Gene Therapy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

GENE

THERAPY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

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., 1960Gene Therapy: 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: 0-597-83954-9 1. Gene Therapy-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.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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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 gene therapy. 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 GENE THERAPY......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Gene Therapy ................................................................................ 7 E-Journals: PubMed Central ....................................................................................................... 65 The National Library of Medicine: PubMed ................................................................................ 76 CHAPTER 2. NUTRITION AND GENE THERAPY ............................................................................. 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Gene Therapy............................................................................. 121 Federal Resources on Nutrition ................................................................................................. 123 Additional Web Resources ......................................................................................................... 123 CHAPTER 3. ALTERNATIVE MEDICINE AND GENE THERAPY ...................................................... 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 138 General References ..................................................................................................................... 139 CHAPTER 4. DISSERTATIONS ON GENE THERAPY ........................................................................ 141 Overview.................................................................................................................................... 141 Dissertations on Gene Therapy.................................................................................................. 141 Keeping Current ........................................................................................................................ 144 CHAPTER 5. CLINICAL TRIALS AND GENE THERAPY ................................................................... 145 Overview.................................................................................................................................... 145 Recent Trials on Gene Therapy.................................................................................................. 145 Keeping Current on Clinical Trials ........................................................................................... 160 CHAPTER 6. PATENTS ON GENE THERAPY ................................................................................... 163 Overview.................................................................................................................................... 163 Patents on Gene Therapy ........................................................................................................... 163 Patent Applications on Gene Therapy ....................................................................................... 199 Keeping Current ........................................................................................................................ 232 CHAPTER 7. BOOKS ON GENE THERAPY ....................................................................................... 235 Overview.................................................................................................................................... 235 Book Summaries: Federal Agencies............................................................................................ 235 Book Summaries: Online Booksellers......................................................................................... 237 Chapters on Gene Therapy......................................................................................................... 245 Directories.................................................................................................................................. 245 CHAPTER 8. MULTIMEDIA ON GENE THERAPY ............................................................................ 247 Overview.................................................................................................................................... 247 Video Recordings ....................................................................................................................... 247 Audio Recordings....................................................................................................................... 248 Bibliography: Multimedia on Gene Therapy.............................................................................. 248 CHAPTER 9. PERIODICALS AND NEWS ON GENE THERAPY ......................................................... 251 Overview.................................................................................................................................... 251 News Services and Press Releases.............................................................................................. 251 Newsletter Articles .................................................................................................................... 256 Academic Periodicals covering Gene Therapy ........................................................................... 256 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 259 Overview.................................................................................................................................... 259 NIH Guidelines.......................................................................................................................... 259 NIH Databases........................................................................................................................... 261 Other Commercial Databases..................................................................................................... 264

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APPENDIX B. PATIENT RESOURCES ............................................................................................... 265 Overview.................................................................................................................................... 265 Patient Guideline Sources.......................................................................................................... 265 Finding Associations.................................................................................................................. 272 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 275 Overview.................................................................................................................................... 275 Preparation................................................................................................................................. 275 Finding a Local Medical Library................................................................................................ 275 Medical Libraries in the U.S. and Canada ................................................................................. 275 ONLINE GLOSSARIES................................................................................................................ 281 Online Dictionary Directories ................................................................................................... 281 GENE THERAPY DICTIONARY ............................................................................................... 283 INDEX .............................................................................................................................................. 373

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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 gene therapy 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 gene therapy, 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 gene therapy, 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 gene therapy. 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 gene therapy, 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 gene therapy. 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 GENE THERAPY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on gene therapy.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and gene therapy, 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 “gene therapy” (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: •

Gene Therapy: Future Therapy for Erectile Dysfunction Source: Current Urology Reports. 2(6): 480-487. December 2001. Contact: Current Science, Inc. 400 Market Street, Suite 700, Philadelphia, PA 19106 (800) 427-1796. Fax (215) 574-2225. E-mail: [email protected]. Website: http://www.current-reports.com. Summary: Advances in molecular biological techniques, completion of the Human Genome Project, and the ensuing age of molecular medicine, in conjunction with the sum of a decades-long accumulation of knowledge of the physiology of erection and the pathophysiology of erectile dysfunction (ED, formerly called impotence) have converged to make gene therapy for ED a distinct possibility. This report highlights the goals and strategies of gene therapy for erectile dysfunction and reviews the strategies

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that initially have been employed. Both the intrinsic complexities of mechanisms responsible for ensuring normal erection and the multifactorial nature of ED ensure that there is a relatively vast number of physiologically relevant molecular targets for gene therapy. The authors note that virtually every preclinical gene therapy strategy or target examined thus far has been largely successful in easing conditions associated with compromised erectile function in vivo or in vitro. While this preclinical data is quite preliminary in many regards, the results are nonetheless quite impressive and encouraging. If similar success is obtained in clinical trials, gene therapy for ED may provide the first concrete 'proof of concept' for using gene therapy in the treatment of human smooth muscle disorders. 3 figures. 2 tables. 25 references. •

Immune Gene Therapy in Urology Source: Current Urology Reports. 3(1): 82-89. February 2002. Contact: Current Science, Inc. 400 Market Street, Suite 700, Philadelphia, PA 19106 (800) 427-1796. Fax (215) 574-2225. E-mail: [email protected]. Website: http://www.current-reports.com. Summary: Effective treatments are urgently needed for metastatic disease in bladder, prostate, and renal (kidney) cell cancer. In the past few years, several new approaches for treating these conditions have been proposed, including gene therapy. This article illustrates the recent developments in immune gene therapy that have applications in urology. A number of different strategies have been developed to accomplish urologic cancer gene therapy. Genetic immunomodulation strategies attempt to activate immune defense mechanisms against tumor cells by transfer of tumor antigens, cytokine genes, or strongly immunogenic cell surface molecules. 2 figures. 1 table. 42 references.

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Status of Gene Therapy for Erectile Dysfunction Source: Contemporary Urology. 14(10): 14, 16, 21-22, 25, 28, 30-31. October 2002. Contact: Available from Medical Economics Publishing Inc. Montvale, NJ 07645. (800) 432-4570. Summary: Erectile dysfunction (ED) is defined as the inability of a man to attain or maintain an erection long enough to complete sexual intercourse. Although medical therapy with sildenafil citrate (Viagra, Pfizer) acts by enhancing smooth muscle function, it is effective in only 50 to 65 percent of patients with ED. This article reviews the status of gene therapy for erectile dysfunction. The concept of up-regulating the function of erection-promoting enzymes is simply termed gene therapy. The authors review gene therapy for the treatment of ED, highlighting those genes that are involved in the normal process of cavernosal smooth muscle relaxation of the penis and, more specifically, those involved with the production of nitric oxide (NO), the chemical mediator of penile erections. Topics include penile structure and erectile physiology, how gene therapy works and why the penis is a likely target, current gene therapies in research or clinical application, and future directions. One sidebar offers an editorial comment on this subject. 1 figure. 1 table. 43 references.

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Impact of Gene Therapy on Dentistry: A Revisiting After Six Years Source: JADA. Journal of the American Dental Association. 133(1): 35-44. January 2002. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2867. Website: www.ada.org.

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Summary: Gene therapy is an emerging field of biomedicine that has commanded considerable scientific and popular attention. The procedure involves the transfer of genes to patients for clinical benefit. Transferred genes can be used for either reparative or pharmacological purposes. This article summarizes the impact of gene therapy on dentistry. In 1995, the first author and a colleague described the potential impact of gene therapy on dentistry, on the basis of initial studies of gene transfer applications to salivary glands, keratinocytes and cancer cells. Their conclusion was that gene therapy would have a significant impact on the nature of dental practice within 20 years. In the past six years, remarkable progress has been made in the field of gene therapy, including seven areas relevant to dental practice: bone repair, salivary glands, autoimmune disease, pain, DNA vaccinations, keratinocytes, and cancer. While considerable problems remain, thus impeding the routine clinical use of gene transfer, gene therapy will have a pervasive and significant impact on areas of dental practice that are based in biological science. The authors conclude that by 2015, this will translate into practitioners' having a wide range of novel biological treatment options for their patients. 4 figures. 1 table. 56 references. •

Mouth is a Gateway to the Body: Gene Therapy in 21st Century Dental Practice Source: CDA Journal. California Dental Association Journal. 26(6): 455-460. June 1998. Contact: Available from California Dental Association (CDA). 1201 K Street, Sacramento, CA 95814. (916) 443-0505. Summary: This article contends that gene therapy may become an integral tool in dental practice early in the 21st century. The author discusses how gene therapy and other biological therapies are expected to be applied to oral diseases and disorders during the midpractice lifetime of today's dental students. One area of application is particularly important for oral health professions to recognize: the use of genes as pharmaceutical agents. There are certainly many oral-specific, corrective applications of gene transfer, such as repair of irradiated salivary glands or treatments of oral cancer. It is conceivable that, analogous to conventional medications taken by mouth, a number of systemic gene therapeutics may also follow the convenient route of oral delivery. The author describes the methods of gene transfer, noting use of the salivary glands; the use of gene therapeutics in the upper gastrointestinal (GI) tract; systemic gene therapy; and the role of dentists as gene therapists. 2 tables. 29 references. (AA-M).

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Inherited Liver Disease: What Role for Gene Therapy? Source: Contemporary Gastroenterology. p. 15-20, 22, 24-25. July-August 1991. Summary: This article explores the role of gene therapy in inherited liver disease. The authors note that introducing normal genes into hepatocytes may be a workable alternative to transplantation for such disorders as familial hypercholesterolemia. The genes for many of the disease-related proteins of the liver have already been cloned and efficiently expressed in cultured cells. Several promising methods have been developed to introduce these normally functioning genes into cultured hepatocytes or directly into the recipient's liver. Technical problems remaining include maintaining high levels of expression of the exogenous gene, assuring long-term survival of re-implanted hepatocytes, and minimizing potential continued harmful effects from the endogenous mutant gene. 2 figures. 2 tables. 60 references.

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Impact of Gene Therapy on Dentistry Source: JADA. Journal of the American Dental Association. 126(2): 179-189. February 1995. Summary: This article is designed to provide the dental practitioner with a general understanding of gene therapy, as well as several examples of how it is used to better manage dental and oral problems. Topics covered include a brief review of the recent advances in molecular biology; general principles of gene transfer; methods of gene transfer, including viral methods and non-viral or physical methods; the uses of gene transfer; applying gene therapy to oral cancer; gene transfer to oral mucosal keratinocytes; gene transfer to salivary glands; gene therapy; gene therapeutics; and the future of gene transfer and its impact on dentistry. The authors note that it is likely that gene transfer approaches will not be used initially for any routine care, but rather for patients whose conditions are refractory to more conventional treatment, such as people at especially high risk for caries or periodontal diseases. 6 figures. 2 tables. 33 references. (AA-M).

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Gene Therapy for Type 1 and Type 2 Diabetes Source: Diabetes Reviews. 7(2): 124-138. 1999. Contact: Available from American Diabetes Association, Inc. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Summary: This article reviews gene therapy for type 1 and type 2 diabetes. Gene therapy can be divided into four major approaches: expansion of beta cells and beta cell precursors, gene transfer to primary beta cells, engineering of glucose responsiveness in nonbeta cells, and immunomodulation of pancreatic beta cells. The pathophysiology of type 1 and type 2 diabetes means that some gene therapy approaches can be applied to both variants of the disease, while others will be specific to one variant or the other. For example, insulin deficiency, a prominent feature of both variants, can be approached by in vivo or ex vivo insertion of genes that stimulate the growth of pancreatic beta cells or beta cell precursors. An increasing number of genes involved in the process of beta cell growth and differentiation are being discovered. Induction of differentiation in early endocrine precursors is an attractive, albeit difficult, approach for beta cell expansion. One alternative is engineering glucose responsive insulin secretion in nonbeta cells such as neuroendocrine cells and hepatocytes. Substantial progress has been made in this direction; however, in the absence of intact insulin secretory apparatus, it is difficult to achieve tight coupling between glucose stimulation and insulin secretion. In type 2 diabetes, insulin resistance increases the secretory demand on failing beta cells. Recent progress in understanding the regulation of body weight, adiposity, and insulin resistance, as well as the interaction between insulin resistance, hyperglycemia, and beta cell dysfunction, provides a new direction for gene therapy strategies to reduce insulin resistance and protect pancreatic beta cells. Finally, gene therapy may be valuable for primary prevention of autoimmune destruction of pancreatic beta cells in type 1 diabetes and for the prevention of immune rejection, recurrent autoimmunity, and apoptosis in transplanted islets. 4 figures. 1 table. 138 references. (AA-M).

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Gene Therapy and Tissue Engineering in Sports Medicine Source: Physician and Sportsmedicine. 28(2):. February 2000.

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Contact: Available from McGraw-Hill Healthcare Information. 4530 West 77th Street, Floor 3, Minneapolis, MN 55435. (800) 525-5003 or (609) 426-7070 (for subscriptions) or (952) 835-3222 (for back issues). Summary: This journal article provides health professionals with information on gene therapy and tissue engineering in sports medicine. Although treatment of sports injuries has improved during the past two decades with the use of sophisticated rehabilitation programs, novel operative approaches, and advances in biomechanical engineering, deficits in injury treatment remain because of the limited healing capacity of certain musculoskeletal system tissues. Gene therapy is a promising new option that delivers therapeutic genes into cells and tissues. The article discusses gene therapy in terms of vectors, delivery strategies, and limitations. Another promising technology is tissue engineering. This technology is based on developing biological substitutes for the repair, reconstruction, regeneration, or replacement of tissues. The article describes possible gene therapy or tissue engineering techniques for treating skeletal muscle injuries, articular cartilage damage, anterior cruciate ligament injuries, meniscal tears, and bone fractures. In addition, the article comments on future directions for gene therapy and tissue engineering techniques. 2 figures, 2 tables, and 64 references. •

Current Progress in Gene Therapy Source: American Porphyria Foundation. Winter, 1992. p. 1-3. Contact: Available from American Porphyria Foundation. P.O. Box 22712, Houston, TX 77227. (713) 266-9617. Summary: This newsletter article addresses current progress in gene therapy, with a focus on considerations for gene therapy in the treatment of porphyria. Topics include safety concerns about gene therapy, social and ethical questions, how gene therapy works, the history of gene transfer, current clinical uses of gene therapy around the world, the use of gene therapy for different types of cancer, and the long-term sideeffects of gene therapy.

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Potential of Gene Therapy for Treatment of Kidney Diseases Source: Seminars in Nephrology. 15(1): 57-69. January 1995. Contact: Available from W.B. Saunders Company. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Summary: To provide a framework for understanding the concepts and problems involved in gene therapy for the treatment of kidney diseases, the authors of this article discuss basic aspects of gene structure and regulation. Topics include gene delivery vectors, steps necessary to achieve tissue-and cell-specific expression of delivered genes, and some present and future applications of gene therapy in kidney diseases. The authors conclude that, although the potentials for gene therapy are exciting, gene therapy for human kidney diseases is a long way from being practical at this stage. 1 figure. 2 tables. 82 references. (AA-M).

Federally Funded Research on Gene Therapy The U.S. Government supports a variety of research studies relating to gene therapy. These studies are tracked by the Office of Extramural Research at the National Institutes of

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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 gene therapy. 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 gene therapy. The following is typical of the type of information found when searching the CRISP database for gene therapy: •

Project Title: A CILIATED CELL-SPECIFIC PROMOTER FOR GENE THERAPY OF CF Principal Investigator & Institution: Ostrowski, Lawrence E.; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The long-term objective of this research is to develop a ciliated cell-specific promoter that will improve the effectiveness of gene therapy or cystic fibrosis (CF). In normal airways, the cystic fibrosis transmembrane conductance regulator (CFTR) protein is expressed primarily at the apical surface of ciliated cells and in the submucosal glands. For gene therapy of CF to be successful, the normal CFTR protein must be expressed in the proper location. However, many of the gene therapy vectors currently under investigation have no specificity for the differentiated airway epithelium. In addition, these vectors frequently use viral promoter elements or promoters of constitutively expressed genes to drive high-level expression of reporter genes. A major drawback to the use of these vectors therefore is that they may result in high levels of CFTR expression in unwanted cell types (e.g., macrophages, basal cells). These promoters may also be less efficient at providing stable, long-term expression in the non-dividing ciliated cell population. Our hypothesis is that the use of a specific promoter to direct expression of the CFTR protein to the ciliated cells located at the apical surface of the airways will correct the CF phenotype. In addition, we hypothesize that by using an endogenous promoter in an integrating vector, we will achieve stable long-term expression of the CFTR protein. The use of a ciliated cell-specific promoter will also increase the safety of gene therapy for CF by preventing potentially deleterious expression of CFTR in the wrong cell types. To test our hypothesis, we propose the following specific aims: Specific Aim 1: To identify and clone the promoter regions of ciliated cell-specific genes. Specific Aim 2: To identify the essential regulatory elements responsible for ciliated cell specific gene expression. Specific Aim 3: To demonstrate correction of the CF phenotype in both in vitro and in vivo models by targeted expression of the normal CFTR gene in ciliated cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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Project Title: A HYPERTENSION

GENE-BASED

THERAPEUTIC

FOR

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PULMONARY

Principal Investigator & Institution: Brigham, Kenneth L.; Professor of Medicine; Generx+, Inc. 3200 West End Ave, Ste 500 Nashville, Tn 372011322 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-OCT-2002 Summary: (Adapted from the Investigator's abstract) Primary pulmonary hypertension is a uniformly fatal disease of young and middle aged people; there is little understanding of the pathogenesis and no specific therapy. The principal pharmacologic therapy in current use is chronic constant intravenous infusion of the vasodilator prostanoid, prostacyclin. This therapy is effective, but requires maintenance of an intravenous catheter and continuous intravenous infusion; the only alternative is lung transplantation. The investigators showed some time ago that it is possible to transfect the lungs with the arachidonate cyclooxygenase (COX) gene and achieve selective increases in prostacyclin and PGE2 prostanoids which are potentially therapeutic for pulmonary hypertension. Studies supported by this phase I grant have documented that aerosol delivery of the COX gene as a plasmid-cationic liposome complex can decrease pulmonary vascular reactivity significantly in an animal model which is anatomically and physiologically similar to humans with no adverse effects on lung function. The investigators hypothesize that aerosol delivery of the COX gene in an expression plasmid complexed with cationic liposomes will prevent development and/or progression of the physiologic and pathologic changes of chronic pulmonary hypertension. The investigators further speculate that this therapy will prove superior to any current therapy for the treatment of patients with primary pulmonary hypertension and may provide a new therapeutic modality for treatment of a much larger group of patients with secondary pulmonary hypertension. In this Phase II application, the PI will determine: 1) effects of repeated administration of the COX gene in a plasmidcationic liposome complex by aerosol on lung function, 2) prostanoid generation and pulmonary vascular reactivity in unanesthetized sheep; 3) determine whether administration of the COX gene by aerosol in a plasmid-liposome complex will prevent development or progression of sustained pulmonary hypertension and pulmonary vascular remodeling in a well-characterized chronic air embolization model of sustained pulmonary hypertension in sheep; and 4) increase the efficiency of aerosol delivery of plasmid-cationic liposome complexes by using newer generation aerosol delivery devices and improved liposome-DNA formulations. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AD OC TK/VAL GENE THERAPY CLINICAL CORRELATES Principal Investigator & Institution: Chung, Leland W.; Professor; Urology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 11-APR-2000; Project End 31-JUL-2003 Summary: The objective of the proposed study is to obtain clinical correlates on an ongoing investigator-initiated investigational new drug (IND) at the University of Virginia. There are two major components to this proposed study. First, we request funding to test the hypothesis that an adenoviral toxic gene, Ad-OC-TK, plus an orally bioavailable Valacyclovir (Val) could induce maximal cell-kill in recurrent primary and metastatic prostate cancers. Laboratory evidence suggests that both cancer epithelium and its supporting stroma express a common protein, osteocalcin (OC). Delivering and expressing a toxic gene, herpes simplex thymidine kinase (TK), in an adenoviral

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construct could result in the most efficacious control of recurrent prostate cancer and its metastases. We propose to take advantage of the availability of cancer tissue specimens and biologic fluids such as blood and urine from patients to conduct the evaluation of the immunological status of the prostate cancer tissues obtained prior to, during, and after toxic gene therapy. Clinical correlates on apoptosis, activated partial thrombosplatin time (aPTT) and radiographic imaging in patients treated with toxic gene therapy will be obtained. Second, we request funding to expand our on-going clinical trial to treat additional prostate cancer patients with skeletal metastasis. The hypothesis to be tested is that Ad-OC-TK/Val will cause most effective tumor regression at the skeletal site. We propose to evaluate parallely the clinical correlates in biopsy tissue, blood, and urine samples obtained from patients treated with maximum doses of Ad-OC-TK. The specific aims of this proposal are: 1) to determine the level and distribution of Ad-OC-TK expression In prostate cancer cells at recurrent primary and metastatic lymph node and bone sites. A number of markers will be evaluated to assess viral distribution and delivery. Detection of other bone matrix protein expression of proteins such as OC, osteonectin (OSN), and bone sialoprotein (BSP) will be studied; 2) to assess and compare Ad-OC-TK induced anti-tumor immunity in tumor specimens obtained from recurrent primary and metastatic lymph node and bone sites. Immunohistochemistry, RT-PCR, bioassay, and enzyme linked immunoassay will be used to assess both local anti-tumor immunity and circulating anti-adenoviral antibodies; 3) to obtain clinical correlates in tumor and blood specimens obtained from patients before, during, and after Ad-OC-TK/Val therapy. Apoptotic indices, blood coagulation profiles, and radiographic imaging analyses will be evaluated; 4) to recruit at least 12 patients with minimum bone metastasis, and to treat these patients with intratumoral Ad-OC-TK/Val injection. We hope this will allow us to evaluate whether this form of gene therapy will be safe and efficacious in patients with bone metastasis. The ultimate goal of this study is to provide strong background information, which will assist us in development of future trials to incorporate "re-targeted" virus injected systemically to eradicate disseminated prostate cancer at both bone and soft tissue sites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADENOVIRUS LIMITATIONS AND TUMOR TARGETED GENE THERAPY Principal Investigator & Institution: O'malley, Bert W.; Professor & Chairman; Surgery; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Squamous cell carcinoma of the oral cavity and head and neck (HNSCC) is a devastating disease in which surgery, radiation and/or chemotherapy have not improved the 50 percent overall 5 year survival over the past 20 years. In an attempt to improve survival and reduce morbidity, gone therapy strategies are being developed for oral cancer. Despite encouraging preclinical data in many tumor types, initial clinical studies with adenovirus gene therapy have been disappointing. We posit that cellular differences exist even among head and neck cancers of the same histology that limit gone therapy responses. We further posit that variations in shared Coxsackie and adenovirus receptor (CAR) and integrin receptors play a major role in the transduction efficiency and translates to a significant variation in multi-tumor responses to adenovirus gene therapy strategies. We will test five hypotheses by addressing the following Specific Aims: 1) Determine the concentration of CAR, integrins, and FGF2 receptor on fresh human HNSCC samples and derived cell lines; 2) Establish the correlation between expression of CAR or integrin and Ad-tk anti-tumor effects and

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develop a FGF2 retargeting strategy in vitro that circumvents these limitations; 3) Quantify gene expression and therapeutic response to Ad-tk using both standard adenovirus and FGF2-R retargeted vectors in tumors established from 11NSCC lines. 4) Optimize direct linter-tumor injection therapy using circumventing treatment strategies and introduce systemic FGF2 retargeting therapy. We focus on a newly created fibroblast growth factor (FGF) conjugated adenovirus vector to develop a! Circumventing strategy that will improve gone transfer efficiency and corresponding therapeutic response. This novel FGF-2 receptor-based retargeting strategy may also allow safe and effective systemic delivery of tumor targeted adenovirus vectors. Five investigations regarding the role of adenovirus receptor and integrin expression on tumor cells will provide a platform of important gone therapy information that will lead to more effective and applicable preclinical animal studies and human clinical investigation. Adenovirus receptor or integrin testing prior to enrollment into a clinical trial may provide a means of selecting, stratifying, or assessing outcomes in head and neck cancer patients. This platform of information will also prove valuable to investigators who wish to circumvent limitations by developing and using alternative strategies such as FGF adenovirus retargeting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANNUAL GENE THERAPY SYMPOSIUM FOR LUNG & BLOOD DISEASES Principal Investigator & Institution: Tarantal, Alice F.; Professor; Primate Research Center; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): This R13 application requests funds to partially support an annual interdisciplinary scientific symposium ("Annual Gene Therapy Symposium for Lung & Blood Diseases") on essential topics associated with gene therapy for the treatment of congenital lung and blood diseases. The goal of this twoday fall symposium will be to bring together junior and senior investigators, and students and postdoctoral fellows that study gene transfer strategies, the pathophysiology of pediatric congenital disorders, and developmental anatomy/ontogeny for the understanding and treatment of human disease. Our aim is to provide an integrated and interactive forum for the presentation of new data and novel hypotheses for gene therapy applications. The annual symposium will be organized such that investigators in gene therapy and those focusing on studies related to lung and blood diseases who do not currently have an opportunity to interact will be present to discuss and identify crucial issues for study. The first day of the symposium will focus on the most current and timely topics in gene therapy. The second day will be dedicated to the theme of the meeting, with keynote and dinner speakers selected based on their areas of expertise. The theme of the 1st Annual Symposium will be stem cells, with subsequent years focusing on the fetus and newborn, in vivo imaging, animal models, and gene expression profiling. A competitive process will be established to provide stipends to graduate students and postdoctoral fellows. Students selected will present their research findings in an informal setting of a poster session. Minorities, women, and individuals with disabilities will be sought and strongly encouraged to apply. The symposium will be held at the Primate Center at the University of California at Davis. Funding is requested for planning and organizing the meeting, and travel and housing costs for speakers and those graduate students and postdoctoral fellows selected for stipends. Matching funds will be provided by the Institution to cover other

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costs. It is anticipated that approximately 100 individuals will attend in the first year, and that this number may increase in subsequent years. The Organizing/Scientific Committee will consist of members from research disciplines that represent the integrated/educational concept of the Symposium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 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

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Project Title: CARDIOVASCULAR CELL AND GENE THERAPY CONFERENCE Principal Investigator & Institution: Hajjar, Roger J.; Assistant Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005 Summary: (provided by applicant): Cardiovascular disease is a major cause of morbidity and mortality in the United States. New treatments are being formulated based on a

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better understanding of the signaling pathways involved in the pathogenesis of cardiovascular diseases. Furthermore cell replacement therapy has recently emerged as a novel way of correcting contractile and vascular deficiencies in cardiovascular diseases. The focus of this yearly symposium will be on the use of somatic gene transfer and cell therapy in cardiovascular diseases. Targeting genes to the heart through somatic gene transfer or transplanting stem cells have the potential to alter our approach to patients with cardiovascular diseases. Gene and cell therapy allow us to test hypotheses about mechanisms of disease, and, it is hoped, tailor therapy accordingly. This symposium will bring together scientists from industry, clinicians and basic scientists. It will be a multidisciplinary meeting that should bring together people who are beginning to have regular dialogues but whose traditions have been somewhat separate Through this combination of investigators with multidisciplinary backgrounds, diverse scientific perspectives will be brought into focus on gene and cell therapy. The conference will consist of cover nine separate sessions over two and a half days. The topics of the sessions are 1) Viral vectors, 2) Delivery approaches, 3) Lessons from development, 4) Cell therapy, 5) Targeting Ischemic Heart Disease, 6) Targeting hypertrophy and growth, 7) Targeting heart failure and arrhythmias, 8) Targeting vascular disease, and 9) NIH programs and regulatory issues.The conference will be organized on a yearly basis in April. All the logistics of the first conference along with speaker commitments have been completed and the assigned date of the first conference is April 8-20, 2002. The convergence of investigators from different fields which are typically separate will hopefully foster greater collaborative efforts in gene and cell therapy and provide better understanding and treatment modalities for cardiovascular diseases. 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

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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 •

Project Title: COMBINATION OF GM-CSF WITH TKR GENE THERAPY Principal Investigator & Institution: Chhikara, Madhu; Advantagene, Inc. 160 Paulson Rd Waban, Ma 02468 Timing: Fiscal Year 2003; Project Start 04-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Combined gene therapy (Herpes Simplex Virus Thymidine Kinase + Anti-herpetic Prodrug) and radiation therapy (TKR therapy) is a novel approach in the armamentarium against cancer. This radio-gene therapy combination creates a new spatial co-operation whereby two local treatment modalities have demonstrated enhanced local and metastatic tumor control and prolongation of survival. We have taken TKR therapy into clinical studies and currently have more than 60 patients in a Phase II trial in prostate cancer. Our corporate strategy is to add novel therapies (gene therapy) with distinct, non-additive toxicity profiles to the standard-ofcare (surgery, chemo- or radio-therapy) to enhance cancer cure or decrease treatment morbidity. TKR shows a potent systemic anti-metastatic effect, however, we believe this effect could be significantly enhanced by the addition of a cytokine that could further stimulate antigen presentation to the immune system. This Phase I application proposes to develop the reagents and single gene animal data to adequately evaluate the use of GM-CSF in combination with TKR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMBINED IL-2 AND MHC CLASS II GENE THERAPY FOR CANCER Principal Investigator & Institution: Xu, Minzhen; Antigen Express, Inc. 100 Barber Ave Worcester, Ma 01606 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2002 Summary: Antigen Express has developed technology to force the presentation of endogenous tumor antigens in a manner that produces an effective tumor cell vaccine. The key to this strategy is the generation of tumor cells that express MHC Class II molecules in the absence of the MHC Class II associated invariant chain (Ii protein). We are now developing an in vivo gene therapy strategy for inhibition of Ii protein expression (using Ii reverse gene constructs) in tumors. As not all tumors are MHC Class II positive, we are combining Ii inhibition with IL-2 and/or MHC Class II transactivator (CIITA) gene therapy. IL-2 is advantageous in that it stimulates the expansion of antigen specific T cells and causes interferon-gamma production (which is a good inducer of MHC Class II molecules) while CIITA is a potent and direct MHC Class II inducer. We will establish the ability of IL-2 and CIITA gene therapy vectors to induce MHC Class II molecules in vivo using a murine renal cell carcinoma model and an ovarian ascites model. Selective inhibition of Ii will be accomplished using a reverse

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gene construct. Finally, we will establish the therapeutic efficacy of combined IL-2 (or CIITA) and Ii reverse construct gene therapy on established Renca tumors and MOT ascites in vivo. Success will trigger Phase II studies, wherein we will develop appropriate constructs using human gene sequences, demonstrate activity in primary human tumor samples and complete all necessary studies requisite to an IND filing. PROPOSED COMMERCIAL APPLICATION: Immunotherapy represents a novel form of cancer therapy that complements existing treatment modalities. Successful demonstration of the augmentation of tumor immunogenicity in a manner that generates a robust anti-tumor immune response will satisify a significant unmet need in modern health care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONFERENCE ON GENE THERAPY 2001: A GENE ODYSSEY Principal Investigator & Institution: Kay, Mark A.; Professor; Keystone Symposia Drawer 1630, 221 Summit Pl #272 Silverthorne, Co 80498 Timing: Fiscal Year 2001; Project Start 01-JAN-2001; Project End 31-DEC-2001 Summary: (taken from the application) Gene therapy approaches have made important strides in the last several years. This is in large part due to the technical advances in vector delivery approaches. A number of preclinical studies has demonstrated reduced toxicity, with prolonged and therapeutic levels of clinically relevant gene products from various tissues. This is likely to lead to early success in new clinical trials under development. However, not all problems have been solved and there are many diseases with complex pathophysiology for which gene therapy has yet to show promise. Moreover, there are new safety obstacles that have arisen that will likely preclude treating less severe medical conditions. The meeting will highlight recent successes and barriers that still challenge the gene therapy community as it relates to basic science, preclinical animal studies, and clinical trials. The meeting will be held approximately 6 months away from the American Society for Gene Therapy (ASGT) meeting and will feature important new results that have occurred during the intervals of the yearly ASGT meetings. The meeting will also offer a format for research summaries as well as new primary data for newcomers to the field. The environment will be conducive for young investigators to interact directly with more senior investigators. This interaction is likely to allow trainees to find new mentors for advanced training (e.g., senior students who wish to pursue post-doctoral training; therefore, student participation is a critical component of the meeting.The plenary speakers blend a mix of senior, middle career, and young rising stars. The senior scientists who we anticipate will have new important accomplishments in 2001 were selected to help attract trainees to the conference. Session chairs were selected from the senior leaders in the specific target areas. All of the speakers (including the younger investigators) were selected on their recent past record of superb scientific accomplishment and verbal articulation. The younger scientists were included to add more depth and present fresh new ideas. We have selected 7 more "junior" speakers who have presented outstanding data at a session during the last ASGT meeting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONSUMER PERSPECTIVES ON THE PROMISE OF CF GENE THERAPY Principal Investigator & Institution: Stockdale, Alan; Education Development Center, Inc. 55 Chapel St Newton, Ma 02458

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Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2003 Summary: (Adapted from the Investigator's Abstract): Although gene therapy has been widely publicized as an impending cure for numerous diseases, including cystic fibrosis (CF), little empirical research has been conducted to determine the impact of this publicity, and its promise of cure, on patients and their families. Such knowledge of consumer perspectives is essential for enhancing trust in the biomedical establishment, for protecting vulnerable consumer groups from potential harms, and for the design of effective consumer and clinician educational materials. The Education Development Center, Inc., in collaboration with the International Association of Cystic Fibrosis Adults (IACFA), Temple University, St. Vincent's Hospital, and Brigham and Women's Hospital propose a study to (a) assess how gene therapy research, and the publicity surrounding it, are perceived by adults with CF, parents of children with CF, and CF Center physicians; (b) determine the knowledge, beliefs and attitudes that inform consumer perceptions and felt needs; (c) discover how those needs and perceptions affect patients' and families' treatment decisions and life plans; and (d) identify the ethical and psychosocial implications of gene therapy developments on patients, families, and their physicians. The team will do a content analysis of information materials disseminated to CF patients and the public; conduct qualitative interviews with 30 adult CF patients, 30 parents of children with CF, and 30 physicians. These interviews will be used to develop a survey questionnaire to be administered to al consenting adult CF patients and parents of children with CF cared for at all 13 New England CF treatment centers (N=1595) and to IACFA members in the U.S. (N=713). Findings will be presented to an expert advisory group of CF consumers, researchers, clinicians, ethicists, and representatives of other disease perspectives, such as AIDS and cancer. This goup will assist the study team in drafting recommendations for how best to reconcile the promise with the reality of CF gene therapy and identify the possible implications for other areas of gene therapy research. Recommendations will focus on consumer and clinician education; however, they will also have relevance for a broader array of issues, such as recruitment into gene therapy trials and priorities for research and care delivery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE CENTER FOR GENE THERAPY Principal Investigator & Institution: Miller, Arthur D.; Member; Pathology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 15-JAN-1994; Project End 31-DEC-2003 Summary: The Core Center for Gene Therapy at the University of Washington School of Medicine (UWSM) is under the direction of A. Dusty Miller, Ph.D. (Program Director), Affiliate Professor of Pathology and a Member of the Fred Hutchinson Cancer Research Center, and Associate Program Direction Bonnie W. Ramsey, M.D., Professor of Pediatrics. The Center brings together gene therapy research efforts at UWSM, the Fred Hutchinson Cancer Research Center, Children's Hospital and Medical Center, and the Veteran's Administration Medical Center in Seattle, and includes close ties with the Cystic Fibrosis Research Program headed by Dr. Bonnie Ramsey, and the General Clinical Research Center (GCRC) headed by John Brunzell, M.D. The Center will focus on three main areas of research: 1) development of viral vectors and procedures for the treatment of cystic fibrosis, 2) development of retroviral vectors for gene transfer and expression of therapeutic genes in hematopoietic and lymphoid cells in humans, and 3) development of retroviral vectors of gene transfer and expression of therapeutic genes in hematopoietic and lymphoid cells in humans, and 3) development of methods to

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deliver circulating proteins such as erythropoietin and clotting factors fro treatment of human disease. A total of 35 investigators who receive over $10 million in independent external support will regulatory use the core, facilities and collaborate in development of gene therapy protocols. This work will be supported by an Administrative Component and five other core facilities: Human Applications Core, Vector Development Core, Immunohistochemistry Core, Hematopoietic Cell Transduction Core, and Animal Core. In addition, the pilot and feasibility program will consist of 8 projects which are related to CF gene therapy and 2 projects which are directed towards gene therapy in other genetic disorders. The CF-related projects include the following: 1) The Biology of Adeno-Associated Virus and Vector (J. Allen and D. Miller), 2) Recruitment of the Adenoviral Pre-terminal Protein (pTP) for nuclear Import of LVDNA in Non-Dividing Cells (A. Lieber), 3) Identification of P. aeruginosa Virulence Determinants using an Invertebrate Model (C. Manoil), 4) Organ immunosuppression for donor lungs: Optimizing a safe approach using non-viral gene therapy (M. Allen), 5) Evaluation of lentiviral vectors for airway gene therapy (C. Halbert), 6) Refining nonviral gene therapy approaches for CF (M. Horowitz), 7) CFTR gene targeting by adenoassociated virus vectors (D. Russell), 8) Improving transgene expression by adenoviral vectors modified to co-express murine CD8 molecules (P. Fink). The 2 non CF-related projects include 1) Development of a coumermycin-responsive proliferation switch (C.A. Blau) and 2) A Novel approach for the modulation of host immune responses to gene modified cells (H.P. Kiem). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE REGULATION OF GENE THERAPY VECTORS Principal Investigator & Institution: Bromberg, Jonathan S.; Surgical Director; Center for Gene Therapy & Molecular Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: (Adapted from the applicant's abstract) Gene transfer offers unprecedented potential to modify physiologic phenomena. Unfortunately, insufficient and transient gene expression limit this potential. For example, the investigators have been able to use gene transfer methods to introduce immunosuppressive cytokines (IL-10, TGFb) into cardiac allografts to prolong graft survival, but have been unable to achieve permanent engraftment or tolerance. Although the use of strong viral promoters has improved efficacy somewhat, limited gene expression is still the major barrier to gene therapy. It is increasingly recognized now that specific immune responses to vector components and gene transfer products result in destruction of vectors or infected cells and are a significant impediment to stable expression. Preliminary data now demonstrate that the T lymphocyte derived cytokines IFNg and TNFa limit gene expression, without killing cells, by mechanisms involving negative regulation of transcription, especially from certain viral promoters and enhancers such as HCMVie and RSV-LTR. Since gene therapy is considered for treatment of diseases which are associated with many changes in cytokines (e.g., cancer, AIDS, transplantation, atherosclerosis, autoimmunity, ischemia-reperfusion); it is hypothesized that cytokines inhibit vector gene expression in transduced cells and that determination of the mechanisms involved in cytokineregulated gene expression will fundamentally alter the design of vectors for gene transfer and gene therapy. The objectives of the proposal are to define how cytokines regulate the expression from gene transfer vectors in order to improve strategies for gene delivery and control and thereby optimize protocols for gene therapy. The specific aims are: (1) demonstrate that TNFa and IFNg differentially regulate expression from

