, 19, 25, 82, 98, 132, 146, 165, 222, 333, 341 Low Back Pain, 6, 341 Low-density lipoprotein, 341 Lucida, 339, 341 Luciferase, 101, 151, 341 Lumbar, 6, 300, 306, 337, 341, 342 Lupus, 342, 374 Lymph, 115, 307, 309, 320, 331, 342, 367, 373 Lymph node, 115, 307, 342, 367 Lymphatic, 320, 335, 342, 345, 367, 371, 372, 376 Lymphatic system, 342, 367, 371, 372, 376 Lymphocyte Depletion, 334, 342 Lymphocytic, 15, 128, 130, 342 Lymphoid, 298, 340, 342 Lymphokines, 342 Lymphoma, 4, 22, 114, 130, 270, 342 Lysine, 316, 331, 332, 342, 358, 378 Lysosome, 159, 342 Lytic, 51, 73, 75, 95, 99, 196, 209, 241, 242, 342, 369, 382 M Macrophage, 28, 34, 57, 140, 248, 336, 342 Macrophage Activation, 35, 140, 342 Magnetic Resonance Imaging, 342, 343 Magnetic Resonance Spectroscopy, 213, 342 Major Histocompatibility Complex, 95, 112, 166, 343 Malabsorption, 306, 343 Malaria, 214, 215, 255, 256, 258, 343 Malaria, Falciparum, 343 Malaria, Vivax, 343 Malignancy, 4, 343, 354 Malignant mesothelioma, 343, 345 Malignant tumor, 200, 305, 343, 347, 353, 366 Malnutrition, 295, 300, 304, 343 Mammary, 58, 77, 105, 111, 162, 173, 343, 375 Manifest, 8, 32, 52, 194, 343 Mannans, 325, 343 Mastitis, 343, 369 Matrix metalloproteinase, 246, 343
395
Maximum Tolerated Dose, 66, 318, 343 Measles Virus, 5, 343 Medial, 299, 344, 367 Mediator, 52, 260, 308, 337, 344, 358, 369 Medical Oncology, 128, 344, 363 Medicament, 229, 344 MEDLINE, 277, 344 Megakaryocytes, 246, 303, 344 Meiosis, 344, 347, 374, 375, 379 Melanin, 338, 344, 356, 379 Melanocytes, 344 Melanoma, 122, 126, 129, 137, 174, 175, 200, 226, 227, 344 Membrane, 10, 16, 21, 27, 34, 40, 48, 57, 69, 102, 108, 140, 155, 189, 190, 213, 219, 220, 222, 247, 252, 295, 299, 307, 308, 309, 310, 311, 315, 319, 321, 322, 329, 338, 339, 344, 347, 348, 349, 351, 352, 353, 356, 358, 359, 365, 366, 367, 370, 378, 381, 382 Membrane Proteins, 16, 21, 344 Memory, 73, 202, 297, 344 Meninges, 307, 318, 344 Meningitis, 313, 344, 357 Meningoencephalitis, 114, 344 Menopause, 25, 344, 359, 360 Menorrhagia, 25, 344 Menstruation, 344 Mental, iv, 7, 36, 60, 276, 278, 308, 316, 323, 344, 345, 357, 362, 368, 379 Mental Disorders, 345, 357 Mental Processes, 316, 345, 362 Mental Retardation, 36, 60, 345 Mentors, 14, 345 Mesenchymal, 128, 137, 321, 345 Mesothelial, 63, 345 Mesothelioma, 213, 343, 345 Metabolite, 253, 345, 360 Metaphase, 345, 375, 379 Metastasis, 67, 162, 199, 343, 345 Metastatic, 23, 67, 124, 137, 166, 226, 227, 345, 368 Metastatic cancer, 226, 345 Methotrexate, 67, 185, 345 Mice Minute Virus, 345, 355 Microbe, 345, 377 Microcirculation, 41, 345, 358 Microglia, 300, 345 Microgram, 325, 346 Microorganism, 310, 346, 355, 382 Microscopy, 10, 12, 17, 21, 30, 48, 64, 70, 116, 152, 166, 180, 182, 301, 325, 331, 346