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selected viral and cellular promoters; (2) determine how cytokine response elements regulate transcription; (3) map the cytokine-responsive negative regulatory elements; and (4) demonstrate that manipulation of cytokine responses and response elements will improve gene transfer and gene therapy in an in vivo transplantation model. Experiments will entail the manipulation of cytokines and vector promoter-reporter constructs in vitro in primary myoblasts and the C2C12 myoblast cell line to define cytokine-initiated, promoter-dependent regulation of transcription. Promoter constructs will be transfected into murine cardiac allografts to probe cytokine initiated regulation of transferred gene expression in vivo, and to show that this regulation may be manipulated to improve the utility of gene transfer and gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF RTVP-1 GENE THERAPY FOR PROSTATE CANCER Principal Investigator & Institution: Kadmon, Dov; Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Although limitations regarding the delivery and targeted expression of potentially therapeutic genes remain, it is important to continue to work toward effective cancer gene therapy including gene therapy for prostate cancer. We have previously developed in situ adenoviral vector-mediated gene therapy for HSV-tk+GCV gene therapy. More recently, we have continued with more immunomodulatory gene therapy based approaches and a Phase I clinical trial involving adenoviral vector-delivered IL-12 gene therapy in patients with prostate cancer is pending. We recently identified a gene, RTVP-1 (related to testes-specific vespid and pathogenesis proteins), that possessed direct cytotoxic and immunomodulatory activities that could offer unique opportunities for specific gene therapy approaches. We have recently demonstrated that mouse RTVP-1 (mRTVP-1) is a direct p53 target gene and is upregulated by p53 in mouse and human prostate cancer cells. Further analysis revealed that RTVP-1 mRNA is abundant in normal mouse and human prostatic epithelial cells, but is progressively downregulated in primary tumors and has only low-level expression in metastatic tissues. In an orthotopic mouse model of metastatic prostate cancer adenoviral vector-mediated mRTVP-1 (AdmRTVP-1) expression leads to apoptosis, potent growth suppression, anti-angiogenic and antimetastatic activities, and importantly local and systemic immune response. We propose to conduct further preclinical studies to develop optimized adenoviral vector systems for RTVP-1 gene therapy. We will also evaluate specific RTVP-1 gene-modified cell-based strategies including RTVP-1 gene-modified tumor cell vaccines. We have considerable experience with alternative promoters for adenoviral vectors and will fully evaluate non-specific promoters such as CMV relative to a prostate selective promoter such as ARR2PB and a prostate cancer/endothelium targeting promoter (caveolin-1) in replication-defective and attenuated replication competent adenoviral vector systems. These preclinical studies will proceed concurrently with the initiation of a Phase I trial in which replication-defective adenoviral vectors will be used to transfer the human RTVP1 gene directly into prostate cancer in patients who will subsequently be subjected to radical prostatectomy. Comprehensive analysis of the effects of RTVP-1 locally and systemically will be completed in this clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOPAMINE REGULATION IN PARKINSONIAN RAT BY GENE THERAPY Principal Investigator & Institution: Kang, Un Jung.; Associate Professor; Neurology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-1993; Project End 31-MAR-2007 Summary: (provided by applicant): L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay of therapy for Parkinson's disease (PD). Chronic L-DOPA therapy is limited, however, by the development of motor response complications, such as progressively shorter duration of improvement in akinesia (wearing-off) and the appearance of LDOPA-induced abnormal involuntary movements. Innovative methods of sustained and localized central nervous system (CNS) dopamine delivery may further optimize LDOPA therapy. Such methods are being explored clinically by CNS transplantation studies with fetal dopaminergic neurons and experimentally by neuronal stem cell implants and gene therapy. Our studies during the past funding cycles have defined optimal sets of genes necessary for dopamine replacement using ex vivo gene therapy using genetically modified fibroblasts. We also developed rat behavioral models that are relevant to the akinesia of PD patients. Using akinesia behaviors, we have noted that lesion severity has a major influence on the shortening of the response duration with minor contribution by the chronic intermittent L-DOPA therapy. Therefore, studies proposed in this continuing renewal application will determine the optimal parameters of gene therapy to improve akinesia and minimize and prevent motor response complications. We will use adeno-associated virus vectors to deliver tyrosine hydroxylase and guanosine triphosphate (GTP) cyclohydrolase 1 genes. The optimal combination of anatomical targets for gene therapy to improve akinesia will be defined by examining the effects of gene therapy delivered to basal ganglia structures, such as subthalamic nucleus, substantia nigra par reticulata, that receive dopaminergic inputs, in addition to the striatum. The optimal timing to initiate dopamine replacement gene therapy to forestall development of motor response complications will also be examined. These results will have significant implications beyond dopamine replacement gene therapy proposed here and guide other therapies such as fetal dopaminergic cell transplantation, neurotrophic factor therapy, stem cell therapy, and other CNS targeted delivery systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DUAL GENE THERAPY FOR HEART FAILURE Principal Investigator & Institution: Nuss, H B.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JAN-2002 Summary: Heart failure is a multifactorial disease, having both electrical and contractile components. Downregulation of key potassium channels and concomitant prolongation and instability of repolarization, predispose the heart to arrhythmias. Meanwhile, downregulation of the sarcoplasmic reticulurn Ca2+ ATPase and concomitant calcium handling abnormalities contribute to depressed myocardial contractility. The electrical abnormalities and the contractile abnormalities are not mutually exclusive. Alterations in the control of membrane voltage will modulate the triggered release of Ca2+ from the sarcoplasmic reticulurn and, conversely, alterations in the intracellular calcium transient will influence membrane potential. It is the interplay between the electrical and contractile abnormalities of heart failure which compounds the complexity of abnormalities and confounds the design of successful treatments. Novel antiarrhythmic

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gene therapy based upon manipulation of a select K channel gene alone to decrease susceptibility to arrhythmias may lead to depressed contractility, which is already depressed in heart failure. Conversely, genetic manipulation of a SR Ca2+ ATPase protein alone, to amplify contractility, may create a proarrhythmic substrate in a failing heart which is already predisposed to fatal arrhythmic events. Thus, monogenic strategies, based upon selective overexpression of a single gene, may not suffice to correct heart failure abnormalities because of the interplay between excitation and contraction in cardiac muscle. This proposal seeks to offset abnormalities of tachycardia, pacing- induced heart failure in rabbits using combination gene therapy: overexpression of a select K channel gene and a SR Ca2+ ATPase gene in tandem. As a prelude we will test the hypotheses that gene therapy targeted to correct the electrical abnormalities alone or the calcium handling abnormalities alone will result in adverse conditions. The proposal focuses on potassium channels and SR Ca2+ ATPase's that are highly relevant to repolarization and contractility in the human heart failure. In vivo adenoviral mediated gene transfer, cellular and cardiac electrophysiology, and quantitative modeling will be used to investigate repolarization and calcium handling with the goal of correcting the electrical and contractile abnormalities in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EBV BASED STRATEGIES FOR AIDS RELATED MALIGNANCIES Principal Investigator & Institution: Kenney, Shannon C.; Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 13-FEB-1995; Project End 31-JAN-2003 Summary: AIDS patients frequently develop central nervous system (CNS) lymphomas, for which there is currently no effective treatment. These AIDS-related CNS lymphomas all carry the Epstein-Barr virus (EBV) genome and express the EBV protein, EBNA 1. The ubiquitous presence of EBV in the AIDS- related CNS lymphomas presents unique opportunities for targeting these malignant cells for destruction using gene therapy approaches. In addition, gene therapy strategies which distinguish between proliferating (tumor) versus nonproliferating (neuronal) cells, and which have already been shown to cure glioblastomas in animal models, may likewise be useful in the treatment of CNS lymphomas. In these studies, we propose to use a recently developed SCID mouse model of CNS lymphoma to develop a variety of gene therapy approaches for the potential treatment of CNS lymphomas in AIDS. In our first specific aim, we will exploit the presence of EBV in AIDS-related CNS lymphomas and insert the "suicide" gene HSV-TK (herpes simplex virus thymidine kinase), which confers ganciclovir sensitivity to cells, into a retroviral vector under the control of the EBV element, oriP. OriP, which contains both an origin of replication and a transcriptional enhancer element, requires the EBV protein EBNA 1 for function. In our second specific aim, we will insert the HSV-TK gene (under the control of the EBNA 1 dependent oriP enhancer element) into a plasmid vector and use the molecular-conjugate method to deliver DNA. The molecular conjugates will include a peptide containing the CD21 ligand (expressed on B cells) to specifically deliver the HSV-TK DNA only to tumor cells. In our third specific aim, we will attempt to induce lytic destruction of the EBV-infected lymphoma cells by using gene therapy to over-express the EBV immediate-early protein, BZLF1. Over-expression of BZLF1 is known to induce lytic EBV infection and consequent lysis of the host cell. In the final specific aim, we will examine the ability of defective HSV mutants to lyse EBV-transformed B cells in vitro, and cure EBV-induced CNS lymphomas in vivo. The studies proposed will not only be important in the

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development of an animal model system for AIDS-related CNS lymphomas, but should provide critical information regarding which therapeutic approaches are most promising for eventual human trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENHANCEMENT OF HUMAN ISLET ENGRAFTMENT BY GENE THERAPY Principal Investigator & Institution: Gaber, Osama A.; Chief; Surgery; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2001; Project Start 15-JUN-2000; Project End 31-MAY-2004 Summary: Results of clinical islet transplantation remain disappointing despite sporadic reports of short-term insulin independence. Failure of a large proportion of islet grafts to function has been ascribed to poor islet recovery from cadaveric pancreas, lack of adequate islet vascularization following transplantation and nonspecific immune mediated islet destruction or allogenic rejection. To overcome the problem of primary nonfunction, our laboratory has developed procedures to improve viability of isolated islets including novel culture techniques. In addition, we developed a NOD-SCID mouse model that allows viability testing of islets in vivo prior to transplantation. Furthermore, we embarked on a gene immunotherapy approach to improve human islet survival in vivo. We hypothesized that transfection of human islets with TGFbeta1 will prevent structural and immune mediated destruction of islets. Reconstitution of the NOD-SCID mouse with human CD34+ cells in the presence or absence of thymic fragments, will allow us to test the impact of the genetic manipulation in a clinically relevant model. Our specific aims are to test the hypothesis that: l) transient, low level of TGFbeta1 expression by human islets transduced with Ad-RSV-TGFbeta1 vector will improve and prolong in vivo function; 2) transient TGFbeta1 expression by human islets will promote their implantation by enhancing extracellular matrix formation and neovascularization, resulting in preservation or improvement of in vivo function; 3) expression of TGFbeta1 by human islets will protect against nonspecific inflammatory destruction in vivo; and 4) expression of TGFbeta1 by human islets will protect against allogenic immune destruction. The proposed work emphasizes the utilization of human islets for genetic modification and should provide clinically relevant data regarding the structural and immunological requirement for successful engraftment. The long-term goal of this multidisciplinary research is to develop an effective gene therapy approach that could be clinically utilized to achieve successful human islet transplantation. Future experiments based on the findings of this research would allow us to examine the utility of other gene candidates or other vectors that could complement our gene therapy program in islet transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENZYME AND GENE THERAPY OF MPS I IN ANIMAL MODELS Principal Investigator & Institution: Neufeld, Elizabeth F.; Professor and Chair; Biological Chemistry; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-AUG-1987; Project End 31-JUL-2003 Summary: The molecular basis of Mucopolysaccharidosis I (MPS I, Hurler, Hurler/Scheie and Scheie syndromes) is mutations in the gene encoding alpha-Liduronidase, resulting in absence of enzyme activity, accumulation of undegraded glycosaminoglycans, and systemic disease. Because alpha-L-iduronidase, a lysosomal

22

Gene Therapy

enzyme, can be secreted as well as taken up by receptor-mediated endocytosis, MPS I has long been considered a prime candidate for replacement therapy. Alpha-LIduronidase provided by donor cells of hematopoietic origin (probably macrophages) is thought to be responsible for changes in disease progression that are seen after bone marrow transplantation. The course of the disease can also be altered by administration of recombinant alpha-L-iduronidase. The therapeutic effect of the enzyme previously observed in the canine MPS I model had been promising enough to generate a clinical trial in MPS I patients. But even though recombinant alpha-L-iduronidase may soon become available as a pharmaceutical, there is still a need for developing effective and long-lasting gene therapy. To have a suitable animal model, we have produced mutant mice by targeted disruption of the alpha-L-iduronidase gene. Aim 1 is to define the phenotype of the MPS I mouse model at the biochemical, pathological, behavioral and clinical levels. Aim 2 is to determine the effect of administration of human recombinant alpha-L-iduronidase on the disease phenotype, in order to provide a basis of comparison for gene-based procedures. Aim 3 is to compare transplantation of genemodified bone marrow over-expressing human alpha-L-iduronidase with transplantation of bone marrow expressing normal levels of the enzyme, for effectiveness in altering the disease phenotype. Aim 4 is to determine the effectiveness of tetracycline-inducible alpha-L-iduronidase expression in macrophages as a means of enzyme delivery to affected organs, in particular to the brain, as well as to compare it with the above procedures for ability to alter the disease phenotype. The proposed studies represent steps in our long-term program to develop treatment for patients affected with MPS I. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF CELLULAR GENE THERAPY FOR OI Principal Investigator & Institution: Niyibizi, Christopher; Associate Professor; Orthopaedic Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 18-AUG-2000; Project End 31-JUL-2002 Summary: (Taken from the application): Ontogenesis imperfecta (0I) is a group of heritable disorders of connective tissue whose common feature is bone fragility. Most forms of OI are the result of mutations in the genes that encode proalpha1 and proalpha2 polypeptide chains of type I collagen the major protein of bone. The longterm objective of the proposal is to develop strategies using cell therapy or gene therapy for the treatment of some forms of OI and other bone related diseases. The focus of this research proposal is to utilize a mouse model of human OI (oim) that has defective synthesis of proalpha2(I) chains to evaluate the feasibility of reversing OI defects and other bone related disease by either bone marrow stromal cell transplantation or delivery of normal collagen genes to bone. The aims are: (1) to evaluate the potential of bone marrow stromal cells from normal donor mice transplanted into syngeneic OI mice to engraft, synthesize and deposit normal type I collagen in bone matrix of the recipient mice and (2), to test the feasibility of gene therapy by evaluating the potential of bone marrow stromal to be transduced with collagens and to deliver and express the genes in bone. As a prelude to this, bone marrow stromal cells will be established from the normal mice by flushing the marrow from femurs and tibias. The established bone marrow stromal cells will be transduced with a retroviral vector containing LacZ and neo~ genes (BAG-LacZ neo) prior to transplanting them to the recipient mice to aid in cell tracking. The bone marrow stromal cells established from normal mice will be injected in the femurs of the irradiated or non-irradiated OI mice and the expression of

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the proalpha2(I) chains will be determined by immunofluorescence localization using a mouse alpha2(I) antiserum and cyanogen bromide digestion of the bone collagen of the recipient mice. To test for the collagen gene expression by bone marrow stromal cells, the cells will be transduced with an adenovirus containing the mouse proalpha2(I) collagen gene and the transduced cells will be injected in the femurs of the o=s mice. The alpha2(I) collagen expression will be determined by immunofluorescence localization using the mouse proalpha2(I) and the cyanogen bromide digestion of the tissue. Future plans will involve determination of the amount of collagen made by the transplanted cells in the bones of the recipient mice and the assessment of the bone quality by radiographic, histological and biomechanical analysis of the bones of the recipient mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF DELIVERY SYSTEMS FOR RENAL GENE THERAPY Principal Investigator & Institution: Klotman, Mary E.; Professor and Chief; Mount Sinai School of Medicine of Cuny New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2003 Summary: A number of renal diseases are either a result of a genetic defect or the result of a chronic systemic disease resulting in renal injury from both local as well as systemic production of specific mediators. Gene therapy either to replace a missing factor or to suppress the production of deleterious exogenous (virus) or endogenous mediators represents a promising new therapeutic approach for chronic renal disease. The success and safety of genetic therapy will depend on both the successful expression of the exogenous gene as well as the efficient and specific delivery of the gene to the appropriate target cell. Thus, optimum genetic constructs for expression in specific renal cell types and optimum systems for either ex vivo or in vivo delivery of an exogenous gene to the kidney need to be defined. The function of strong constitutive promoters as well as potentially more renal-specific promoters will be examined in primary cells from human and mouse kidney (including mesangial and fibroblasts as well as proximal tubule, thick ascending limb and distal tubule cells) as well as in vivo. Each of these promoters will be inserted upstream from the indicator genes, beta-gal(alone) and luciferase (with therapeutic genes), which will allow convenient tracking and quantitation of expression in vivo. Since many of the diseases resulting in renal failure are chronic in nature, a delivery system that will result in the long-term stability and expression of a therapeutic gene is desirable; best achieved through integration of the gene into the host chromosome. The defective parvovirus, adeno-associated virus (AAV), efficiently integrates into the host genome and has the added advantage of efficient transduction into non-dividing cells making it an attractive candidate for gene therapy in the kidney. Furthermore, data suggest that delivery of a therapeutic gene flanked by genetic components of AAV system delivered as DNA in a liposome might result in the efficient integration of a delivered gene in a host cell without the use of a recombinant virus. These two delivery systems will be used to define the efficiency of gene delivery in vitro to primary renal cells and in vivo (using a murine model) to renal cells. Specific issues that will be addressed will include the efficiency of delivery to specific cell types, strategies to enhance transduction particularly to non-dividing renal cells, integration characteristics of the AAV-based constructs and the potential toxicity when a gene is delivered in this vector system. A model of disease, HIV-1 associated nephropathy in the transgenic mouse will be utilized to define efficacy of gene inhibition in a pathogenic model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Gene Therapy

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Project Title: FUSOGENIC MEMBRANE GLYCOPROTEINS FOR GENE THERAPY Principal Investigator & Institution: Vile, Richard G.; Consultant; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 31-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to exploit the highly potent cytotoxic properties of a novel class of genes, called Fusogenic Membrane Glycoproteins (FMG), for the gene therapy of prostate cancer. Many viruses kill their target cells by causing cell fusion through binding of the viral envelope protein on an infected cell with its cellular receptor on neighboring cells. The result is the formation of large, multinucleated syncytia which eventually become non-viable and die. We have used gene transfer of the cDNAs of three different types of FMG to prostate tumor cells. The cytotoxicities of these FMG were consistently greatly superior to that of conventional suicide genes and the local bystander killing effects were at least one log greater than those of the HSVtk/Ganciclovir system. FMG tested so far kill target cells via nonapoptotic mechanisms with the concomitant induction of immune stimulatory signals such as heat shock proteins. We now hypothesize that these properties of FMGmediated tumor cell killing can be exploited, and enhanced, to generate more effective gene therapies for prostate cancer. We will characterize in detail the mechanisms by which FMG gene transfer leads to cell death to understand what regulates the efficiency of syncytial killing and how to improve it for therapeutic purposes. We will investigate how the mechanisms of syncytial killing can be enhanced in vivo to stimulate potent immune responses against tumor metastases. This will be done by constructing vectors in which additional immune stimulatory genes, such as GM-CSF, are co-expressed with FMG. In addition, we will take full advantage of collaborations within the SPORE group to investigate whether co-expression of an FMG with the sodium iodide symporter (NIS) gene can augment the cytotoxicity of FMG alone by and allowing increased tumor cell killing in combination with radioiodine treatment. We will also generate FMGinduced prostate tumor cell-dendritic cell hybrids for anti-tumor vaccination, in close collaboration with the expertise of Dr. Esteban Celis as a co-member of the SPORE group. We propose to make a series of viral vectors to transfer the cDNAs of different FMG into prostate tumor cells to identify the most effective FMG for the gene therapy of prostate cancer. Finally, we will construct retroviral and adenoviral vectors which incorporate tight transcriptional regulatory elements of the PSA promoter to allow targeting of FMG expression to prostate cells to increase the safety of these potent genes for progression to clinical trials. We propose using a GALV adenoviral vector system for a Phase I/II clinical trial in years 4 and 5 of the funding period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUSOGENIC TRANSGENES

MEMBRANE

PROTEINS

AS

THERAPEUTIC

Principal Investigator & Institution: Galanis, Evanthia; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 31-MAR-2005 Summary: Measles virus exerts its cytopathic effect by cell-cell fusion which eventually leads to cell death. We have cloned the cDNA for the measles F and H fusogenic membrane glycoproteins into eukaryotic expression vectors and have shown significant cytotoxicity through induction of cell-cell fusion in different human tumor cell lines including A431 (epithelial carcinoma), C170 (colon cancer), HeLa (cervical cancer), TE671 (rhabdomyosarcoma), and the glioma cell lines U87 and U118. In addition, we

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have shown significantly higher bystander effects as compared to the herpes simplex thymidine kinase (HSV-tk) system. This proposal utilizes the fusogenic membrane proteins F and H of the measles virus to develop a clinician investigator's career in gene transfer/gene therapy. The applicant proposes to: 1) Investigate the use of fusogenic measles virus proteins F and H as novel therapeutic transgenes using the U87 and U118 glioma models. Gliomas were selected because they are highly lethal tumors despite the therapeutic use of surgery, radiation therapy, and chemotherapy. They also offer the further advantage of their limited metastatic potential that makes them appropriate targets for intratumoral gene transfer/gene therapy. We plan to a) construct retroviral vectors encoding the F and H transgenes, b) compare the developed vectors with the gold standard of cytotoxicity which is HSV-tk producing retroviral vectors in both glioma cell lines and tumor xenografts, and c) target vectors to the tumor environment by exploiting the over-expression of matrix metalloproteinases in gliomas. The longterm goal is to introduce this novel transgene system into clinical trials as a new therapeutic alternative. 2) Develop expertise to pursue an independent clinician scientist career within the area of gene transfer/gene therapy. In addition to the interaction with the mentor and co-mentors, this will be achieved through attending Mayo Graduate School courses and major scientific meetings, such as the American Association for Cancer Research and the American Society of Gene Therapy meetings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GAMMA HEMOGLOBINOPATHIES

GLOBIN

VECTORS

FOR

TREATMENT

OF

Principal Investigator & Institution: Persons, Derek A.; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: This application is focused on the candidate's immediate career goal, which is to enhance and further his laboratory-based training to date by acquiring new skills in the development, testing and use of globin vectors designed for gene therapy approaches to the beta-chain hemoglobinopathies. With the applicant's clinical background, previous doctoral research experience and three years of post-doctoral work in the laboratory of Dr. Arthur Nienhuis at St. Jude Children's Research Hospital (SJCRH) most recently, the candidate is now entering a transitional phase in his career with the goal of becoming an independent investigator as a clinician-scientist. However, the candidate and the sponsor strongly believe that further training involving the new vectors and animal models outlined in this application will facilitate this transition and greatly enhance the potential for early success as an independent investigator. As an independent faculty member in an academic medical setting, it is the candidate's longterm career goal to continue in the area of gene therapy for hematologic disorders with specific interest in developing a research program compatible with the translation of successful preclinical gene therapy approaches to the clinic. In this application, the candidate proposes to obtain additional training and specific expertise in the development and testing of new therapeutic globin vectors with his current mentor, Dr. Arthur Nienhuis, at SJCRH. Within the Div. of Experimental Hematology in which Dr. Nienhuis is a member and Chief, there is significant expertise in retroviral and lentiviral vector development, in techniques of gene transfer into murine and human hematopoietic stem cells, in animal models of thalassemia, and in the use of the NOD/SCID murine transplant model for human stem cells. Thus, the further training the applicant requires for the execution of the proposed research is readily available. The proposed research project is based on the need for the development of improved

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Gene Therapy

globin vectors for use in a gene therapy approach to both thalassemia and sickle cell anemia. The focus of this project involves a gene addition strategy based on the hypothesis that delivery of an optimized gamma-globin gene cassette can achieve a sufficient level of expression in developing erythroid cells to reverse the thalassemic or sickle cell disease phenotype. The project contains 3 specific aims: 1) to design and test novel gamma-globin retroviral and lentiviral vectors, 2) to use a murine model of betathalassemia to model gene therapy approaches using optimized gamma-globin vectors. and 3) to characterize and use primitive hematopoietic cells from patients with betathalassemia to evaluate the therapeutic potential of optimized gamma-globin vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR BLOOD PROTEIN DEFICIENCIES Principal Investigator & Institution: Ponder, Katherine P.; Associate Professor of Internal Medicine; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 15-SEP-1996; Project End 31-DEC-2005 Summary: Hemophilia B occurs in 1:30,000 males and is associated with a life-long bleeding diathesis. Although IV injection of Factor IX can prevent or stop bleeding, this treatment is inconvenient, expensive, and can transmit infections. Hepatic gene therapy could permanently correct the clinical manifestations of hemophilia. Retroviral vectors (RV) can result in long-term and therapeutic levels of expression of coagulation factors from the liver in rodents, and are currently being used in a clinical trial for Hemophilia A in humans. However, there are two major problems that must be solved before RVmediated hepatic gene therapy will be used routinely: 1) identify ways to achieve a higher efficiency of stable gene transfer without major toxicity; and 2) identify methods for blocking an immune response to the therapeutic gene in the context of RV-mediated hepatic gene therapy. This project will address both of these issues. The first aim is to determine if delivery of an RV expressing the canine Factor IX (cFIX) cDNA into the liver can reduce the bleeding manifestations of Hemophilia B dogs obtained from a colony that rarely makes antibodies to the canine protein. This should allow us to quantify gene expression without the confounding issue of an immune response. Initial studies will use neonatal dogs, as their high baseline level of hepatocyte replication allows transduction of 9 percent of liver cells. Subsequent studies will use hepatocyte growth factor to induce replication in young adult dogs. Animals will be evaluated for cFIX levels, development of antibodies, bleeding, and for other adverse effects. The second aim will address the second major problem of RV-mediated hepatic gene therapy, that of immune responses to the therapeutic gene product. In this aim, we will try to block immune responses to the de novo expression of a transgene from an RV in mice by either performing neonatal gene transfer, or by injecting immunoinhibitory agents at the time of gene therapy in young adults. Although mice are optimal for initial studies due to cost considerations, approaches that function in inbred mice sometimes fail in outbred larger animals. We will therefore test any immunomodulatory approaches that function in mice for their efficacy in normal and Hemophilia B dogs in Aim III. Success in this project might lead to a safe, effective, and permanent therapy for Hemophilia B. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISORDERS

GENE

THERAPY

FOR

CHRONIC

NEURODEGENERATIVE

Principal Investigator & Institution: Castro, Maria G.; Professor; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048

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Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Parkinson's disease (PD) is a chronic neurodegenerative disorder. Although we do not yet understand its cause, there is extensive degeneration of nigro-striatal DA neurons. Powerful neurotrophic factors which could be used for the treatment of PD, like GDNF, have been described recently. The ultimate goal of this proposal is to develop novel high-capacity adenoviral systems for cell-type specific, inducible, long term, stable, and non-immunogenic delivery of neuroprotective genes to the brain for both experimental transgene expression in adult animals, and for the future treatment of chronic neurodegenerative diseases such as PD and Alzheimer's disease by gene therapy. Currently the use of adenovirus vectors has been limited by the low efficiency of transcriptional promoter elements currently used, which directly leads to the need to use higher doses of vectors, and the cytotoxicity and immunogenicity of viral proteins expressed from the genornes of first generation adenoviral vectors. We now wish to develop novel cell-type specific and inducible vectors, that will allow efficient, safe, and long-term gene delivery vectors for neurological gene therapy. We will construct high-capacity helper-dependent adenoviral vectors that express no adenoviral genes. We will utilize the powerful, astrocyte specific major immediate early murine Cytomegalovirus promoter, driving novel tetracycline-dependent transcriptional activators to achieve cell-type specific and regulatable expression of GDNF. The efficacy, cell-type specificity, and inducibility of these vectors will be tested stringently to assess their capacity to deliver cell-type specific and regulatable GDNF, and also to determine any potential side effects caused either by the vectors or the long term expression of powerful neurotrophic agents. The reagents and principles established by this work will be of substantial value to those with interests in the basic and clinical neurosciences, and will lead to the development of novel, efficient, and safe approaches for the treatment of human chronic neurodegenerative diseases. This research will facilitate the development of the tools needed to achieve long-lived, safe, cell-type specific, regulatable, non-cytotoxic transgene expression, and, ultimately, for the treatment of patients suffering from chronic neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR ERYTHROPOIETIC PROTOPORPHYRIA Principal Investigator & Institution: Mathews-Roth, Micheline M.; Associate Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: Erythropoietic protoporphyria (EPP) is a genetic disease in which ferrochelatase, the enzyme that inserts iron into protoporphyrin, is defective. In EPP, protoporphyrin accumulate in erythrocytes, leaks into about 5% of patients. Since it has been demonstrated that the vast majority of the protoporphyrin found in plasma, skin and liver derives from the erythrocytes, we propose that gene therapy directed at the bone marrow could cure EPP. This would be especially beneficial for patients with severe photosensitivity or incipient liver disease resistant to pharmacological treatment. Using a mouse model of EPP (homozygous recessive mutation), we have recently demonstrated that transplantation of bone marrow from normal syngeneic Balb/C donors into irradiated EPP recipients completely cures the disease phenotype. We have also shown that retrovirus-mediated transfer of human ferrochelatase cDNA into peripheral blood BFU-E from human EPP patients corrects the specific protoporphyrinmediated fluorescence. In addition, we are developing improved gene transfer methods for hematopoietic stem cells by means of Lentiviral vectors and in vivo selection

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Gene Therapy

protocols, which will be validated and optimized in the EPP gene therapy model. Based on these preliminary results, our Specific Aims are as follows: Specific Aim 1: To demonstrate that retroviral transfer of human ferrochelatase cDNA into hematopoietic stem cells of EPP donor mice followed by their transplantation into EPP recipient mice will cure or significantly ameliorate the disease phenotype. Specific Aim 2: To compare the efficiencies of Murine Leukemia Virus-verus HIV-1 Lentivirus-based vectors to transduce murine hematopoietic stem cells and correct the EPP phenotype by bone marrow transplantation. Specific Aim 3: To evaluate the efficacy of gene therapy protocols for EPP that combine minimal myeloablation prior to bone marrow transplantation, Multi-drug Resistance (MDR) or Dihydrofolate Reductase (DHFR) retroviral vectors and corresponding in vivo selection regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR INHERITED JAUNDICE Principal Investigator & Institution: Roy-Chowdhury, Jayanta R.; Professor of Medicine and Molecular Gene; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2001; Project Start 01-AUG-1993; Project End 31-JUL-2003 Summary: Our long-term objective is to develop safe and efficient methods for liverdirected gene therapy for genetic disorders of hepatic metabolism, using inherited jaundice due to bilirubin-uridinediphospho-glucuronate glucuronosyltransferase (bilirubin-UGT) deficiency as a model target. Absence of hepatic bilirubin-UGT activity leads to accumulation of the bilirubin in plasma and consequent brain damage, resulting in the potentially lethal Crigler-Najjar syndrome type I (CN-I). Currently, liver transplantation is the only definitive therapy. Gunn rats, the animal model for CN-I, will be used for these studies. During the last four years, both viral and non-viral vehicles for delivery of normal human bilirubin-UGT genes to Gunn rat liver were devised and tested. In this continuation application, two strategies for correcting hepatic bilirubinUGT deficiency in vivo will be pursued. In the first approach, recombinant viral vectors will be used to substitute hepatic bilirubin-UGT by delivering a normal gene. Recombinant adenoviruses are very efficient in transferring genes into the liver in vivo, but the transgene expression is transient because the virus is episomal and the host immune response precludes its repeated administration. Three methods for specific tolerization of the host to adenoviral antigens, developed in our laboratory, show promise for long-term adenovirusmediated gene therapy without immunosuppression. To refine these methods for future clinical application, the mechanisms by which they induce specific tolerance will be elucidated. In addition, a much less immunogenic vector, based on the SV40 virus, will be developed and tested. The second approach will utilize RNA/DNA chimeric molecules to repair the genetic lesion in Gunn rats, using our highly efficient vectors for liver-specific nucleic acid delivery by receptor-mediated endocytosis. The gene transfer efficiency will be assessed by molecular, enzymatic and metabolic studies. Successful completion of these studies will provide a basis for gene therapies for CN-I and other inherited metabolic disorders, such as deficiency of alpha1-antitrypsin and urea cycle enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY FOR LEBER CONGENITAL AMAUROSIS Principal Investigator & Institution: Hauswirth, William; Ophthalmology; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006

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Summary: (Applicant?s Abstract) A multi-investigator, multi-center research/clinical plan is proposed to develop a viral vector-based gene therapy for RPE65 Leber congenital amaurosis (LCA), to complete preclinical safety testing for an Investigational New Drug (IND) submission to the FDA and to begin Phase I/II clinical testing. Seven coordinated modules are described, each with a distinct set of specific aims that contributes in a unique and complimentary way towards the therapeutic goal. Module 1, RPE65 Vector Production will improve AAV vector production for the LCA clinical trial and will provide research and GMP grade vectors for other modules. Module 2, RPE65 Vector improvement will enhance the in vivo efficiency and specificity of Rpe65 gene delivery/expression in RPE cells in animal models by promoter and vector modifications. Module3, RPE65 Mouse Studies will optimize the therapeutic effect of viral (AAV and Lentivirus) vector-delivered RPE65 genes and evaluate any toxic effects in the Rpe65 knock out mouse. Module 4, RPE65 Canine Studies will evaluate vector administration options on the therapeutic outcome of RPE65 gene augmentation in the RPE65 mutant dog. Module 5, RPE65 LCA Human Studies will identify RPE65 LCA patients suitable for entry into a Phase I/II gene therapy trial and develop standardized trial outcome measures. Module 6, RPE65 LCA Clinical Trial, has two aspects: 6A, Preclinical Testing and IND Development, will determine the potential for human toxicity and the range of efficacious doses of subretinal AAV-RPE65 in animal models and develop an FDA approved clinical protocol for 613; 6B, Phase IM Trial will evaluate the safety and preliminary efficacy of AAVRPE65 gene replacement therapy for RPE65 LCA-The basic science Modules 1, 2, 3, and 4. and the clinical screening Module 5 also develop information that feeds into the preclinical toxicity study, Module 6A- Data generated in the first 3 years by these modules will help guide the clinical trial design of Module 6B that is scheduled to begin in year 3/4. The University of Florida leads this collaboration with the University of Pennsylvania and Cornell University. The Universities of Iowa and Washington are subcontracting collaborators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR PROSTATE CANCER Principal Investigator & Institution: Thompson, Timothy; Associate Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2002 Summary: It is important to develop additional therapeutic approaches for prostate cancer which can be applied separately or in conjunction with current modalities. Various strategies for gene therapy may provide therapeutic benefits for this important disease. The mouse prostate reconstitution (MPR) model system can be used as a preclinical model for gene therapy in prostate cancer. The validity of thi in vivo model for prostate cancer is well established and its unique features provide an opportunity to test important parameters of specific gene therapy protocols including; general efficacy; appropriate timing o therapy; as well s the comparative efficiency of various delivery systems. We have tested a replication- defective recombinant adenovirus carrying the Herpes Simplex Virus thymidine kinase (HSV-tk) gene followed by grancicylovir (GCV) in vivo and in vivo using cell lines derived from a ras + myc=induced mouse prostate carcinoma as well as from human prostate-cancer. Following inoculation of the mouse prostate cancer line cell into immunocompetent male hosts, we found that subcutaneous tumors in treated animals (n=5) were reduced in volume to 18% that in untreated animals (n-15). On histologic evaluation athe treated tumors demonstrated significantly higher levels of apoptosis and necrosis than control tumors. The efficacy of HSV-tk gene therapy was further demonstrated using the C57BL/6 MPR carcinogenesis model.

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Primary site lesions were injected with Ad/HSV-tk virus and the virus and the mice were treated with GCV for 6 days. In the control group (n=5), 4 of the MPRs produced poorly differentiated carcinomas (wt= 939 + 875 mg) and ! was hyperplastic (wt=77 mg). In the treated group (n-5), although malignant cells were present, extensive necrosis and growth suppression was apparent in all cases (wt+19 + 3 mg). These results demonstrate the efficacy of HSV-tk/GCV gene therapy as well as the utility of the MPR model system as a preclinical model. The metastatic MPR model using p53 knock-out mice allows extension of these studies to all aspects of clinically relevant disease. The primary site lesion, under the renal capsule, is suitable for injection of gene therapy vectors as we have done with Ad(HSV-tk and systemic factors which influence metastasis can be evaluated. The parameters we will evaluate include overall growth response of the primary tumor, number and location of metastases, apoptotic response, and development of an immune response by evaluating activation of tumor infiltrating lymphocytes as well as by evaluating the ability to reject subsequent challenge with tumor cells. We propose to use these preclinical models to test genes involved in growth suppression (e.g.,p53 and p21) a well as genes which may enhance the localized immune response (e.g., IL-2 and GM-CSF) together with in HSV-tk/GCV gene therapy protocol. The efficacy of the combination of gene therapy with anti-androgen therapy or radiothermy will also be evaluated. Phase I clinical trials will be developed for a select groups of patient based on the results of preclinical trials and after vector safety has been established. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR PROSTATE CANCER Principal Investigator & Institution: Ponnazhagan, Selvarangan; Associate Professor of Molecular; Pathology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 07-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The mortality associated with prostate cancer is primarily due to systemic dissemination of the disease to which conventional therapies such as surgery, androgen-depletion and chemotherapy fail to provide long-term cure. Thus, development of novel approaches is important for the treatment of both primary and metastatic prostate disease. Among the possible therapeutic targets, the tumor endothelium appears promising since endothelial cell growth during angiogenesis is crucial for tumor growth and metastasis. A majority of earlier studies using purified anti-angiogenic factors to modulate disease have been unsuccessful due to a requirement for constant administration, clinical side effects, and/or high cost. Thus, gene therapy approaches to achieve stable expression of anti-angiogenic factors in vivo have the potential to overcome many of these limitations. Recombinant adenoassociated virus (rAAV) vectors are a unique group of viruses that are less immunogenic than other viral vectors and arc integrating, hence, have greater advantage for long-term expression. We have recently shown that genetic transfer of an anti-angiogenic factor, sFlt-I abrogated the growth of human fibro sarcoma in nude mice. We also demonstrated with targeted-vectors, that high-efficiency, tumor cellspecific delivery is achievable. Further, by generating a genetically deficient transgenic adenocarcinoma mouse prostate cancer (TRAMP) model for the early growth response protein-I (Egr-l), we recently demonstrated a role for Egr-1 in delaying the progression of prostatic intra-epithelial neoplasia(PIN) to invasive carcinoma. Additional preliminary studies with rAAV encoding the anti-angiogenic factors human angiostatin, endostatin and sFlt-1 have shown protection against the growth of a human epithelial

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ovarian tumor cell line in athymic mice indicating the efficacy of AAV-mediated antiangiogenic gene therapy. Based on these results, we hypothesize that gene therapy for prostate Cancer by AAV-mediated stable expression of anti-angiogenic factors will be efficacious both as a primary therapy, and as an adjuvant. Further, development of prostate cancer-specific rAAV containing anti-angiogenic genes would not only increase targeted-transduction but also minimize the vector dose and thus any associated toxicities. The present proposal will determine the efficacy of sustained anti-angiogenic gene therapy both as a primary therapy, and as an adjuvant therapy against recurrence in the TRAMP model. A successful outcome of these studies will form the basis for the development of Phase I clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR THE HEMOPHILIAS Principal Investigator & Institution: Walsh, Christopher E.; Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-OCT-2002 Summary: (provided by applicant): Effective gene therapy will revolutionize the treatment of the hemophilias. Recombinant adeno-associated virus (rAAV) vectors are considered among the most promising viral vectors for hemophilia gene therapy. The non-pathogenic nature of AAV, the ability to transduce mitotic and post-mitotic cells, and the capacity for stable persistence of rAAV/transgene sequences are unique among all viral vectors. A major obstacle in the application of rAAV in gene therapy for hemophilia A (factor VIII deficiency) is the conflict of the limited packaging capacity of rAAV and the large size of the human FVIII gene. The major rate-limiting aspect of this delivery system has always been the small packaging capacity (5kb) of rAAV. Factor VIII with its large cDNA (7.0 Kb) is an excellent model to test a variety of new approaches for AAV-mediated gene transfer. Here we present compelling evidence supporting the use of AAV vectors for the expression human factor VIII gene therapy. We developed several different novel approaches for the expression of functional factor VIII. First, we developed rAAV vectors carrying a truncated version of the full-length FVIII cDNA. Removal of the B-domain sequence of factor VIII (~4.0 Kb) results in a fully functional protein (termed B-domain deleted, BDD FVIII which express therapeutic levels of functional FVIII in vivo. Despite truncation of the FVIII sequence, the use of small (<250 bp) enhancer/promoter elements is still required for AAV packaging. Further truncation of the FVIII sequence and modification of the transcriptional elements are proposed. Second, AAV dimerization can be used to overcome vectorpackaging limitations. AAV proviral DNA is characterized by head-to-tail concatamers. Here, the FVIII gene is divided and packaged into two individual AAV vectors. Dimerization dramatically increased by amplifying the conversion of single to doublestrand intermediates. Third, a totally novel RNA repair strategy relies on the use of spliceosome-mediated trans-splicing. Here two independent pre-messenger RNA transcripts are spliced together via the native cellular splicing machinery. We present molecular, protein and functional data demonstrating correction of the FVIII knockout mouse phenotype using this method. Fourth, AAV type 2 is the predominant serotype used for gene transfer studies. We propose that alternate AAV serotypes differ in terms of their cellular tropism. We demonstrate that non-type 2 AAV serotypes effect significantly higher levels of factor IX expression and will be used to test factor VIII expression. Each method will be optimized and in AAV vectors for FVIII production

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and tested in vivo using immunodeficient and FVIII knockout mice and hemophilic A canines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYSPLASIA

GENE

THERAPY

FOR

TREATMENT

OF

CRANIOFACIAL

Principal Investigator & Institution: Kyrkanides, Stephanos; Assistant Professor in Orthodontics; Eastman Dentistry; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The purpose of this study is the development of a novel gene therapy regime for the perinatal treatment of craniofacial dysplasia, a cardinal characteristic of many genetic disorders, including Apert, Crouzon, Treacher Collins, Hurler and Hunter syndromes, just to name a few. Clinically, they present with abnormal size and shape of the jaws, frontal bossing and midface hypoplasia, as well as skeletal anomalies in other areas of the body (Hurler & Hunter). Recent advances in molecular biology have allowed scientists to investigate the etiologic factors for many of these disorders, in which distinct genetic mutations cause abnormal bone growth and skeletal development, giving rise to abnormal craniofacial phenotype. Cells of mesenchymal origin are primarily involved in skeletal growth and development, including chondrocytes, osteocytes, endothelial cells and fibroblasts, whereby normal cellular function appears central to physiologic bone growth and development. Therefore we hypothesize that genetic factors deleterious to cells involved in bone formation and growth can adversely affect skeletal development, ultimately resulting in craniofacial dysplasia. Depending on the particular genetic anomaly, the correlate phenotype may be diagnosed prenatally, at birth (neonatally) or soon after (perinatally), using clinical as well as molecular approaches. The purpose of this study is to determine whether timely restoration of a mutation by gene therapy can attenuate or even prevent craniofacial dysplasia. For this purpose, we will employ an animal model with craniofacial dysplasia, growth retardation and facial dysmorphism secondary to abnormal bone growth due to cellular dysfunction resulting from beta-hexosaminidase deficiency (hexA-/-/hexB-/- double knockout mice). Interestingly, these mice display only mild phenotypic changes at birth, but quickly develop their aberrant features by 45 weeks of age. Furthermore, they have progressive decline in motor function, and limited life span (1-4 months). Utilizing a pseudotyped feline immunodeficiency viral vector developed in our laboratory for beta-hexosaminidase gene therapy, FIV(Hex), we will test whether restoration of the underlying genetic deficiency in hexA-/-/hexB-/mice will result in restitution of beta-hexosaminidase activity and normalization of skeletal development. Based on our Preliminary Results, we anticipate successful transfer and expression of our therapeutic gene in vivo, leading to normalization of cellular function and attenuation of the hexA-/-/hexB-/- phenotype. Completion of this study will aid in the development of novel therapies for the management of genetic disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY IN ANIMAL MODEL OF AUTOIMMUNE DISEASE Principal Investigator & Institution: Seroogy, Christine M.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2003

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Summary: (adapted from applicant's abstract) The application of gene therapy in animal models of autoimmune disease will address questions relevant to autoimmune diseases and the alteration of immune responses. Meaningful T-cell gene therapy investigative approaches in animal models of autoimmune disease have been limited by the inability to efficiently transduce murine T cells. Work over the past 1.5 years in the Fathman laboratory has resulted in efficient retroviral transduction of antigen-reactive murine T cells. Furthermore, characterization of the transduced T cells has provided critical insight needed to begin gene therapy studies in animal models of autoimmune disease. This proposal will use antigen-specific retrovirally-modified T cells to locally deliver anti-inflammatory proteins to the site of tissue inflammation. The results from these studies will provide insight into disease pathogenesis, the ability to locally deliver disease-modifying proteins with autoantigen-reactive T cells, and the ability to alter immune responses. The findings from this work will have important implications for the future of gene therapy in human diseases that are the result of aberrant immune responses, i.e. autoimmune diseases and allergic diseases. The Principal Investigator, Dr. Christine Seroogy, is trained in pediatric allergy/immunology and is committed to a career in academic medicine. Previous research experience has provided the foundation for continuing along this career path. Dr. Seroogy joined the Fathman laboratory at Stanford University 1.5 years ago. Since that time she has acquired new skills in cellular immunology and gene therapy. Additional years of training, provided by the MCSDA, will allow her to develop into an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY IN MUCOPOLYSACCHARIDOSIS VII Principal Investigator & Institution: Haskins, Mark E.; Professor of Pathology; Pathobiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-APR-1994; Project End 31-MAR-2003 Summary: The mucopolysaccharidoses (MPS), a major class of lysosomal storage diseases, are a promising target for somatic cell gene therapy. That normal enzyme is synthesized and exported by normal cells and can be taken up by, and can correct, the metabolic defect in affected cells (defined as cross-correction) has been demonstrated in cocultures of affected and normal cells, as well as by bone marrow transplantation in a limited number of human and animal patients. These studies indicate that if a sufficient number of cells producing normal enzyme can be introduced into the patient, significant improvement can be expected. The number of cells need not be large. If the transplanted cells engraft and continue to multiply in sufficient numbers, improvement should be long-term. However, problems associated with histocompatibility limit heterologous transplantation as an approach to therapy. Somatic cell gene therapy is potentially a way of circumventing the problems associated with the immune response, as well as providing a more adequate source of normal enzyme for diverse tissues. In gene therapy studies of a number of different cultured cell types from human and canine patients with MPS VII, we have previously shown that the metabolic defect, including storage of glycosaminoglycans (GAG), is corrected by retroviral transfer of the normal gene for beta- glucuronidase (GUSB). In this proposal, we extend those in vitro studies to therapeutic strategies conducted in vivo in the mouse and canine homologues of MPS VII. These studies will serve as models for correction of MPS diseases by somatic cell gene therapy, and more generally, for the large class of lysosomal storage diseases. The following approaches will be tested: 1) An organoid system using autologous vectorcorrected fibroblasts first in MPS VII mice and then dogs to choose long-term, high expression candidate vectors; 2) Autologous bone marrow transplantation in canine

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MPS VII using vector-mediated transfer to hematopoietic cells; and 3) Gene transfer to hepatocytes in vivo. The effects of the therapeutic strategies will be determined by experiments utilizing littermate controls and will include extensive clinical evaluations, comprehensive light and electron microscopic studies of tissues, enzyme assays, and quantitation of stored substrate in various tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY OF AIDS DEMENTIA Principal Investigator & Institution: Pomerantz, Roger J.; Chief, Infectious Diseases Division; Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 25-JUL-2002; Project End 31-MAY-2005 Summary: (provided by applicant): Human immunodeficiency virus type- I (HIV-1) infection can lead to a series of devastating clinical conditions in the central nervous system (CNS) of certain HIV-1-infected individuals. AIDS dementia complex (ADC) is a collective term to describe AIDS-related cognitive dysfunction, motor difficulties, coordination abnormalities and other neurological signs and symptoms. Blood-brain barrier mainly constituted of micro vascular endothelial cells (MVECs) a protective sheath is a potential obstacle for conventional antiretroviral penetration into the brain. Gene therapy is one the most promising avenues for treatment of neurodegenerative disorders in general and AIDS dementia in particular. Our laboratories in recent past have utilized retroviral vectors for gene delivery in CNS based cells both in vitro and in vivo. Cell-type-specific gene delivery into distinct cells of the central nervous system will be one of the major prerequisites for successful human gene therapy of neurological disorders. In the past decade, Dr. Dornburg's laboratory has gained extensive experience in the construction of cell-type-specific retroviral vectors, derived from the avian reticuloendotheliosis viruses REV-A and spleen necrosis virus, SNV, which display single chain antibodies (scAs) or other targeting ligands on the viral surface. Moreover, pseudotyping REV-derived vectors with the envelope protein of a neurotropic rabies virus strain enabled cell-type-specific gene delivery into neurons in vitro and in vivo. The main goals of this research project are the further development of retroviral vectors, which enable cell-type-specific gene delivery into neurons and brain MVECs. A series of novel retroviral vectors will be developed which transduce therapeutic genes useful for gene therapy of AIDS dementia. The vector design will enable expression of the therapeutic gene from cell-type-specific or inducible promoters. These vectors will be tested in vitro and in vivo. In vitro testing include long-term studies of the efficiency of the therapeutic gene, microarray assays to determine changes of normal gene expression in neurons or brain MVECs, and the testing of the vectors in vitro blood brain barrier systems. Dr. Mukhtar has extensive experience in this area. In vivo experiments will be performed in mice to test long-term gene expression and to determine whether macroscopic or microscopic changes occur in the brains of animals which express the therapeutic genes. The development of cell-type-specific vector specific for neurons and brain MVECs will not only be useful for possible future application of gene therapy of AIDS dementia, but also for numerous other disorders of the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY OF PROSTATE CANCER USING RADIOIODINE Principal Investigator & Institution: Morris, John C.; Associate Professor & Chair; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905

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Timing: Fiscal Year 2001; Project Start 31-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Prostate cancer is the second leading cause of cancer death of American men. Metastatic prostate cancer is considered essentially incurable. In marked contrast, thyroid cancers can be effectively treated and, at times, cured even when widespread metastasis is present, because of the ability of the cells to concentrate iodine, making therapy with radioactive iodine possible and effective. The studies described in this proposal are aimed at transferring the gene for the thyroidal sodiumiodide symporter (NIS), the structure that is responsible for iodide trapping by thyroid cells, into prostate cancer cells. In addition, the potential role of this transfer as a means of gene therapy for metastatic prostate cancer is examined. The studies involve targeting expression of the NIS gene using prostate specific promoters in order to achieve prostate specific gene expression. Our preliminary studies have demonstrated the feasibility of this gene transfer in vitro and in vivo, in that high level and prostate specific iodide uptake has been established in LNCaP cell tumors in mice and those tumors have been successfully treated with 131I. The experiments outlined in this proposal will further examine the feasibility and efficacy of NIS gene transfer in vivo using mouse models, mechanisms of maximizing NIS protein expression and activity, and the cell killing effect of 131I in these models in vitro and in vivo. Further, our studies will examine the immune response within immunocompetent host mice following radioiodine killing of NIS transfected murine prostate tumors and the influence of that response upon the appearance and progression of native prostate cancer in transgenic mice (TRAMP), which naturally develop prostate cancer. Finally the proposal describes a phase I/II clinical trial of adenoviral mediated NIS gene transfer in patients with recurrent prostate cancer. Our studies, will serve to examine the potential of NIS gene transfer to prostate cancer as a method of therapy of metastatic disease and are the first so described. In addition, successful demonstration of radioiodine effect in our prostate cancer model will serve to stimulate interest in NIS as a therapeutic gene for other cancer types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY TARGETING HYPOXIC GLIOMA CELLS Principal Investigator & Institution: Deen, Dennis F.; Berthold and Belle N. Guggenhime Profess; Neurological Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: Radiation is a primary treatment modality for patients with malignant gliomas, and in most patients radiation therapy is clearly beneficial. However, the overall outcome of therapy for these patients is dismal, and most patients with glioblastoma multiforme (GBM) die within a year of diagnosis. The presence of hypoxic cells in brain tumors is a major obstacle for radiation therapy, because these cells are notoriously resistant to radiation-induced damage. Therefore, we propose to devise a gene therapy approach for killing hypoxic brain tumor cells during the course of radiation therapy. The DNA construct to be delivered to the tumor cells contains hypoxia-responsive elements (HREs) in the enhancer region of the promoter and a suicide gene. Under hypoxic conditions, the transcriptional complex hypoxia inducible factor-1 (HIF- 1) builds up in cells and binds to HREs. This, in turn, activates the adjacent promoter and causes expression of the downstream suicide gene that kills the cell. This project has 2 goals. The first is to investigate how several cellular or intratumoral characteristics impact on this gene therapy strategy. The second is to investigate whether the gene therapy enhances the radiation response of the tumor cells.

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Gene Therapy

We propose 4 specific aims to accomplish these goals. 1) investigate the relationship between HIF-1 and oxygenation status in brain tumor and normal brain; 2) evaluate suicide genes under low pH and in noncycling brain tumor cells; 3) reveal and investigate any bystander effect (BE) produced by specific suicide genes under hypoxic conditions; 4) determine whether expression of suicide genes in hypoxic and oxic cells enhances their response to radiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY USING HEMATOPOIETIC STEM CELLS Principal Investigator & Institution: Kohn, Donald B.; Professor of Pediatrics and Microbiology; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The central theme of this Program is gene transfer to hematopoietic stem cells (HSC) or progenitor cells to correct genetic diseases affecting the production and/or function of blood cells. While the concept of gene therapy using HSC to provide safe and effective methods to treat congenital disorders has been under study for at least two decades, there have been only a few rare cases of successful clinical application. The techniques currently in use for gene transfer and expression in HSC are inadequate in most cases to yield clinical benefits. The goal of this Program is to investigate the mechanisms limiting successful clinical applications of gene transfer and to develop improved techniques which will broaden the range of diseases which may be treated effectively. The Project leaders have complementary expertise in the relevant areas of experimental hematology, immunology, signal transduction, and gene therapy and have a long-standing record of interactive collaborations. These advances can only be realized by combining each of these individual projects into a unified Program. This Program has five projects: 1. Transduction of human stem and progenitor cells, 2. Minimal Lentiviral Vectors for Gene Therapy of beta-thalassemia, 3. Optimized Gene Therapy for Human X-linked Agammaglobulinemia, 4. Gene Therapy for SCID due to Cytokine Receptor Defects, and 5. Gene Therapy for ADA-deficient SCID. Four Cores (Administrative, Cell Isolation and Analysis, Vectors and Animals) will support the projects with integrated services for optimal quality and efficiency. The information generated by these investigations will provide valuable knowledge to the field to increase the effectiveness of gene therapy interventions for hematologic disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY, OBESITY AND HYPOTHALAMIC SIGNALING Principal Investigator & Institution: Kalra, Satya P.; Professor; Neuroscience; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 01-JUN-1986; Project End 31-MAY-2006 Summary: (Scanned from the Applicant's Description): With one out of every two adult Americans rated as medically obese, obesity is the number one health problem in the United States. Since it is a major risk factor for heart disease, diabetes, stroke, hypertension, and morbidity, the treatment of obesity and associated diseases entails enormous medical costs. The major objective of this proposal is (1) to examine whether viral vector mediated delivery of weight-reducing signals, such as leptin, is a viable therapy (gene therapy), alternative to the pharmacologic approach, to control body weight (BW) gain for extended periods in normal male and female rats and in rodents with obesity due to environmental (diet-induced) and genetic factors. We believe that leptin acts by (1) augmenting energy expenditure (thermogenesis) and/or curbing

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appetite and (2) that the beneficial effects of leptin gene therapy are manifest at sites that enhance energy expenditure and modify hypothalamic appetite regulating signals such as the orexigenic signals, NPY, AgrP and GABA, and the anorexigenic melanocortin signal alpha-MSH, and intracellular signal transduction sequalae involving STAT3 and SOCS-3. We have successfully generated a recombinant adenoassociated virus (rAAV) vector to efficiently transfer the naturally occurring body weight reducing peptide, leptin (rAAV-lep). Aim 1: Examine the long-term (one-year) efficacy of rAAV-lep to reduce BW gain when delivered intracerebroventricular (icv) or systemically in out-bred Sprague-Dawley (SD) rats and obese rats maintained on a highenergy (HE) diet. Aim 2: Evaluate the efficacy of icv and peripheral rAAV-lep in those genetic models of obesity that (1) lack leptin (ob/ob mice) and (2) display resistance to peripheral and not central leptin (New Zealand obese mice); and (3) lack NPY (-/-) and display obesity when maintained on HE diet. Finally, we will also characterize the underlying mechanism(s) if excessive ectopic leptin itself induces leptin ineffectiveness (resistance) in these experiments. The causal mechanisms responsible for phenotype changes will be identified by evaluation of hypothalamic leptin expression and signaling through analysis of gene expression, and peptide levels, signal transduction sequalae (pSTAT3 and SOCS-3) and metabolic indices (body temperature, 24h urinary NE activity, oxygen consumption, UCP1 mRNA, and blood leptin, insulin glucose, and corticosterone levels). The outcome of these investigations will provide fundamental information on the broader potential of using gene delivery of naturally occurring anorectic molecules for BW control and their mechanism of action. This new knowledge will be applied to the ultimate goal of site-directed gene delivery aimed at the newly identified vulnerable loci in hypothalamic signaling to curb overeating and abnormal weight gain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE TRANSFER TO AIRWAY EPITHELIAL CELLS Principal Investigator & Institution: Cheng, Pi-Wan; Professor; Biochem and Molecular Biology; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2000; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: (Applicant's abstract): Cystic Fibrosis (CF) is the most common lethal genetic disease among Caucasians. Lung diseases account for greater than 95 percent of the morbidity and mortality. Hence, CF lungs have been targeted for gene therapy. Current gene therapy vectors suffer from low transfection efficiency or induction of host immune response, which preclude them from being used for gene therapy in vivo and invite development of alternative vectors. We have developed a novel gene transfer vector composed of a receptor ligand and a cationic liposome, which yields high transfection efficiency in HeLa cells and immortalized tracheal epithelial cells of a cystic fibrosis patient (CFT1). The formation of liposome-transferrin-DNA complexes correlates with high transfection efficiency. The transfection vectors which contain transferrin, insulin, or cholera toxin could correct the cAMP-dependent chloride conductance defect in CFT1 cells. We propose to test the hypothesis that the liposomereceptor ligand-DNA complex by Sepharose gel chromatography and then characterize the physicochemical properties of the putative transfection complex by biochemical and transmission electron microscopic methods. We will examine if this complex alone or in combination with the receptor ligand and/or liposome yields high transfection efficiency in CFT1 cells, primary cultures of mouse and human airway epithelial cells, respiratory epithelial explants, and then in mouse airway epithelia in vivo. We will also characterize the kinetics of the receptor ligand-facilitated gene transfer using confocal

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Gene Therapy

microscopic, biochemical, molecular biological, and immunological techniques to identify the step(s) responsible for the enhancement of the transfection efficiency of liposome-mediated gene transfer. The efficacy of the gene therapy protocols employing a plasmid containing the cDNA encoding wild-type cystic fibrosis transmembrane conductance regulator will be examined in the primary cultures of airway epithelial cells and nasal and tracheal epithelia of CF mouse in vivo. The gene transfer vectors will be assessed for inflammatory and immune responses and cytopathology in normal and CF mouse. Correction of cAMP-dependent chloride conductance defect coupled with no immune response to the vectors in CF mouse should be the crucial information needed for planning future human gene therapy trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC THERAPY FOR SICKLE CELL DISEASE Principal Investigator & Institution: Malik, Punam; Assistant Professor of Pediatrics and Pa; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: Sickle cell anemia (SCA) is characterized by repeated vascular occlusions and hemolysis, primarily resulting from the sickle-shaped RBCs formed under hypoxia. Treatment for the disease is mainly symptomatic. Bone marrow transplantation, a curative modality, is limited to a few with matched donors and has potential side effects. Increasing expression of the "anti-sickling" gamma-globin in the RBCs by longterm administration of hydroxyurea reduces the frequency of sickling events. Gene therapy using the "gamma-globin gene in hematopoietic stem cells (HSCs) can improve the survival of RBCs derived from the genetically modified HSCs permanently. Gene therapy for hemoglobinopathies with onco-retroviral vectors has suffered from problems of vector instability, low titers and variable expression. With the advent of better vectors, improved gene transfer techniques and a better understanding of stem cell and vector biology, gene therapy is going from the bench to the bedside, in disorders like SCID and hemophilia B. The recently developed, lentiviral vectors transduce the non-dividing HSCs and stably export large genomic fragments required for high-level regulated "globin' gene expression. Self-inactivating (SIN) lentiviral vectors are even more advantageous: the viral long terminal repeat is deleted upon integration into cells, completely inactivating viral transcription, a feature ideal for the expression of a highly lineage-restricted gene, and additionally improves the bio-safety. We have recently shown remarkably lineage-specific and long-term expression of GFP and a therapeutic correction of the murine erythropoietic porphyria in primary and secondary mice with SIN-lentiviral vectors. We would like to extend these results and examine the properties of SIN-lentiviral vectors in carrying the human gamma-globin gene and erythroid regulatory elements for gene transfer into HSCs, resulting in highlevel, stable and sustained expression of gamma-globin in RBCs. The aims of the study are: 1) Develop SIN-lentiviral vectors carrying the human y-globin gene and erythroid regulatory elements, and screen them in MEL cells for stable transmission and highlevel expression. 2) Determine the efficacy, lineage-specificity and long term expression of these vectors in transgemc sickle mice. 3) Determine gene transfer and efficacy of these vectors in the RBC progeny of human SCA progenitor cells, using the unique model of human RBC production from normal and SCA progenitors developed in our laboratory. Together, these aims comprise a focused research to produce sustained and therapeutic levels of gamma-globin in human SCA RBCs, and form the basis of future preclinical studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HUMAN ANTITAT INTRABODY GENE THERAPY AGAINST SHIV Principal Investigator & Institution: Marasco, Wayne A.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: Gene therapy for the treatment of HIV-1 infection and AIDS represents an attractive addition to conventional pharmacologic therapies due to the limited success of even highly active anti- retroviral therapies (HAART) and because genetic alteration of the host cell could potentially confer permanent suppression of viral replication after infection. Pre-clinical evaluation of new anti-HIV-1 gene therapies in an animal model is required to address many of current limitations of gene therapy including the duration of in vivo survival of transduced cells, loss of detectable anti-viral transgene expression and rapid clearing of transduced cells due to immune responses against the marker gene. Chimeric primate lentiviruses (SHIVs) composed of SIV and HIV genes have proven useful in the analysis of the role of discrete HIV genes in viral pathogenesis in macaque monkeys. Non-pathogenic SHIVs establish chronic infection and pathogenic SHIVs cause high levels of viremia, rapid and profound CD4+ T cell depletion and AIDS. Thus, the SHIV-macaque model offers a unique and important experimental system, to evaluate the effects of anti-viral genes without anti-viral Rx, to control input virus, to evaluate for development of resistance and to analyze for immune responses against the anti-viral gene products. We have characterized a human anti-tat intracellular single-chain antibody, termed sFvhutat2 "intrabody" with potent anti-HIV1/SHIV activity in vitro and we now propose to test this gene therapy strategy in the SHIV-macaque model. In this proposal, we will optimize conditions for CD4+-enriched macaque T cell activation, transduction (with MuLV vectors either empty (control) or encoding sFvhutat2), phenotypic selection (via human NGFR) and ex vivo expansion and will complete in vitro challenge experiments to choose an isogeneic pair of nonpathogenic and pathogenic SHIVs that can be used for in vivo gene therapy studies. Both a pre-SHIV infection model and post-SHIV infection model are proposed using both non-pathogenic and pathogenic SHIVs in both models. For both models, we infuse equal numbers of both empty vector transduced or sFvhutat2 transduced CD4+enriched T cells into 4 macaques (gene therapy arm) and mock transduced CD4+enriched T cells into 4 macaques (control arm). The primary goal of these studies is to determine if there is increased survival of sFvhutat2 verses vector transduced cells. The secondary goal of these studies is to determine if in vivo resistance to sFvhutat2 develops. These studies will establish a valuable new primate model for the testing of anti-HIV-1 gene therapies. In addition, the results from these studies will substantially advance our understanding of how to apply and improve this promising technology for the treatment of HIV-1 infection and AIDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HUMAN CTL RESPONSES TO ADENOVIRUS GENE THERAPY VECTORS Principal Investigator & Institution: Flomenberg, Phyllis R.; Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 15-JAN-1999; Project End 31-DEC-2001 Summary: The goal of this proposal is to define the mechanisms involved in the generation of human adenovirus-specific cytotoxic T lymphocytes (CTLs) in order to help design new strategies for evading the immune response to adenovirus gene therapy vectors. Adenoviruses are under extensive investigation as gene therapy

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vectors for a broad spectrum of heart, lung, and blood diseases including cystic fibrosis, hemophilia, and atherosclerosis. However, data from animal models indicate that the immunogenicity of adenovirus vectors interferes with the efficacy of adenovirusmediated gene therapy. Administration of early region 1(E1)-deleted adenovirus vectors to mice, a host in which adenovirus infection is naturally restricted, results in the generation of adenovirus-specific CTLs which destroy adenovirus-transduced cells within a few weeks. Further analysis of this problem requires study of human CTL responses against adenovirus. We have successfully amplified memory adenovirusspecific CTLs in peripheral blood mononuclear cells from healthy adults and documented that these responses are major histocompatiblity complex (MHC)-restricted and mediated by CD8+ T cells. Based on our studies, it is likely that the presence of memory cellular immune responses will pose a major additional obstacle for adenovirus-mediated gene therapy in man. We postulate, however, that human adenovirus-specific CTLs may be targeted against a limited number of immunodominant epitopes. Therefore, it may be possible to reduce the immunogenicity of adenovirus vectors by elimination of such epitopes. As a second approach, it may be possible to take advantage of mechanisms which adenovirus has developed to evade host immune responses. The Ad early region 3 (E3) codes for proteins which help make cells resistant to CTLs and tumor necrosis factor, but this region is deleted or poorly expressed from most adenovirus vectors. We postulate that constitutive expression of E3 region proteins may help reduce the immunogenicity of adenovirus vectors. We propose to address these hypotheses by analysis of human CTL responses against adenovirus in vitro. These studies will provide an experimental basis for the design of more effective adenovirus gene therapy vectors for future human trials. 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

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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. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN PRODUCING VECTORS FOR GENE THERAPY OF DIABETES Principal Investigator & Institution: Ripps, Michael E.; Laboratory Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 15-FEB-1999; Project End 31-DEC-2003 Summary: Strong impetus exists for developing improved modes of insulin delivery for the treatment of diabetes mellitus. The insertion of appropriately regulated insulin genes into non-islet tissues is a potential strategy for the treatment of type I diabetes, in which islet cells are destroyed by autoimmune mechanism. The objective of the proposed project is to explore an approach to gene therapy for diabetes for engineering glucose regulated insulin production in extra-pancreatic sites. Our approach will be to target insulin expression to hepatocytes and intestinal epithelial cells in vivo using an insulin gene construct driven by the liver-type pyruvate kinase (L-PK) promoter. Since L-PK promoter activity is stimulated by glucose and blocked by glucagon and cyclic AMP, we expect that insulin synthesis and secretion will increase after a carbohydrate meal, and that possible over-production of insulin leading to severe hypoglycemia may be prevented by the cAMP-mediated actions of glucagon and epinephrine. Since the L-PK promoter requires permissive amounts of insulin to be active, a second gene construct expressing insulin from a modified metallothionein promoter will be transferred along with the L-PK/insulin gene to provide a basal level of insulin. Double gene cassettes will be packaged into adeno-associated virus vectors and transferred in vivo to mice rendered diabetic by ablation of pancreatic beta cells using the drug streptozotocin. The time course of L-PK/insulin gene activation and repression will be determine after glucose loads and during insulin-induced hypoglycemia. Possible amelioration of the diabetic state will be assessed by oral glucose tolerance tests and measurement of glycohemoglobin levels. New initiatives in gene therapy will undoubtedly require the development of control systems to achieve the desired expression level for varying physiological or therapeutic circumstances. This project will assess a new therapeutic approach to diabetes and may also serve as a model for future attempts to engineer control systems for gene transfer. Furthermore, the Research Center Award will enhance

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my development as a physician-scientist and allow me to reach my long-term goal of an independent research career in academic medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRAMARROW GENE TRANSFER IN NEONATES Principal Investigator & Institution: Bunnell, Bruce A.; Assistant Professor; Children's Research Institute 700 Children's Dr Columbus, Oh 43205 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 31-MAR-2002 Summary: (Adapted from Investigators' Abstract) The ultimate goal of HIV-1 directed gene therapy is to inhibit virus replication and the development of AIDS. Clinical studies have focused on human cell and gene transfer for this purpose, and studies have revealed both a low frequency of marked cells and a very low level of gene expression. Thus, several essential issues will need to be addressed before gene therapy will become a treatment reality, particularly for HIV-1 infected children. As an alternative to ex vivo transduction of hematopoietic stem cells (HSC), these investigators propose to investigate the in vivo transduction of HSC in their native environment, the milieu of the bone marrow. Studies in uninfected rhesus neonates will initially be performed to determine the requirements for efficient gene transfer to the HSC. The investigators will explore the most effective vector system (Moloney murine leukemia virus {MLV} versus HIV-1-derived lentivirus), the effects of cytokines on the in vivo transduction efficiency of HSC, and the number of intramarrow infusions necessary for efficient marking of HSC and their progeny (Specific Aim 1). Newborns will be transferred intramarrow with either MLV/VSV-G or HIV/VSV-G each marked with the enhanced green fluorescent protein (EGFP) as a reporter gene. Blood and marrow will be collected 2 weeks then monthly post-transfer for 12 months. Samples will be assessed for transduction and expression (flow cytometry, PCR, hematopoietic progenitor assays). While it is clear that juvenile/adult animals generate a potent immune response to retrovirus vectors and their transgenes, the immune consequences of the proposed studies are uncertain due to the age of the recipients, and will be investigated (Western blots, antibody titers, lymphocyte proliferation assays. The investigators will then utilize the best in vivo transduction approach developed in Specific Aim 1 to deliver an antisense Tat/Rev gene cassette to the HSC of SIV-infected rhesus neonates (Specific Aim 2). Siv-infected newborns on antiretroviral chemotherapy (PMPA) will receive intramarrow transfers, and blood and marrow collected 2 weeks than monthly posttransfer for 12 months. The presence of the vector transduced cells in samples will be detected by Southern blot of DNA-PCR, and expression measured by Northern blot, RTPCR, or FACS analysis. Plasma- and PBMC-associated veremia, and levels of SIV in plasma will be quantitated (bDNA assay). Studies will focus on the generation of antiSIV gene-marked HSC and mature lymphohematopoietic cells, and the expression of the antiviral elements(s) in these cells. Thus, the goal of the investigators is to explore a safe and efficacious approach for pediatric gene therapy of HIV-1 infection targeting HSC using in vivo transduction for the delivery of antiviral genes. These studies are directly relevant to infants and adults infected with HIV-1. 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

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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 •

Project Title: MDR1 GENE THERAPY IN CD34+ CELLS AND SCID MICE Principal Investigator & Institution: Doroshow, James H.; Associate Director for Clinical Research; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 01-JUL-1996; Project End 31-DEC-2003 Summary: The human MDR1 gene encodes a multispecific drug transporter, Pglycoprotein (Pgp), that prevents drug accumulation in resistant cells. Overexpression of MDR1 is sufficient for conferring multidrug resistance on otherwise normal cells. This suggests that MDR1 might be used in gene therapy to protect hematopoietic cells against chemotherapy-related myelotoxicity. Of 164 cancer- related gene therapy trials currently in force, nine incorporate the concept of hematopoietic cell chemoprotection; six of these use the MDR1 gene. Another application of MDR1 is to use it as an in vivo selectable marker to enhance the expression of linked foreign genes in transfected or virally transduced cells. Mouse experiments indicate that MDR1 can be chemoprotective and selectable in vivo, but attempts to use MDR1 as a chemoprotective agent in human gene therapy trials have, so far, been disappointing. Evidence will be provided suggesting that the reason for its poor in vivo performance in humans is that MDR1 is a stringent selectable marker that requires very high levels of P-glycoprotein, the MDR1

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gene product, to mediate survival of transduced cells. Indeed, the most significant barriers to successful gene therapy with MDR1 appear to be transduction efficiency and gene expression--i.e., the number of cells that can be transduced and that can express high enough levels of MDR1 to survive selection. We hypothesize that MDR1 will serve as an effective in vivo selectable marker or chemoprotective gene only if the problem of stringency can be overcome. Four specific aims are designed to test this hypothesis and to develop the optimal strategy for overcoming selection stringency: 1) Determine if MDR1 selection stringency can be overcome by maximizing gene transduction efficiency and gene expression levels with state-of- the-art gene therapy tools. 2) Determine if selection stringency can be overcome by using mutant versions of MDR1/Pgp as the selectable marker. 3) Determine if selection stringency can be overcome by using a twostep selection strategy. 4) Determine if MDR1 can confer an in vivo survival advantage on human hematopoietic cells. Building on results in Specific Aims 1-3, this aim will use primary human hematopoietic progenitors to study the survival of MDR1-transduced cells in NOD/SCID and SCID- hu mouse model systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BREEDING OF GENE THERAPY VECTORS Principal Investigator & Institution: Drogemuller, Chris; Senior Research Associate; Applied Genetic Technologies Corporation 12085 Research Dr, Ste 110 Alachua, Fl 32615 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JUL-2004 Summary: (provided by applicant): We propose to develop Gene Therapy vectors that are targeted to particular cell membrane receptors, cell types and/or tissues. Development of these precise delivery systems will help overcome potential adverse reactions and high dosing requirements imposed by the current, non-targeted, traditional Gene Therapy vectors. The goal in Phase I is to construct a combinatorial library of chimeric Adeno-associated virus (AAV) vectors to screen for tissue-specific targeting during Phase II. Because of technical limitations, AAV-based combinatorial libraries were not previously available. We plan to use a unique new technology for building and subsequent selection of AAV vector libraries. Specifically, we will exploit molecular breeding of viruses by DNA shuffling to direct evolution in vitro of AAV capsid genes through recombination of multiple homologous parental sequences of known AAV serotypes. To construct the library, we will use a new AAV production technology based on insect cells and genome pseudotyping. Researchers at AGTC and UF Powell Gene Therapy Center, with proven track records in the AAV field, will join efforts to complete the project. During the feasibility study, we will demonstrate whether it is possible to build an AAV-based library of viable viral clones of at least 106 complexity using recombination of capsid genes of AAV1 and AAV2 serotypes. The successful completion of this step will allow us to proceed to the next stage of selection of vectors with a particular cell/tissue tropism completed during Phase II of the project. We anticipate to market AAV combinatorial libraries to users within the gene therapy community, as a product to select for delivery vectors targeted to a particular tissue or tailored to a particular application, e.g. targeted delivery of pro- apoptotic or suicidal genes to tumors. This project will represent a significant advance in the development of therapeutic gene delivery systems with precise targeting to improve patient outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR IMAGING OF RESPONSES TO CANCER THERAPY Principal Investigator & Institution: Graham, Michael M.; Director of Nuclear Medicine; Radiology; University of Iowa Iowa City, Ia 52242

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Timing: Fiscal Year 2001; Project Start 06-JUN-2001; Project End 31-MAY-2004 Summary: (provided by applicant) The goal of this Pre-ICMIC planning effort is to bring clinical oncologists, basic scientists, and imaging scientists together to develop new research collaborations. This will be through weekly seminars and monthly research retreats. These interdisciplinary collaborations are likely to lead to novel and significant advances in the use of imaging in caring for cancer patients. We intend to particularly emphasize the use of imaging in evaluating cancer therapy. Medical imaging, with Xrays, CT, MRI, PET, and nuclear medicine scans, has been used successfully for many years in diagnosing cancer. It has been used for evaluating therapy, but in a very unsophisticated way; simply determining if a tumor has increased or decreased in size. There are far more sensitive ways to determine tumor viability including measurements of blood flow, oxygenation, metabolism, and membrane integrity. There are also methods to evaluate delivery of drugs to tumors, by labeling with radioactive or magnetic tracers and imaging with PET or MRI. We intend to discuss and possibly study many of these approaches. Gene therapy is an area of specific focus. There is strong support for studies in this area and we plan to take advantage of the existing Gene Transfer Vector Core and Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases that are active centers at the University of Iowa. There is strong institutional support for oncology research in general. The University of Iowa recently was designated an NCI Cancer Center. This designation helps solidify and strengthen our commitment to cancer research. An unusual resource within the Department of Radiology is the section of Free Radical and Radiation Biology. This is a strong research group with a specific interest in using gene therapy. This interest has led to work with the iodine symporter gene as a reporter gene and the possibility of imaging it with a wide variety of iodine isotopes and iodine analogs. Three of the potential developmental projects are involved with this reporter gene: in validating its use in vivo, its use for tracking insertion of a gene for manganese superoxide dismutase, a free radical scavenger, and for tracking insertion and expression of p53 injected into tumors by subselective catheterization. We also intend to explore the use of novel heavy metal labels to follow viral vector delivery with MRI and CT. PET imaging of F18 fluorothymidine will be used as a way to assess the response to chemotherapy very early after treatment. Tumor glucose metabolism will be imaged to assess oxidative stress and as an indicator of tumor susceptibility to treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR THERAPY FOR RENAL DISEASE Principal Investigator & Institution: Klotman, Paul E.; Professor of Medicine; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-JUL-2003 Summary: This Program Project will address in a coordinated fashion several of the key questions that must be answered before molecular therapy (systemic antisense and gene therapy) can be successfully introduced to patients for the treatment of renal diseases. These include: What are appropriate molecular targets? What are effective approaches to inhibit gene expression? Can vectors be targeted to renal tissue? Can long-term benefits be achieved? In addressing these questions, we will utilize a multidisciplinary approach to accomplish the following specific aims: 1: To determine the molecular basis of antisense DNA uptake into kidney, to clone and characterize a channel that conducts DNA into renal cells; to determine whether this form of therapy can be modified to enhance or reduce delivery to kidney, and to determine whether therapy can ameliorate renal disease in vivo. 2: To develop ribozymes directed to likely renal targets such as

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TGFbeta1, bFGF, and HIV-1, to maximize their enzymatic cleavage kinetics, and to assess in vivo efficacy and toxicity. 2/3: To utilize constitutive promoters to direct ribozyme therapy initially and then to define renal-specific and segment-specific promoters that can be used for gene therapy constructs for the treatment of renal diseases in the future. 3: To develop viral (adeno-associated virus) and non-viral (liposome) vectors for gene delivery, to test the efficiency and specificity of delivering exogenous genes to specific cell types within the kidney (mesangial and epithelial) using these vectors, to determine the efficiency, distribution and duration of expression of exogenous genes in kidney, and to optimize vectors for the successful delivery of ribozymes and/or antisense in vivo using small animal models. Efficiency of gene delivery, extent of cellular transduction, site of integration, and duration of expression will be explored using indicator and therapeutic constructs. Once antisense and ribozyme therapies have been optimized and the delivery systems characterized, efficacy and toxicity will be addressed using transgenic technology. For therapeutic benefit, promising constructs will be tested in an animal model in which renal expression of a foreign gene induces progressive renal insufficiency. The results from this program project should assist the renal community by providing the needed information to facilitate the movement of molecular therapies to patients with diseases of the kidney. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROTROPHIC FACTOR GENE THERAPY FOR BRAIN INJURY Principal Investigator & Institution: Kozlowski, Dorothy A.; Biological Sciences; De Paul University 1 E Jackson Blvd Chicago, Il 60604 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): The main objective of this application is to begin to develop a new therapeutic approach for traumatic brain injury - neurotrophic factor gene therapy with adenoviral vectors. While great strides have been made in the management of traumatic brain injury, no treatments exist which prevent and minimize neuronal loss following brain injury, the main cause of long-term disabilities in headinjured patients. Animal studies have revealed many potential therapeutic agents for brain injury, however, these compounds are administered in a global manner, producing possible side effects detrimental to the maintenance of the trauma patient. Gene therapy is a way in which to chronically present these therapeutic agents to a specific area of the brain, using genetically engineered viruses, without major global side effects. In order to develop gene therapy for traumatic brain injury, two factors must be addressed: 1) the production of novel genes in injured brain tissue, induced by an adenoviral vector, must be demonstrated, measured, and optimized in the rat and 2) the neuroprotective ability of a therapeutic gene in an animal model of brain injury must be demonstrated. These are the focus of the specific aims of this proposal. They are: 1) to determine the optimal viral vector concentration that will provide the greatest number of infected brain cells with minimal amounts of neural toxicity when injected into the normal and injured cortex, 2) to examine the neuroprotective effects of virally mediated glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) expression in the cortex following a cortical contusion, and 3) to explore whether a virally mediated neurotrophic factor (either GDNF or BDNF) injected after a cortical contusion can rescue and protect neurons and behavioral function. In addition, this proposal will measure transgene expression in compromised cortical tissue. Together, these studies will develop a framework for further investigations of gene therapy for traumatic brain injury. Future questions will address the therapeutic

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windows of opportunity, long-term behavioral and cognitive function, and the optimization of new therapeutic genes and viral vectors for traumatic brain injury. In addition, these studies will provide a comprehensive research-training program for undergraduates in the fields of neurobiology, molecular biology, and animal behavior. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NONHUMAN ADENOVIRUS VECTORS FOR GENE THERAPY Principal Investigator & Institution: Mittal, Suresh K.; Veterinary Pathobiology; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-MAR-2003 Summary: Designing a suitable delivery vehicle is very important to obtain the desired results in a gene therapy protocol. Human adenoviruses have attracted considerable interest lately for their potential use as delivery vehicles for gene therapy especially for treating genetic disorders, and cancer. Now it has been fully realized that currently available vectors do express some of the viral genes, and therefore, the cells carrying the desired vector are removed from the circulation resulting in transgene expression for a short duration. This suggests that there is a need to cripple the virus further to obtain transgene expression for an extended period of time. Non-human adenoviruses, such as bovine adenovirus type 3 (BAd3) and porcine adenovirus type 3 (PAd3) that do not replicate in human cells but can infect human cells in culture, could provide an attractive alternative to human adenovirus vectors for gene therapy. The long-term objectives are to develop replication-deficient BAd3 and PAd3 vectors for human gene therapy with a purpose of obtaining expression of the desired gene for a long period of time without significant side effects. Initially these vectors containing a reporter gene will be tested in human cell lines and experimental animals to evaluate the level and duration of transgene expression, the levels of vector's early and late gene expression, the state and duration of the presence of vector DNA, the inflammatory response at the site of inoculation in animals, and the host immune response against the vector. These experiments will form the basis for the future studies initially in human tissues and subsequently in a small human trial using either BAd3 or PAd3 vector for correcting a respiratory, hepatic or cardiovascular disorder or in cancer therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL THERAPIES FOR LYSOSOMAL STORAGE DISEASES Principal Investigator & Institution: Sands, Mark S.; Associate Professor; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 31-DEC-2004 Summary: (Copied from Applicant Abstract): Lysosomal storage diseases are progressive heritable disorders usually caused by deficiencies in lysosomal enzymes. We recently showed that systemic and tissue-directed delivery of recombinant adenoassociated virus (AAV) in neonatal mice with the lysosomal storage disease mucopolysaccharidosis type VII (MPS VII) results in persistent (16 week) betaglucuronidase (GUSB) expression. The level of expression reduces lysosomal storage in multiple tissues including the central nervous system (CNS). We will now determine if neonatal gene therapy can result in improvements in auditory, visual, cognitive and immune functions. Since these diseases are progressive in nature, it is of interest to determine if in utero gene therapy for LSDs is more efficacious than neonatal therapy. Finally, it has yet to be determined if functional improvements can be achieved in a setting where lysosomal storage is well established, and the clinical defects are present.