Microsomal, 131, 346 Microtubules, 179, 182, 346, 353 Migration, 14, 30, 32, 49, 52, 199, 342, 346 Mitochondria, 57, 346, 348, 352, 378 Mitosis, 298, 346 Mitotic, 166, 178, 181, 317, 322, 346, 375 Mitotic inhibitors, 317, 346, 375 Modeling, 59, 106, 155, 346 Modulator, 228, 346 Molecular Probes, 318, 346 Molecular Structure, 40, 346 Monensin, 179, 346 Monitor, 31, 66, 198, 305, 346, 351 Monoclonal, 11, 83, 85, 87, 97, 100, 128, 332, 338, 347, 363, 383 Monoclonal antibodies, 11, 85, 97, 347 Monocyte, 57, 126, 347 Monocyte Chemoattractant Protein-1, 126, 347 Mononuclear, 347, 379 Morbillivirus, 317, 343, 347 Morphogenesis, 200, 252, 347 Morphological, 17, 252, 319, 325, 344, 347 Morphology, 66, 299, 306, 342, 347 Motility, 96, 200, 347, 369 Mucins, 27, 347 Mucolytic, 293, 347 Mucosa, 4, 25, 342, 347, 373 Mucositis, 347, 376 Mucus, 26, 318, 322, 347, 379 Multidose, 185, 347 Multiple Myeloma, 255, 256, 347 Multiple sclerosis, 255, 256, 347 Multivalent, 21, 238, 246, 247, 300, 347 Muscle Contraction, 347, 368 Muscle Fibers, 69, 295, 348 Mutagenesis, 11, 191, 348 Mutagens, 348 Myalgia, 268, 335, 348 Mycobacterium, 214, 215, 258, 340, 348, 378 Mycobacterium tuberculosis, 214, 215, 258, 348 Mycoplasma, 177, 348 Mycoplasma pneumoniae, 177, 348 Myelin, 347, 348 Myelogenous, 348 Myocardial infarction, 255, 302, 312, 348 Myocardial Reperfusion, 348, 365 Myocardial Reperfusion Injury, 348, 365 Myocarditis, 122, 348 Myocardium, 29, 270, 348
396
Adenovirus
Myofibrils, 305, 349 Myometrium, 25, 349 N Naloxone, 302, 349 Nasal Mucosa, 335, 349 Natural killer cells, 99, 336, 349 Natural selection, 302, 349 Nausea, 314, 317, 326, 349, 379 NCI, 1, 230, 275, 309, 349 Necrosis, 298, 314, 327, 335, 348, 349, 365 Necrotizing Enterocolitis, 5, 349 Neomycin, 56, 120, 349 Neonatal, 35, 95, 122, 349 Neoplasia, 162, 173, 200, 225, 349 Neoplasm, 214, 215, 258, 349, 354, 367, 379 Nephritis, 114, 234, 349 Nephropathy, 339, 349 Nerve Growth Factor, 349, 350 Nervous System, 69, 90, 233, 293, 307, 308, 326, 327, 328, 330, 340, 344, 345, 347, 349, 350, 352, 355, 359, 363, 369 Neural, 74, 136, 324, 331, 345, 349 Neural tube defects, 324, 349 Neuroblastoma, 174, 350 Neurodegenerative Diseases, 233, 250, 350 Neurologic, 4, 317, 327, 350 Neuromuscular, 69, 293, 350, 379 Neuromuscular Junction, 69, 293, 350 Neuronal, 40, 68, 350 Neurons, 69, 150, 250, 315, 326, 349, 350, 372, 374 Neuropathy, 350, 368 Neuropeptides, 305, 350 Neurophysiology, 315, 350 Neurotoxic, 350, 375 Neurotransmitter, 40, 293, 304, 317, 328, 338, 350, 351, 370, 373 Neurotrophins, 69, 350 Neutralization, 76, 83, 350 Neutrons, 295, 338, 350, 363 Neutrophil, 32, 350 Night Blindness, 308, 350 Nitric Oxide, 15, 35, 49, 62, 121, 350 Nitrogen, 59, 295, 314, 323, 324, 328, 350, 378 Nonmalignant, 239, 351 Non-small cell lung cancer, 59, 166, 181, 183, 351 Norepinephrine, 294, 317, 350, 351 Nuclear Envelope, 351 Nuclear Matrix, 76, 112, 186, 351 Nuclear Pore, 33, 169, 179, 201, 351
Nuclear Proteins, 203, 351 Nuclei, 68, 177, 295, 318, 326, 327, 331, 337, 342, 343, 346, 350, 351, 352, 361, 367 Nucleic Acid Hybridization, 167, 332, 351 Nucleocapsid, 206, 351, 381 Nucleoprotein, 101, 351 Nucleotidases, 332, 351 Nucleus, 6, 64, 68, 108, 114, 153, 159, 201, 218, 220, 235, 298, 300, 301, 308, 314, 318, 320, 322, 326, 337, 342, 344, 347, 350, 351, 360, 361, 362, 367, 373 Nursing Care, 4, 351 O Octamer, 181, 351 Ocular, 10, 11, 32, 80, 106, 118, 189, 