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The goals of this proposal are to determine the consequences of neonatal, in utero and adult AAV-mediated gene transfer in the murine model of MPS VII. We will accomplish these goals with the following specific aims: 1. We will determine the long term clinical effects of systemic and liver-directed AAV-mediated gene transfer in neonatal MPS VII mice. 2. We will determine the effects of direct gene transfer to the brain and eye in young adult MPS VII mice with established disease. 3. We will characterize AAVmediated in utero gene therapy. A) We will determine the efficacy of in utero gene therapy in the MPS VU mouse. B) We will determine whether in utero gene transfer reduces the immune response to repeated AAV injections in immunocompetent mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PAIN CONTROL VIA SPINAL INTERLEUKIN-10 GENE THERAPY Principal Investigator & Institution: Watkins, Linda R.; Professor; Psychology; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Human pathological pain is a major unresolved problem. Recent data strongly support the argument that spinal cord glia (astrocytes and microglia) are critically involved in the creation and maintenance of diverse pathological pain states. Spinal cord glia create exaggerated pain states via the release of proinflammatory cytokines (PICs). Recognition of the key importance of spinal cord glia and glial PICs in pathological pain opens new avenues for pain control. There are various treatments available to control glial activation involved in enhanced pain. Interleukin-10 (IL10) is the most promising from a clinical point of view. IL10 is an excellent candidate for preventing and reversing PIC-driven pathological pain states. However, two practical problems need to be overcome. First, control of chronic pain requires chronic delivery of IL10. Second, IL10 cannot cross the blood-brain barrier, thus negating systemic administration. To resolve these issues, we have explored the feasibility of using prolonged spinal release of IL10 induced by gene therapy. Here, adenoviral vectors encoding IL10 are injected into the cerebrospinal fluid surrounding the spinal cord. Our preliminary data provide strong support for the possibility that spinal gene therapy with IL10 will prevent and reverse pathological pain. The aims of the present proposal are three-fold: (1) To determine the breadth of clinically relevant exaggerated pain states that can be prevented and/or reversed by gene therapy-induced IL10 in spinal CSF; (2) To construct a "gutless" adenoviral vector of IL10 which allows virally infected cells to avoid detection and destruction by the immune system; and (3) To characterize the patterns of IL10 release, characterize viral spread and clarity whether peripheral immune functions are impacted by this procedure. Together these studies will test the premise that intrathecal IL10 delivery via gene therapy is worthy of clinical development for controlling diverse pathological pain states. This approach to pain control represents a dramatic departure from all other available therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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

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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 adenovirusbased 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: PRECLINICAL STUDY OF GENE TRANSFER IN DMD Principal Investigator & Institution: Chamberlain, Jeffrey S.; Professor; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2003; Project Start 26-SEP-2003; Project End 31-JUL-2008 Summary: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, is among the most common human genetic diseases and is the most common lethal genetic disorder of children. There is no cure for DMD and current treatment options serve only to slow somewhat progression of muscle wasting and loss of mobility while maintaining ventilation. Gene therapy represents a promising approach to treating or curing this recessively inherited disorder. However, numerous obstacles must be overcome before gene therapy can be applied routinely. These obstacles include a lack of knowledge of the safety and efficacy of dystrophin gene transfer to human muscle and an inability to target all the muscles of the body. Recently, a variety of mini-, micro- and full-length dystrophin cassettes have been shown to prevent the development of most or all dystrophic symptoms in mdx mice, a model for DMD. These cassettes can also be delivered efficiently to adult mdx mouse muscles using several viral vectors, including adeno-associated virus (AAV), resulting in a reversal of many dystrophic features. To explore the potential for gene therapy of DMD we propose to

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conduct a phase 1 human clinical trial of AAV-mediated gene transfer of a microdystrophin expression cassette. We propose to conduct extensive pre-clinical studies in the mdx mouse to explore the safety and efficacy of micro-dystrophin gene transfer using AAV serotype 6, which is enormously efficient at transducing skeletal muscle. The results of these studies will complement those of the other projects described in this Center application that are focused on dystrophic dogs and DMD patients. The combined results from these studies will be used to design, obtain regulatory approval for and implement a phase 1 clinical trial of AAV6-mediated micro-dystrophin gene transfer to DMD patients. Together, these studies will provide important new information on the potential for gene therapy for DMD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RADIOSENSITIZATION WITH RECOMBINANT ANTIBODIES TO EGFR Principal Investigator & Institution: Bonner, James A.; Chief, Sec. on Med. Biophysics; Radiation Oncology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: It is known that the anti-EGFr monoclonal antibody C225 and its smaller Fab fragment cause growth inhibition and accentuate radiation-induced growth inhibition in vitro and in vivo in cells that overexpress EGFr. This finding has been suggested in the human model as well, and currently a National Phase III trial (J Bonner, PI) is underway to test the efficacy of C225 and radiotherapy vs radiotherapy alone in advanced head and neck malignancies as almost all head and neck malignancies express EGFr and the majority overexpress it. It is known that monoclonal antibodies are limited by the size of the molecule (with respect to penetration into tumor) and the possibility of immune responses against the antibody. These facts may prevent the monoclonal antibodies from eliciting the best possible response in target tumors. Recently technology has been developed to make human recombinant antibodies that are single chain molecules (scFvs) and contain just the critical variable light and heavy chain regions of the antibody and target antigens of interest. We have constructed these molecules for other antigens and have isolated several candidate clones against EGFr. We have also developed the technology to deliver these agents through an adenoviral vector gene therapy-based approach that allows for the secretion of these agents from the cells by the insertion of appropriate peptides. Therefore, it is hypothesized that this gene therapy-based approach will allow for the delivery of high concentrations of anti-EGFr scFv in close proximity to the antigen of interest in a manner that is not possible with the full antibody. Therefore, it is proposed to derive several recombinant antibodies (scFvs) against EGFr and, 1) maximize the anti-proliferative effects of these scFvs; 2) maximize the radiosensitizing properties of these scFvs; and 3) deliver secretory scFvs through a gene therapy-based approach in a manner that will capitalize on the anti-proliferative and radiosensitizing properties of the agents. Human head and neck carcinoma lines will be used to test these questions in vitro and in vivo with an aim toward understanding viable effects with respect to the cells inherent EGFr expression and radiosensitivity. Preliminary data suggests that monoclonal antibody-induced blockade of EGFr results in growth inhibition and radiosensitization through an apoptotic mechanisms. Additionally, the apoptotic events are associated with a dramatic redirection in the anti-apoptotic protein; phosphorylated STAT-3. Studies will be performed to assess the mechanism of scFv-induced growth inhibition and radiosensitization in the context of the above finding.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECEPTOR MEDIATED TRANSPORT OF LYSOSOMAL ENZYMES Principal Investigator & Institution: Sly, William S.; Chairman and Professor; Biochem and Molecular Biology; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2001; Project Start 01-JUN-1984; Project End 31-JUL-2002 Summary: The broad goal of this research is to continue studies of receptor- mediated transport of lysosomal enzymes and its relevance to enzyme replacement and gene therapy using beta-glucuronidase as a model lysosomal enzyme, and mucopolysaccharidosis type VII (Sly disease) as a model lysosomal storage disease. Previous studies focused on the biochemistry of the enzyme, the cell biology of its targeting and transport, the molecular genetics underlying the disease, and the mouse model of MPS VII which provided unique opportunities to study enzyme replacement therapy and gene therapy. We seek continued support to extend these studies. We have six specific aims: 1) Produce monoclonal antibodies to murine beta-glucuronidase in MPS VII mice treated from birth with the human enzyme. 2) Define the active site residues of human beta-glucuronidase by site-directed mutagenesis. 3) Use active site mutations in the human gus transgene and targeted active site mutations in the endogenous mouse gus gene to produce tolerant MPS VII mice models for enzyme and gene therapy. 4) Compare the responses to Man 6-P targeted and mannose-targeted human beta-glucuronidase in tolerant MPS VII mice. 5) Produce PEG-modified, Man 6P-targeted stealth human beta-glucuronidase that is shielded from the immune response in non-tolerant MPS VII mice but still corrects the lysosomal storage. 6) Test the effects of transgene-conferred tolerance on persistence of expression and response to gene therapy in MPS VII mice. We will use a variety of biochemical, cell biological, immunological, and molecular genetic approaches. We will also use transgenic mouse and mouse gene knockout technology as well as sophisticated histochemistry and histopathology. The answers sought have fundamental significance, and should provide information leading to novel therapeutic approaches to enzyme replacement and gene therapy for lysosomal storage diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RECOMBINANT ABNORMALITIES

AAV

FOR

CORRECTION

OF

GENETIC

Principal Investigator & Institution: Flotte, Terence R.; Professor; Pediatrics; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 25-SEP-2000; Project End 31-JUL-2005 Summary: The liver plays a pivotal role in numerous biochemical processes, including intermediary metabolism, synthesis and secretion of serum proteins, energy metabolism, and detoxification of drugs and other xenobiotics. Hepatocytes are, therefore, an important target for gene therapy, and important target for gene therapy in many genetic diseases that disrupt these processes. In the current application, our group is seeking to optimize the conditions for gene transfer into hepatocytes using recombinant adeno-associated virus (rAAV) vectors, which possess the inherent advantages of long-term stability, safety, and low immunogenicity. rAAV-mediated gene transfer is very efficient in myofibers and some other cell types, but previous reports have indicated that long-term rAAV transduction of the liver may be limited to maximum of approximately 5% of hepatocytes using current methods. This may not be sufficient for many genetic/metabolic disorders. The primary goal of the current

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application is to identify and circumvent the rate-limiting steps in rAAV-mediated transduction of hepatocytes and thereby increase the efficiency of rAAV-mediated transduction of hepatocytes to a point where it is sufficient for widespread clinical use. The optimization of hepatocyte gene transfer will be accomplished in the context of three gene therapy projects, each of which typifies a defect in one of the major hepatic functions: Project 1: gene therapy for phenylketonuria (a disorder of amino acid metabolism), Project 2: gene therapy for alpha 1-anti-trypsin deficiency (a defect in hepatic synthesis and secretion), and Project 3: gene therapy for glycogen storage (that affect a key process in energy metabolism, the release of free glucose from glycogen). In addition, a pilot study will investigate the feasibility of gene therapy in the murine mdr2 knock-out mouse (a model defect in bile salt secretion analogous to progressive familial Intrahepatic cholestasis), in a paradigm whereby corrected cells could selectively repopulate the liver due to their survival advantage. In order to fully develop rAAV transduction of the liver, it may be necessary to enhance delivery to the hepatocyte, increase attachment to the cell membrane, improve internalization, nuclear entry and uncoating, maximize the transcriptional activity of vector genomes, and optimize conditions for therapeutic protein secretion. Since these disorders may ultimately require therapy in the newborn period or during child-bearing years, biological safety issues related to long-term genetic stability and biodistribution of rAAV genomes will also be addressed. These studies will be supported by the UF Vector Core Facility, for the production of high-titer, highly purified rAAV stocks, and the UF Immunology/Pathology Core. It is anticipated that by the end of this grant period, these basic improvements in rAAV-mediated delivery of genes to the liver will have improved the changes for successful gene therapy in one or more of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGIONAL GENE THERAPY TO ENHANCE BONE REPAIR Principal Investigator & Institution: Lieberman, Jay R.; Professor; Orthopaedics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-JAN-2005 Summary: (Verbatim from the Applicant): Regional gene therapy is a novel approach to enhance bone repair in humans. There is concern that a single exposure to exogenous recombinant protein may not induce a satisfactory osteoinductive stimulus in patients with significant bone loss. In previous work, we have demonstrated the efficacy of an ex vivo gene transfer strategy using BMP-2-producing rat bone marrow cells created via adenoviral gene transfer. These cells were used to heal a critical-sized femoral defect in rats. Our goal now is to further explore the potential of regional gene therapy so we can better adapt this technology for humans. The plan is to enhance our understanding of the biology of the bone repair process with ex vivo gene transfer by assessing the duration of BMP production in vivo and localizing the BMP secretion in the defect site over time. In addition, the role of the transduced bone marrow cells and host cells in the bone repair process will be determined, evaluating both the immune response to gene therapy and the presence of adenovirus at various anatomic sites. The research proposed in Specific Aim 1 will evaluate another cell type (skin fibroblasts) as a potential cellular delivery vehicle to heal critical-sized bone defects. The research proposed in Specific Aim 2 will investigate the efficacy of the ex vivo adenoviral gene transfer in a more stringent and clinically relevant model by trying to heal femoral defects in adult (12 month old) and elderly (18 month old) rats. In both Specific Aims 1

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and 2, the duration of BMP production in vivo and the localization of BMP in the defect will be assessed. In Specific Aim 3, the role of the BMP-2-producing bone marrow cells in the bone repair process and the donor cells will be assessed in a mouse model. In Specific Aim 4, we will: (a) compare the efficacy of the ex vivo gene transfer strategy with BMP-2-producing bone marrow cells and direct in vivo injection of the virus; and (b) compare the safety and toxicity of these two gene therapy strategies. This proposed research will enhance our knowledge with respect to the potential pitfalls of gene therapy in enhancing bone repair and hopefully take us a step closer to adapting this technology for use in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE

REGULATION

OF

BETA

GLOBIN

LOCUS

CHROMATIN

Principal Investigator & Institution: Lowrey, Christopher H.; Associate Professor; Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2001; Project Start 01-DEC-1994; Project End 31-JUL-2003 Summary: The beta-globin genes were among the first human genes to be cloned. This led to expectations that hemoglobinopathy diseases such as sickle cell anemia and betathalassemia would be among the first diseases to be treated by gene therapy. And yet, nearly ten years after the first gene therapy protocol was approved and after a total of 200 therapeutic protocols have been submitted, no hemoglobinopathy patient has been treated with gene replacement therapy. This is largely due to technical problems involving the gene therapy vectors to be used for the hemoglobinopathies. One of these problems is that consistent, long-lasting, high-level expression has yet to be attained in pre-clinical systems. Evidence indicates that this problem is, at least in part, due to an inability of current vectors to efficiently create a transcriptionally active or "open" chromatin structure surrounding the integrated vector. The normal beta-globin genes, in the context of the beta-globin gene locus, are able to efficiently perform this process in erythroid cells. Our long term goals are to study the processes by which the normal locus is able to open chromatin structure in an erythroid- specific fashion and to then apply these findings to help develop new gene therapy vectors which are able to independently open chromatin structure wherever they insert into the human genome. We are attacking these problems on four fronts. First we will continue to characterize a 101bp element from HS4 of the beta-globin LCR which is able to locally open chromatin structure in erythroid cells. Our current data implicates the transcription factors NF-E2, GATA-1 and Sp1 in this process. GATA-1 seems to be particularly important in this process. In our second aim we will perform structural studies on this factor gain insight the mechanisms by which it is able to reorganize chromatin structure. In our third aim we will continue our efforts to locate the boundaries of the domain of open chromatin structure which forms around the globin gene locus. Finally, we will continue to test the ability of chromatin structure-determining elements (i.e., HS4 HSFE, chicken beta-globin boundary element, HS3 core, HS2 enhancer) alone and in combination to yield positionindependent, high-level, non-silencing expression. These experiments provide a comprehensive approach to understanding the regulation of beta-globin locus chromatin structure and potential applications to development of gene therapy strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RESCUE OF THE RD PHENOTYPE USING SOMATIC GENE THERAPY Principal Investigator & Institution: Semple-Rowland, Susan Lynn.; Associate Professoir; Neuroscience; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 01-APR-1996; Project End 31-MAR-2003 Summary: (Adapted from applicant's abstract): The long-term goal of this research program is to understand the biochemical processes in photoreceptor cells that if disrupted, lead to cell dysfunction and degeneration. The model system studied in this program is the retinal degeneration (rd) chicken, the only animal model for inherited retinal disease that possesses a cone-dominant retina. In the previous funding period, the investigators determined that the rd gene encoded photoreceptor guanylate cyclase 1 (GC1), a gene critical for cone and rod phototransduction. The results of their analyses show that the rd chicken is a model for Leber's congenital amaurosis (LCA1), an inherited retinal disease of the retinitis pigmentosa family of retinal degenerations that causes blindness in newborn infants. They propose that the GC1 null mutation in the rd chicken leads to abnormally low levels of cGMP in cone and rod cells, loss of phototransduction, and eventually to photoreceptor degeneration. The goal of the studies outlined in this proposal is to rescue the retinal degeneration phenotype of the rd chicken using somatic gene therapy. They will test the hypothesis that expression of normal GC1 in rd photoreceptor cells is sufficient to restore photoreceptor function and prevent photoreceptor cell death. The aims of this proposal are: (1) to identify fragments of the GCAP1 promoter that are capable of directing expression of reporter genes to photoreceptors in vitro (embryonic chicken retina cell culture) and in vivo (chicken embryos); (2) to examine the ability of selected GCAP1 promoters to drive expression of GC1 in photoreceptor cells in rd/rd retinal cultures; and (3) to rescue the retinal degeneration phenotype in the rd chicken using lentivirus to deliver a GCAP1/GC1 transgene to retinal progenitor or post-mitotic retinal cells. They will determine the transcription start point of GCAP1 and examine the specificity and activity levels of GCAP1 promoter fragments by transient transfection of chicken retinal cell cultures and by viral transduction of stage 9-11 chicken embryos. The ability of the GCAP1 promoter to drive GC1 expression in transiently-transfected rd/rd retinal cultures will be examined by measuring GC1 activity. To assess the effectiveness of the GC1 gene therapy, they will examine (1) the electroretinographic responses of the rd/rd retina, (2) retinal morphology, (3) GC1 expression, and (4) expression profiles of circadianregulated genes whose normal temporal expression pattern is disrupted in rd/rd retina. Comparisons of rd/rd chickens treated during embryonic development versus at hatching will allow one to determine if the efficacy of the therapy is enhanced if it is administered to the earliest expression of the normal gene in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REV DECOYS FOR GENE THERAPY AND DRUG DEVELOPMENT Principal Investigator & Institution: Ellington, Andrew D.; Wilson M & Kathryn Fraser Research Profe; Chemistry and Biochemistry; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-MAR-2005 Summary: (Provided by the applicant): The goal of this proposal is to develop novel reagents, approaches, and delivery systems for anti-HIV gene therapies. This is the second renewal of a proposal that began with the development of anti-Rev aptamers as potential gene therapy agents. Our initial goals have been largely reached (as will be

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seen in the Progress Report, C), and the nature of treatment has changed during the last several years. Therefore, this incarnation of the proposal represents a shift from earlier efforts. While we continue to develop anti-Rev aptamers as gene therapy agents, we recognize that drug resistance has become one of the chief problems confronting clinicians, and have therefore expanded our goals to include the development of multiple gene therapy agents that will simultaneously target multiple HIV proteins. Moreover, we recognize that there are numerous problems with the inauguration of gene therapy strategies for the treatment of disease, and we have therefore also begun to develop novel methods for the delivery and regulation of gene therapy agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SF/HGF GENE TRANSFER FOR PERIPHERAL ISCHEMIA Principal Investigator & Institution: Paka, Latha; Angion Biomedica Corporation 350 Community Dr, Room 145 Manhasset, Ny 11030 Timing: Fiscal Year 2002; Project Start 15-FEB-1999; Project End 31-MAR-2004 Summary: (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in the US, afflicting over 58 million Americans. Angiogenic factors can increase vascularization and improve perfusion in ischemia. Scatter factor/hepatocyte growth factor (SF/HGF) may be superior to other angiogenic factors because of multiple actions on components of the angiogenic cascade and anti-apoptotic properties. Our Phase I studies demonstrated therapeutic angiogenesis by SF/HGF gene therapy in rat and mouse models of peripheral ischemia. We will confirm and extend this work by obtaining detailed dose and time course information with long-term follow-up for therapeutic benefit as well as adverse effects in the mouse hindlimb ischemia model. We will also examine the benefits of SF/HGF gene therapy in treating peripheral ischemia in aging mice and in mice with diabetes. The rabbit model of peripheral ischemia will be used to assess the effectiveness of SF/HGF gene therapy by physiological assessment of blood flow and hindlimb perfusion pressure and anatomical assessment of collateral vessel development, capillary density and muscle atrophy. In additional studies we will compare the effectiveness of SF/HGF gene therapy with VEGF therapy. The goal of these studies is to bring SF/HGF gene therapy to clinical practice. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOMATIC CELL GENE THERAPY AND NITROGEN FLUX IN UREA CYCLE PATIENTS Principal Investigator & Institution: Lee, Brendan; Associate Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2002 Summary: The group of inborn errors of hepatic metabolism continue to be a prominent cause of mental retardation because of ineffective treatment strategies. Gene replacement therapy offers the theoretic advantage of correcting the basic protein deficiency. However, progress in hepatocyte directed gene therapy has been limited by questions involving pathophysiologic processes, choice of promoter and vector delivery system, route of delivery, host immune clearance, duration of expression, availability or small and large animal disease models, and quantitative measures of clinical efficacy. The three parts of this proposal attempt to address some of these issues using the group of urea cycle defects a model system. The first goal is to better understand the pathophysiologic disturbances in patients with urea cycle defects by correlating

56

Gene Therapy

genotype and clinical severity with in vivo measurement of nitrogen flux and ureagenesis, while also developing a quantitative measure for future in vivo gene therapeutic interventions in both animal and humans. Flux through the urea cycle pathway will be measured by quantifying the conversion of [15/N-amide]glutamine to [15/N] urea. This flux will be correlated with genetic status (homozygosity, heterozygosity, hemizygosity), nature of mutation (null versus hypomorphic), and clinical severity (neonatal versus later presentation) in affected patients, heterozygous family members, and normal controls. In the second part of the study, the relative safety and efficacy of first generation (E1a deleted) and second generation (E1a/E2a deleted and all coding sequence deleted) adenovirus vectors will be determined after intravenous (i.v.) delivery in animals. In addition, potential avenues permitting long term transgene expression will be investigated. The efficacy of transient immunosuppression for the readministration of viral vectors will be evaluated, and the potential use of mariner transposon elements in mediating transgene integration in a host mammalian genome will be studied. In the third part, the urea cycle disorders, specifically murine and bovine models of citrullinemia, will be used a model systems in applying these basic findings to a clinical setting. The efficacy of the hybrid, ubiquitously active, CAG and liver-specific human albumin promoters will be compared in vivo. These data will form the preclinical basis for designing phase I clinical trials involving gene therapy in urea cycle patients. These results together will also be more generally applicable to other inborn errors of hepatocyte metabolism and to the production of extracellular products by hepatocytes. Early and long term biochemical correction would be expected to greatly decrease the great neurologic morbidity associated with these conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STEM CELL GENE THERAPY FOR AIDS Principal Investigator & Institution: Johnson, R. Paul.; Associate Professor of Medicine; Immunology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 10-FEB-1997; Project End 31-MAR-2007 Summary: (Provided by the applicant): Despite the dramatic success of highly active antiretroviral therapy (HAART) in inhibiting viral replication in HIV-infected subjects, it is increasingly clear that there is a compelling need for the development of complementary therapies. Accumulating experience with HAART is documenting a significant incidence of serious side effects, an increasing prevalence of resistant viruses, and failure rates of HAART that exceed 50 percent in some cohorts. A wide range of genetic strategies are now able to achieve potent inhibition of HIV replication in vitro, and introduction of these inhibitory genes into hematopoietic stem cells offers the potential to offer long- lived immune reconstitution. However, the successful translation of these in vitro successes to clinically- applicable therapies has been limited by the disappointing rates of gene transfer to hematopoietic cells in human gene therapy clinical trials. Multiple ethical and practical considerations significantly constrain the ability to address basic questions regarding stem cell gene therapy for AIDS in human clinical trials. Experiments in nonhuman primates offer the opportunity to rigorously address these issues in an in vivo experimental model. Experiments conducted during the initial funding period of this grant have shown that significant levels of geneticallymodified cells can be obtained in nonhuman primates following autologous bone marrow transplantation with hematopoietic stem cells transduced with murine leukemia virus (MLV) vectors. Specific aims of the current proposal are: 1. To optimize

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MLV and lentiviral vectors for the delivery of RNA decoys into hematopoietic stem cells and evaluate their ability to inhibit SIV/HIV replication; 2. To examine levels of gene marking in uninfected macaques transplanted with hematopoietic stem cells transduced with MLV and lentiviral vectors; 3. To determine the ability of inhibitory genes to protect hematopoietic cells from SHIV infection in vivo; and 4. To examine the ability of genetically-modified hematopoietic stem cells to reconstitute immune function in SHIVinfected macaques. These studies should yield important information regarding the efficacy and safety of stem cell gene therapy for AIDS and facilitate the development of similar trials in HIV- infected people. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETED VECTORS TO BLOCK HIV1 REPLICATION Principal Investigator & Institution: Dornburg, Ralph C.; Associate Professor of Medicine; Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 15-FEB-2000; Project End 31-JAN-2004 Summary: This proposal seeks funding for the systemic build-up and testing of retroviral vectors, which transduce anti-HIV-1 therapeutic genes into human hematopoietic cells relevant in vivo gene therapy of HIV-1 infection. In the past years, our laboratories have made significant progress in the development of two important areas in gene therapy for HIV-1 infection: (1) Dr. Pomerantz's lab has developed a series of anti- HIV-1 single chain antibodies, which significantly inhibit HIV-1 replication at early stages of the retroviral life cycle. (2) Dr. Dornburg's laboratory has developed retroviral vectors, which display single chain antibodies (scAs) or other ligands on the viral surface of spleen necrosis virus, SV. Such vectors enabled an efficient (up to 10/6 cfu/ml), cell-type- specific gene transfer into various human hematopoietic cells. Celltype- specificity was mediated by the scA. Now, experiments will be performed to combined these two technologies to establish potent anti-HIV-1 therapeutic gene transfer systems for in vivo gene therapy for HIV-1 infection. (1) Recently, three different SNV-derived packaging systems have been developed to transduce gene specifically into various human T- cells or CD34-positive hematopoietic stem cells with efficiencies above 10/6 cfu/ml. Using these systems, vectors will be developed and systematically improved to transduce anti-HIV-1 therapeutic genes developed and tested in Dr. Pomerantz's laboratory into human T-cells. The efficiency of the gene transfer and the level of protection against HIV-1 will be determined and compared to other vector systems. (2) Cell- type specificity and the efficiency of infection of all targeting vectors will be tested in SCID mice model systems. E.G., human target and non-target cells will be implanted into SCID mice, followed by the injection of retroviral vector preparations, specific for one cell type. First, human cells as well as various mouse tissues will be investigated for the presence of marker genes transduced by the targeting vector particles. Next, the experiments will be expanded to test the therapeutic effect of anti-HIV-1 genes in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TARGETING BACTERIOPHAGE FOR DNA DELIVERY Principal Investigator & Institution: Larocca, David J.; Selective Genetics, Inc. 11588 Sorrento Valley Rd, Ste 21 San Diego, Ca 921211336 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2002

58

Gene Therapy

Summary: Current gene therapy vectors employ animal viruses or condensed DNA/protein complexes to deliver DNA. The use of animal viruses has been limited because of tropism for normal cells, associated toxicity the cost of large-scale production, and the difficulty of genetically altering a complicated virus. Nonverbal systems offer an alternative but are difficult to produce with the same homogeneity of a virus. We aim to improve current gene therapy methods by developing an alternative gene delivery vehicle, the bacteriophage that is simple and economical to produce and lacks native tropism for mammalian cells. Having demonstrated that genetically targeted phage can transduce mammalian cells we propose here to add improved cell trafficking and other accessory peptides and DNA elements involved in trafficking, phage replication and integration to the phage vector with the goal of enhancing the transduction efficiency such that the targeted phage will be useful for gene therapy. We will then test the improved phage for delivery of a therapeutic gene in vivo using several tumor models. The long-term goal of this proposal is, therefore, to develop a safe, economical, and effective alternative to existing gene therapy vectors for therapeutic gene delivery to treat cancer and other diseases. PROPOSED COMMERCIAL APPLICATIONS: We propose to develop bacteriophage as an improved alternative to existing gene delivery methods. The commercial applications include reduced production costs and improved gene therapy of cancer and gene replacement therapy. Our strategy will be to genetically incorporate peptide and DNA elements that confer efficient mammalian cell tropism on a bacteriophage vector. The vector will be targeted to specific receptor bearing cells using a ligand that is displayed on the tip of the phage particle as a genetic fusion to a phage coat protein. We will test the improved vector in an in-vivo disease model to demonstrate the use of phage as a safe and effective alternative vehicle for therapeutic gene delivery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING THERAPY OF HUMAN BREAST CANCER Principal Investigator & Institution: Fisher, Paul B.; Professor/ Chernow Research Scientist; Urology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2003 Summary: (Applicant's Description) Abnormalities in differentiation and growth control are common occurrences in human cancers. Treatment of human melanoma cells with the combination of recombinant human fibroblast interferon and the protein kinase Cactivating, antileukemic compound mezerein results in a loss of tumorigenic potential that correlates with an irreversible suppression in proliferative ability and induction of terminal differentiation. It is hypothesized that this process is associated with differential expression of genes that may directly regulate cancer cell growth and differentiation. Through the use of subtraction hybridization, we have identified a gene associated with induction of irreversible growth arrest, cancer reversion and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). Ectopic expression of mda-7 using a recombinant adenovirus, Ad.mda-7 S, results in growth suppression and apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb. Additionally, Ad.mda-7 S inhibits the growth and progression of human breast and cervical cancer cells in vivo in nude mice. In contrast to its effect on cancer cells, mda-7 displays no apparent negative effect on growth or survival in normal human skin fibroblast or mammary epithelial cells. In this context, mda-7 may prove useful for selectively targeting human breast cancer cells for eradication. Studies will be conducted to determine the effect of Ad.mda-7 S alone, and in combination with chemotherapy or

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radiation, on the in vitro and in vivo growth in nude mice of human breast cancers. Subtraction hybridization has also been used to clone a gene directly associated with cancer progression, progression elevated gene-3 (PEG-3). Genomic walking permitted the isolation of the promoter region of the PEG-3 gene, PEG-Prom. PEG-Prom-luciferase reporter constructs display high-levels of activity in human cancer cells, including breast cancer cells, and low or no activity in normal human cells. We propose to construct cancer inhibitory recombinant adenoviruses (CIRAs) utilizing the PEG-Prom to control expression of indicator genes [luciferase and green fluorescence protein (GFP)] and genes that induce growth suppression, apoptosis or toxicity [mda-7, wild-type p53 or the herpes simplex virus thymidine kinase gene (HSV-TK)]. These viruses will be used to determine if the PEG-Prom can specifically target the expression of genes to human breast carcinoma cells. If successful, this approach, termed CURE (cancer utilized reporter execution), could provide a novel means of therapy for human breast cancer without inducing nonspecific damage to normal tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TESTING GENE THERAPY FOR EPIDERMOLYSIS BULLOSA SIMPLEX Principal Investigator & Institution: Roop, Dennis; Professor; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomaldominant fashion. Besides symptomatic care, no effective therapeutic treatment is available for EBS. Therefore, gene therapy is the only option for a permanent corrective therapy for these patients. Prior to testing gene therapy approaches for EBS in humans, it is desirable to utilize a pre-clinical animal model to determine the safety and efficacy of these approaches. We have recently generated a transgenic mouse model that mimics EBS-DM at the genetic level. This mouse model differs from the human disease in that expression of the mutant K14 allele, which contains an Arg 131 Cys mutation equivalent to the Arg 125 Cys mutation found in the majority of EBS-DM patients, can be restricted to a small area of the skin. This mouse model has provided an explanation for the lack of mosaic forms of EBS. Patients with mostly normal skin that have patches of diseased skin are referred to as mosaics. Mosaic patients have been described for several skin diseases, but not for EBS. Focal activation of the mutant K14 gene by topical application of an inducer results in blister formation. However, after a few weeks, the blister heals and never reappears. We have demonstrated that the mutant K14 gene was activated in epidermal stern cells. However, the defective EBS stem cells were replaced by normal epidermal stem cells that migrate in from the untreated area surrounding the blister. This mouse model predicts that if a mosaic patch of EBS skin formed during development of an embryo, these defective EBS epidermal stem cells would not survive, but be replaced by normal stem cells. This explains the absence of mosaic forms of EBS. This observation also has important implications for gene therapy approaches for EBS, since it suggests that if EBS stem cells were removed from a patient, genetically corrected and then returned to a blistered area, they would have a selective growth advantage over defective EBS stem cells. Of further interest was the observation that mice which express the mutant K14 allele at levels approximately 50% of wild type K14 fail to exhibit a skin phenotype. This suggests that as long as the ratio of wild type to mutant K14 is above a threshold, possibly as low as 2:1, the skin will have a normal appearance and be fully functional. Thus, successful gene therapy approaches may not

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require correction or complete suppression of the mutant allele. This proposal will use epidermal stem cells isolated from the EBS-DM mouse model to test new gene therapy strategies that are based on these novel findings. 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 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

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Project Title: METASTASIS

TISSUE

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THERAPY

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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 2001; 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 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: TRIMODAL GENE THERAPY FOR PROSTATE CANCER Principal Investigator & Institution: Freytag, Svend O.; Division Head; Molecular Biology; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 31-MAY-2004 Summary: (adapted from application) Prostate cancer is the most commonly diagnosed malignancy in men. Although conventional therapies (surgery, radiation, androgen ablation) produce high cure rates of early stage disease, many tumors recur and an effective therapeutic regimen is still lacking for advanced stages of the disease. Our

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research program has developed a novel, multifaceted, gene therapy approach for the treatment of prostate cancer. Our approach utilizes a modified, replication competent adenovirus (FGR) to selectively and efficiently deliver a pair of therapeutic suicide genes to prostate tumors. Preclinical studies in animals have demonstrated that the FGR virus itself generates a potent antitumor effect by replicating in and preferentially destroying human prostate cancer cells that lack a functional p53 tumor suppressor protein. The therapeutic effect of the FGR virus can be enhanced by invoking two suicide gene systems (CD/5FC and HSV1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents (prodrugs), and more importantly, sensitizes them to radiation. A strength of our approach is that it simultaneously makes use of three modalities viral, double suicide gene, and radiation therapies to selectively destroy prostate cancer cells with minimal toxicity towards normal tissues. Our research efforts are currently at the cusp of preclinical/phase I clinical studies. A phase I clinical protocol involving the FGR virus concomitant with double prodrug therapy has been approved by our IRB. A pre-IND meeting with the FDA has been held, and we expect to begin phase I trials in 1999. As a means to further enhance the efficacy of our approach, this application will: 1) evaluate the merit of adding androgen ablation as a fourth therapeutic arm, 2) evaluate the effectiveness of FGR viral therapy against disseminated disease, and 3) evaluate the specificity of each therapeutic arm with respect to tumor p53 status and determine whether treatment failure correlates with p53 status. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VECTORS FOR SUSTAINED EXPRESSION OF GENES IN THE LIVER Principal Investigator & Institution: Herweijer, Hans; Director of Preclinical Research; Mirus Corporation 505 S Rosa Rd, #104 Madison, Wi 53711 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JAN-2002 Summary: (adapted from applicant's abstract) Gene therapy promises to be a singular advance in treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Specifically, the development of gene transfer methods into hepatocytes is very attractive given the central role that the liver plays in many inborn errors of metabolism and acquired disorders. One of the problem areas in gen therapy is the sustained expression of transgenes at high levels in the liver. This project will use an innovative approach to develop regulatory elements that will enable high and stable levels of foreign gene expression in the liver. These regulatory elements can include transcriptional elements such as promoters, enhancers and locus control regions, but also other elements like introns, 5' and 3' untranslated regions and polyadenylation (polyA) addition signals. These elements should be directly applicable to generate both improved viral and non-viral gene therapy vectors. In phase I studies, the development of a system is proposed that will allow for the efficient selection of such regulatory elements. This system will also enable selection for sequences that direct persistence of foreign DNA by chromosomal integration or extrachromosomal maintenance. During the phase II studies, the in vivo selection system will be applied to the development of promoters that enable high and stable levels of foreign gene expression in the liver. Such promoters will be used in phase III for the internal development of non-viral vectors for gene therapy applications such as for hemophilia A (factor VIII) within Mirus and licensed to other gene therapy, biotechnology and pharmaceutical companies for use within their non-viral and viral vectors. The development of a clinically viable gene expression system should have tremendous commercial value, given the critical role that it would play in gene therapy (estimated to be a multibillion market by the year 2000). PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL AND MOLECULAR CHEMOTHERAPY OF MALIGNANT CNS TUMORS Principal Investigator & Institution: Buchsbaum, Donald J.; Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-MAY-2007 Summary: This multi-disciplinary group of investigators has several years' experience working together designing and characterizing viral vector approaches to gene therapy of malignant brain tumors. A major focus has been producing and testing both nonreplicative and replicative adenovirus (Ad) and conditionally replicative herpes simplex virus (HSV) vectors that express foreign gene products within infected tumor cells. These studies have been conducted at both the in vitro and in vivo levels to demonstrate proof-of-principle, safety and efficacy in experimental mouse models of intracranial gliomas. We have conducted Phase I and III clinical trials using retrovirus, Ad and HSV administered intratumorally in patients with malignant gliomas. In keeping with the translational theme of this SPORE application, this project seeks to design and deploy effective viral vector therapies of malignant glioma by utilizing rational combinations of foreign gene-viral vectors, oncolytic virus and irradiation., defined by additive, synergistic or antagonistic interactions determined for these various modalities. Aim 1 seeks to optimize the timing and dose of irradiation to achieve greater viral replication and spread and/or enhanced foreign gene expression in glioma cells and in intracranial experimental gliomas. In athymic nude mice. Aim 2 will develop and characterize both replicative HSV and replicative Ad that expression the pro-drug converting enzyme cytosine deaminase and optimize its use in intracranial preclinical models of malignant gliomas in combination with systemic 5-fluorocytosine. Other genetic constructs (uracil phosphoribosyl transferase) and drugs (dihydropyrimidine inhibitors) that facilitate appropriate 5-FU incorporation into host cell DNA synthesis pathways will also be tested to improve the therapeutic effect. Further, the radiation sensitization properties of certain pro-drugs products (5-FU) will be characterized to achieve a greater anti-glioma effect. Aim 3 will combine findings in Aims 1 and 2 to design and test strategies that rationally combine intratumoral viral vector injection, systemic pro-drug administration and low dose external beam irradiation to achieve the most effective and safe antiglioma therapy (ies). Aim 4 will translate our findings in preclinical models for brain tumor therapy into pilot, Phase I and Phase II clinical trials in patients with malignant gliomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRAL VECTORS FOR TARGETED ANTI ANIOGENIC GENE THERAPY Principal Investigator & Institution: Sano, Takeshi; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2003 Summary: (Applicant's Description) The need for repeated administration of anti-factors for long-term therapy of cancer makes gene therapy approaches particularly attractive because sustained expression of anti-angiogenic factors at the tumor site could be achieved. The ability to deliver the anti-angiogenic genes specifically and efficiently to the tumor site will be a key issue for future in vivo anti-angiogenic gene therapy. This exploratory project (R21) aims to design and produce, by using chemical modifications

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as primary means, retroviral gene transfer vectors that have specific infectivity for target tumor cells for in vivo anti-angiogenic gene therapy of cancer. We will use the retroviral gene transfer vectors, consisting of the viral core of spleen necrosis virus (SNV) and the SNV envelope glycoprotein, which have no infectivity for human cells. However, once these retroviral vectors are made capable of binding specifically to the surface of the target human cell, they can mediate efficient infection by using their natural infection capability. We will use a chemical approach, taking advantage of the extremely tight affinity between streptavidin and biotin, to attach a tumor-specific binding reagent to the surface of retroviral gene transfer vectors such that a tumor-specific infectivity can be generated. Glioma cells that over-express the human epidermal growth factor receptor (hEGFR) and monoclonal antibodies against the extracellular domain of hEGFR will be used as targets and binding mediators, respectively, to see if such modified retroviral gene transfer vectors can infect hEGFR-expressing cells specifically and efficiently. In particular, we will characterize, quantitatively, the degree of modification of the retroviral surface and how each of these modifications affects the binding specificity and infectivity of the modified retroviral gene transfer vectors for the glioma cells over- expressing hEGFR. We will then apply this strategy to SNV-based retroviral gene transfer vectors carrying the angiostatin and endostatin cDNA's to see if these genes can be delivered specifically to the target tumor cells over- expressing hEGFR and if they can be expressed efficiently in the tumor cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VP22 TRAFFICKING FOR MAXIMAL GENE THERAPY Principal Investigator & Institution: Splitter, Gary A.; Professor; Animal Hlth & Biomedical Scis; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2004 Summary: (Copied from Applicant Abstract): Gene therapy is a highly promising strategy for a wide variety of biomedical applications including cancer treatment, immunization and gene restoration. VP22 possesses novel trafficking ability where protein produced in one expressing cell, traffics to the nuclei of neighboring nonexpressing cells. Further, VP22 chimerics can carry large, effector proteins without altering the function of the attached proteins. In addition to trafficking, VP22 has novel intracellular localization properties including microtubule association and nuclear targeting. Although most VP22 data have been obtained from studies with herpes simplex virus (HSV-1), we have found bovine herpesvirus-l (BHV-l) VP22 to have improved biotherapeutic potential compared to HSV-VP22. Importantly, BHV- 1 VP22 can traffic a fused effector protein up to 20 times more efficiently than HSV-l. BHV- and HSV-VP22 possess only 28.7 percent amino acid homology with numerous motif differences suggesting the opportunity for considerable diversity in structure and function. Our long-term goal is to maximize VP22-mediated gene therapy by defining VP22 intercellular transport mechanisms as well as in vivo repercussions regarding VP22 biotherapeutic delivery. To accomplish our long-range goal, we have plasmids expressing VP22 of BHV-1 as well as defined VP22 mutants and will elucidate the mechanisms of VP22 that contribute to gene delivery by achieving the following Objectives: 1. We will functionally map the regions of VP22 that govern trafficking and localization. (a) We will engineer truncations of VP22 to evaluate regions responsible for trafficking and nuclear localization. We will build on our data that that the carboxyterminal half of VP22 is essential for trafficking. (b) We will assess the effects of VP22 mutants (tyrosine residues that are phosphorylated and two important cysteines in

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VP22) on trafficking and nuclear localization. (c) We will utilize a novel cross-linking agent and MALDI-mass spectrometry to identify the specific interaction of VP22 with nuclear and cytoplasmic proteins. 2. We will develop and analyze VP22 delivery of thymidine kinase to tumors for suicide gene therapy. (a) We will evaluate the efficiency of VP22 delivery using a suicide gene therapy approach, where fusion genes will be constructed encoding VP22-tk chimeric polypeptides. This construct will be compared to vector-tk only by testing in vitro. (b) We will also evaluate the efficacy of VP22-tk chimeric polypeptides in vivo tumor killing in the presence of ganciclovir. 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 “gene therapy” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for gene therapy in the PubMed Central database: •

A factor IX-deficient mouse model for hemophilia B gene therapy. by Wang L, Zoppe M, Hackeng TM, Griffin JH, Lee KF, Verma IM.; 1997 Oct 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23538

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A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon [alpha]. by Horton HM, Anderson D, Hernandez P, Barnhart KM, Norman JA, Parker SE.; 1999 Feb 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15514

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A Gene Therapy Strategy Using a Transcription Factor Decoy of the E2F Binding Site Inhibits Smooth Muscle Proliferation in vivo. by Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakajima M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ.; 1995 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41600

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A high-throughput hybridization method for titer determination of viruses and gene therapy vectors. by Atkinson EM, Debelak DJ, Hart LA, Reynolds TC.; 1998 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147595

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A model for gene therapy of human hereditary lymphedema. by Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K.; 2001 Oct 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60113

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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A Murine Model for B-Lymphocyte Somatic Cell Gene Therapy. by Sutkowski N, Kuo M, Varela-Eschavarria A, Dougherty JP, Ron Y.; 1994 Sep 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44709

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A Rev-Inducible Mutant gag Gene Stably Transferred into T Lymphocytes: An Approach to Gene Therapy Against Human Immunodeficiency Virus Type 1 Infection. by Smythe JA, Sun D, Thomson M, Markham PD, Reitz MS Jr, Gallo RC, Lisziewicz J.; 1994 Apr 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43640

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Adeno-Associated Virus as a Vector for Liver-Directed Gene Therapy. by Xiao W, Berta SC, Lu MM, Moscioni AD, Tazelaar J, Wilson JM.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=110575

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Adenoviral vectors can impair adrenocortical steroidogenesis: Clinical implications for natural infections and gene therapy. by Alesci S, Ramsey WJ, Bornstein SR, Chrousos GP, Hornsby PJ, Benvenga S, Trimarchi F, Ehrhart-Bornstein M.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124257

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Adenovirus Vectors with the 100K Gene Deleted and Their Potential for Multiple Gene Therapy Applications. by Hodges BL, Evans HK, Everett RS, Ding EY, Serra D, Amalfitano A.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114306

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Adenovirus-Mediated Interleukin-12 Gene Therapy for Metastatic Colon Carcinoma. by Caruso M, Pham-Nguyen K, Kwong Y, Xu B, Kosai K, Finegold M, Woo SL, Chen S.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38052

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Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. by Smith DE, Roberts J, Gage FH, Tuszynski MH.; 1999 Sep 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17979

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An autoregulated dual-function antitat gene for human immunodeficiency virus type 1 gene therapy. by Lisziewicz J, Sun D, Trapnell B, Thomson M, Chang HK, Ensoli B, Peng B.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=188565

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An Efficient Deletion Mutant Packaging System for Defective Herpes Simplex Virus Vectors: Potential Applications to Human Gene Therapy and Neuronal Physiology. by Geller AI, Keyomarsi K, Bryan J, Pardee AB.; 1990 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=55078

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Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. by Lin P, Buxton JA, Acheson A, Radziejewski C, Maisonpierre PC, Yancopoulos GD, Channon KM, Hale LP, Dewhirst MW, George SE, Peters KG.; 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21162

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Antiangiogenic gene therapy. by Folkman J.; 1998 Aug 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33874

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Beta-Adrenergic gene therapy for cardiovascular disease. by Eckhart AD, Koch WJ.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59618

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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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Brain-directed gene therapy for lysosomal storage disease: Going well beyond the blood -- brain barrier. by Sly WS, Vogler C.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122848

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Bronchoalveolar Fluid Is Not a Major Hindrance to Virus-Mediated Gene Therapy in Cystic Fibrosis. by Rooney CP, Denning GM, Davis BP, Flaherty DM, Chiorini JA, Zabner J.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136549

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Cellular and humoral immune responses to viral antigens create barriers to lungdirected gene therapy with recombinant adenoviruses. by Yang Y, Li Q, Ertl HC, Wilson JM.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=188865

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Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: Implications for gene therapy. by Kafri T, Morgan D, Krahl T, Sarvetnick N, Sherman L, Verma I.; 1998 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21650

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Cellular Immunity to Viral Antigens Limits E1-Deleted Adenoviruses for Gene Therapy. by Yang Y, Nunes FA, Berencsi K, Furth EE, Gonczol E, Wilson JM.; 1994 May 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43794

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CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis. by Liu Z, Xu X, Hsu HC, Tousson A, Yang PA, Wu Q, Liu C, Yu S, Zhang HG, Mountz JD.; 2003 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=228459

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Combination Gene Therapy for Liver Metastasis of Colon Carcinoma in vivo. by Chen S, Chen XH, Wang Y, Kosai K, Finegold MJ, Rich SS.; 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42261

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Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model. by Griscelli F, Li H, Cheong C, Opolon P, Bennaceur-Griscelli A, Vassal G, Soria J, Soria C, Lu H, Perricaudet M, Yeh P.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18707

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Construction of a Single-Chain Interleukin-12-Expressing Retroviral Vector and Its Application in Cytokine Gene Therapy against Experimental Coccidioidomycosis. by Jiang C, Magee DM, Cox RA.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96611

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Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. by Muzzin P, Eisensmith RC, Copeland KC, Woo SL.; 1996 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26217

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Creation of Drug-Specific Herpes Simplex Virus Type 1 Thymidine Kinase Mutants for Gene Therapy. by Black ME, Newcomb TG, Wilson HP, Loeb LA.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39643

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Development of HIV Vectors for Anti-HIV Gene Therapy. by Poeschla E, Corbeau P, Wong-Staal F.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38068

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Development of optimized vectors for gene therapy. by Nabel GJ.; 1999 Jan 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33542

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Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. by Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O'Doherty R, Newgard CB, Unger RH.; 1996 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26215

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Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility. by Ennis IL, Li RA, Murphy AM, Marban E, Nuss HB.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150851

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E- vectors: development of novel self-inactivating and self-activating retroviral vectors for safer gene therapy. by Julias JG, Hash D, Pathak VK.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189597

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Elimination of both E1 and E2 from adenovirus vectors further improves prospects for in vivo human gene therapy. by Gorziglia MI, Kadan MJ, Yei S, Lim J, Lee GM, Luthra R, Trapnell BC.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190312

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Epitope Mapping of Human Anti-Adeno-Associated Virus Type 2 Neutralizing Antibodies: Implications for Gene Therapy and Virus Structure. by Moskalenko M, Chen L, van Roey M, Donahue BA, Snyder RO, McArthur JG, Patel SD.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111652

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Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor [beta] Antisense Gene Therapy. by Fakhrai H, Dorigo O, Shawler DL, Lin H, Mercola D, Black KL, Royston I, Sobol RE.; 1996 Apr 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39733

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Evaluation of beta-globin gene therapy constructs in single copy transgenic mice. by Ellis J, Pasceri P, Tan-Un KC, Wu X, Harper A, Fraser P, Grosveld F.; 1997 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146564

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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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Exchange of Viral Promoter/Enhancer Elements with Heterologous Regulatory Sequences Generates Targeted Hybrid Long Terminal Repeat Vectors for Gene Therapy of Melanoma. by Diaz RM, Eisen T, Hart IR, Vile RG.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109437

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Expression of Human Factor IX in Rabbit Hepatocytes by Retrovirus-Mediated Gene Transfer: Potential for Gene Therapy of Hemophilia B. by Armentano D, Thompson AR, Darlington G, Woo SL.; 1990 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54488

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Expression of Human Factor IX in Rat Capillary Endothelial Cells: Toward Somatic Gene Therapy for Hemophilia B. by Yao S, Wilson JM, Nabel EG, Kurachi S, Hachiya HL, Kurachi K.; 1991 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52454

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Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy. by Minter RM, Ferry MA, Rectenwald JE, Bahjat FR, Oberholzer A, Oberholzer C, La Face D, Tsai V, Ahmed CM, Hutchins B, Copeland EM III, Ginsberg HS, Moldawer LL.; 2001 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14581

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FHIT gene therapy prevents tumor development in Fhit-deficient mice. by Dumon KR, Ishii H, Fong LY, Zanesi N, Fidanza V, Mancini R, Vecchione A, Baffa R, Trapasso F, During MJ, Huebner K, Croce CM.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30656

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Full Functional Rescue of a Complete Muscle (TA) in Dystrophic Hamsters by Adeno-Associated Virus Vector-Directed Gene Therapy. by Xiao X, Li J, Tsao YP, Dressman D, Hoffman EP, Watchko JF.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=111478

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Fusigenic Viral Liposome for Gene Therapy in Cardiovascular Diseases. by Dzau VJ, Mann MJ, Morishita R, Kaneda Y.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38072

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Future of adenoviruses in the gene therapy of arthritis. by Evans CH, Ghivizzani SC, Oligino TA, Robbins PD.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128890

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Gene Therapy for Brain Tumors: Regression of Experimental Gliomas by Adenovirus-Mediated Gene Transfer in vivo. by Chen S, Shine HD, Goodman JC, Grossman RG, Woo SL.; 1994 Apr 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43513

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Gene Therapy for Diabetes Mellitus in Rats by Hepatic Expression of Insulin. by Kolodka TM, Finegold M, Moss L, Woo SL.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42152

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Gene therapy for established murine collagen-induced arthritis by local and systemic adenovirus-mediated delivery of interleukin-4. by Kim SH, Evans CH, Kim S, Oligino T, Ghivizzani SC, Robbins PD.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17812

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Gene Therapy for Hemophilia A: Production of Therapeutic Levels of Human Factor VIII in vivo in Mice. by Dwarki VJ, Belloni P, Nijjar T, Smith J, Couto L, Rabier M, Clift S, Berns A, Cohen LK.; 1995 Feb 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42629

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Gene Therapy for Infectious Diseases. by Bunnell BA, Morgan RA.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=121375

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Gene therapy for lipid disorders. by Kawashiri MA, Rader DJ.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59613

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Gene Therapy for Long-Term Expression of Erythropoietin in Rats. by Osborne WR, Ramesh N, Lau S, Clowes MM, Dale DC, Clows AW.; 1995 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41285

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Gene therapy for the hemoglobin disorders: Past, present, and future. by Persons DA, Nienhuis AW.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33980

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Gene therapy for the hemophilias. by Kay MA, High K.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33717

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Gene therapy in allergic encephalomyelitis using myelin basic protein-specific T cells engineered to express latent transforming growth factor-[beta]1. by Chen LZ, Hochwald GM, Huang C, Dakin G, Tao H, Cheng C, Simmons WJ, Dranoff G, Thorbecke GJ.; 1998 Oct 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22862

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Gene therapy in plants. by Hohn B, Puchta H.; 1999 Jul 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33619

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Gene therapy in rheumatoid arthritis: how to target joint destruction? by Pap T, Muller-Ladner U, Gay R, Gay S.; 1999; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128862

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Gene Therapy Inhibiting Neointimal Vascular Lesion: In vivo Transfer of Endothelial Cell Nitric Oxide Synthase Gene. by von der Leyen HE, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ.; 1995 Feb 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42653

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Gene therapy moves forward - The Second International Meeting on Gene and Cell Therapies of Arthritis and Related Disorders, 17-18 May 2001, Montpellier, France. by Robbins PD, Jorgensen C, Evans CH.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128905

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Gene Therapy of Murine Teratocarcinoma: Separate Functions for Insulin-Like Growth Factors I and II in Immunogenicity and Differentiation. by Trojan J, Johnson TR, Rudin SD, Blossey BK, Kelley KM, Shevelev A, Abdul-Karim FW, Anthony DD, Tykocinski ML, Ilan J, Ilan J.; 1994 Jun 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44143

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Gene Therapy of Rat 9L Gliosarcoma Tumors by Transduction with Selectable Genes Does Not Require Drug Selection. by Tapscott SJ, Miller AD, Olson JM, Berger MS, Groudine M, Spence AM.; 1994 Aug 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44570

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Gene therapy to promote thromboresistance: Local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. by Waugh JM, Kattash M, Li J, Yuksel E, Kuo MD, Lussier M, Weinfeld AB, Saxena R, Rabinovsky ED, Thung S, Woo SL, Shenaq SM.; 1999 Feb 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15351

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Gene Therapy Vectors Based on Adeno-Associated Virus Type 1. by Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104178

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Gene Therapy Via Primary Myoblasts: Long-Term Expression of Factor IX Protein Following Transplantation in vivo. by Dai Y, Roman M, Naviaux RK, Verma IM.; 1992 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50448

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Gene therapy with a single chain interleukin 12 fusion protein induces T celldependent protective immunity in a syngeneic model of murine neuroblastoma. by Lode HN, Dreier T, Xiang R, Varki NM, Kang AS, Reisfeld RA.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19380

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Gene therapy. by Kay MA, Liu D, Hoogerbrugge PM.; 1997 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34169

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Gene Therapy. by Weissman SM.; 1992 Dec 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50498

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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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Genetically Engineered Vesicular Stomatitis Virus in Gene Therapy: Application for Treatment of Malignant Disease. by Fernandez M, Porosnicu M, Markovic D, Barber GN.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136833

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Hematopoietic stem cell gene therapy: selecting only the best. by Bank A.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=259135

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Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver. by Zhang HG, Xie J, Xu L, Yang P, Xu X, Sun S, Wang Y, Curiel DT, Hsu HC, Mountz JD.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=137014

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Hepatic Gene Therapy: Adenovirus Enhancement of Receptor-Mediated Gene Delivery and Expression in Primary Hepatocytes. by Cristiano RJ, Smith LC, Woo SL.; 1993 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46037

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Hepatic Gene Therapy: Efficient Gene Delivery and Expression in Primary Hepatocytes Utilizing a Conjugated Adenovirus-DNA Complex. by Cristiano RJ, Smith LC, Kay MA, Brinkley BR, Woo SL.; 1993 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48021

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Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia. by Lee B, Dennis JA, Healy PJ, Mull B, Pastore L, Yu H, Aguilar-Cordova E, O'Brien W, Reeds P, Beaudet AL.; 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22406

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Highly efficient electro-gene therapy of solid tumor by using an expression plasmid for the herpes simplex virus thymidine kinase gene. by Goto T, Nishi T, Tamura T, Dev SB, Takeshima H, Kochi M, Yoshizato K, Kuratsu JI, Sakata T, Hofmann GA, Ushio Y.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26667

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Human Immunodeficiency Virus (HIV) Type 2-Mediated Inhibition of HIV Type 1: A New Approach to Gene Therapy of HIV Infection. by Arya SK, Gallo RC.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39565

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In vivo Hepatic Gene Therapy: Complete Albeit Transient Correction of Factor IX Deficiency in Hemophilia B Dogs. by Kay MA, Landen CN, Rothenberg SR, Taylor LA, Leland F, Wiehle S, Fang B, Bellinger D, Finegold M, Thompson AR, Read M, Brinkhous KM, Woo SL.; 1994 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43369

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Inhibition of Human Immunodeficiency Virus Type 1 Replication by Regulated Expression of a Polymeric Tat Activation Response RNA Decoy as a Strategy for Gene Therapy in AIDS. by Lisziewicz J, Sun D, Smythe J, Lusso P, Lori F, Louie A, Markham P, Rossi J, Reitz M, Gallo RC.; 1993 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47275

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Interferon-[beta] gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice. by Qin XQ, Tao N, Dergay A, Moy P, Fawell S, Davis A, Wilson JM, Barsoum J.; 1998 Nov 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24387

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Interleukin-10 Gene Therapy-Mediated Amelioration of Bacterial Pneumonia. by Morrison DF, Foss DL, Murtaugh MP.; 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98427

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Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. by Chu P, Deforce D, Pedersen IM, Kim Y, Kitada S, Reed JC, Kipps TJ.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122613

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Liver-Directed Gene Therapy: Quantitative Evaluation of Promoter Elements by Using in vivo Retroviral Transduction. by Rettinger SD, Kennedy SC, Wu X, Saylors RL, Hafenrichter DG, Flye MW, Ponder KP.; 1994 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43179

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Long-Term Expression of Human Adenosine Deaminase in Vascular Smooth Muscle Cells of Rats: A Model for Gene Therapy. by Lynch CM, Clowes MM, Osborne WR, Clowes AW, Miller AD.; 1992 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48401

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Lymphocytes as Cellular Vehicles for Gene Therapy in Mouse and Man. by Culver K, Cornetta K, Morgan R, Morecki S, Aebersold P, Kasid A, Lotze M, Rosenberg SA, Anderson WF, Blaese RM.; 1991 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51404

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Murine leukemia virus-based Tat-inducible long terminal repeat replacement vectors: a new system for anti-human immunodeficiency virus gene therapy. by Cannon PM, Kim N, Kingsman SM, Kingsman AJ.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190909

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Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. by Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM.; 2002 Sep 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129358

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Osteoblast-specific gene expression after transplantation of marrow cells: Implications for skeletal gene therapy. by Hou Z, Nguyen Q, Frenkel B, Nilsson SK, Milne M, van Wijnen AJ, Stein JL, Quesenberry P, Lian JB, Stein GS.; 1999 Jun 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22079

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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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Plasmoviruses: Nonviral/Viral Vectors for Gene Therapy. by Noguiez-Hellin P, Meur MR, Salzmann J, Klatzmann D.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39507

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Polyamine structural effects on the induction and stabilization of liquid crystalline DNA: potential applications to DNA packaging, gene therapy and polyamine therapeutics. by Saminathan M, Thomas T, Shirahata A, Pillai CK, Thomas TJ.; 2002 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=137425

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Preselective gene therapy for Fabry disease. by Qin G, Takenaka T, Telsch K, Kelley L, Howard T, Levade T, Deans R, Howard BH, Malech HL, Brady RO, Medin JA.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30670

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Prevention of renovascular and cardiac pathophysiological changes in hypertension by angiotensin II type 1 receptor antisense gene therapy. by Martens JR, Reaves PY, Lu D, Katovich MJ, Berecek KH, Bishop SP, Raizada MK, Gelband CH.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19454

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Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. by Malech HL, Maples PB, Whiting-Theobald N, Linton GF, Sekhsaria S, Vowells SJ, Li F, Miller JA, DeCarlo E, Holland SM, Leitman SF, Carter CS, Butz RE, Read EJ, Fleisher TA, Schneiderman RD, Van Epps DE, Spratt SK, Maack CA, Rokovich JA, Cohen LK, Gallin JI.; 1997 Oct 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23727

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Recombinant Human Hemoglobins Designed for Gene Therapy of Sickle Cell Disease. by McCune SL, Reilly MP, Chomo MJ, Asakura T, Townes TM.; 1994 Oct 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44915

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Repression of retrovirus-mediated transgene expression by interferons: implications for gene therapy. by Ghazizadeh S, Carroll JM, Taichman LB.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230218

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Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: Amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters. by Kawada T, Nakazawa M, Nakauchi S, Yamazaki K, Shimamoto R, Urabe M, Nakata J, Hemmi C, Masui F, Nakajima T, Suzuki JI, Monahan J, Sato H, Masaki T, Ozawa K, Toyo-oka T.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117403

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Retroviral Transfer of a Human [beta]-Globin/[delta]-Globin Hybrid Gene Linked to [beta] Locus Control Region Hypersensitive Site 2 Aimed at the Gene Therapy of Sickle Cell Disease. by Takekoshi KJ, Oh YH, Westerman KW, London IM, Leboulch P.; 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42349

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Retroviral-Mediated Gene Therapy for the Treatment of Hepatocellular carcinoma: An Innovative Approach for Cancer Therapy. by Huber BE, Richards CA, Krenitsky TA.; 1991 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52441

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RNA Enzyme-Directed Gene Therapy. by Altman S.; 1993 Dec 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=47887

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Safety-modified episomal vectors for human gene therapy. by Cooper MJ, Lippa M, Payne JM, Hatzivassiliou G, Reifenberg E, Fayazi B, Perales JC, Morrison LJ, Templeton D, Piekarz RL, Tan J.; 1997 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21070

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Self-deleting retrovirus vectors for gene therapy. by Russ AP, Friedel C, Grez M, von Melchner H.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190443

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Sparing of neuronal function postseizure with gene therapy. by McLaughlin J, Roozendaal B, Dumas T, Gupta A, Ajilore O, Hsieh J, Ho D, Lawrence M, McGaugh JL, Sapolsky R.; 2000 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18845

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Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. by Wang L, Takabe K, Bidlingmaier SM, Ill CR, Verma IM.; 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22393

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Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1[beta] converting enzyme cDNA. by Oshikawa K, Shi F, Rakhmilevich AL, Sondel PM, Mahvi DM, Yang NS.; 1999 Nov 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23951

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Systemic Gene Therapy: Biodistribution and Long-Term Expression of a Transgene in Mice. by Thierry AR, Lunardi-Iskandar Y, Bryant JL, Rabinovich P, Gallo RC, Mahan LC.; 1995 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40878

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Taking stock of gene therapy for cystic fibrosis. by Stern M, Geddes DM, Alton EW.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59546

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The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. by Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T, Azzi A, Chapman MS.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124927

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The Human Genome Project: ethical and social implications. by Murray TH, Livny E.; 1995 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=225990

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The lung as a metabolic factory for gene therapy. by Engelhardt JF.; 2002 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150422

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Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs. by Ponder KP, Melniczek JR, Xu L, Weil MA, O'Malley TM, O'Donnell PA, Knox VW, Aguirre GD, Mazrier H, Ellinwood NM, Sleeper M, Maguire AM, Volk SW, Mango RL, Zweigle J, Wolfe JH, Haskins ME.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130593

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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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Towards integrating vectors for gene therapy: expression of functional bacteriophage MuA and MuB proteins in mammalian cells. by Schagen FH, Rademaker HJ, Cramer SJ, van Ormondt H, van der Eb AJ, van de Putte P, Hoeben RC.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115188

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Transcriptional control of viral gene therapy by cisplatin. by Park JO, Lopez CA, Gupta VK, Brown CK, Mauceri HJ, Darga TE, Manan A, Hellman S, Posner MC, Kufe DW, Weichselbaum RR.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151093

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Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. by Fisher KJ, Gao GP, Weitzman MD, DeMatteo R, Burda JF, Wilson JM.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189840

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Transgenic studies with a keratin promoter-driven growth hormone transgene: Prospects for gene therapy. by Wang X, Zinkel S, Polonsky K, Fuchs E.; 1997 Jan 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19291

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Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. by Yan Z, Zhang Y, Duan D, Engelhardt JF.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18714

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Treatment of a Human Breast Cancer Xenograft with an Adenovirus Vector Containing an Interferon Gene Results in Rapid Regression due to Viral Oncolysis and Gene Therapy. by Zhang J, Hu C, Geng Y, Selm J, Klein SB, Orazi A, Taylor MW.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39570

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Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12. by Lode HN, Xiang R, Duncan SR, Theofilopoulos AN, Gillies SD, Reisfeld RA.; 1999 Jul 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17561

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VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. by Yoon YS, Murayama T, Gravereaux E, Tkebuchava T, Silver M, Curry C, Wecker A, Kirchmair R, Hu CS, Kearney M, Ashare A, Jackson DG, Kubo H, Isner JM, Losordo DW.; 2003 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151891

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Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency. by Bunting KD, Flynn KJ, Riberdy JM, Doherty PC, Sorrentino BP.; 1999 Jan 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15122

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Yaba-Like Disease Virus: an Alternative Replicating Poxvirus Vector for Cancer Gene Therapy. by Hu Y, Lee J, McCart JA, Xu H, Moss B, Alexander HR, Bartlett DL.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114604

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 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

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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 gene therapy, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “gene therapy” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for gene therapy (hyperlinks lead to article summaries): •

A highly efficient, stable, and rapid approach for ex vivo human liver gene therapy via a FLAP lentiviral vector. Author(s): Giannini C, Morosan S, Tralhao JG, Guidotti JE, Battaglia S, Mollier K, Hannoun L, Kremsdorf D, Gilgenkrantz H, Charneau P. Source: Hepatology (Baltimore, Md.). 2003 July; 38(1): 114-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829993&dopt=Abstract

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A model for antimicrobial gene therapy: demonstration of human beta-defensin 2 antimicrobial activities in vivo. Author(s): Huang GT, Zhang HB, Kim D, Liu L, Ganz T. Source: Human Gene Therapy. 2002 November 20; 13(17): 2017-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12489997&dopt=Abstract

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A model for the analysis of nonviral gene therapy. Author(s): Banks GA, Roselli RJ, Chen R, Giorgio TD. Source: Gene Therapy. 2003 September; 10(20): 1766-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939643&dopt=Abstract

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A new colloidal lipidic system for gene therapy. Author(s): Fahr A, Muller K, Nahde T, Muller R, Brusselbach S. Source: Journal of Liposome Research. 2002 February-May; 12(1-2): 37-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604036&dopt=Abstract

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A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. Author(s): Grines CL, Watkins MW, Mahmarian JJ, Iskandrian AE, Rade JJ, Marrott P, Pratt C, Kleiman N; Angiogene GENe Therapy (AGENT-2) Study Group. Source: Journal of the American College of Cardiology. 2003 October 15; 42(8): 1339-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563572&dopt=Abstract

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.

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A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. Author(s): Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A. Source: The New England Journal of Medicine. 2003 January 16; 348(3): 255-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529469&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571646&dopt=Abstract

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Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice. Author(s): Liu P, Wang Y, Li YH, Yang C, Zhou YL, Li B, Lu SH, Yang RC, Cai YL, Tobelem G, Caen J, Han ZC. Source: Leukemia Research. 2003 August; 27(8): 701-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801528&dopt=Abstract

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Adenovirus-mediated interleukin-2 gene therapy of nociception. Author(s): Yao MZ, Gu JF, Wang JH, Sun LY, Liu H, Liu XY. Source: Gene Therapy. 2003 August; 10(16): 1392-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883536&dopt=Abstract

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Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer. Author(s): Sasaki Y, Morimoto I, Ishida S, Yamashita T, Imai K, Tokino T. Source: Gene Therapy. 2001 September; 8(18): 1401-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11571580&dopt=Abstract

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Advances in a gene therapy-based approach to treat proliferative vitreoretinopathy. Author(s): Kazlauskas A. Source: Archivos De La Sociedad Espanola De Oftalmologia. 2003 January; 78(1): 3-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571766&dopt=Abstract

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Advances in Duchenne muscular dystrophy gene therapy. Author(s): van Deutekom JC, van Ommen GJ. Source: Nature Reviews. Genetics. 2003 October; 4(10): 774-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526374&dopt=Abstract

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Advances in gene therapy for bladder cancer. Author(s): Irie A. Source: Current Gene Therapy. 2003 February; 3(1): 1-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553531&dopt=Abstract

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Aerosol gene therapy. Author(s): Gautam A, Waldrep JC, Densmore CL. Source: Molecular Biotechnology. 2003 January; 23(1): 51-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12611269&dopt=Abstract

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Alphavirus vectors as tools in cancer gene therapy. Author(s): Lundstrom K. Source: Technology in Cancer Research & Treatment. 2002 February; 1(1): 83-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614181&dopt=Abstract

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Alphavirus vectors for vaccine production and gene therapy. Author(s): Lundstrom K. Source: Expert Rev Vaccines. 2003 June; 2(3): 447-59. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12903809&dopt=Abstract

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Angiogenic gene therapy. Author(s): Sylven C. Source: Drugs Today (Barc). 2002 December; 38(12): 819-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12582471&dopt=Abstract

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Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene. Author(s): Ishikawa H, Nakao K, Matsumoto K, Ichikawa T, Hamasaki K, Nakata K, Eguchi K. Source: Hepatology (Baltimore, Md.). 2003 March; 37(3): 696-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601367&dopt=Abstract

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Applied gene therapy in preclinical models of vascular injury. Author(s): Janssens SP. Source: Current Atherosclerosis Reports. 2003 May; 5(3): 186-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667430&dopt=Abstract

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Approaches to gene therapy with sodium/iodide symporter. Author(s): Spitzweg C, Morris JC. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2001; 109(1): 56-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11573142&dopt=Abstract

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Baculovirus as mammalian cell expression vector for gene therapy: an emerging strategy. Author(s): Ghosh S, Parvez MK, Banerjee K, Sarin SK, Hasnain SE. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 July; 6(1): 5-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095297&dopt=Abstract

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Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Author(s): Ferrari S, Geddes DM, Alton EW. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1373-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458150&dopt=Abstract

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Basic studies on gene therapy of human malignant melanoma by use of the human interferon beta gene entrapped in cationic multilamellar liposomes. 1. Morphology and growth rate of six melanoma cell lines used in transfection experiments with the human interferon beta gene. Author(s): Benga G. Source: Journal of Cellular and Molecular Medicine. 2001 October-December; 5(4): 402-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067474&dopt=Abstract

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Bax-induced apoptosis as a novel gene therapy approach for carcinoma of the cervix. Author(s): Huh WK, Gomez-Navarro J, Arafat WO, Xiang J, Mahasreshti PJ, Alvarez RD, Barnes MN, Curiel DT. Source: Gynecologic Oncology. 2001 November; 83(2): 370-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11606099&dopt=Abstract

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Bax-induction gene therapy of pancreatic cancer. Author(s): Pirocanac EC, Nassirpour R, Yang M, Wang J, Nardin SR, Gu J, Fang B, Moossa AR, Hoffman RM, Bouvet M. Source: The Journal of Surgical Research. 2002 August; 106(2): 346-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12175991&dopt=Abstract

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Bi-functional cytokine fusion proteins for gene therapy and antibody-targeted treatment of cancer. Author(s): Gillies SD, Lan Y, Brunkhorst B, Wong WK, Li Y, Lo KM. Source: Cancer Immunology, Immunotherapy : Cii. 2002 October; 51(8): 449-60. Epub 2002 July 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12202906&dopt=Abstract

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Biochemical and biophysical characteristics of lipoplexes pertinent to solid tumour gene therapy. Author(s): Dass CR. Source: International Journal of Pharmaceutics. 2002 July 8; 241(1): 1-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12086717&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11249755&dopt=Abstract

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Bioreductive and gene therapy approaches to hypoxic diseases. Author(s): Jaffar M, Williams KJ, Stratford IJ. Source: Advanced Drug Delivery Reviews. 2001 December 17; 53(2): 217-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731027&dopt=Abstract

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Biotechnology on the RAC--FDA/NIH regulation of human gene therapy. Author(s): Rainsbury JM. Source: Food Drug Law J. 2000; 55(4): 575-600. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12025851&dopt=Abstract

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Bone marrow mesenchymal cells for haemophilia A gene therapy using retroviral vectors with modified long-terminal repeats. Author(s): Van Damme A, Chuah MK, Dell'accio F, De Bari C, Luyten F, Collen D, VandenDriessche T. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. 2003 January; 9(1): 94-103. Erratum In: Haemophilia. 2003 May; 9(3): 345. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558785&dopt=Abstract

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Bone marrow stem cell gene therapy of arylsulfatase A-deficient mice, using an arylsulfatase A mutant that is hypersecreted from retrovirally transduced donor-type cells. Author(s): Matzner U, Schestag F, Hartmann D, Lullmann-Rauch R, D'Hooge R, De Deyn PP, Gieselmann V. Source: Human Gene Therapy. 2001 June 10; 12(9): 1021-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11399225&dopt=Abstract

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Bone marrow stromal cells as targets for gene therapy. Author(s): Van Damme A, Vanden Driessche T, Collen D, Chuah MK. Source: Current Gene Therapy. 2002 May; 2(2): 195-209. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109216&dopt=Abstract

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Bone morphogenetic protein 7 ex vivo gene therapy. Author(s): Rutherford RB, Nussenbaum B, Krebsbach PH. Source: Drug News Perspect. 2003 January-February; 16(1): 5-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682667&dopt=Abstract

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Bone morphogenetic protein gene therapy. Author(s): Alden TD, Varady P, Kallmes DF, Jane JA Jr, Helm GA. Source: Spine. 2002 August 15; 27(16 Suppl 1): S87-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205425&dopt=Abstract

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Brain games. Alzheimer's gene therapy. Author(s): Gorman C. Source: Time. 2001 April 23; 157(16): 64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11330026&dopt=Abstract

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Brain ischemia as a potential target of gene therapy. Author(s): Ooboshi H, Ibayashi S, Takada J, Kumai Y, Iida M. Source: Experimental Gerontology. 2003 January-February; 38(1-2): 183-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543276&dopt=Abstract

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Brain-directed gene therapy for lysosomal storage disease: going well beyond the blood- brain barrier. Author(s): Sly WS, Vogler C. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 April 30; 99(9): 5760-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11983877&dopt=Abstract

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Breakthroughs in cancer gene therapy. Author(s): Liu K. Source: Semin Oncol Nurs. 2003 August; 19(3): 217-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962011&dopt=Abstract

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Bronchoalveolar fluid is not a major hindrance to virus-mediated gene therapy in cystic fibrosis. Author(s): Rooney CP, Denning GM, Davis BP, Flaherty DM, Chiorini JA, Zabner J. Source: Journal of Virology. 2002 October; 76(20): 10437-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239320&dopt=Abstract

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Cancer fears cast doubts on future of gene therapy. Author(s): Check E. Source: Nature. 2003 February 13; 421(6924): 678. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610583&dopt=Abstract

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Cancer gene therapy. Author(s): Douglas JT. Source: Technology in Cancer Research & Treatment. 2003 February; 2(1): 51-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625754&dopt=Abstract

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Cancer risk prompts US to curb gene therapy. Author(s): Check E. Source: Nature. 2003 March 6; 422(6927): 7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621402&dopt=Abstract

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CaSm antisense gene therapy: a novel approach for the treatment of pancreatic cancer. Author(s): Kelley JR, Fraser MM, Hubbard JM, Watson DK, Cole DJ. Source: Anticancer Res. 2003 May-June; 23(3A): 2007-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894573&dopt=Abstract

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Celiac disease: a model autoimmune disease with gene therapy applications. Author(s): Londei M, Quaratino S, Maiuri L. Source: Gene Therapy. 2003 May; 10(10): 835-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732869&dopt=Abstract