226, 351 Ointments, 317, 352 Omentum, 330, 352 Oncogene, 30, 57, 59, 113, 118, 121, 126, 138, 162, 164, 168, 169, 178, 196, 214, 330, 352 Oncogenic, 83, 86, 95, 109, 142, 145, 189, 191, 218, 336, 340, 352, 361, 362 Oncolysis, 44, 129, 148, 152, 183, 195, 352 Oncolytic, 19, 30, 42, 51, 55, 56, 85, 113, 116, 120, 125, 126, 131, 134, 148, 150, 154, 159, 195, 242, 352 Opacity, 306, 352 Open Reading Frames, 224, 227, 340, 352 Operon, 352, 360, 365 Opiate, 301, 320, 349, 352 Opportunistic Infections, 265, 352 Opsin, 352, 365, 366 Optic Nerve, 352, 365, 366, 368 Orf, 263, 352, 354 Orf Virus, 263, 352 Organ Culture, 352, 376 Organelles, 302, 307, 309, 314, 344, 352 Oropharynx, 65, 352 Osmosis, 352 Osmotic, 256, 295, 352, 369 Ossification, 353 Osteoarthritis, 255, 256, 353 Osteoblasts, 353 Osteocalcin, 226, 353 Osteoclasts, 246, 353 Osteogenesis, 137, 148, 353 Osteogenic sarcoma, 353 Osteoporosis, 26, 246, 255, 256, 304, 353 Osteosarcoma, 67, 128, 174, 226, 245, 353 Ovalbumin, 165, 353 Ovary, 353, 373
397
Overexpress, 55, 57, 220, 221, 353 Ovum, 340, 353, 360 Oxidation, 57, 232, 293, 314, 353 Oxygenase, 14, 166, 181, 353 P P53 gene, 66, 149, 152, 176, 177, 183, 185, 186, 245, 353 Paclitaxel, 164, 175, 176, 177, 178, 179, 181, 353 Paediatric, 121, 354 Palate, 354, 373 Palliative, 354, 375 Pancreas, 16, 27, 115, 132, 153, 293, 302, 303, 330, 336, 340, 354, 378 Pancreas Transplant, 153, 354 Pancreas Transplantation, 153, 354 Pancreatic, 16, 60, 101, 115, 124, 131, 132, 138, 140, 165, 176, 180, 213, 255, 256, 308, 354 Pancreatic cancer, 60, 115, 131, 132, 138, 140, 176, 213, 354 Pancreatitis, 17, 354 Papilla, 354 Papillary, 66, 354 Papilloma, 5, 71, 237, 354, 366 Papillomavirus, 71, 354 Parapoxvirus, 263, 352, 354 Parasite, 354 Parasitic, 5, 318, 327, 354 Parenchyma, 227, 354 Parenteral, 232, 354 Paresthesia, 268, 354 Parietal, 354, 356, 358 Paroxysmal, 355, 356, 382 Particle, 72, 75, 209, 218, 220, 222, 223, 229, 230, 233, 243, 258, 262, 341, 355, 377, 382 Parvovirus, 6, 209, 224, 240, 241, 267, 345, 355 Patch, 50, 355 Pathogen, 26, 29, 140, 214, 215, 219, 236, 258, 267, 270, 334, 335, 355, 374 Pathologic, 65, 298, 302, 312, 332, 355, 362, 365 Pathologic Processes, 298, 355 Pathophysiology, 4, 6, 355 Pelvic, 25, 355, 361 Pelvis, 293, 342, 355, 380 Peptide Hydrolases, 322, 332, 355 Peptide T, 41, 355 Perception, 6, 355, 368 Percutaneous, 6, 49, 355 Perfusion, 67, 182, 333, 355, 376
Pericardium, 355, 374 Peripheral blood, 30, 145, 336, 355 Peripheral Nervous System, 350, 355, 373 Peritoneal, 63, 145, 299, 355, 356 Peritoneal Cavity, 63, 299, 356 Peritoneum, 352, 355, 356 Peroxide, 256, 356 Pertussis, 219, 356, 382 Pharmaceutical Solutions, 317, 356 Pharmacologic, 297, 313, 329, 356, 376, 377 Pharyngitis, 219, 356 Pharynx, 335, 352, 356 Phenotype, 20, 25, 51, 58, 59, 66, 121, 183, 224, 225, 262, 311, 326, 356 Phenylalanine, 356, 379 Phospholipases, 356, 370 Phospholipids, 323, 339, 341, 356 Phosphoric Monoester Hydrolases, 332, 356 Phosphorus, 304, 356, 357 Phosphorylase, 305, 356 Phosphorylate, 68, 357 Phosphorylated, 68, 198, 357 Phosphorylation, 