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Chemo-radio-gene therapy for colorectal cancer cells using Escherichia coli uracil phosphoribosyltransferase gene. Author(s): Koyama F, Fujii H, Mukogawa T, Ueno M, Hamada H, Ishikawa H, Doi S, Nakao T, Matsumoto H, Shimatani H, Takeuchi T, Nakajima Y. Source: Anticancer Res. 2003 March-April; 23(2B): 1343-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820392&dopt=Abstract

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Chromosome-based vectors for gene therapy. Author(s): Lipps HJ, Jenke AC, Nehlsen K, Scinteie MF, Stehle IM, Bode J. Source: Gene. 2003 January 30; 304: 23-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568712&dopt=Abstract

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Clinical applications of p53-directed gene therapy. Author(s): Wadler S, Makower D, Yu B, Tan JY, Rozenblit A, Kaufman H, Edelman M, Lane ME, Zwiebel J. Source: Suppl Tumori. 2002 November-December; 1(6): S21. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658897&dopt=Abstract

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Clinical development of gene therapy for colorectal cancer. Author(s): Kerr D. Source: Nature Reviews. Cancer. 2003 August; 3(8): 615-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894249&dopt=Abstract

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Clinical trials for cancer gene therapy. Author(s): Cusack JC Jr. Source: Surg Oncol Clin N Am. 2002 July; 11(3): 717-825. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487064&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810206&dopt=Abstract

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Combined radiation and cytochrome CYP4B1/4-ipomeanol gene therapy using the EGR1 promoter. Author(s): Hsu H, Rainov NG, Quinones A, Eling DJ, Sakamoto KM, Spear MA. Source: Anticancer Res. 2003 May-June; 23(3B): 2723-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894565&dopt=Abstract

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Construction of a high efficiency retroviral vector for gene therapy of Hunter's syndrome. Author(s): Hong Y, Yu SS, Kim JM, Lee K, Na YS, Whitley CB, Sugimoto Y, Kim S. Source: The Journal of Gene Medicine. 2003 January; 5(1): 18-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516048&dopt=Abstract

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Construction of a regulable gene therapy vector targeting for hepatocellular carcinoma. Author(s): Lu SY, Sui YF, Li ZS, Pan CE, Ye J, Wang WY. Source: World Journal of Gastroenterology : Wjg. 2003 April; 9(4): 688-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679911&dopt=Abstract

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Correspondence re: Y. S. Haviv, J. L. Blackwell, A. Kanerva, P. Nagi, V. Krasnykh, I. Dmitriev, M. Wang, S. Naito, X. Lei, A. Hemminki, D. Carey, and D. T. Curiel, Adenoviral gene therapy for renal cancer requires retargeting to alternative cellular receptors. Cancer Res., 62: 4273-4281, 2002. Author(s): Jongmans W, Tiemessen DM, Oosterwijk E, Mulders PF. Source: Cancer Research. 2003 April 15; 63(8): 1994-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702594&dopt=Abstract

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Coxsackie B and adenovirus receptor, integrin and major histocompatibility complex class I expression in human prostate cancer cell lines: implications for gene therapy strategies. Author(s): Pandha HS, Stockwin LH, Eaton J, Clarke IA, Dalgleish AG, Todryk SM, Blair GE. Source: Prostate Cancer and Prostatic Diseases. 2003; 6(1): 6-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12664058&dopt=Abstract

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Current concepts of gene therapy and cartilage repair. Author(s): Martinek V, Ueblacker P, Imhoff AB. Source: The Journal of Bone and Joint Surgery. British Volume. 2003 August; 85(6): 7828. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12931792&dopt=Abstract

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Current developments in the design of onco-retrovirus and lentivirus vector systems for hematopoietic cell gene therapy. Author(s): Brenner S, Malech HL. Source: Biochimica Et Biophysica Acta. 2003 April 7; 1640(1): 1-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676350&dopt=Abstract

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Current status of gene therapy for hemophilia. Author(s): Nathwani AC, Nienhuis AW, Davidoff AM. Source: Curr Hematol Rep. 2003 July; 2(4): 319-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901329&dopt=Abstract

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Current status of gene therapy for inherited lung diseases. Author(s): Driskell RA, Engelhardt JF. Source: Annual Review of Physiology. 2003; 65: 585-612. Epub 2002 May 01. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524461&dopt=Abstract

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Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy. Author(s): Brown BD, Lillicrap D. Source: Blood. 2002 August 15; 100(4): 1133-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149189&dopt=Abstract

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Defining gene transfer before expecting gene therapy: putting the horse before the cart. Author(s): Pislaru S, Janssens SP, Gersh BJ, Simari RD. Source: Circulation. 2002 July 30; 106(5): 631-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12147548&dopt=Abstract

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Delivering gene therapy. Author(s): Seymour LW. Source: Journal of Drug Targeting. 2002 March; 10(2): 91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074544&dopt=Abstract

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Demonstration of feasibility of in vivo gene therapy for Gaucher disease using a chemically induced mouse model. Author(s): Marshall J, McEachern KA, Kyros JA, Nietupski JB, Budzinski T, Ziegler RJ, Yew NS, Sullivan J, Scaria A, van Rooijen N, Barranger JA, Cheng SH. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 August; 6(2): 179-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161184&dopt=Abstract

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Dendritic cell gene therapy. Author(s): Onaitis M, Kalady MF, Pruitt S, Tyler DS. Source: Surg Oncol Clin N Am. 2002 July; 11(3): 645-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487060&dopt=Abstract

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Design of gene therapy clinical trials in CF patients. Author(s): Curlee KV, Sorscher EJ. Source: Methods in Molecular Medicine. 2002; 70: 575-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11917552&dopt=Abstract

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Development of a biosensor-based method for detection and isotyping of antibody responses to adenoviral-based gene therapy vectors. Author(s): Abad LW, Neumann M, Tobias L, Obenauer-Kutner L, Jacobs S, Cullen C. Source: Analytical Biochemistry. 2002 November 1; 310(1): 107-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12413480&dopt=Abstract

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Development of a gene therapy strategy for the restoration of survival motor neuron protein expression: implications for spinal muscular atrophy therapy. Author(s): DiDonato CJ, Parks RJ, Kothary R. Source: Human Gene Therapy. 2003 January 20; 14(2): 179-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614569&dopt=Abstract

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Development of an adenovirus-shedding assay for the detection of adenoviral vectorbased vaccine and gene therapy products in clinical specimens. Author(s): Wang F, Patel DK, Antonello JM, Washabaugh MW, Kaslow DC, Shiver JW, Chirmule N. Source: Human Gene Therapy. 2003 January 1; 14(1): 25-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573056&dopt=Abstract

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Development of gene therapy for blood disorders by gene transfer into haematopoietic stem cells. Author(s): Karlsson S, Ooka A, Woods NB. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. 2002 May; 8(3): 255-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12010420&dopt=Abstract

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Development of gene therapy for hematopoietic stem cells using lentiviral vectors. Author(s): Woods NB, Ooka A, Karlsson S. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 April; 16(4): 563-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11960333&dopt=Abstract

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Development of gene therapy for hemoglobin disorders. Author(s): Nienhuis AW, Hanawa H, Sawai N, Sorrentino BP, Persons DA. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 101-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799288&dopt=Abstract

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Development of gene therapy using prostate-specific membrane antigen promoter/enhancer with Cre Recombinase/LoxP system for prostate cancer cells under androgen ablation condition. Author(s): Ikegami S, Tadakuma T, Suzuki S, Yoshimura I, Asano T, Hayakawa M. Source: Japanese Journal of Cancer Research : Gann. 2002 October; 93(10): 1154-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417046&dopt=Abstract

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Developments in cochlear gene therapy. Author(s): Lalwani AK, Jero J, Mhatre AN. Source: Advances in Oto-Rhino-Laryngology. 2002; 61: 28-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12408059&dopt=Abstract

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Diabetes gene therapy: potential and challenges. Author(s): Xu R, Li H, Tse LY, Kung HF, Lu H, Lam KS. Source: Current Gene Therapy. 2003 February; 3(1): 65-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553537&dopt=Abstract

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Direct injection of naked DNA and cytokine transgene expression: implications for keratinocyte gene therapy. Author(s): Sawamura D, Akiyama M, Shimizu H. Source: Clinical and Experimental Dermatology. 2002 September; 27(6): 480-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372091&dopt=Abstract

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Displaced agendas: current regulatory strategies for germline gene therapy. Author(s): Marden E, Nelkin D. Source: Mcgill Law J. 2000 May; 45(2): 461-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12688283&dopt=Abstract

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DNA nanoparticles and development of DNA delivery vehicles for gene therapy. Author(s): Vijayanathan V, Thomas T, Thomas TJ. Source: Biochemistry. 2002 December 3; 41(48): 14085-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12450371&dopt=Abstract

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Dosimetric and technical considerations for interstitial adenoviral gene therapy as applied to prostate cancer. Author(s): Li S, Simons J, Detorie N, O'Rourke B, Hamper U, DeWeese TL. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 January 1; 55(1): 204-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504055&dopt=Abstract

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Durability of transgene expression and vector integration: recombinant SV40-derived gene therapy vectors. Author(s): Strayer D, Branco F, Zern MA, Yam P, Calarota SA, Nichols CN, Zaia JA, Rossi J, Li H, Parashar B, Ghosh S, Chowdhury JR. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 August; 6(2): 227-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161189&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907616&dopt=Abstract

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E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells. Author(s): Elliott MJ, Farmer MR, Atienza C Jr, Stilwell A, Dong YB, Yang HL, Wong SL, McMasters KM. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2002 March-April; 23(2): 76-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065845&dopt=Abstract

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Ebola glycoprotein: the key to successful gene therapy? Author(s): Sutherland S. Source: Drug Discovery Today. 2003 July 15; 8(14): 609-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867139&dopt=Abstract

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Effects of CD/5-FC suicide gene therapy system on human malignant glioma cells in vitro. Author(s): Lv SQ, Yang H, He JQ, Wang B, Yoshimura I, Liu YS. Source: Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica Et Biophysica Sinica. 2003 May; 35(5): 430-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766803&dopt=Abstract

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Efficacy of CD40 ligand gene therapy in malignant mesothelioma. Author(s): Friedlander PL, Delaune CL, Abadie JM, Toups M, LaCour J, Marrero L, Zhong Q, Kolls JK. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Pt 1): 321-30. Epub 2003 April 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676804&dopt=Abstract

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Efficient trans-splicing in the retina expands the utility of adeno-associated virus as a vector for gene therapy. Author(s): Reich SJ, Auricchio A, Hildinger M, Glover E, Maguire AM, Wilson JM, Bennett J. Source: Human Gene Therapy. 2003 January 1; 14(1): 37-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573057&dopt=Abstract

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Electroporation-mediated pain-killer gene therapy for mononeuropathic rats. Author(s): Lin CR, Yang LC, Lee TH, Lee CT, Huang HT, Sun WZ, Cheng JT. Source: Gene Therapy. 2002 September; 9(18): 1247-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215892&dopt=Abstract

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Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer. Author(s): Dehari H, Ito Y, Nakamura T, Kobune M, Sasaki K, Yonekura N, Kohama G, Hamada H. Source: Cancer Gene Therapy. 2003 January; 10(1): 75-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12489031&dopt=Abstract

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Enhanced suicide gene therapy by chimeric tumor-specific promoter based on HSF1 transcriptional regulation. Author(s): Wang J, Yao M, Zhang Z, Gu J, Zhang Y, Li B, Sun L, Liu X. Source: Febs Letters. 2003 July 10; 546(2-3): 315-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832060&dopt=Abstract

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Enhancement of bone healing based on ex vivo gene therapy using human musclederived cells expressing bone morphogenetic protein 2. Author(s): Lee JY, Peng H, Usas A, Musgrave D, Cummins J, Pelinkovic D, Jankowski R, Ziran B, Robbins P, Huard J. Source: Human Gene Therapy. 2002 July 1; 13(10): 1201-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12133273&dopt=Abstract

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Epidermal growth factor receptor targeting enhances adenoviral vector based suicide gene therapy of osteosarcoma. Author(s): Witlox MA, Van Beusechem VW, Grill J, Haisma HJ, Schaap G, Bras J, Van Diest P, De Gast A, Curiel DT, Pinedo HM, Gerritsen WR, Wuisman PI. Source: The Journal of Gene Medicine. 2002 September-October; 4(5): 510-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221644&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12189522&dopt=Abstract

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Evaluation of TNF-alpha/Bax gene therapy and radiation against C6 glioma xenografts. Author(s): Gridley DS, Timiryasova TM, Miller GM, Andres ML, Dutta-Roy R, Bayeta EJ, Fodor I. Source: Technology in Cancer Research & Treatment. 2003 February; 2(1): 41-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625753&dopt=Abstract

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Ex vivo gene therapy for skeletal regeneration in cranial defects compromised by postoperative radiotherapy. Author(s): Nussenbaum B, Rutherford RB, Teknos TN, Dornfeld KJ, Krebsbach PH. Source: Human Gene Therapy. 2003 July 20; 14(11): 1107-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885349&dopt=Abstract

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Exploiting the differential production of angiogenic factors within the tumor microenvironment in the design of a novel vascular-targeted gene therapy-based approach to the treatment of cancer. Author(s): Carpenito C, Davis PD, Dougherty ST, Dougherty GJ. Source: International Journal of Radiation Oncology, Biology, Physics. 2002 December 1; 54(5): 1473-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12459373&dopt=Abstract

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Expression of mutant non-cleavable Fas ligand on retrovirus packaging cells causes apoptosis of immunocompetent cells and improves prodrug activation gene therapy in a malignant glioma model. Author(s): Nafe C, Cao YJ, Quinones A, Dobberstein KU, Kramm CM, Rainov NG. Source: Life Sciences. 2003 August 22; 73(14): 1847-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888123&dopt=Abstract

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Expression of the coxsackie adenovirus receptor in normal prostate and in primary and metastatic prostate carcinoma: potential relevance to gene therapy. Author(s): Rauen KA, Sudilovsky D, Le JL, Chew KL, Hann B, Weinberg V, Schmitt LD, McCormick F. Source: Cancer Research. 2002 July 1; 62(13): 3812-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12097294&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708477&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12743315&dopt=Abstract

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Extrachromosomal plasmid vectors for gene therapy. Author(s): Stoll SM, Calos MP. Source: Curr Opin Mol Ther. 2002 August; 4(4): 299-305. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12222867&dopt=Abstract

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FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo. Author(s): Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, Kyo S, Kondo S. Source: Anticancer Res. 2001 May-June; 21(3B): 1937-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11497281&dopt=Abstract

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FDA halts 27 gene therapy trials after illness: leukemia-like cases in 2 children in France prompt the action. Author(s): Pollack A. Source: Ny Times (Print). 2003 January 15; : A1, A17. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12647754&dopt=Abstract

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FDA halts gene therapy trials after leukaemia case in France. Author(s): Marwick C. Source: Bmj (Clinical Research Ed.). 2003 January 25; 326(7382): 181. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543825&dopt=Abstract

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FDA panel recommends easing gene therapy trial limits. Author(s): Fox JL. Source: Nature Biotechnology. 2003 April; 21(4): 344-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665806&dopt=Abstract

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Feasibility of gene therapy for late neuronal ceroid lipofuscinosis. Author(s): Sondhi D, Hackett NR, Apblett RL, Kaminsky SM, Pergolizzi RG, Crystal RG. Source: Archives of Neurology. 2001 November; 58(11): 1793-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11708986&dopt=Abstract

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Feasibility of using autologous transplantation to evaluate hematopoietic stem cellbased gene therapy strategies in transgenic mouse models of human disease. Author(s): Miller CL, Imren S, Antonchuk J, Kalberer C, Fabry ME, Nagel RL, Humphries RK, Eaves CJ. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 September; 6(3): 422-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12231180&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11809531&dopt=Abstract

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Fifteen-year follow up for gene therapy patients. Author(s): Birmingham K. Source: Nature Medicine. 2001 December; 7(12): 1263. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11726945&dopt=Abstract

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Five years of vector service for gene therapy. Author(s): Mezzina M, Danos O. Source: Trends in Genetics : Tig. 2002 March; 18(3): 118-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11858829&dopt=Abstract

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Flow cytometry analysis of adenosine deaminase (ADA) expression: a simple and reliable tool for the assessment of ADA-deficient patients before and after gene therapy. Author(s): Otsu M, Hershfield MS, Tuschong LM, Muul LM, Onodera M, Ariga T, Sakiyama Y, Candotti F. Source: Human Gene Therapy. 2002 February 10; 13(3): 425-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11860709&dopt=Abstract

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For gene therapy, now-quantified risks are deemed troubling. Author(s): Twombly R. Source: Journal of the National Cancer Institute. 2003 July 16; 95(14): 1032-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865444&dopt=Abstract

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Formulation of synthetic vectors for cystic fibrosis gene therapy. Author(s): Marshall J, Cheng SH. Source: Methods in Molecular Medicine. 2002; 70: 585-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11917553&dopt=Abstract

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Fratricidal retroviruses: a new twist in gene therapy. Author(s): Rabson AB. Source: Cancer Biology & Therapy. 2003 January-February; 2(1): 100-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12673128&dopt=Abstract

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French gene therapy group reports on the adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position statement from the European Society of Gene Therapy. Author(s): European Society of Gene Therapy. Source: The Journal of Gene Medicine. 2003 January; 5(1): 82-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516054&dopt=Abstract

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Frequent, moderate-dose cyclophosphamide administration improves the efficacy of cytochrome P-450/cytochrome P-450 reductase-based cancer gene therapy. Author(s): Jounaidi Y, Waxman DJ. Source: Cancer Research. 2001 June 1; 61(11): 4437-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389073&dopt=Abstract

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From reverse transcriptase to gene therapy: a marvelous journey. Author(s): Verma IM. Source: Harvey Lect. 1999-2000; 95: 43-66. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11446110&dopt=Abstract

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Functional genomic analysis of type II IL-1beta decoy receptor: potential for gene therapy in human arthritis and inflammation. Author(s): Attur MG, Dave MN, Leung MY, Cipolletta C, Meseck M, Woo SL, Amin AR. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 February 15; 168(4): 200110. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11823537&dopt=Abstract

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Functional impairment of human T-lymphocytes following PHA-induced expansion and retroviral transduction: implications for gene therapy. Author(s): Duarte RF, Chen FE, Lowdell MW, Potter MN, Lamana ML, Prentice HG, Madrigal JA. Source: Gene Therapy. 2002 October; 9(20): 1359-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365001&dopt=Abstract

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Functional near-infrared fluorescence imaging for cardiac surgery and targeted gene therapy. Author(s): Nakayama A, del Monte F, Hajjar RJ, Frangioni JV. Source: Molecular Imaging : Official Journal of the Society for Molecular Imaging. 2002 October; 1(4): 365-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12940233&dopt=Abstract

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Future strategy: gene therapy for diabetic nephropathy. Author(s): Isaka Y, Imai E. Source: Contrib Nephrol. 2001; (134): 127-32. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11665283&dopt=Abstract

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Gene therapy delivery of endostatin enhances the treatment efficacy of radiation. Author(s): Shi W, Teschendorf C, Muzyczka N, Siemann DW. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2003 January; 66(1): 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559515&dopt=Abstract

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Gene therapy for ischemic brain diseases. Author(s): Saitoh Y, Kato A, Hagihara Y, Kaneda Y, Yoshimine T. Source: Current Gene Therapy. 2003 February; 3(1): 49-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553535&dopt=Abstract

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Gene therapy for ocular angiogenesis. Author(s): Bainbridge JW, Mistry AR, Thrasher AJ, Ali RR. Source: Clinical Science (London, England : 1979). 2003 June; 104(6): 561-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570869&dopt=Abstract

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Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system. Author(s): Miyagi T, Koshida K, Hori O, Konaka H, Katoh H, Kitagawa Y, Mizokami A, Egawa M, Ogawa S, Hamada H, Namiki M. Source: The Journal of Gene Medicine. 2003 January; 5(1): 30-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516049&dopt=Abstract

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Gene therapy for psychiatric disorders. Author(s): Sapolsky RM. Source: The American Journal of Psychiatry. 2003 February; 160(2): 208-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562564&dopt=Abstract

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Gene therapy for the treatment of oral squamous cell carcinoma. Author(s): Xi S, Grandis JR. Source: Journal of Dental Research. 2003 January; 82(1): 11-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508038&dopt=Abstract

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Gene therapy for tissue regeneration. Author(s): Cutroneo KR. Source: Journal of Cellular Biochemistry. 2003 February 1; 88(2): 418-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520545&dopt=Abstract

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Gene therapy in medicine. Author(s): Ray J, Ray K. Source: Indian J Ophthalmol. 2002 December; 50(4): 261-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532490&dopt=Abstract

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Gene therapy in psychiatric disorders: too early, too complex? Author(s): Neumaier JF. Source: Current Opinion in Pharmacology. 2003 February; 3(1): 68-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12550744&dopt=Abstract

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Gene therapy of prostate cancer with the soluble vascular endothelial growth factor receptor Flk1. Author(s): Becker CM, Farnebo FA, Iordanescu I, Behonick DJ, Shih MC, Dunning P, Christofferson R, Mulligan RC, Taylor GA, Kuo CJ, Zetter BR. Source: Cancer Biology & Therapy. 2002 September-October; 1(5): 548-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12496487&dopt=Abstract

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Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase. Author(s): Barzon L, Bonaguro R, Castagliuolo I, Chilosi M, Franchin E, Del Vecchio C, Giaretta I, Boscaro M, Palu G. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 January; 148(1): 73-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534360&dopt=Abstract

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Gene therapy of X-linked severe combined immunodeficiency. Author(s): Hacein-Bey-Abina S, de Saint Basile G, Cavazzana-Calvo M. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 215: 247-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512304&dopt=Abstract

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Gene therapy progress and prospects: alpha-1 antitrypsin. Author(s): Stecenko AA, Brigham KL. Source: Gene Therapy. 2003 January; 10(2): 95-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571637&dopt=Abstract

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Gene therapy progress for HIV. Author(s): Clayton J. Source: Drug Discovery Today. 2002 August 15; 7(16): 841-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546941&dopt=Abstract

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Gene therapy trials for cystic fibrosis. Author(s): Brown M. Source: Drug Discovery Today. 2002 August 1; 7(15): 788-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546958&dopt=Abstract

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Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization. Author(s): Su EJ, Cioffi CL, Stefansson S, Mittereder N, Garay M, Hreniuk D, Liau G. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 April; 284(4): H1429-40. Epub 2002 December 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505877&dopt=Abstract

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Gene therapy with vascular endothelial growth factor reduces angina. Author(s): Merkle CJ, Montgomery DW. Source: The Journal of Cardiovascular Nursing. 2003 January-March; 18(1): 38-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12537088&dopt=Abstract

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Gene therapy. Second child in French trial is found to have leukemia. Author(s): Marshall E. Source: Science. 2003 January 17; 299(5605): 320. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531981&dopt=Abstract

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Gene therapy. Seeking the cause of induced leukemias in X-SCID trial. Author(s): Kaiser J. Source: Science. 2003 January 24; 299(5606): 495. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543948&dopt=Abstract

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Green fluorescent protein-adenoviral construct as a model for transient gene therapy for human cultured keratinocytes in an athymic mouse model. Author(s): Campbell C, Hultman S, Cairns B, DeSerres S, Meyer A. Source: The Journal of Trauma. 2003 January; 54(1): 72-9; Discussion 79-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544902&dopt=Abstract

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Haematopoietic stem cell transplantation and gene therapy in the fetus: ready for clinical use? Author(s): Surbek DV, Holzgreve W, Nicolaides KH. Source: Human Reproduction Update. 2001 January-February; 7(1): 85-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11212081&dopt=Abstract

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Haemophilia B: from molecular diagnosis to gene therapy. Author(s): Castaldo G, Nardiello P, Bellitti F, Santamaria R, Rocino A, Coppola A, di Minno G, Salvatore F. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 April; 41(4): 445-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747585&dopt=Abstract

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Harmful potential of viral vectors fuels doubts over gene therapy. Author(s): Check E. Source: Nature. 2003 June 5; 423(6940): 573-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789298&dopt=Abstract

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Hematopoietic stem cell gene therapy for inherited bone marrow disorders: past accomplishments and continued challenges. Author(s): Becker PS. Source: J Cell Biochem Suppl. 2002; 38: 55-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12046850&dopt=Abstract

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Hematopoietic stem cell gene therapy: towards clinically significant gene transfer efficiency. Author(s): Heim DA, Dunbar CE. Source: Immunological Reviews. 2000 December; 178: 29-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11213804&dopt=Abstract

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Heme oxygenase 1 mediates the immunomodulatory and antiapoptotic effects of interleukin 13 gene therapy in vivo and in vitro. Author(s): Ke B, Shen XD, Zhai Y, Gao F, Busuttil RW, Volk HD, Kupiec-Weglinski JW. Source: Human Gene Therapy. 2002 October 10; 13(15): 1845-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12396617&dopt=Abstract

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Hemophilia gene therapy: update. Author(s): Monahan PE, White GC 2nd. Source: Current Opinion in Hematology. 2002 September; 9(5): 430-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172462&dopt=Abstract

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Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. Author(s): Yang J, Dai C, Liu Y. Source: Journal of the American Society of Nephrology : Jasn. 2002 October; 13(10): 246477. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239235&dopt=Abstract

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High transduction efficiency of circulating first trimester fetal mesenchymal stem cells: potential targets for in utero ex vivo gene therapy. Author(s): Campagnoli C, Bellantuono I, Kumar S, Fairbairn LJ, Roberts I, Fisk NM. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2002 August; 109(8): 952-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12197378&dopt=Abstract

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Highly active antiretroviral therapy corrects hematopoiesis in HIV-1 infected patients: interest for peripheral blood stem cell-based gene therapy. Author(s): Baillou C, Simon A, Leclercq V, Azar N, Rosenzwajg M, Herson S, Klatzmann D, Lemoine FM. Source: Aids (London, England). 2003 March 7; 17(4): 563-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598777&dopt=Abstract

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Highly variable expression of virus receptors in the human cardiovascular system. Implications for cardiotropic viral infections and gene therapy. Author(s): Poller W, Fechner H, Noutsias M, Tschoepe C, Schultheiss HP. Source: Zeitschrift Fur Kardiologie. 2002 December; 91(12): 978-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490988&dopt=Abstract

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HIV-1 proprotein processing as a target for gene therapy. Author(s): Cordelier P, Zern MA, Strayer DS. Source: Gene Therapy. 2003 March; 10(6): 467-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621451&dopt=Abstract

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Horseradish peroxidase-mediated gene therapy: choice of prodrugs in oxic and anoxic tumor conditions. Author(s): Greco O, Rossiter S, Kanthou C, Folkes LK, Wardman P, Tozer GM, Dachs GU. Source: Molecular Cancer Therapeutics. 2001 December; 1(2): 151-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467232&dopt=Abstract

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Human gene therapy and the slippery slope argument. Author(s): Launis V. Source: Medicine, Health Care, and Philosophy. 2002; 5(2): 169-79. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12168992&dopt=Abstract

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Human gene therapy. Harsh lessons, high hopes. Author(s): Thompson L. Source: Fda Consumer. 2000 September-October; 34(5): 19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11590787&dopt=Abstract

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Human gene therapy: ensuring progress in the next millennium. Author(s): Knorr D. Source: National Forum. 1999 Summer; 79(3): 31-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12455554&dopt=Abstract

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Human neural stem and progenitor cells: in vitro and in vivo properties, and potential for gene therapy and cell replacement in the CNS. Author(s): Martinez-Serrano A, Rubio FJ, Navarro B, Bueno C, Villa A. Source: Current Gene Therapy. 2001 September; 1(3): 279-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109143&dopt=Abstract

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Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Author(s): Nagaya N, Kangawa K, Kanda M, Uematsu M, Horio T, Fukuyama N, Hino J, Harada-Shiba M, Okumura H, Tabata Y, Mochizuki N, Chiba Y, Nishioka K, Miyatake K, Asahara T, Hara H, Mori H. Source: Circulation. 2003 August 19; 108(7): 889-95. Epub 2003 June 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835224&dopt=Abstract

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Hydroxyurea significantly enhances tumor growth delay in vivo with herpes simplex virus thymidine kinase/ganciclovir gene therapy. Author(s): Boucher PD, Ostruszka LJ, Murphy PJ, Shewach DS. Source: Gene Therapy. 2002 August; 9(15): 1023-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12101433&dopt=Abstract

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Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Author(s): Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE. Source: American Journal of Pathology. 2003 October; 163(4): 1233-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507633&dopt=Abstract

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IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene therapy approach. Author(s): Selleck WA, Canfield SE, Hassen WA, Meseck M, Kuzmin AI, Eisensmith RC, Chen SH, Hall SJ. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 February; 7(2): 185-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12597906&dopt=Abstract

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Imaging of vascular gene therapy. Author(s): Yang X. Source: Radiology. 2003 July; 228(1): 36-49. Epub 2003 May 08. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738874&dopt=Abstract

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Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma. Author(s): Voges J, Reszka R, Gossmann A, Dittmar C, Richter R, Garlip G, Kracht L, Coenen HH, Sturm V, Wienhard K, Heiss WD, Jacobs AH. Source: Annals of Neurology. 2003 October; 54(4): 479-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520660&dopt=Abstract

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Immune gene therapy for kidney cancer: the search for a magic trigger. Author(s): Kim HL, Belldegrun AS, Figlin RA. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 February; 7(2): 153-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12597902&dopt=Abstract

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Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy. Author(s): Bowers WJ, Olschowka JA, Federoff HJ. Source: Gene Therapy. 2003 June; 10(11): 941-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756414&dopt=Abstract

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Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy. Author(s): Jooss K, Chirmule N. Source: Gene Therapy. 2003 June; 10(11): 955-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756416&dopt=Abstract

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Immunity to the alpha(1,3)galactosyl epitope provides protection in mice challenged with colon cancer cells expressing alpha(1,3)galactosyl-transferase: a novel suicide gene for cancer gene therapy. Author(s): Unfer RC, Hellrung D, Link CJ Jr. Source: Cancer Research. 2003 March 1; 63(5): 987-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615713&dopt=Abstract

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Immuno-gene therapy of established prostate tumors using chimeric receptorredirected human lymphocytes. Author(s): Pinthus JH, Waks T, Kaufman-Francis K, Schindler DG, Harmelin A, Kanety H, Ramon J, Eshhar Z. Source: Cancer Research. 2003 May 15; 63(10): 2470-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750268&dopt=Abstract

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Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo. Author(s): Yanagi K, Nagayama Y, Nakao K, Saeki A, Matsumoto K, Ichikawa T, Ishikawa H, Hamasaki K, Ishii N, Eguchi K. Source: International Journal of Oncology. 2003 February; 22(2): 345-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527933&dopt=Abstract

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Immunological hurdles to lung gene therapy. Author(s): Ferrari S, Griesenbach U, Geddes DM, Alton E. Source: Clinical and Experimental Immunology. 2003 April; 132(1): 1-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653829&dopt=Abstract

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Immunopathology and the gene therapy of lupus. Author(s): Mageed RA, Prud'homme GJ. Source: Gene Therapy. 2003 May; 10(10): 861-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732872&dopt=Abstract

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Improvement of carcinoembryonic antigen-specific prodrug gene therapy for experimental colon cancer. Author(s): Ueda K, Iwahashi M, Nakamori M, Nakamura M, Matsuura I, Ojima T, Yamaue H. Source: Surgery. 2003 March; 133(3): 309-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660644&dopt=Abstract

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In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL, HCL, BCLL). Author(s): Misumi M, Suzuki T, Moriuchi S, Glorioso JC, Bessho M. Source: Leukemia Research. 2003 August; 27(8): 695-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801527&dopt=Abstract

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In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Author(s): Tanaka M, Grossman HB. Source: Gene Therapy. 2003 September; 10(19): 1636-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923562&dopt=Abstract

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Inhibition of tumor angiogenesis by angiostatin: from recombinant protein to gene therapy. Author(s): Dell'Eva R, Pfeffer U, Indraccolo S, Albini A, Noonan D. Source: Endothelium : Journal of Endothelial Cell Research. 2002; 9(1): 3-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901356&dopt=Abstract

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Intramuscular vascular endothelial growth factor gene therapy in patients with chronic critical leg ischemia. Author(s): Shyu KG, Chang H, Wang BW, Kuan P. Source: The American Journal of Medicine. 2003 February 1; 114(2): 85-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586226&dopt=Abstract

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Intramuscular vascular endothelial growth factor gene therapy: fact or fiction? Author(s): Baumgartner I. Source: The American Journal of Medicine. 2003 February 1; 114(2): 156-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586239&dopt=Abstract

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Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism. Author(s): Zhang Y, Calon F, Zhu C, Boado RJ, Pardridge WM. Source: Human Gene Therapy. 2003 January 1; 14(1): 1-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573054&dopt=Abstract

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Intravitreal gene therapy reduces lysosomal storage in specific areas of the CNS in mucopolysaccharidosis VII mice. Author(s): Hennig AK, Levy B, Ogilvie JM, Vogler CA, Galvin N, Bassnett S, Sands MS. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 April 15; 23(8): 3302-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716937&dopt=Abstract

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Introduction to cancer gene therapy. Author(s): Cusack JC Jr, Tanabe KK. Source: Surg Oncol Clin N Am. 2002 July; 11(3): 497-519, V. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487054&dopt=Abstract

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K cells: a novel target for insulin gene therapy for the prevention of diabetes. Author(s): Corbett JA. Source: Trends in Endocrinology and Metabolism: Tem. 2001 May-June; 12(4): 140-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11295563&dopt=Abstract

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Keratinocyte gene therapy: cytokine gene expression in local keratinocytes and in circulation by introducing cytokine genes into skin. Author(s): Meng X, Sawamura D, Ina S, Tamai K, Hanada K, Hashimoto I. Source: Experimental Dermatology. 2002 October; 11(5): 456-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12366699&dopt=Abstract

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Keratinocyte gene therapy: inducible promoters and in vivo control of transgene expression. Author(s): Itai K, Sawamura D, Meng X, Hashimoto I. Source: Clinical and Experimental Dermatology. 2001 September; 26(6): 531-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11678883&dopt=Abstract

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Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. Author(s): Chu P, Deforce D, Pedersen IM, Kim Y, Kitada S, Reed JC, Kipps TJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 March 19; 99(6): 3854-9. Epub 2002 Mar 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11891278&dopt=Abstract

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Latest development in viral vectors for gene therapy. Author(s): Lundstrom K. Source: Trends in Biotechnology. 2003 March; 21(3): 117-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628368&dopt=Abstract

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Lentiviral vectors for gene therapy of HIV-1 infection. Author(s): Mautino MR. Source: Current Gene Therapy. 2002 February; 2(1): 23-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12108972&dopt=Abstract

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Lentiviral vectors for gene therapy of HIV-induced disease. Author(s): Amado RG, Chen IS. Source: Curr Top Microbiol Immunol. 2002; 261: 229-43. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11892250&dopt=Abstract

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Lentiviral vectors for the gene therapy of lympho-hematological disorders. Author(s): Salmon P, Trono D. Source: Curr Top Microbiol Immunol. 2002; 261: 211-27. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11892249&dopt=Abstract

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Lentivirus and foamy virus vectors: novel gene therapy tools. Author(s): Pandya S, Klimatcheva E, Planelles V. Source: Expert Opinion on Biological Therapy. 2001 January; 1(1): 17-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11727544&dopt=Abstract

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Lentiviruses in gene therapy clinical research. Author(s): Connolly JB. Source: Gene Therapy. 2002 December; 9(24): 1730-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12457288&dopt=Abstract

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Lessons learned from human gene therapy in patients with chronic critical limb ischemia. Author(s): Baumgartner I. Source: J Invasive Cardiol. 2001 April; 13(4): 330-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11287725&dopt=Abstract

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Life or death of T cells with antigen-specific receptors--using T cells for cancer adoptive immunotherapy/gene therapy. Author(s): Ren-Heidenreich L, Lum LG. Source: Current Gene Therapy. 2001 September; 1(3): 253-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109140&dopt=Abstract

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Ligand-inducible transgene regulation for gene therapy. Author(s): Ye X, Schillinger K, Burcin MM, Tsai SY, O'Malley BW. Source: Methods Enzymol. 2002; 346: 551-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11883090&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11960287&dopt=Abstract

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Limited gene therapy trials to restart. Author(s): Ready T. Source: Nature Medicine. 2001 March; 7(3): 265. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422872&dopt=Abstract

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Liposome-mediated gene therapy using HSV-TK/ganciclovir under the control of human PSA promoter in prostate cancer cells. Author(s): Suzuki S, Tadakuma T, Kunitomi M, Takayama E, Sato M, Asano T, Nakamura H, Hayakawa M. Source: Urologia Internationalis. 2001; 67(3): 216-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11598449&dopt=Abstract

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LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Author(s): Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, StoppaLyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M. Source: Science. 2003 October 17; 302(5644): 415-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564000&dopt=Abstract

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Local inflammation and devascularization--in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma. Author(s): Floeth FW, Shand N, Bojar H, Prisack HB, Felsberg J, Neuen-Jacob E, Aulich A, Burger KJ, Bock WJ, Weber F. Source: Cancer Gene Therapy. 2001 November; 8(11): 843-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11773974&dopt=Abstract

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Long-term bone marrow culture-derived stromal fibroblasts as a potential target for gene therapy in acute myelogenous leukemia. Author(s): Min YH, Li GX, Jang JH, Suh HC, Kim JS, Cheong JW, Lee ST, Hahn JS, Ko YW. Source: Leukemia Research. 2002 April; 26(4): 369-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11839380&dopt=Abstract

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Long-term survival after gene therapy for a recurrent glioblastoma. Author(s): Valery CA, Seilhean D, Boyer O, Marro B, Hauw JJ, Kemeny JL, Marsault C, Philippon J, Klatzmann D. Source: Neurology. 2002 April 9; 58(7): 1109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11940704&dopt=Abstract

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Macrophages in gene therapy: cellular delivery vehicles and in vivo targets. Author(s): Burke B, Sumner S, Maitland N, Lewis CE. Source: Journal of Leukocyte Biology. 2002 September; 72(3): 417-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12223508&dopt=Abstract

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Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line. Author(s): Zhang L, Gu J, Lin T, Huang X, Roth JA, Fang B. Source: Gene Therapy. 2002 September; 9(18): 1262-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215894&dopt=Abstract

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Mechanisms of cytotoxicity induced by horseradish peroxidase/indole-3-acetic acid gene therapy. Author(s): Greco O, Dachs GU, Tozer GM, Kanthou C. Source: Journal of Cellular Biochemistry. 2002; 87(2): 221-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12244574&dopt=Abstract

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Medical malpractice in the new eugenics: relying on innovative tort doctrine to provide relief when gene therapy fails. Author(s): Marshall EA. Source: Georgia Law Rev. 2001 Summer; 35(4): 1277-327. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12683393&dopt=Abstract

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Medical, ethical and legal aspects of somatic gene therapy. Author(s): Winter SF, Roger HD. Source: European Journal of Health Law. 1995; 2(1): 45-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680384&dopt=Abstract

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Medicine. Gene therapy--new challenges ahead. Author(s): Williams DA, Baum C. Source: Science. 2003 October 17; 302(5644): 400-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563994&dopt=Abstract

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Mesenchymal stem cells for bone gene therapy and tissue engineering. Author(s): Pelled G, G T, Aslan H, Gazit Z, Gazit D. Source: Current Pharmaceutical Design. 2002; 8(21): 1917-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12171527&dopt=Abstract

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Modeling antiangiogenesis gene therapy. Author(s): Tsai JH, Lee WM. Source: Cancer Biology & Therapy. 2002 September-October; 1(5): 554-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12496488&dopt=Abstract

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Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Author(s): Harper SQ, Hauser MA, DelloRusso C, Duan D, Crawford RW, Phelps SF, Harper HA, Robinson AS, Engelhardt JF, Brooks SV, Chamberlain JS. Source: Nature Medicine. 2002 March; 8(3): 253-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11875496&dopt=Abstract

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Molecular aspects of bladder cancer IV: gene therapy of bladder cancer. Author(s): Ardelt P, Bohle A. Source: European Urology. 2002 April; 41(4): 372-80; Discussion 380-1. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074806&dopt=Abstract

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Molecular imaging boosts effectiveness of gene therapy. Author(s): Larkin M. Source: The Lancet Oncology. 2003 August; 4(8): 455. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918523&dopt=Abstract

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Mutational effects of retrovirus insertion on the genome of V79 cells by an attenuated retrovirus vector: implications for gene therapy. Author(s): Themis M, May D, Coutelle C, Newbold RF. Source: Gene Therapy. 2003 September; 10(19): 1703-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923569&dopt=Abstract

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Myocardial gene therapy. Author(s): Mercadier JJ, Logeart D. Source: Arch Mal Coeur Vaiss. 2002 March; 95(3): 197-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11998335&dopt=Abstract

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Myocardial gene therapy. Author(s): Isner JM. Source: Nature. 2002 January 10; 415(6868): 234-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11805848&dopt=Abstract

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Nerve entrapment and gene therapy. Author(s): Sud V. Source: Journal of Long-Term Effects of Medical Implants. 2002; 12(2): 97-104. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463066&dopt=Abstract

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Neuroprotective gene therapy against acute neurological insults. Author(s): Sapolsky RM. Source: Nature Reviews. Neuroscience. 2003 January; 4(1): 61-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511862&dopt=Abstract

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Neuroprotective gene therapy for Parkinson's disease. Author(s): Tenenbaum L, Chtarto A, Lehtonen E, Blum D, Baekelandt V, Velu T, Brotchi J, Levivier M. Source: Current Gene Therapy. 2002 December; 2(4): 451-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477256&dopt=Abstract

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New reporting rules for gene therapy and xeno trials. Author(s): Dove A. Source: Nature Medicine. 2001 March; 7(3): 265. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422866&dopt=Abstract

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Nitric oxide synthase gene therapy for cardiovascular disease. Author(s): Chen AF, Ren J, Miao CY. Source: Japanese Journal of Pharmacology. 2002 August; 89(4): 327-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12233810&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968530&dopt=Abstract

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Non-viral and hybrid vectors in human gene therapy: an update. Author(s): Schmidt-Wolf GD, Schmidt-Wolf IG. Source: Trends in Molecular Medicine. 2003 February; 9(2): 67-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615040&dopt=Abstract

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Non-viral cancer gene therapy--what is best? Author(s): Ogris M. Source: Drug Discovery Today. 2003 January 15; 8(2): 63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12565006&dopt=Abstract

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Non-viral gene therapy: polycation-mediated DNA delivery. Author(s): Thomas M, Klibanov AM. Source: Applied Microbiology and Biotechnology. 2003 July; 62(1): 27-34. Epub 2003 April 29. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719940&dopt=Abstract

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Novel gene therapy approach for nasopharyngeal carcinoma. Author(s): Liu FF. Source: Seminars in Cancer Biology. 2002 December; 12(6): 505-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12450736&dopt=Abstract

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Obesity and metabolic syndrome: long-term benefits of central leptin gene therapy. Author(s): Kalra PS, Kalra SP. Source: Drugs Today (Barc). 2002 November; 38(11): 745-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12582458&dopt=Abstract

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Occurrence of leukaemia following gene therapy of X-linked SCID. Author(s): Kohn DB, Sadelain M, Glorioso JC. Source: Nature Reviews. Cancer. 2003 July; 3(7): 477-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835668&dopt=Abstract

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Oligonucleotide-mediated gene repair at DNA level: the potential applications for gene therapy. Author(s): Liu CM, Liu DP, Liang CC. Source: Journal of Molecular Medicine (Berlin, Germany). 2002 October; 80(10): 620-8. Epub 2002 August 28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395146&dopt=Abstract

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Oligonucleotide-mediated gene therapy for muscular dystrophies. Author(s): Rando TA. Source: Neuromuscular Disorders : Nmd. 2002 October; 12 Suppl 1: S55-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12206797&dopt=Abstract

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Oncolytic viral gene therapy for prostate cancer using two attenuated, replicationcompetent, genetically engineered herpes simplex viruses. Author(s): Cozzi PJ, Burke PB, Bhargav A, Heston WD, Huryk B, Scardino PT, Fong Y. Source: The Prostate. 2002 October 1; 53(2): 95-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12242723&dopt=Abstract

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Oncoselective parvoviral vector-mediated gene therapy of cancer. Author(s): Zeicher M, Spegelaere P, Horth M, Gancberg D, Karim A, Dupont F. Source: Oncology Research. 2003; 13(6-10): 437-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725535&dopt=Abstract

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One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Author(s): Prockop DJ, Gregory CA, Spees JL. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 30; 100 Suppl 1: 11917-23. Epub 2003 Sep 17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679583&dopt=Abstract

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Opinion paper on the current status of the regulation of gene therapy in Europe. Author(s): Cohen-Haguenauer O, Rosenthal F, Gansbacher B, Bolhuis R, Dorsch-Hasler K, Eshhar Z, Gahrton G, Hokland P, Melani C, Rankin E, Thielemans K, Vile R, Zwierzina H, Cichutek K; Euregenethy Network. Source: Human Gene Therapy. 2002 November 20; 13(17): 2085-110. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490003&dopt=Abstract

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Optimizing aptamer activity for gene therapy applications using expression cassette SELEX. Author(s): Martell RE, Nevins JR, Sullenger BA. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 July; 6(1): 30-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095300&dopt=Abstract

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Overcoming the immune response to permit ex vivo gene therapy for spine fusion with human type 5 adenoviral delivery of the LIM mineralization protein-1 cDNA. Author(s): Kim HS, Viggeswarapu M, Boden SD, Liu Y, Hair GA, Louis-Ugbo J, Murakami H, Minamide A, Suh DY, Titus L. Source: Spine. 2003 February 1; 28(3): 219-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567021&dopt=Abstract

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p53 gene therapy for esophageal cancer. Author(s): Shimada H, Matsubara H, Ochiai T. Source: Journal of Gastroenterology. 2002 November; 37 Suppl 14: 87-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12572873&dopt=Abstract

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Perspectives on gene therapy for lysosomal storage diseases that affect hematopoiesis. Author(s): Grabowski GA. Source: Curr Hematol Rep. 2003 July; 2(4): 356-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901334&dopt=Abstract

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Pharmacologically regulated production of targeted retrovirus from T cells for systemic antitumor gene therapy. Author(s): Crittenden M, Gough M, Chester J, Kottke T, Thompson J, Ruchatz A, Clackson T, Cosset FL, Chong H, Diaz RM, Harrington K, Alvarez Vallina L, Vile R. Source: Cancer Research. 2003 June 15; 63(12): 3173-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810645&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839017&dopt=Abstract

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Plasticity: advantages over cloning and gene therapy. Author(s): Vassiliadis S, Kalmanti M, Athanassakis I. Source: Haematologia. 2002; 32(4): 337-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803108&dopt=Abstract

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Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Author(s): Grimm D, Zhou S, Nakai H, Thomas CE, Storm TA, Fuess S, Matsushita T, Allen J, Surosky R, Lochrie M, Meuse L, McClelland A, Colosi P, Kay MA. Source: Blood. 2003 October 1; 102(7): 2412-9. Epub 2003 June 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791653&dopt=Abstract

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Preclinical models of lymphatic disease: the potential for growth factor and gene therapy. Author(s): Rockson SG. Source: Annals of the New York Academy of Sciences. 2002 December; 979: 64-75; Discussion 76-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543717&dopt=Abstract

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Progress and limitations in cancer gene therapy. Author(s): Heo DS. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 November-December; 4(6 Suppl): 52S-55S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544489&dopt=Abstract

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Protection against collagen-induced arthritis by intramuscular gene therapy with an expression plasmid for the interleukin-1 receptor antagonist. Author(s): Kim JM, Jeong JG, Ho SH, Hahn W, Park EJ, Kim S, Yu SS, Lee YW, Kim S. Source: Gene Therapy. 2003 September; 10(18): 1543-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907945&dopt=Abstract

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Pulmonary gene therapy. Realistic hope for the future, or false dawn in the promised land? Author(s): Jenkins RG, McAnulty RJ, Hart SL, Laurent GJ. Source: Monaldi Arch Chest Dis. 2003 January-March; 59(1): 17-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14533278&dopt=Abstract

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Quantitation of bystander effects in nitroreductase suicide gene therapy using threedimensional cell cultures. Author(s): Wilson WR, Pullen SM, Hogg A, Helsby NA, Hicks KO, Denny WA. Source: Cancer Research. 2002 March 1; 62(5): 1425-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11888915&dopt=Abstract

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Recent developments in ocular gene therapy. Author(s): Borras T. Source: Experimental Eye Research. 2003 June; 76(6): 643-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742346&dopt=Abstract

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Recent progress in gene therapy for cardiovascular disease. Author(s): Morishita R. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2002 December; 66(12): 1077-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499610&dopt=Abstract

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Recombinant adeno-associated virus: formulation challenges and strategies for a gene therapy vector. Author(s): Wright JF, Qu G, Tang C, Sommer JM. Source: Curr Opin Drug Discov Devel. 2003 March; 6(2): 174-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669452&dopt=Abstract

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Recombinant adenovirus-mediated cytotoxic gene therapy of lymphoproliferative disorders: is CAR important for the vector to ride? Author(s): Turturro F. Source: Gene Therapy. 2003 January; 10(2): 100-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571638&dopt=Abstract

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Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy. Author(s): Pagliaro LC, Keyhani A, Williams D, Woods D, Liu B, Perrotte P, Slaton JW, Merritt JA, Grossman HB, Dinney CP. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 June 15; 21(12): 2247-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805322&dopt=Abstract

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Report of a second serious adverse event in a clinical trial of gene therapy for Xlinked severe combined immune deficiency (X-SCID). Position of the European Society of Gene Therapy (ESGT). Author(s): Gansbacher B; European Society of Gene Therapy. Source: The Journal of Gene Medicine. 2003 March; 5(3): 261-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666192&dopt=Abstract

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Report of the inaugural meeting of the Israeli Society of Gene Therapy (ISGT). Author(s): Mitchell LA. Source: The Journal of Gene Medicine. 2003 March; 5(3): 258-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666191&dopt=Abstract

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Restoring public trust in gene therapy. Author(s): Kennedy EM. Source: J Biolaw Bus. 2001; 4(3): 3-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962103&dopt=Abstract

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Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular selfcorrection. Author(s): Gross M, Hanenberg H, Lobitz S, Friedl R, Herterich S, Dietrich R, Gruhn B, Schindler D, Hoehn H. Source: Cytogenetic and Genome Research. 2002; 98(2-3): 126-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697994&dopt=Abstract

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Risks and benefits of gene therapy. Author(s): Noguchi P. Source: The New England Journal of Medicine. 2003 January 16; 348(3): 193-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529458&dopt=Abstract

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Safety of adeno-associated virus gene therapy vectors: a current evaluation. Author(s): Monahan PE, Jooss K, Sands MS. Source: Expert Opinion on Drug Safety. 2002 May; 1(1): 79-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904163&dopt=Abstract

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Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Author(s): Bilsland AE, Anderson CJ, Fletcher-Monaghan AJ, McGregor F, Evans TR, Ganly I, Knox RJ, Plumb JA, Keith WN. Source: Oncogene. 2003 January 23; 22(3): 370-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12545158&dopt=Abstract

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Semliki Forest virus (SFV) vectors in neurobiology and gene therapy. Author(s): Lundstrom K, Ehrengruber MU. Source: Methods in Molecular Medicine. 2003; 76: 503-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526182&dopt=Abstract

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Short overview of potential gene therapy approaches in orthopedic spine surgery. Author(s): Glant TT. Source: Spine. 2003 February 1; 28(3): 207-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567019&dopt=Abstract

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Single-chain antibody and its derivatives directed against vascular endothelial growth factor: application for antiangiogenic gene therapy. Author(s): Afanasieva TA, Wittmer M, Vitaliti A, Ajmo M, Neri D, Klemenz R. Source: Gene Therapy. 2003 October; 10(21): 1850-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960975&dopt=Abstract

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siRNAs, ribozymes and RNA decoys in modeling stem cell-based gene therapy for HIV/AIDS. Author(s): Akkina R, Banerjea A, Bai J, Anderson J, Li MJ, Rossi J. Source: Anticancer Res. 2003 May-June; 23(3A): 1997-2005. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894572&dopt=Abstract

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Size-exclusion chromatography purification of high-titer vesicular stomatitis virus G glycoprotein-pseudotyped retrovectors for cell and gene therapy applications. Author(s): Transfiguracion J, Jaalouk DE, Ghani K, Galipeau J, Kamen A. Source: Human Gene Therapy. 2003 August 10; 14(12): 1139-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12908966&dopt=Abstract

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Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Author(s): Fillat C, Carrio M, Cascante A, Sangro B. Source: Current Gene Therapy. 2003 February; 3(1): 13-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553532&dopt=Abstract

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Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice. Author(s): Kanazawa T, Mizukami H, Okada T, Hanazono Y, Kume A, Nishino H, Takeuchi K, Kitamura K, Ichimura K, Ozawa K. Source: Gene Therapy. 2003 January; 10(1): 51-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525837&dopt=Abstract

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Suicide gene therapy using keratin 19 enhancer and promoter in malignant mesothelioma cells. Author(s): Ishiwata N, Inase N, Fujie T, Tamaoka M, Yoshizawa Y. Source: Anticancer Res. 2003 March-April; 23(2B): 1405-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820402&dopt=Abstract

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The c-myc oncogene: use of a biological prognostic marker as a potential target for gene therapy in melanoma. Author(s): Chana JS, Grover R, Tulley P, Lohrer H, Sanders R, Grobbelaar AO, Wilson GD. Source: British Journal of Plastic Surgery. 2002 December; 55(8): 623-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12550114&dopt=Abstract

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The Journal of Gene Medicine 2002 Young Investigator Award. Japan Society of Gene Therapy. Author(s): Nishino T. Source: The Journal of Gene Medicine. 2003 January; 5(1): 87-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516056&dopt=Abstract

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The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system. Author(s): Furlan R, Pluchino S, Martino G. Source: Current Opinion in Neurology. 2003 June; 16(3): 385-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858077&dopt=Abstract

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Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection. Author(s): Weinberger LS, Schaffer DV, Arkin AP. Source: Journal of Virology. 2003 September; 77(18): 10028-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941913&dopt=Abstract

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Those in gene therapy should pay closer attention to lessons from hyperthermia. Author(s): Dewhirst MW, Sneed PK. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 October 1; 57(2): 597-9; Author Reply 599-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957278&dopt=Abstract

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Trans-splicing vectors expand the packaging limits of adeno-associated virus for gene therapy applications. Author(s): Duan D, Yue Y, Yan Z, Engelhardt JF. Source: Methods in Molecular Medicine. 2003; 76: 287-307. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526170&dopt=Abstract

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Tumor vaccines: from gene therapy to dendritic cells--the emerging frontier. Author(s): Vieweg J, Dannull J. Source: The Urologic Clinics of North America. 2003 August; 30(3): 633-43, X. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12953761&dopt=Abstract

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Tumor-specific gene therapy for undifferentiated thyroid carcinoma utilizing the telomerase reverse transcriptase promoter. Author(s): Takeda T, Inaba H, Yamazaki M, Kyo S, Miyamoto T, Suzuki S, Ehara T, Kakizawa T, Hara M, DeGroot LJ, Hashizume K. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3531-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915632&dopt=Abstract

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Tumor-targeted gene therapy: strategies for the preparation of ligand-polyethylene glycol-polyethylenimine/DNA complexes. Author(s): Ogris M, Walker G, Blessing T, Kircheis R, Wolschek M, Wagner E. Source: Journal of Controlled Release : Official Journal of the Controlled Release Society. 2003 August 28; 91(1-2): 173-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12932649&dopt=Abstract

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Type XVII collagen gene mutations in junctional epidermolysis bullosa and prospects for gene therapy. Author(s): Bauer JW, Lanschuetzer C. Source: Clinical and Experimental Dermatology. 2003 January; 28(1): 53-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558632&dopt=Abstract

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Ultrasound gene therapy: on the road from concept to reality. Author(s): Newman CM, Lawrie A, Brisken AF, Cumberland DC. Source: Echocardiography (Mount Kisco, N.Y.). 2001 May; 18(4): 339-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11415507&dopt=Abstract

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Unfulfilled promise of endostatin in a gene therapy-xenotransplant model of human acute lymphocytic leukemia. Author(s): Eisterer W, Jiang X, Bachelot T, Pawliuk R, Abramovich C, Leboulch P, Hogge D, Eaves C. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 April; 5(4): 352-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11945061&dopt=Abstract

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Update on the use of nonhuman primate models for preclinical testing of gene therapy approaches targeting hematopoietic cells. Author(s): Donahue RE, Dunbar CE. Source: Human Gene Therapy. 2001 April 10; 12(6): 607-17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11426461&dopt=Abstract

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US authorities uphold suspension of SCID gene therapy. Author(s): Fox JL. Source: Nature Biotechnology. 2003 March; 21(3): 217. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610555&dopt=Abstract

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Use of blood outgrowth endothelial cells for gene therapy for hemophilia A. Author(s): Lin Y, Chang L, Solovey A, Healey JF, Lollar P, Hebbel RP. Source: Blood. 2002 January 15; 99(2): 457-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11781225&dopt=Abstract

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Use of H19 regulatory sequences for targeted gene therapy in cancer. Author(s): Ohana P, Bibi O, Matouk I, Levy C, Birman T, Ariel I, Schneider T, Ayesh S, Giladi H, Laster M, de Groot N, Hochberg A. Source: International Journal of Cancer. Journal International Du Cancer. 2002 April 10; 98(5): 645-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11920631&dopt=Abstract

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Use of hypoxia-regulated gene expression in tumor-specific gene therapy. Author(s): Ruan H, Deen DF. Source: Curr Opin Investig Drugs. 2001 June; 2(6): 839-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11572667&dopt=Abstract

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Use of the herpes simplex viral genome to construct gene therapy vectors. Author(s): Burton EA, Huang S, Goins WF, Glorioso JC. Source: Methods in Molecular Medicine. 2003; 76: 1-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526156&dopt=Abstract

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Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Author(s): Kanyama H, Tomita N, Yamano T, Aihara T, Miyoshi Y, Ohue M, Sekimoto M, Sakita I, Tamaki Y, Kaneda Y, Senter PD, Monden M. Source: Cancer Research. 2001 January 1; 61(1): 14-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11196152&dopt=Abstract

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Validation in mesenchymal progenitor cells of a mutation-independent ex vivo approach to gene therapy for osteogenesis imperfecta. Author(s): Millington-Ward S, Allers C, Tuohy G, Conget P, Allen D, McMahon HP, Kenna PF, Humphries P, Farrar GJ. Source: Human Molecular Genetics. 2002 September 15; 11(19): 2201-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217948&dopt=Abstract

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Vascular gene therapy: a reality of the 21st century. Author(s): Zuckerbraun BS, Tzeng E. Source: Archives of Surgery (Chicago, Ill. : 1960). 2002 July; 137(7): 854-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12093346&dopt=Abstract

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Vascular growth factor and gene therapy to induce new vessels in the ischemic myocardium. Therapeutic angiogenesis. Author(s): Kastrup J, Jorgensen E, Drvota V. Source: Scandinavian Cardiovascular Journal : Scj. 2001 October; 35(5): 291-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11771818&dopt=Abstract

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Vector delivery methods and targeting strategies for gene therapy of brain tumors. Author(s): Rainov NG, Kramm CM. Source: Current Gene Therapy. 2001 November; 1(4): 367-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109063&dopt=Abstract

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Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and antiangiogenesis gene therapy of cancer. Author(s): Zhang L, Yang N, Mohamed-Hadley A, Rubin SC, Coukos G. Source: Biochemical and Biophysical Research Communications. 2003 April 18; 303(4): 1169-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12684059&dopt=Abstract

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VEGF gene therapy for coronary artery disease and peripheral vascular disease. Author(s): Rasmussen HS, Rasmussen CS, Macko J. Source: Cardiovascular Radiation Medicine. 2002 April-June; 3(2): 114-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12699842&dopt=Abstract

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Viral based gene therapy for prostate cancer. Author(s): Lu Y. Source: Current Gene Therapy. 2001 July; 1(2): 183-200. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12108954&dopt=Abstract

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Viral imaging in gene therapy noninvasive demonstration of gene delivery and expression. Author(s): Schellingerhout D, Bogdanov AA Jr. Source: Neuroimaging Clin N Am. 2002 November; 12(4): 571-81, Vi-Vii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687912&dopt=Abstract

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Viral vector-mediated gene therapy for hemophilia. Author(s): VandenDriessche T, Collen D, Chuah MK. Source: Current Gene Therapy. 2001 September; 1(3): 301-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109144&dopt=Abstract

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Virology and immunology of gene therapy, or virology and immunology of high MOI infection with defective viruses. Author(s): Lowenstein PR. Source: Gene Therapy. 2003 June; 10(11): 933-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756412&dopt=Abstract

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Web alert. Gene therapy in cancer treatment. Author(s): O'Neil D. Source: Curr Opin Mol Ther. 2000 August; 2(4): 359. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11249764&dopt=Abstract

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What can SV40-derived vectors do for gene therapy? Author(s): Strayer DS, Zern MA, Chowdhury JR. Source: Curr Opin Mol Ther. 2002 August; 4(4): 313-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12222869&dopt=Abstract

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What has happened to gene therapy? Author(s): Nevin NC. Source: European Journal of Pediatrics. 2000 December; 159 Suppl 3: S240-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11216908&dopt=Abstract

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What next for human gene therapy? Gene transfer often has multiple and unpredictable effects on cells. Author(s): Juengst ET. Source: Bmj (Clinical Research Ed.). 2003 June 28; 326(7404): 1410-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829528&dopt=Abstract

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Who needs to know? Confusion reigns over the reporting of gene therapy deaths. Author(s): Boyce N. Source: New Scientist (1971). 1999 November 13; 164(2212): 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11885629&dopt=Abstract

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Why did p53 gene therapy fail in ovarian cancer? Author(s): Zeimet AG, Marth C. Source: The Lancet Oncology. 2003 July; 4(7): 415-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850192&dopt=Abstract

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CHAPTER 2. NUTRITION AND GENE THERAPY Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and gene therapy.

Finding Nutrition Studies on Gene Therapy 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 “gene therapy” (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 “gene therapy” (or a synonym): •

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 interferon gamma gene therapy for allergic asthma: involvement of interleukin 12 and STAT4 signaling. Author(s): Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Center, University of South Florida College of Medicine, Tampa, FL 33620, USA. Source: Behera, A K KuMarch, M Lockey, R F Mohapatra, S S Hum-Gene-Ther. 2002 September 20; 13(14): 1697-709 1043-0342

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Functional impairment of human T-lymphocytes following PHA-induced expansion and retroviral transduction: implications for gene therapy. Author(s): The Anthony Nolan Research Institute and Department of Haematology, Royal Free and UCL School of Medicine, London, UK. Source: Duarte, R F Chen, F E Lowdell, M W Potter, M N Lamana, M L Prentice, H G Madrigal, J A Gene-Ther. 2002 October; 9(20): 1359-68 0969-7128

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Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases. Author(s): Program in Gene Therapy, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Source: Alisky, J M Davidson, B L Hum-Gene-Ther. 2000 November 20; 11(17): 2315-29 1043-0342

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Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer. Author(s): Department of Obstetrics and Gynecology, Freiburg University Medical Center, Freiburg, Germany. [email protected] Source: Kieback, D G Fischer, D C Engehausen, D G Sauerbrei, W Oehler, M K Tong, X W Aguilar Cordova, E Cancer-Gene-Ther. 2002 May; 9(5): 478-81 0929-1903

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Modulation of cyclophosphamide-based cytochrome P450 gene therapy using liver P450 inhibitors. Author(s): Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts 02215, USA. Source: Huang, Z Waxman, D J Cancer-Gene-Ther. 2001 June; 8(6): 450-8 0929-1903

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Pulmonary irradiation-induced expression of VCAM-I and ICAM-I is decreased by manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) gene therapy. Author(s): Department of Radiation Oncology, University of Pittsburgh Cancer Center Institute, Pennsylvania 15213, USA. Source: Epperly, M W Sikora, C A DeFilippi, S J Gretton, J E Bar Sagi, D Archer, H Carlos, T Guo, H Greenberger, J S Biol-Blood-Marrow-Transplant. 2002; 8(4): 175-87 1083-8791

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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/

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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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WebMD®Health: 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 GENE THERAPY Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to gene therapy. 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 gene therapy 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 “gene therapy” (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 gene therapy: •

A fully automated one pot synthesis of 9-(4-[18F]fluoro-3-hydroxymethylbutyl) guanine for gene therapy studies. Author(s): Penuelas I, Boan JF, Marti-Climent JM, Barajas MA, Narvaiza I, Satyamurthy N, Barrio JR, Richter JA. Source: Molecular Imaging and Biology : Mib : the Official Publication of the Academy of Molecular Imaging. 2002 November; 4(6): 415-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14537106&dopt=Abstract

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A new United States Pharmacopeia (USP) Chapter 1046: cell and gene therapy products. Author(s): Seaver S. Source: Cytotherapy. 2000; 2(1): 45-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042054&dopt=Abstract

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A novel approach using transcomplementing adenoviral vectors for gene therapy of adrenocortical cancer. Author(s): Wolkersdorfer GW, Bornstein SR, Higginbotham JN, Hiroi N, Vaquero JJ, Green MV, Blaese RM, Aguilera G, Chrousos GP, Ramsey WJ. Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2002 June; 34(6): 279-87. Erratum In: Horm Metab Res. 2002 October; 34(10): 604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173067&dopt=Abstract

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A prototype transduction tag system (delta LNGFR/NGF) for noninvasive clinical gene therapy monitoring. Author(s): Lauer UM, Staehler P, Lambrecht RM, Oberdorfer F, Spiegel M, Wybranietz WA, Gross CD, Gregor M. Source: Cancer Gene Therapy. 2000 March; 7(3): 430-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10766349&dopt=Abstract

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A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. Author(s): Grines CL, Watkins MW, Mahmarian JJ, Iskandrian AE, Rade JJ, Marrott P, Pratt C, Kleiman N; Angiogene GENe Therapy (AGENT-2) Study Group. Source: Journal of the American College of Cardiology. 2003 October 15; 42(8): 1339-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563572&dopt=Abstract

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A simplified one-pot synthesis of 9-[(3-[18F]fluoro-1-hydroxy-2propoxy)methyl]guanine([18F]FHPG) and 9-(4-[18F]fluoro-3hydroxymethylbutyl)guanine ([18F]FHBG) for gene therapy. Author(s): Shiue GG, Shiue CY, Lee RL, MacDonald D, Hustinx R, Eck SL, Alavi AA. Source: Nuclear Medicine and Biology. 2001 October; 28(7): 875-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11578910&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11961663&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571646&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713766&dopt=Abstract

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Allium sativum potentiates suicide gene therapy for murine transitional cell carcinoma. Author(s): Moon DG, Cheon J, Yoon DH, Park HS, Kim HK, Kim JJ, Koh SK. Source: Nutrition and Cancer. 2000; 38(1): 98-105. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11341051&dopt=Abstract

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Alternative therapy si, gene therapy no? Author(s): Dienstag JL. Source: Gastroenterology. 2000 November; 119(5): 1189. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11054375&dopt=Abstract

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Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. Author(s): Shimizu H, Maruyama S, Yuzawa Y, Kato T, Miki Y, Suzuki S, Sato W, Morita Y, Maruyama H, Egashira K, Matsuo S. Source: Journal of the American Society of Nephrology : Jasn. 2003 June; 14(6): 1496-505. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761250&dopt=Abstract

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Approaches for skeletal gene therapy. Author(s): Niyibizi C, Wallach CJ, Mi Z, Robbins PD. Source: Critical Reviews in Eukaryotic Gene Expression. 2002; 12(3): 163-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12449341&dopt=Abstract

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Bone morphogenetic protein 7 ex vivo gene therapy. Author(s): Rutherford RB, Nussenbaum B, Krebsbach PH. Source: Drug News Perspect. 2003 January-February; 16(1): 5-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682667&dopt=Abstract

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Cancer gene therapy using a pro-apoptotic gene, caspase-3. Author(s): Yamabe K, Shimizu S, Ito T, Yoshioka Y, Nomura M, Narita M, Saito I, Kanegae Y, Matsuda H. Source: Gene Therapy. 1999 December; 6(12): 1952-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10637446&dopt=Abstract

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Cancer gene therapy using a survivin mutant adenovirus. Author(s): Mesri M, Wall NR, Li J, Kim RW, Altieri DC.

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Source: The Journal of Clinical Investigation. 2001 October; 108(7): 981-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11581299&dopt=Abstract •

Changes of tumor vascularity during gene therapy monitored with color Doppler US. Author(s): Delorme S, Haberkorn U, Kinscherf R, Zuna I, Bahner ML, van Kaick G. Source: Ultrasound in Medicine & Biology. 2001 December; 27(12): 1595-603. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11839404&dopt=Abstract

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Characterization and quality control of recombinant adenovirus vectors for gene therapy. Author(s): Roitsch C, Achstetter T, Benchaibi M, Bonfils E, Cauet G, Gloeckler R, L'h te H, Keppi E, Nguyen M, Spehner D, Van Dorsselaer A, Malarme D. Source: J Chromatogr B Biomed Sci Appl. 2001 March 10; 752(2): 263-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270866&dopt=Abstract

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CL1-SR39: A noninvasive molecular imaging model of prostate cancer suicide gene therapy using positron emission tomography. Author(s): Pantuck AJ, Berger F, Zisman A, Nguyen D, Tso CL, Matherly J, Gambhir SS, Belldegrun AS. Source: The Journal of Urology. 2002 September; 168(3): 1193-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187266&dopt=Abstract

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Clinical trials in gene therapy. Author(s): Isner JM. Source: Current Cardiology Reports. 2000 January; 2(1): 11-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10980866&dopt=Abstract

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Complete reversal of ischemic wall motion abnormalities by combined use of gene therapy with transmyocardial laser revascularization. Author(s): Sayeed-Shah U, Mann MJ, Martin J, Grachev S, Reimold S, Laurence R, Dzau V, Cohn LH. Source: The Journal of Thoracic and Cardiovascular Surgery. 1998 November; 116(5): 763-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9806383&dopt=Abstract

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CT and radionuclide study of BMP-2 gene therapy-induced bone formation. Author(s): Varady P, Li JZ, Alden TD, Kallmes DF, Williams MB, Helm GA. Source: Academic Radiology. 2002 June; 9(6): 632-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12061736&dopt=Abstract

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Current status of stem cell therapy and prospects for gene therapy for the disorders of globin synthesis. Author(s): Blau CA.

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Source: Baillieres Clin Haematol. 1998 March; 11(1): 257-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10872481&dopt=Abstract •

Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models. Author(s): Wen SF, Xie L, McDonald M, DiGiacomo R, Chang A, Gurnani M, Shi B, Liu S, Indelicato SR, Hutchins B, Nielsen LL. Source: Cancer Gene Therapy. 2000 November; 7(11): 1469-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11129289&dopt=Abstract

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Development of artificial chimerical gene regulatory elements specific for cancer gene therapy. Author(s): Shin JH, Yi JK, Lee YJ, Kim AL, Park MA, Kim SH, Lee H, Kim CG. Source: Oncol Rep. 2003 November-December; 10(6): 2063-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534744&dopt=Abstract

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E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells. Author(s): Elliott MJ, Farmer MR, Atienza C Jr, Stilwell A, Dong YB, Yang HL, Wong SL, McMasters KM. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2002 March-April; 23(2): 76-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065845&dopt=Abstract

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Engineering membrane proteins for nuclear medicine: applications for gene therapy and cell tracking. Author(s): Bogdanov AA Jr, Simonova M, Weissleder R. Source: Q J Nucl Med. 2000 September; 44(3): 224-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11105587&dopt=Abstract

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Enhanced transgene expression in androgen independent prostate cancer gene therapy by taxane chemotherapeutic agents. Author(s): Li Y, Okegawa T, Lombardi DP, Frenkel EP, Hsieh JT. Source: The Journal of Urology. 2002 January; 167(1): 339-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11743353&dopt=Abstract

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Establishment and characterization of a rectal cancer model in mice: application to cytokine gene therapy. Author(s): Chen Y, Chang KJ, Hwang LH, Chen CN, Tseng SH.

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Source: International Journal of Colorectal Disease. 2002 November; 17(6): 388-95. Epub 2002 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12355214&dopt=Abstract •

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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12189522&dopt=Abstract

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Experience of gene therapy in the United Kingdom. Author(s): Nevin NC. Source: Annals of the New York Academy of Sciences. 1998 December 30; 862: 184-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9928223&dopt=Abstract

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Gene therapy and tissue engineering based on muscle-derived stem cells. Author(s): Deasy BM, Huard J. Source: Curr Opin Mol Ther. 2002 August; 4(4): 382-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12222876&dopt=Abstract

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Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Author(s): Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, Ashare AB, Lathi K, Isner JM. Source: Circulation. 1998 December 22-29; 98(25): 2800-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9860779&dopt=Abstract

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Gene therapy for prostate cancer by targeting poly(ADP-ribose) polymerase. Author(s): Trofimova I, Dimtchev A, Jung M, Rosenthal D, Smulson M, Dritschilo A, Soldatenkov V. Source: Cancer Research. 2002 December 1; 62(23): 6879-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12460902&dopt=Abstract

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Gene therapy for prostate cancer: toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters. Author(s): Ebara S, Shimura S, Nasu Y, Kaku H, Kumon H, Yang G, Wang J, Timme TL, Aguilar-Cordova E, Thompson TC. Source: Prostate Cancer and Prostatic Diseases. 2002; 5(4): 316-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627218&dopt=Abstract

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Gene therapy for spine fusion. Author(s): Boden SD, Hair GA, Viggeswarapu M, Liu Y, Titus L.

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Source: Clinical Orthopaedics and Related Research. 2000 October; (379 Suppl): S225-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11039774&dopt=Abstract •

Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Author(s): Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A. Source: Science. 2000 April 28; 288(5466): 669-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10784449&dopt=Abstract

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Gene therapy of neoplastic liver diseases. Author(s): Sangro B, Herraiz M, Prieto J. Source: The International Journal of Biochemistry & Cell Biology. 2003 February; 35(2): 135-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12479864&dopt=Abstract

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Gene therapy of X-linked severe combined immunodeficiency. Author(s): Hacein-Bey-Abina S, de Saint Basile G, Cavazzana-Calvo M. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 215: 247-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512304&dopt=Abstract

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Gene therapy of X-linked severe combined immunodeficiency. Author(s): Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M. Source: International Journal of Hematology. 2002 November; 76(4): 295-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463590&dopt=Abstract

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Gene therapy technology applied to disorders of glucose metabolism: promise, achievements, and prospects. Author(s): Giannoukakis N, Trucco M. Source: Biotechniques. 2003 July; 35(1): 122-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866413&dopt=Abstract

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Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure. Author(s): Leotta E, Patejunas G, Murphy G, Szokol J, McGregor L, Carbray J, Hamawy A, Winchester D, Hackett N, Crystal R, Rosengart T. Source: The Journal of Thoracic and Cardiovascular Surgery. 2002 June; 123(6): 1101-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12063456&dopt=Abstract

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Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Author(s): Symes JF, Losordo DW, Vale PR, Lathi KG, Esakof DD, Mayskiy M, Isner JM.

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Source: The Annals of Thoracic Surgery. 1999 September; 68(3): 830-6; Discussion 836-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10509970&dopt=Abstract •

Gene therapy: clinical considerations. Author(s): Scully SP. Source: Clinical Orthopaedics and Related Research. 2000 October; (379 Suppl): S55-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11039751&dopt=Abstract

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Guidance for human somatic cell therapy and gene therapy. Author(s): U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Source: Human Gene Therapy. 2001 February 10; 12(3): 303-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11177566&dopt=Abstract

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Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Author(s): Ito A, Shinkai M, Honda H, Kobayashi T. Source: Cancer Gene Therapy. 2001 September; 8(9): 649-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11593333&dopt=Abstract

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Herpes simplex virus thymidine kinase as a marker/reporter gene for PET imaging of gene therapy. Author(s): Blasberg RG, Tjuvajev JG. Source: Q J Nucl Med. 1999 June; 43(2): 163-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10429512&dopt=Abstract

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How realistic is cutaneous gene therapy? Author(s): Hengge UR, Taichman LB, Kaur P, Rogers G, Jensen TG, Goldsmith LA, Rees JL, Christiano AM. Source: Experimental Dermatology. 1999 October; 8(5): 419-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10536970&dopt=Abstract

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Human gene therapy and the slippery slope argument. Author(s): Launis V. Source: Medicine, Health Care, and Philosophy. 2002; 5(2): 169-79. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12168992&dopt=Abstract

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IL-12 gene therapy for cancer: in synergy with other immunotherapies. Author(s): Melero I, Mazzolini G, Narvaiza I, Qian C, Chen L, Prieto J. Source: Trends in Immunology. 2001 March; 22(3): 113-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11286714&dopt=Abstract

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Imaging methods in gene therapy of cancer. Author(s): Haberkorn U, Altmann A. Source: Current Gene Therapy. 2001 July; 1(2): 163-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12108953&dopt=Abstract

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Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma. Author(s): Voges J, Reszka R, Gossmann A, Dittmar C, Richter R, Garlip G, Kracht L, Coenen HH, Sturm V, Wienhard K, Heiss WD, Jacobs AH. Source: Annals of Neurology. 2003 October; 54(4): 479-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520660&dopt=Abstract

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Immunomodulation of glioma cells after gene therapy: induction of major histocompatibility complex class I but not class II antigen in vitro. Author(s): Parsa AT, Chi JH, Hurley PT, Jeyapalan SA, Bruce JN. Source: Neurosurgery. 2001 September; 49(3): 681-8; Discussion 688-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11523680&dopt=Abstract

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Insulinoma-induced hypoglycemic death in mice is prevented with beta cell-specific gene therapy. Author(s): Tirone TA, Fagan SP, Templeton NS, Wang X, Brunicardi FC. Source: Annals of Surgery. 2001 May; 233(5): 603-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11323498&dopt=Abstract

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Intralesional lipid-complexed cytokine/superantigen immunogene therapy for spontaneous canine tumors. Author(s): Thamm DH, Kurzman ID, Macewen EG, Feinmehl R, Towell TL, Longhofer SL, Johnson CM, Geoly FJ, Stinchcomb DT. Source: Cancer Immunology, Immunotherapy : Cii. 2003 August; 52(8): 473-80. Epub 2003 May 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768328&dopt=Abstract

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Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer. 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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11961671&dopt=Abstract

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Local gene delivery: arterial thrombosis model for endothelial cell-targeted thrombolytic gene therapy research. Author(s): Shenaq SM, Kattash MM, Weinfeld AB, Waugh JM, Yuksel E, Yuksel M, Gura DH.

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Source: Journal of Reconstructive Microsurgery. 1999 January; 15(1): 73-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10025534&dopt=Abstract •

Mdr1 promoter-driven tumor necrosis factor-alpha expression for a chemotherapycontrollable combined in vivo gene therapy and chemotherapy of tumors. Author(s): Walther W, Stein U, Fichtner I, Alexander M, Shoemaker RH, Schlag PM. Source: Cancer Gene Therapy. 2000 June; 7(6): 893-900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10880020&dopt=Abstract

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Monitoring gene therapy with reporter gene imaging. Author(s): Ray P, Bauer E, Iyer M, Barrio JR, Satyamurthy N, Phelps ME, Herschman HR, Gambhir SS. Source: Semin Nucl Med. 2001 October; 31(4): 312-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11710773&dopt=Abstract

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MR imaging and single-photon emission CT findings after gene therapy for human glioblastoma. Author(s): Floeth FW, Aulich A, Langen KJ, Burger KJ, Bock WJ, Weber F. Source: Ajnr. American Journal of Neuroradiology. 2001 September; 22(8): 1517-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11559499&dopt=Abstract

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Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Author(s): Bachoud-Levi AC, Deglon N, Nguyen JP, Bloch J, Bourdet C, Winkel L, Remy P, Goddard M, Lefaucheur JP, Brugieres P, Baudic S, Cesaro P, Peschanski M, Aebischer P. Source: Human Gene Therapy. 2000 August 10; 11(12): 1723-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10954906&dopt=Abstract

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New approaches for imaging in gene therapy. Author(s): Wunderbaldinger P, Bogdanov A, Weissleder R. Source: European Journal of Radiology. 2000 June; 34(3): 156-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10927158&dopt=Abstract

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Novel treatment for neuronopathic lysosomal storage diseases--cell therapy/gene therapy. Author(s): Eto Y, Ohashi T. Source: Current Molecular Medicine. 2002 February; 2(1): 83-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898850&dopt=Abstract

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Optimizing prostate cancer suicide gene therapy using herpes simplex virus thymidine kinase active site variants.