64, 68, 78, 92, 98, 100, 118, 138, 167, 198, 228, 314, 357 Photophobia, 32, 357 Phylogeny, 145, 357 Physicochemical, 39, 357 Physiologic, 60, 213, 225, 294, 302, 329, 344, 357, 364, 365 Physiology, 30, 350, 357, 374, 380 Pigment, 308, 344, 357 Pilot Projects, 20, 357 Pilot study, 18, 53, 357 Pituitary Gland, 313, 324, 357 Plants, 295, 303, 308, 328, 340, 347, 351, 357, 367, 372, 377, 378 Plaque, 20, 260, 297, 357 Plaque Assay, 20, 357 Plasma cells, 298, 347, 357 Plasma protein, 295, 320, 339, 357, 369 Plasmid, 24, 59, 82, 95, 120, 224, 231, 260, 358, 380 Plasmin, 199, 358 Plasminogen Activators, 358 Platelet Activation, 358, 370 Platelet Aggregation, 14, 177, 246, 297, 350, 358, 376 Platelet Factor 4, 337, 358 Platelet-Derived Growth Factor, 129, 358 Platelets, 246, 302, 305, 350, 358, 376 Pleura, 358
398
Adenovirus
Pleural, 213, 345, 358 Pneumonia, 72, 104, 110, 219, 234, 312, 348, 358 Podophyllotoxin, 322, 358 Poisoning, 267, 326, 337, 349, 358, 367 Polyarthritis, 267, 358 Polyethylene, 255, 358 Polylysine, 124, 358 Polymerase, 73, 74, 84, 91, 92, 96, 100, 111, 112, 122, 152, 157, 158, 227, 359, 360, 365 Polymerase Chain Reaction, 84, 122, 152, 158, 359 Polymers, 220, 359, 361 Polyploidy, 166, 181, 359 Polyposis, 294, 310, 359 Polysaccharide, 298, 328, 359, 361 Polyvalent, 219, 359 Pons, 301, 359 Posterior, 37, 296, 300, 301, 308, 317, 338, 354, 359, 368 Postmenopausal, 353, 359 Postnatal, 359, 372 Postsynaptic, 69, 359, 370 Potentiates, 199, 336, 359 Potentiating, 30, 359 Potentiation, 167, 359, 370 Practice Guidelines, 278, 359 Precancerous, 359, 360 Precipitation, 229, 360 Preclinical, 29, 31, 42, 55, 63, 176, 179, 360 Precursor, 76, 150, 206, 229, 247, 299, 314, 317, 318, 320, 323, 351, 356, 360, 377, 378, 379 Prednisolone, 164, 360 Premalignant, 65, 360 Premenopausal, 25, 360 Presynaptic, 69, 350, 360 Prevalence, 18, 100, 150, 360 Primary tumor, 55, 207, 226, 360 Primary vaccination, 71, 360 Probe, 85, 157, 243, 360 Prodrug, 57, 68, 158, 173, 174, 180, 360 Progeny, 69, 72, 149, 196, 235, 241, 360 Progesterone, 360, 372, 380 Progression, 42, 52, 57, 59, 65, 66, 68, 143, 200, 246, 270, 297, 314, 360, 378 Progressive, 299, 307, 317, 322, 349, 350, 353, 358, 360, 379 Proline, 310, 316, 332, 360 Promotor, 360, 365 Prophase, 347, 360, 374, 375, 379 Prophylaxis, 22, 255, 360, 367, 380
Prostaglandins, 169, 299, 360 Prostate, 23, 31, 43, 53, 66, 134, 149, 151, 175, 176, 177, 226, 302, 361, 378 Prostatectomy, 47, 361 Protease, 162, 199, 204, 205, 206, 252, 310, 361 Protein Binding, 361, 376 Protein Conformation, 296, 339, 361 Protein Isoforms, 296, 361 Protein Subunits, 41, 201, 361 Proteinuria, 328, 347, 361 Proteoglycan, 134, 213, 358, 361 Proteolytic, 17, 199, 295, 311, 320, 324, 358, 361 Protocol, 31, 47, 167, 220, 230, 361 Protons, 295, 332, 338, 343, 361, 363 Proto-Oncogene Proteins, 353, 361, 362 Proto-Oncogene Proteins c-mos, 353, 362 Protozoa, 318, 327, 346, 362, 372 Protozoal, 362 Protozoan, 214, 259, 343, 362 Provirus, 206, 209, 362 Proximal, 24, 317, 360, 362 Psoriasis, 255, 256, 362 Psychic, 344, 362, 368 Psychoactive, 362, 382 Psychology, 316, 362 Public Policy, 277, 362 Publishing, 71, 218, 362 Pulmonary, 35, 62, 67, 104, 166, 168, 170, 227, 303, 304, 340, 362, 374, 380 Pulmonary Artery, 303, 362, 381 Pulmonary hypertension, 35, 362 Pulposus, 6, 337, 362 Pulse, 62, 346, 362 Pupil, 312, 362 Purifying, 209, 240, 242, 244, 315, 362 Purines, 362, 369 Pyrimidines, 363, 369 Q Quiescent, 9, 42, 243, 249, 363 R Rabies, 214, 215, 258, 363 Race, 346, 363 Radiation Oncology, 42, 46, 213, 363 Radiation therapy, 43, 149, 212, 213, 221, 293, 323, 325, 337, 338, 363, 364, 383 Radiculopathy, 363, 368 Radioactive, 44, 329, 332, 334, 337, 338, 346, 347, 351, 352, 363, 371, 379, 383 Radioimmunoassay, 302, 325, 363 Radioimmunotherapy, 363, 364
399
Radiolabeled, 213, 338, 363, 383 Radiological, 25, 355, 363 Radiology, 124, 363 Radiosensitization, 213, 364 Radiosensitizers, 213, 364 Radiotherapy, 43, 200, 212, 213, 304, 338, 363, 364, 383 Randomized, 46, 318, 364 Reactivation, 190, 364 Reading Frames, 53, 364 Reagent, 54, 341, 364 Recombinant Proteins, 62, 253, 364 Recombination, 24, 72, 104, 132, 204, 209, 215, 216, 236, 260, 326, 364 Rectum, 200, 298, 304, 310, 316, 325, 326, 335, 339, 361, 364 Recurrence, 53, 364 Red blood cells, 321, 330, 353, 364 Reductase, 31, 57, 345, 364 Refer, 1, 43, 304, 310, 324, 331, 341, 350, 363, 364, 377 Refraction, 364, 371 Refractory, 4, 128, 153, 183, 243, 364 Refractory cancer, 183, 364 Regeneration, 169, 295, 324, 364 Regimen, 113, 206, 309, 318, 364 Rehydration Solutions, 5, 364 Remission, 364 Renal cell carcinoma, 154, 155, 365 Renal pelvis, 365, 377 Reperfusion, 29, 255, 256, 348, 365 Reperfusion Injury, 255, 256, 365 Repopulation, 66, 365 Repressor, 37, 69, 266, 352, 365 Resection, 198, 200, 365, 378 Residual disease, 58, 245, 365 Resorption, 304, 353, 365 Respiration, 346, 365 Respiratory distress syndrome, 255, 256, 304, 365 Respiratory syncytial virus, 122, 137, 237, 365 Response Elements, 20, 365 Response rate, 65, 365 Retina, 254, 308, 311, 314, 340, 352, 365, 366, 367, 380, 382 Retinal, 39, 138, 178, 308, 314, 352, 365, 366, 382 Retinal Neovascularization, 138, 366 Retinal Vein, 366 Retinitis, 314, 366
Retinoblastoma, 19, 54, 89, 109, 138, 228, 239, 366 Retinoblastoma Protein, 19, 109, 138, 366 Retinoid, 39, 366 Retinol, 365, 366 Retinopathy, 36, 138, 366 Retrograde, 70, 366 Retropubic, 361, 366 Retrotransposons, 366, 375 Retroviral vector, 326, 366 Retrovirus, 31, 199, 207, 220, 227, 258, 366 Rhabdomyosarcoma, 129, 366 Rheumatoid, 255, 256, 366 Rheumatoid arthritis, 255, 256, 366 Rhinitis, 304, 366, 369 Rhinovirus, 17, 366 Rhodopsin, 352, 365, 366 Ribavirin, 153, 367 Ribonucleoproteins, 310, 351, 367 Ribonucleoproteins, Small Nuclear, 310, 367 Ribosome, 144, 200, 367, 377 Risk factor, 6, 321, 367 Rod, 222, 300, 301, 367, 369 Rotavirus, 5, 92, 127, 150, 236, 267, 367 Rubella, 5, 6, 267, 268, 367 Rubella Virus, 6, 367 Ryanodine, 64, 367 S Sagittal, 37, 367 Saline, 46, 367 Salivary, 314, 354, 367, 373 Salivary glands, 314, 367 Salmonella, 5, 267, 326, 367 Saponin, 237, 367 Sarcolemma, 136, 348, 367 Sarcoma, 163, 164, 175, 236, 367 Sarcoplasmic Reticulum, 64, 368 Schizoid, 368, 382 Schizophrenia, 368, 382 Schizotypal Personality Disorder, 368, 382 Sciatica, 6, 368 Sclera, 308, 311, 368, 380 Sclerosis, 299, 347, 368 Screening, 4, 20, 52, 211, 217, 248, 251, 309, 368 Secondary tumor, 345, 368 Secretory, 10, 16, 248, 368 Secretory Vesicles, 10, 368 Sedimentation, 307, 368, 378 Segmental, 327, 368, 371 Segregation, 364, 368
400
Adenovirus
Seizures, 327, 355, 368 Selective estrogen receptor modulator, 368, 374 Semen, 361, 369 Semisynthetic, 322, 369 Senile, 353, 369 Sensitization, 175, 369 Sepsis, 255, 256, 369 Septic, 255, 256, 299, 369 Septicaemia, 369 Sequence Analysis, 82, 105, 165, 369 Sequence Homology, 218, 355, 369 Sequencing, 53, 54, 112, 359, 369 Serial Passage, 241, 369 Serine, 52, 199, 252, 305, 362, 369, 378 Serologic, 4, 268, 333, 369 Serotonin, 350, 369, 378 Serous, 320, 358, 369 Serum Albumin, 232, 363, 369 Sharpness, 369, 382 Shigella, 5, 369 Shock, 37, 255, 256, 258, 297, 370, 378 Side effect, 25, 36, 45, 210, 212, 233, 252, 294, 302, 314, 317, 370, 377 Signal Transduction, 32, 49, 68, 250, 370 Silicon, 17, 370 Silicon Dioxide, 370 Sindbis Virus, 295, 370 Skeletal, 9, 97, 229, 347, 349, 368, 370 Skeleton, 304, 370 Skull, 313, 349, 370, 375 Small cell lung cancer, 370 Small intestine, 267, 309, 318, 331, 337, 370, 378 Smallpox, 370, 380 Smooth muscle, 14, 25, 49, 70, 93, 233, 246, 297, 305, 324, 340, 349, 370, 373 Sneezing, 356, 370 Sodium, 45, 140, 169, 346, 370, 371 Sodium Iodide, 45, 140, 371 Soft tissue, 303, 370, 371 Solid tumor, 12, 24, 200, 297, 303, 317, 319, 371 Solvent, 352, 356, 371 Soma, 141, 371 Somatic, 204, 254, 319, 331, 344, 346, 355, 371, 375 Somatic cells, 204, 344, 346, 371 Spasmodic, 356, 371 Specialist, 20, 283, 371 Specificity, 11, 12, 15, 19, 22, 28, 55, 56, 63, 208, 222, 226, 248, 249, 294, 333, 371, 376
Spectrum, 4, 30, 31, 249, 345, 371 Sperm, 308, 371, 378 Spermatogenesis, 125, 371 Spermatozoa, 369, 371 Sphincter, 339, 371 Spinal cord, 212, 299, 300, 306, 307, 308, 318, 321, 326, 344, 349, 350, 355, 363, 371 Spinal Nerve Roots, 363, 368, 371 Spinal Stenosis, 6, 372 Spinous, 321, 339, 372 Spleen, 167, 202, 314, 342, 372 Spondylitis, 255, 256, 372 Spondylolisthesis, 6, 372 Sporadic, 5, 350, 366, 372 Spores, 335, 372 Sprains and Strains, 341, 372 Squamous, 65, 245, 321, 351, 372 Squamous cell carcinoma, 66, 245, 321, 351, 372 Squamous cells, 372 Stabilization, 232, 372 Statistically significant, 36, 372 Stem Cells, 137, 295, 372 Sterile, 242, 299, 372 Sterility, 314, 335, 372 Steroid, 270, 372 Stimulus, 317, 322, 337, 338, 372, 376 Stomach, 200, 293, 300, 316, 322, 326, 330, 331, 349, 352, 356, 370, 372, 373 Stomatitis, 71, 93, 373 Stool, 87, 100, 104, 105, 310, 339, 373 Strand, 24, 359, 373 Streptavidin, 257, 373 Stress, 37, 256, 326, 349, 366, 373, 379 Stringency, 196, 373 Stroke, 255, 276, 305, 373 Stroma, 32, 60, 199, 338, 354, 373 Stromal, 60, 303, 373 Stromal Cells, 60, 303, 373 Subacute, 335, 373 Subarachnoid, 212, 329, 357, 373 Subclinical, 5, 335, 368, 373 Subcutaneous, 25, 54, 55, 318, 326, 340, 354, 373, 382 Submaxillary, 321, 373 Subspecies, 371, 373, 380 Substance P, 322, 345, 368, 373 Substrate, 40, 64, 105, 320, 332, 373 Subtraction Technique, 263, 373 Suction, 324, 373 Sulfur, 323, 374 Superinfection, 95, 374
401
Superoxide, 16, 102, 374 Suppression, 24, 27, 48, 54, 67, 93, 127, 134, 152, 168, 174, 185, 202, 245, 313, 374 Suppressive, 156, 374 Surface Plasmon Resonance, 64, 374 Surfactant, 62, 374 Symphysis, 308, 361, 374 Symptomatic, 268, 354, 374 Synapse, 69, 294, 295, 350, 360, 374, 378 Synapsis, 374 Synaptic, 40, 69, 295, 350, 370, 374 Synergistic, 29, 176, 185, 374 Systemic lupus erythematosus, 139, 374 Systolic, 332, 374 T Tamoxifen, 25, 368, 374 Taxanes, 176, 375 Telomerase, 54, 113, 121, 176, 220, 221, 375 Telomere, 54, 375 Temporal, 29, 37, 69, 73, 111, 149, 375 Terminal Repeat Sequences, 218, 375 Terminator, 231, 310, 375 Testis, 125, 375 Testosterone, 364, 375 Tetani, 50, 375 Tetanic, 375 Tetanus, 50, 214, 215, 258, 375 Tetanus Toxin, 50, 214, 215, 258, 375 Tetracycline, 20, 55, 317, 375 Tetravalent, 8, 375 Therapeutics, 18, 56, 121, 185, 198, 207, 223, 375 Thermal, 299, 316, 350, 359, 375 Thoracic, 123, 213, 300, 316, 342, 358, 375, 382 Threonine, 52, 355, 362, 369, 375 Threshold, 222, 322, 332, 376 Thrombin, 324, 358, 361, 376 Thrombocytes, 358, 376 Thrombomodulin, 361, 376 Thrombosis, 159, 302, 336, 361, 373, 376 Thromboxanes, 299, 376 Thymidine, 31, 43, 67, 93, 115, 119, 126, 198, 226, 253, 376 Thymidine Kinase, 31, 43, 67, 93, 115, 119, 126, 198, 226, 253, 376 Thymus, 333, 342, 376 Thyroid, 140, 143, 148, 183, 207, 338, 371, 376, 379 Tissue Culture, 59, 62, 92, 376, 381 Tissue Distribution, 99, 222, 376 Tolerance, 9, 30, 95, 202, 230, 231, 293, 376
Tomography, 21, 31, 343, 376 Tooth Preparation, 294, 376 Topical, 27, 50, 185, 258, 376 Topotecan, 176, 181, 376 Toxic, iv, 4, 48, 55, 67, 78, 198, 213, 226, 239, 255, 256, 295, 315, 320, 333, 350, 358, 376, 377 Toxicology, 278, 377 Toxin, 50, 258, 267, 320, 375, 376, 377 Trace element, 370, 377 Trachea, 323, 339, 356, 376, 377 Transcriptase, 205, 206, 366, 375, 377 Transcription Factors, 31, 60, 68, 218, 225, 228, 235, 365, 377 Transcutaneous, 6, 377 Transduction, 7, 9, 10, 13, 15, 23, 25, 27, 31, 49, 50, 55, 68, 72, 74, 76, 83, 111, 118, 129, 139, 154, 176, 199, 200, 205, 213, 225, 229, 230, 233, 235, 251, 262, 370, 377 Transfer Factor, 333, 377 Transferases, 228, 328, 377 Transforming Growth Factor beta, 37, 79, 377 Transgenes, 9, 34, 101, 230, 377 Transitional cell carcinoma, 66, 377 Translating, 29, 377 Translation, 37, 45, 75, 79, 127, 214, 215, 236, 242, 258, 322, 349, 364, 377 Translational, 14, 44, 200, 228, 378 Translocate, 68, 378 Translocation, 41, 78, 116, 155, 322, 378 Transmitter, 293, 300, 317, 338, 344, 351, 378 Transplantation, 114, 124, 153, 183, 198, 333, 342, 343, 378 Trans-Splicing, 146, 378 Transurethral, 361, 378 Transurethral resection, 361, 378 Transurethral Resection of Prostate, 361, 378 Trauma, 255, 256, 330, 349, 354, 378 Trypsin, 20, 141, 320, 378 Tryptophan, 310, 369, 378 Tuberculosis, 342, 348, 378 Tubulin, 346, 378 Tumor marker, 302, 378 Tumor model, 12, 378 Tumor Necrosis Factor, 63, 74, 79, 87, 93, 94, 107, 109, 162, 256, 378 Tumor suppressor gene, 65, 131, 134, 353, 366, 379 Tumorigenic, 52, 54, 72, 239, 379
402
Adenovirus
Tumour, 136, 179, 228, 326, 352, 379 Tunica, 319, 347, 379 Tyrosine, 53, 58, 112, 142, 186, 306, 317, 379 U Ubiquitin, 71, 379 Ulceration, 352, 379 Ulcerative colitis, 255, 256, 335, 379 Univalent, 238, 353, 379 Uracil, 31, 213, 363, 379 Uraemia, 354, 379 Ureters, 379 Urethra, 361, 378, 379 Urinary, 3, 137, 219, 314, 327, 361, 366, 379 Urinary tract, 3, 219, 379 Urinary tract infection, 3, 379 Urine, 4, 97, 99, 303, 321, 330, 361, 365, 379 Urogenital, 127, 327, 379 Urokinase, 199, 379 Urothelium, 181, 379 Urticaria, 297, 379 Uteroglobin, 139, 380 Uterus, 307, 319, 324, 333, 340, 344, 349, 360, 380 Uvea, 380 Uveitis, 39, 380 V Vaccination, 8, 13, 50, 71, 103, 122, 153, 204, 248, 360, 380 Vaccinia, 82, 220, 240, 263, 267, 380 Vaccinia Virus, 82, 263, 267, 380 Vacuoles, 319, 352, 380 Vagina, 307, 315, 344, 380 Varicella, 5, 267, 268, 380 Variola, 267, 380 Vascular endothelial growth factor, 14, 132, 200, 380 Vasculitis, 354, 380 Vasoconstriction, 35, 321, 380 Vasodilator, 35, 304, 317, 348, 380 Vasomotor, 16, 380 Vein, 299, 337, 351, 366, 380 Venous, 67, 299, 302, 361, 380 Ventilation, 304, 380 Ventricle, 9, 333, 362, 374, 380, 381 Ventricular, 348, 381 Venules, 303, 305, 320, 345, 381 Vertebrae, 337, 371, 372, 381 Vertebral, 301, 321, 381 Vesicular, 71, 93, 305, 331, 346, 370, 380, 381 Vesicular Exanthema of Swine, 305, 381
Vesicular Exanthema of Swine Virus, 305, 381 Veterinary Medicine, 277, 381 Vial, 105, 381 Vibrio, 5, 267, 308, 381 Vibrio cholerae, 5, 308, 381 Villous, 306, 381 Vimentin, 100, 381 Viral Load, 205, 206, 381 Viral Proteins, 60, 71, 194, 237, 249, 381 Viral Regulatory Proteins, 381 Viral Structural Proteins, 201, 218, 381 Viral Vaccines, 7, 381 Viral vector, 9, 31, 35, 50, 71, 142, 199, 202, 203, 205, 208, 213, 214, 220, 221, 223, 227, 229, 235, 245, 257, 259, 262, 381 Virion, 48, 69, 81, 197, 227, 301, 351, 381 Virulence, 300, 369, 374, 377, 381 Virulent, 185, 382 Virus Replication, 54, 109, 198, 200, 225, 382 Viscera, 371, 382 Visceral, 6, 356, 382 Visceral fat, 6, 382 Viscosity, 293, 382 Visual Acuity, 254, 382 Vitellogenin, 248, 382 Vitreous, 340, 365, 382 Vitreous Body, 365, 382 Vitro, 10, 12, 15, 16, 19, 23, 29, 32, 33, 37, 38, 39, 42, 43, 49, 53, 58, 62, 63, 67, 73, 74, 75, 76, 79, 92, 93, 102, 106, 109, 119, 123, 131, 139, 140, 144, 147, 152, 153, 165, 168, 170, 175, 185, 194, 203, 204, 207, 214, 225, 229, 235, 243, 257, 260, 262, 327, 330, 334, 359, 369, 374, 376, 382 W Warts, 331, 358, 382 White blood cell, 298, 309, 329, 340, 342, 347, 349, 350, 357, 382 Whooping Cough, 356, 382 Windpipe, 356, 376, 382 Withdrawal, 29, 382 Wound Healing, 36, 98, 324, 336, 343, 383 X Xenograft, 58, 60, 140, 159, 186, 297, 378, 383 X-ray, 11, 48, 155, 222, 306, 325, 326, 338, 351, 363, 364, 383 X-ray therapy, 338, 383 Y Yeasts, 325, 356, 383
403
Z Zoonoses, 363, 383 Zoster, 5, 267, 383
Zymogen, 16, 361, 383
404
Adenovirus