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Author(s): Pantuck AJ, Matherly J, Zisman A, Nguyen D, Berger F, Gambhir SS, Black ME, Belldegrun A, Wu L. Source: Human Gene Therapy. 2002 May 1; 13(7): 777-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11975845&dopt=Abstract •

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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11023193&dopt=Abstract

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Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Author(s): Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle C, Wagner R, Wienhard K, Heiss WD. Source: Lancet. 2001 September 1; 358(9283): 727-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11551583&dopt=Abstract

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Potential of gene therapy for treating osteogenesis imperfecta. Author(s): Niyibizi C, Smith P, Mi Z, Robbins P, Evans C. Source: Clinical Orthopaedics and Related Research. 2000 October; (379 Suppl): S126-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11039761&dopt=Abstract

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Progress in cancer gene therapy. Author(s): Curiel DT, Gerritsen WR, Krul MR. Source: Cancer Gene Therapy. 2000 August; 7(8): 1197-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10975681&dopt=Abstract

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Regulation of gene expression by herbal medicines--a new paradigm of gene therapy for multifocal abnormalities of genes. Author(s): Sugaya E, Yuyama N, Kajiwara K, Tsuda T, Ohguchi H, Shimizu-Nishikawa K, Kimura M, Sugaya A. Source: Res Commun Mol Pathol Pharmacol. 1999; 106(3): 171-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11485047&dopt=Abstract

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Scintigraphic imaging of HSVtk gene therapy. Author(s): Vries EF, Buursma AR, Hospers GA, Mulder NH, Vaalburg W. Source: Current Pharmaceutical Design. 2002; 8(16): 1435-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052205&dopt=Abstract

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Simultaneous genetic chemoprotection of normal marrow cells and genetic chemosensitization of breast cancer cells in a mouse cancer gene therapy model. Author(s): Hanania EG, Deisseroth AB. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1997 February; 3(2): 281-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9815684&dopt=Abstract

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Syngeneic fibroblasts transfected with a plasmid encoding interleukin-4 as non-viral vectors for anti-inflammatory gene therapy in collagen-induced arthritis. Author(s): Bessis N, Cottard V, Saidenberg-Kermanach N, Lemeiter D, Fournier C, Boissier MC. Source: The Journal of Gene Medicine. 2002 May-June; 4(3): 300-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112647&dopt=Abstract

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Systemic gene therapy in human xenograft tumor models by liposomal delivery of the E1A gene. Author(s): Ueno NT, Bartholomeusz C, Xia W, Anklesaria P, Bruckheimer EM, Mebel E, Paul R, Li S, Yo GH, Huang L, Hung MC. Source: Cancer Research. 2002 November 15; 62(22): 6712-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438271&dopt=Abstract

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Systemic p53 gene therapy of cancer with immunolipoplexes targeted by antitransferrin receptor scFv. Author(s): Xu L, Tang WH, Huang CC, Alexander W, Xiang LM, Pirollo KF, Rait A, Chang EH. Source: Molecular Medicine (Cambridge, Mass.). 2001 October; 7(10): 723-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713371&dopt=Abstract

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The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity. Author(s): Prabhu NS, Somasundaram K, Tian H, Enders GH, Satyamoorthy K, Herlyn M, El-Deiry WS. Source: International Journal of Oncology. 1999 August; 15(2): 209-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10402229&dopt=Abstract

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The common marmoset as a target preclinical primate model for cytokine and gene therapy studies. Author(s): Hibino H, Tani K, Ikebuchi K, Wu MS, Sugiyama H, Nakazaki Y, Tanabe T, Takahashi S, Tojo A, Suzuki S, Tanioka Y, Sugimoto Y, Nakahata T, Asano S. Source: Blood. 1999 May 1; 93(9): 2839-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10216078&dopt=Abstract

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The lung as a metabolic factory for gene therapy. Author(s): Engelhardt JF.

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Source: The Journal of Clinical Investigation. 2002 August; 110(4): 429-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12189234&dopt=Abstract •

The use of bone morphogenetic protein gene therapy in craniofacial bone repair. Author(s): Alden TD, Beres EJ, Laurent JS, Engh JA, Das S, London SD, Jane JA Jr, Hudson SB, Helm GA. Source: The Journal of Craniofacial Surgery. 2000 January; 11(1): 24-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11314095&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10595917&dopt=Abstract

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The WldS protein protects against axonal degeneration: a model of gene therapy for peripheral neuropathy. Author(s): Wang MS, Fang G, Culver DG, Davis AA, Rich MM, Glass JD. Source: Annals of Neurology. 2001 December; 50(6): 773-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11761475&dopt=Abstract

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Three-dimensional cell-scaffold constructs promote efficient gene transfection: implications for cell-based gene therapy. Author(s): Xie Y, Yang ST, Kniss DA. Source: Tissue Engineering. 2001 October; 7(5): 585-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11694192&dopt=Abstract

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Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field. Author(s): Sangro B, Qian C, Ruiz J, Prieto J. Source: Molecular Imaging and Biology : Mib : the Official Publication of the Academy of Molecular Imaging. 2002 January; 4(1): 27-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14538046&dopt=Abstract

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Transplantation of neural stem cells: cellular & gene therapy for hypoxic-ischemic brain injury. Author(s): Park KI. Source: Yonsei Medical Journal. 2000 December; 41(6): 825-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11204833&dopt=Abstract

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Ultrasound-guided stem cell sampling from the early ovine fetus for prenatal ex vivo gene therapy. Author(s): Surbek DV, Young A, Danzer E, Schoeberlein A, Dudler L, Holzgreve W. Source: American Journal of Obstetrics and Gynecology. 2002 October; 187(4): 960-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388986&dopt=Abstract

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Uncoupling of 2-fluoro-2-deoxyglucose transport and phosphorylation in rat hepatoma during gene therapy with HSV thymidine kinase. Author(s): Haberkorn U, Bellemann ME, Gerlach L, Morr I, Trojan H, Brix G, Altmann A, Doll J, van Kaick G. Source: Gene Therapy. 1998 July; 5(7): 880-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9813658&dopt=Abstract

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Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. Author(s): Helm GA, Alden TD, Beres EJ, Hudson SB, Das S, Engh JA, Pittman DD, Kerns KM, Kallmes DF. Source: Journal of Neurosurgery. 2000 April; 92(2 Suppl): 191-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10763690&dopt=Abstract

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Why gene therapy is considered scary but cell therapy isn't. Author(s): Kolata G. Source: Ny Times (Print). 1990 September 16; : E5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11646785&dopt=Abstract

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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WebMD®Health: 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 gene therapy; 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: •

General Overview Cystic Fibrosis Source: Integrative Medicine Communications; www.drkoop.com Phenylketonuria Source: Healthnotes, Inc.; www.healthnotes.com

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 GENE THERAPY Overview In this chapter, we will give you a bibliography on recent dissertations relating to gene therapy. 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 “gene therapy” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on gene therapy, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Gene Therapy 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 gene therapy. 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-basedp53 Gene Therapy: Intraperitoneal Delivery for Ovarian Cancer by Carroll, Jennifer Lynette; PhD from Louisiana State University Health Sciences Center Shreveport, 2002, 166 pages http://wwwlib.umi.com/dissertations/fullcit/3053157

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Antisense and Drug-resistance Gene Therapy in a Mouse Model of Chronic Myeloid Leukemia by Sweeney, Colin Lee; PhD from University of Minnesota, 2003, 216 pages http://wwwlib.umi.com/dissertations/fullcit/3087792

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Combined Gene Transfer of Ifn-gamma-inducible Protein 10 (ip-10) and Interleukin12 Using First Generation Adenoviruses for Gene Therapy against Colon Cancer by Dr. Inigo Narvaiza Cuervas-Mons from Universidad De Navarra (Spain), 2002, 220 pages http://wwwlib.umi.com/dissertations/fullcit/f352017

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Comparison of Transfection Rates and Optimization of Suicide Gene Therapy in Head and Neck Squamous Cell Cancer Utilizing a Novel Targeted Adenovirus in

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Vitro by Beyer, Gregory Robert; MD from Louisiana State Univ. Health Sciences Center School of Medicine, 2002 http://wwwlib.umi.com/dissertations/fullcit/f738641 •

Developing Combination Strategies for the Treatment of Spinal Cord Injury Utilizing Ex Vivo Gene Therapy and Alginate Encapsulation by Tobias, Christopher Alan; PhD from Drexel University College of Medicine, 2002, 375 pages http://wwwlib.umi.com/dissertations/fullcit/3075220

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Development and Characterization of Adenosine Releasing Cellular Grafts for an Ex Vivo Gene Therapy of Focal Epilepsy by Huber, Alexander Felix; DRSCNAT from Eidgenoessische Technische Hochschule Zuerich (Switzerland), 2002, 111 pages http://wwwlib.umi.com/dissertations/fullcit/f364353

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Development and Testing of Mono- and Multimeric Hammerhead Ribozymes for Hiv-1 Gene Therapy by Ramezani, Ali; PhD from University of Toronto (canada), 2002, 214 pages http://wwwlib.umi.com/dissertations/fullcit/NQ69060

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Development of Gene Therapy for Hematopoietic Stem Cells Using Lentiviral Vectors by Woods, Niels-Bjarne R.; PhD from Lunds Universitet (sweden), 2002 http://wwwlib.umi.com/dissertations/fullcit/f327793

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Development of Replication-competent Retroviral Vectors for Efficient, Targeted Gene Therapy of Cancer by Logg, Christopher Reid; PhD from University of Southern California, 2002, 119 pages http://wwwlib.umi.com/dissertations/fullcit/3073808

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Engineering of Retargeted Adenoviruses for in Vivo Gene Therapy by Pai, Sara Isabel; PhD from The Johns Hopkins University, 2002, 79 pages http://wwwlib.umi.com/dissertations/fullcit/3046526

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Gene Manipulations for Cancer Gene Therapy by Vasanwala, Farha Huseini; PhD from The University of Arizona, 2002, 150 pages http://wwwlib.umi.com/dissertations/fullcit/3050309

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Gene Therapy Approach Utilizing Adenovirus to Deliver the Pro-apoptotic Gene, Bax, for Tissue-specific Treatment of Prostate Cancer by Lowe, Stephanie Lewis; PhD from Medical University of South Carolina, 2002, 144 pages http://wwwlib.umi.com/dissertations/fullcit/3050234

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Gene Therapy for Disorders of Cerebellar Development Utilizing Recombinant Feline Immunodeficiency Virus in the Mouse Model, Staggerer by Shirley, Thomas Lloyd; PhD from State University of New York at Albany, 2003, 180 pages http://wwwlib.umi.com/dissertations/fullcit/3083530

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Gene Therapy for Motor Neuron Degeneration in Murine Tissue Culture and Transgenic Mouse Models of Familial Amyotrophic Lateral Sclerosis by Roehmholdt, Brian Francis; PhD from University of Southern California, 2002, 188 pages http://wwwlib.umi.com/dissertations/fullcit/3073841

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Gene Therapy for Treatment of Infected Non-unions and Novel Methods for Early Diagnosis of Impaired Fracture Healing by Southwood, Louise Lesley Parente; PhD from Colorado State University, 2002, 433 pages http://wwwlib.umi.com/dissertations/fullcit/3064012

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Gene Therapy of Orthotopic Hepatocellular Carcinoma in Buffalo Rats Using an Adenovirus Coding for Interleukin-12 by Dr. Miguel Angel Barajas Velez from Universidad De Navarra (Spain), 2002, 168 pages http://wwwlib.umi.com/dissertations/fullcit/f352081

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Genetic Re-targeting of Adenoviral Vectors for Gene Therapy Applications by Magnusson, Maria Kerstin; MEDDR from Goteborgs Universitet (Sweden), 2002, 58 pages http://wwwlib.umi.com/dissertations/fullcit/f336209

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Heat-directed Cancer Gene Therapy by Brade, Anthony Matthew; PhD from University of Toronto (Canada), 2002, 190 pages http://wwwlib.umi.com/dissertations/fullcit/NQ69178

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In Vitro and in Vivo Models for Cytochrome P450-based Anticancer Gene Therapy by Dorfman Hecht, Jodi Elise; PhD from Boston University, 2002, 262 pages http://wwwlib.umi.com/dissertations/fullcit/3043285

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Inhibition of Abnormal Intestinal Epithelial Permeability by Targeted Gene Therapy by Blanchette, Jason Brooks; MSC from University of Calgary (Canada), 2002, 192 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76200

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Justifying Human Gene Therapy: an Assessment of Some of the Central Ethical Considerations Underlying the Application of Genetic Knowledge to Human Subjects from the Perspective of the Traditional Conscience (bioethics, Medical Ethics) by Daniels, Scott Eugene, PhD from The University of Tennessee, 1990, 356 pages http://wwwlib.umi.com/dissertations/fullcit/9030698

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Magnetic Resonance-based Markers of Treatment Response and Transgene Expression for Use in Brain Tumor Gene Therapy by Stegman, Lauren Daniel; PhD from University of Michigan, 2002, 200 pages http://wwwlib.umi.com/dissertations/fullcit/3042174

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New Treatments for Refractory Angina: Transmyocardial Laser Revascularization Versus Gene Therapy with Vegf-165. an Experimental Study by Dr. Juan Cosin Sales from Universidad De Navarra (Spain), 2002 http://wwwlib.umi.com/dissertations/fullcit/f722353

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Novel Approaches for Long-term Gene Therapy by Sclimenti, Christopher Ryan; PhD from Stanford University, 2003, 239 pages http://wwwlib.umi.com/dissertations/fullcit/3085367

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P16 Cancer Gene Therapy: an Efficacious Modality for Nasopharyngeal Carcinoma (NPC) by Lee, Andrew Wing Cheong; MSC from University of Toronto (Canada), 2002, 126 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74054

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Phage Integrases for Gene Therapy: from Concept to Application by Olivares, Eric Chace; PhD from Stanford University, 2003, 170 pages http://wwwlib.umi.com/dissertations/fullcit/3090651

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Structural Flexibilty of the Dystrophin Rod Domain: Implications for Gene Therapy of Duchenne Muscular Dystrophy Using Adeno-associated Viral Vectors by Harper, Scott Quenton; PhD from University of Michigan, 2002, 158 pages http://wwwlib.umi.com/dissertations/fullcit/3057958

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Synthetic,ph-sensitive Polymers That Promote the Intracellular Delivery of Nonviral Gene Therapy Vectors by Cheung, Charles Ying Cheuk; PhD from University of Washington, 2003, 170 pages http://wwwlib.umi.com/dissertations/fullcit/3079209

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The Regulatory Sequences of the Secretory Leukoprotease Inhibitor Gene As a Tissue-specific Promoter for Gene Therapy of Ovarian Carcinoma by Barker, Shannon Doyle; PhD from The University of Alabama at Birmingham, 2002, 81 pages http://wwwlib.umi.com/dissertations/fullcit/3066299

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Tumor Necrosis Factor Receptor Gene Therapy Influences Humoral and Cellular Immune Responses in Collagen Induced Arthritis by Mukherjee, Paramita; PhD from Wayne State University, 2003, 177 pages http://wwwlib.umi.com/dissertations/fullcit/3086457

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Understanding Obstacles to Retroviral Mediated Gene Therapy of Globin Disorders: Implications for Design of Therapeutic Expression Cassettes and Retrovirus Vectors by Pannell, Dylan Geoffrey; PhD from University of Toronto (Canada), 2002, 248 pages http://wwwlib.umi.com/dissertations/fullcit/NQ69192

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Viral Receptor Interactions in Airway Epithelia: Relevance to Gene Therapy and Viral Pathogenesis by Walters, Robert William; PhD from the University of Iowa, 2003, 209 pages http://wwwlib.umi.com/dissertations/fullcit/3087667

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. CLINICAL TRIALS AND GENE THERAPY Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning gene therapy.

Recent Trials on Gene Therapy The following is a list of recent trials dedicated to gene therapy.8 Further information on a trial is available at the Web site indicated. •

A Single Arm, Phase II Study of TNFerade(tm) gene therapy + Radiation + 5-FU and Cisplatin in Locally Advanced, Resectable, Esophageal Cancer Condition(s): Esophageal Cancer Study Status: This study is currently recruiting patients. Sponsor(s): GenVec Purpose - Excerpt: The primary purpose of this study is to assess the safety and feasibility of giving TNFerade(tm) with 5-FU, Cisplatin and radiation therapy to patients with locally advanced, esophageal cancer prior to surgical resection. TNFerade(tm) is a replication deficient (E1, E3 and E4 deleted) adenovirus vector containing the gene for TNF-alpha controlled by a radiation inducible promoter. This allows the expression of TNF-alpha to be greatest in the area receiving radiation. TNF-alpha is a potent cytokine that has been shown to have potent anti-cancer activities but, due to systemic toxicity, could not be delivered at effective doses. TNFerade(tm) is a novel way of selective delivery of TNF-alpha to tumor cells. TNFerade(tm) will be delivered once a week for five weeks by direct intratumoral injection by using endoscopy or Endoscopic Ultrasound. 5-FU (1000 mg/m2/day) will be delivered via continuous infusion for 96 hours during weeks 1 and 4. Cisplatin (75 mg/m2) will be delivered on Day 1 and Day 29 intravenously. The dose of radiation delivered will be 45 Gy in 1.8 Gy fractions for 5 weeks. Phase(s): Phase II Study Type: Interventional

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These are listed at www.ClinicalTrials.gov.

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00051480 •

Chemotherapy Combined With Gene Therapy in Treating Patients Who Have Stage III or Stage IV Breast Cancer Condition(s): Male Breast Cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; stage IV breast cancer Study Status: This study is currently recruiting patients. Sponsor(s): Introgen Therapeutics Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Inserting the p53 gene into the tumor may increase the effectiveness of a chemotherapy drug by making tumor cells more sensitive to the drug. Combining chemotherapy with gene therapy may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining chemotherapy with gene therapy in treating patients who have stage III or stage IV breast cancer. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00044993

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Chemotherapy With or Without Gene Therapy in Treating Patients With Recurrent Head and Neck Cancer Condition(s): Head and Neck Cancer Study Status: This study is currently recruiting patients. Sponsor(s): Introgen Therapeutics Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Inserting the gene for p53 into a person's cancer cells may improve the body's ability to fight cancer or make the cancer more sensitive to chemotherapy. It is not yet known if chemotherapy is more effective with or without gene therapy in treating recurrent head and neck cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy with or without gene therapy in treating patients who have recurrent head and neck cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040716

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Comparison of Gene Therapy With Chemotherapy in Treating Patients With Head and Neck Cancer Condition(s): Head and Neck Cancer Study Status: This study is currently recruiting patients. Sponsor(s): Introgen Therapeutics

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Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Inserting the p-53 gene into a person's cancer cells may improve the body's ability to fight cancer. It is not yet known if gene therapy is more effective than chemotherapy in treating head and neck cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of gene therapy with that of chemotherapy in treating patients who have head and neck cancer that has not responded to previous treatment. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040703 •

Gene Therapy and Surgery Followed by Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Cancer of the Mouth or Throat Condition(s): stage III squamous cell carcinoma of the lip and oral cavity; stage IV squamous cell carcinoma of the lip and oral cavity; stage III squamous cell carcinoma of the oropharynx; stage IV squamous cell carcinoma of the oropharynx Study Status: This study is currently recruiting patients. Sponsor(s): Southwest Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Inserting the p53 gene into a person's cancer cells may improve the body's ability to fight cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy and radiation therapy with the p53 gene may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of gene therapy plus surgery followed by cisplatin and radiation therapy in treating patients who have newly diagnosed resectable stage III or stage IV cancer of the mouth or throat. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00017173

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Gene Therapy Combined With Chemotherapy and Radiation Therapy in Treating Patients With Pancreatic Cancer That Cannot Be Surgically Removed Condition(s): adenocarcinoma of the pancreas; stage III pancreatic cancer Study Status: This study is currently recruiting patients. Sponsor(s): Jonsson Comprehensive Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Inserting a modified adenovirus gene and tumor necrosis factor (TNF) alpha into a person's tumor cells may make the cancer more sensitive to chemotherapy and radiation therapy. PURPOSE: Randomized phase II trial to study the effectiveness of combining gene therapy (using TNFerade(tm)) with chemotherapy and radiation therapy in treating patients who have pancreatic cancer that cannot be surgically removed.

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Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049647 •

Gene Therapy in Preventing Cancer in Patients With Premalignant Carcinoma of the Oral Cavity or Pharynx Condition(s): lip and oral cavity cancer; Oropharyngeal Cancer; stage 0 lip and oral cavity cancer; stage 0 oropharyngeal cancer Study Status: This study is currently recruiting patients. Sponsor(s): M.D. Anderson Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Inserting the p53 gene into a person's tumor cells may improve the body's ability to kill the tumor cells. PURPOSE: Phase I/II trial to study the effectiveness of gene therapy in preventing cancer in patients who have premalignant carcinoma of the oral cavity or pharynx. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064103

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Gene Therapy in Treating Patients With Recurrent Malignant Glioma Condition(s): recurrent adult brain tumor; adult glioblastoma multiforme; adult anaplastic astrocytoma Study Status: This study is currently recruiting patients. Sponsor(s): MediGene Purpose - Excerpt: RATIONALE: Inserting a modified herpesvirus gene into a person's glioma cells may make the body build an immune response to kill tumor cells. PURPOSE: Phase I/II trial to determine the effectiveness of gene therapy in treating patients who have recurrent malignant glioma. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036699

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Gene Therapy in Treating Patients With Recurrent or Progressive Glioblastoma Multiforme Condition(s): recurrent adult brain tumor; adult glioblastoma multiforme Study Status: This study is currently recruiting patients. Sponsor(s): Biogen Purpose - Excerpt: RATIONALE: Inserting the gene for interferon-beta into a person's glioblastoma cells may make the body build an immune response to kill tumor cells. PURPOSE: Phase I trial to study the effectiveness of gene therapy in treating patients who have recurrent or progressive glioblastoma multiforme.

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Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036725 •

Gene Therapy Plus Chemotherapy in Treating Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma Condition(s): adult brain tumor; adult non-Hodgkin's lymphoma; adult solid tumor Study Status: This study is currently recruiting patients. Sponsor(s): Ireland Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Gene therapy may improve the body's ability to fight cancer or make the cancer more sensitive to chemotherapy. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: Phase I trial to study the effectiveness of combining gene therapy with chemotherapy in treating patients who have advanced solid tumors or non-Hodgkin's lymphoma. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00003567

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Gene Therapy Plus Radiation Therapy in Treating Patients With Non-Small Cell Lung Cancer Condition(s): recurrent non-small cell lung cancer Study Status: This study is currently recruiting patients. Sponsor(s): Eastern Cooperative Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Inserting the gene for p53 into a person's cancer cells may improve the body's ability to fight cancer. Radiation therapy uses high-energy xrays to damage tumor cells. PURPOSE: Phase I trial to study the effectiveness of gene therapy plus radiation therapy in treating patients who have non-small cell lung cancer. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004225

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Gene Therapy to Improve Wound Healing in Patients With Diabetes Condition(s): Wounds and Injuries; Diabetes; Diabetic Foot Ulcers; Foot wounds Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: Patients with diabetes may develop chronic wounds that respond poorly to treatment. Gene therapy with the platelet-derived growth factor-B gene has

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been shown to help with the healing of chronic wounds. This study will evaluate a new way to deliver the gene to the wound tissue. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065663 •

IL-2 Gene Therapy for Metastatic Melanoma Condition(s): Melanoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This study will examine the safety and effectiveness of gene therapy for creating special tumor-fighting cells to treat patients with metastatic melanoma (melanoma that has spread from the primary tumor site). A gene for interleukin-2 (IL-2) will be inserted into cells from the patients' tumors. This gene makes the IL-2 protein, which is a growth factor for tumor-fighting white cells called T-cells. The cells with the IL-2 gene will be grown in culture and then given back to the patient. Patients 18 years of age and older with metastatic melanoma who have been treated with IL-2 and have progressive disease may be eligible for this study. Candidates will be screened with blood tests, scans, and x-rays to evaluate the tumor. Participants will undergo the following procedures: - Biopsy and culture of tumor cells. For the biopsy, a small area of skin is numbed and a piece of tumor is removed with a needle or a small incision. The tumor cells are grown in the laboratory for about 40 days. - IL-2 gene insertion into cells. IL-2 genes are inserted into the tumor cells using a virus that has been rendered incapable of causing an infection. - G-CSF administration and leukapheresis. Injections of G-CSF are given under the skin once a day for 5 days, followed by leukapheresis. GCSF is a hormone that causes white cells to increase in number, allowing more cells to be collected through leukapheresis. For leukapheresis, whole blood is drawn from a needle in an arm vein and circulated through a machine that separates it into its components. The white cells are removed, and the plasma and red cells are given back to the patient through a vein in the other arm. - Chemotherapy. Patients receive two anti-cancer drugs, cyclophosphamide and fludarabine, through a catheter (flexible plastic tube) placed into a vein in the arm, upper chest, or neck. The cyclophosphamide is given over 1 hour for 2 days and the fludarabine is given for 30 minutes for 5 days. The drugs are intended not to treat the tumor, but to see if they improve the functioning of the IL-2 gene-modified white cells. Patients who have HLA-A201 blood type may additionally receive vaccine(s) following chemotherapy to increase the body's immune response to the tumor. Each vaccine consists of peptides (pieces of protein) from melanoma tumors, either gp 100, MART-1 or both, and an adjuvant called Montanide ISA-51. The injections are given the morning of the cell infusion (see below) and every other day for a total of 3 days of injections. - Cell infusions. The gene modified cells are given through the catheter over 30 minutes the day after the last dose of chemotherapy. Patients are monitored closely for side effects and are given medicines as needed to treat and prevent as many side effects as possible. Patients whose tumors do not respond to treatment may receive additional gene modified cells along with high-dose IL-2. The IL2 is given as a 15-minute infusion through one of the catheters every 8 hours for up to 5 days after each cell infusion. Four to six weeks after the treatment regimen, patients return to the clinic for a 2-day follow-up evaluation. They may have additional

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treatments with gene-modified cells, with or without chemotherapy or IL-2 infusions. The additional regimens will be designed according to the patient's response to previous cell infusions. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00059163 •

Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID) Condition(s): Severe Combined Immunodeficiency Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This is a clinical trial of gene therapy for X-linked severe combined immunodeficiency (XSCID), a genetic disease caused by defects in a protein called the common gamma chain, which is normally on the surface of immune cells called lymphocytes. XSCID patients cannot make T lymphocytes, and their B lymphocytes fail to make essential antibodies for fighting infections. Without T and B lymphocytes patients develop fatal infections in infancy unless they are rescued by a bone marrow transplant from a healthy donor. However, even transplanted patients may achieve only partial immune recovery and still suffer from many infections, auto-immunity and/or and poor growth. A recent, successful trial in France used gene therapy instead of bone marrow transplantation for infants with XSCID. This experience indicates that gene therapy can provide clinical benefit to XSCID patients. We will enroll six older XSCID patients (2-20 years-old , who have previously received at least one bone marrow transplant, but still have poor T and B lymphocyte function that compromises their quality of life. Before enrollment, these subjects will have had some of their own bloodforming stem cells harvested and frozen in a blood bank. These cells have a defective gene, but a correct copy of the gene will be inserted while the cells are grown in sterile conditions outside the patient's body. To do this, the cells will be unfrozen and exposed for four days in a row to growth factors and particles of a retrovirus we have constructed and tested called "GALV MFGS-gc." Retrovirus particles will attach to the patient cells and introduce a correct copy of the common gamma chain gene into cells capable of growing into all types of blood cells, including T and B ymphocytes. Each XSCID patient enrolled in the study will receive a single dose of his own cells that have been modified by the GALV MFGS-gc treatment. After this, the patients will be monitored to find out if the treatment is safe and to see if their immune function improves. Study endpoints are (1) efficient and safe clinical-scale correction of cells from XSCID patients; (2) administration of treated cells to six subjects: and (3) year follow-up of the treated subjects to see how many of their cells have taken up the correct copy of the gene, how many new T and B lymphocytes express a normal common gamma chain, and whether the patients' immune function and general health improve. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00028236

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Gene Therapy for Alzheimer's Disease Clinical Trial Condition(s): Alzheimer Disease Study Status: This study is no longer recruiting patients. Sponsor(s): The Shiley Family Trust; Institute for the Study of Aging; University of California, San Diego Purpose - Excerpt: This Phase I clinical trial is the first step in testing gene therapy. This study is called a "Safety/Toxicity" study by the Food and Drug Administration, and primarily aims to determine whether the experimental protocol is safe for humans. It will determine whether the study procedure causes side effects in humans, and may also give us a preliminary sense of whether this will be effective in combating Alzheimer's disease in humans. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00017940

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Gene Therapy for Chronic Granulomatous Diseases - Long-term Follow-up Condition(s): Chronic Granulomatous Disease; Communicable Disease Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This protocol will follow patients who participated in NIAID's study Gene Therapy Approach for Chronic Granulomatous Diseases (95-I-0134). No further gene therapy treatments will be given under this protocol. However, because gene therapy is a new technology and involves a permanent change in the genetic code of some cells, patients who have had this treatment require long-term health monitoring. Participants will be asked to provide updated address and telephone information and the names of two contact persons, such as siblings or friends. Patients will be seen about once a year at the NIH Clinical Center to provide an update on their health status and donate a small blood sample (about 2 teaspoons), which will be frozen and stored. If a patient acquires a serious illness, such as cancer, his or her stored blood will be tested; another of blood or tissue sample may also be requested for further study. If a patient develops a medical problem that is thought possibly to be related to gene therapy, the illness will be investigated. The annual follow-up visits will continue indefinitely or until the patient declines to continue participation. Participants may also agree to store some of their blood future research on chronic granulomatous diseases and other medical conditions. Stored samples may be labeled with a code, such as a number, that only the study team can link with the patient. Any identifying information about the patient will be kept confidential as is permitted by law. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001476

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Gene Therapy for Patients with Leukocyte Adherence Deficiency (Follow-Up of Phase 1 Trial) Condition(s): Leukocyte Adhesion Deficiency SyndroMen Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This study will provide long-term monitoring of two patients who received gene therapy for leukocyte adherence deficiency (LAD) under the Food and Drug Administration investigational new drug study BB-IND-7949. The IND protocol has been closed. No other patients are eligible for this study. Patients previously enrolled in BB-IND-7949 (Retrovirus-Mediated Transfer of the cDNA for Human CD18 into Peripheral Blood Repopulating cells of Patients with Leukocyte Adherence Deficiency) will be followed at least yearly for an indefinite period of time to evaluate their medical status and look for treatment side effects. The follow-up visits at the NIH Clinical Center will involve the following: - Interview regarding health status during the past year - Blood draw of approximately 15 milliliters for 3 years, then 5 ml annually thereafter for studies related to LAD and to make sure no unexpected effects of gene therapy have occurred The blood samples collected at the follow-up visits will be frozen and stored. If a serious medical problem arises, the sample may be checked for replication competent virus. If the gene therapy is suspected to be related to a medical problem, investigation may include a review of the patient's medical records or collection of additional blood or tissues for testing. If the patient should die, the family will be asked permission to perform an autopsy, regardless of the cause of death. Tissues taken at autopsy will be tested for any long-term effects from the gene therapy. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023010

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Gene Therapy for the Treatment of Brain Tumors Condition(s): Brain Neoplasm; Neoplasm Metastasis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Malignant brain tumors are responsible for a significant amount of deaths in children and adults. Even with advances in surgery, radiation therapy, and chemotherapy, many patients diagnosed with a malignant brain tumor survive only months to weeks. In an attempt to improve the prognosis for these patients, researchers have developed a new approach to brain tumor therapy. This approach makes use of DNA technology to transfer genes sensitive to therapy into the cells of the tumor. Infections with the herpes simplex virus can cause cold sores in the area of the mouth. A drug called ganciclovir (Cytovene) can kill the virus. Ganciclovir is effective because the herpes virus contains a gene (Herpes-Thymidine Kinase TK gene) that is sensitive to the drug. Researchers have been able to separate this gene from the virus. Using DNA technology, researchers hope to transfer and implant the TK gene into tumor cells making them sensitive to ganciclovir. In theory, giving patients ganciclovir will kill all tumor cells that have the TK gene incorporated into them. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00001328 •

Gene Therapy for the Treatment of Fanconi's Anemia Type C Condition(s): Fanconi's Anemia; Pancytopenia Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Fanconi's Anemia is an inherited disorder that can produce bone marrow failure. In addition, some patients with Fanconi's anemia have physical defects usually involving the skeleton and kidneys. The major problem for most patients is aplastic anemia, the blood counts for red blood cells, white blood cells, and platelets are low because the bone marrow fails to produce these cells. Some patients with Fanconi's anemia can develop leukemia or cancers of other organs. Many laboratory studies have suggested that Fanconi's anemia is caused by an inherited defect in the ability of cells to repair DNA. Recently, the gene for one of the four types of Fanconi's anemia, type C, has been identified. It is known that this gene is defective in patients with Fanconi's anemia type C. Researchers have conducted laboratory studies that suggest Fanconi's anemia type C may be treatable with gene therapy. Gene therapy works by placing a normal gene into the cells of patients with abnormal genes responsible for Fanconi's anemia type C. After the normal gene is in place, new normal cells can develop and grow. Drugs can be given to these patients kill the remaining abnormal cells. The new cells containing normal genes and will not be harmed by these drugs. The purpose of this study is to test whether researchers can safely place the normal Fanconi's anemia type C gene into cells of patients with the disease. The gene will be placed into special cells in the bone marrow called stem cells. These stem cells are responsible for producing new red blood cells, white blood cells, and platelets. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001399

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Gene Therapy in Patients With Colon Cancer That Has Spread to the Liver Condition(s): recurrent colon cancer; liver metastases; stage IV colon cancer; adenocarcinoma of the colon Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); Memorial Sloan-Kettering Cancer Center Purpose - Excerpt: RATIONALE: Gene therapy may make the body build an immune response to kill tumor cells. PURPOSE: Phase I trial to study the safety of NV1020 in patients who have colon cancer that has spread to the liver and has not responded to previous chemotherapy. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00012155

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Gene Therapy in Treating Patients With Non-small Cell Lung Cancer That Cannot Be Surgically Removed Condition(s): stage IV non-small cell lung cancer; bronchoalveolar cell lung cancer; stage IIIB non-small cell lung cancer; recurrent non-small cell lung cancer Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); Eastern Cooperative Oncology Group Purpose - Excerpt: RATIONALE: Exposing tumor cells to the p53 gene may improve the body's ability to fight non-small cell lung cancer. PURPOSE: Phase I trial to study the effectiveness of gene therapy in treating patients who have non-small cell lung cancer that cannot be surgically removed. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00003649

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Gene Therapy in Treating Women With Refractory or Relapsed Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Peritoneal Cancer Condition(s): recurrent ovarian epithelial cancer; peritoneal cavity cancer; Fallopian Tube Cancer Study Status: This study is no longer recruiting patients. Sponsor(s): Human Gene Therapy Research Institute Purpose - Excerpt: RATIONALE: Gene therapy may make the body build an immune response to kill tumor cells. PURPOSE: Phase II trial to study the effectiveness of gene therapy in treating women who have refractory or relapsed ovarian epithelial cancer , fallopian tube cancer, or peritoneal cancer. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005025

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Interleukin-12 Gene Therapy in Treating Patients With Skin Metastases Condition(s): skin metastases Study Status: This study is no longer recruiting patients. Sponsor(s): University of Wisconsin Comprehensive Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Inserting the gene for interleukin-12 into a person's skin tumor cells may make the body build an immune response to kill tumor cells. PURPOSE: Phase I trial to study the effectiveness of interleukin-12 gene therapy in treating patients who have skin metastases. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00028652

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Phase I Pilot Study of Gene Therapy for Cystic Fibrosis Using Cationic Liposome Mediated Gene Transfer Condition(s): Cystic Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama Purpose - Excerpt: Objectives: Determine whether copies of the cystic fibrosis gene (pGT-1) can be delivered to the cells lining the nose of cystic fibrosis patients using cationic liposome (DMRIE/DOPE) mediated gene transfer. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004471

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Gene Therapy for Gaucher's and Fabry Disease Using Viruses and Blood-Forming Cells Condition(s): Gaucher's Disease Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Gaucher's disease is a lysosomal storage disease resulting from glycocerebroside GLUCOCEREBROSIDE (1) accumulation in macrophages due to a genetic deficiency of the enzyme glucocerebrosidase. It may occur in patients of all ages. The most severe form, Type 2 Gaucher's Disease occurs in infants who die in the first years of life (with rapidly progressive neurologic deterioration). The condition is passed from generation to generation through autosomal recessive inheritance. Fabry's disease isa genetic disorder (X-linked recessive) due to the absence of the enzyme agalactosidase A. The disease is characterized by abnormal collections of glycolipids in cells (histiocytes) within blood vessel walls, tumors on the thighs, buttocks, and genitalia(2) decreased sweating, tingling sensations in the extremities, and cataracts. Patients with Fabry's disease die from complications of the kidney, heart, or brain. Both conditions are caused by the absence of specific enzymes (3). Patients with these conditions are missing (3) or have defective genes needed for the normal production of these enzymes. Studies on the blood-forming cells in bone marrow have lead to gene therapies using retroviruses as vehicles to carry and insert working genes into abnormal or diseased cells. This study is designed to measure the safety and effectiveness of transferring working copies of genes responsible for making missing enzymes into the cells of patients with Gaucher's or Fabry disease. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001234

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Gene Therapy for Gyrate Atrophy Condition(s): Gyrate Atrophy Study Status: This study is completed.

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Sponsor(s): National Eye Institute (NEI) Purpose - Excerpt: This study will evaluate the safety and effectiveness of gene therapy for patients with gyrate atrophy, an inherited condition in which areas of the retina-the inner lining of the wall of the eye-become thin. Over several decades, this degeneration of the retina causes tunnel vision, night blindness, and other vision problems. Gyrate atrophy is caused by a defect in the gene responsible for producing an enzyme, ornithine aminotransferase (OAT), that breaks down an amino acid called ornithine. As a result, excessive ornithine buildup causes the retinal thinning. Currently, this condition can only be treated with amino acid tablets and a very low-protein diet with limited fruits and vegetables and more than 2,000 calories a day from carbohydrates and fats. Some patients cannot maintain this diet, and they need another treatment. One possible alternative is to replace the defective gene with one that functions normally. Patients who have been followed in NEI's Ocular Genetics service may be eligible to participate in this study. Study patients will undergo the following gene therapy procedure: 1. Skin biopsy-A small piece of skin is surgically removed from the patient's thigh. 2. Gene transfer-Skin cells called keratinocytes are taken from the biopsied tissue and grown in the laboratory. The normal gene that produces OAT is inserted into the cells, causing them to produce more of the enzyme. 3. Skin graft-Under local anesthesia, a patch of skin about 2 1/4 inches x 2 1/4 inches is surgically removed from the upper thigh and some of the cells with increased OAT are grafted back onto this area. Patients will be followed at 1 week and 2 weeks after the procedure, then monthly for 6 months, again at 9 months and 1 year. Follow-up will continue at 1-year intervals in patients in whom the treatment is successful. During each follow-up visit patients will have 2 to 3 tablespoons of blood drawn for tests. A small biopsy (about 1/4 inch) of transplanted cells will also be done at 1 week, 1 month, 3 months, 6 months, 1 year, and each year or so thereafter. These tests will evaluate whether the treated skin cells are producing the deficient OAT enzyme and, if so, how much and for how long. They will also indicate whether the enzyme produced is sufficient to lower ornithine blood levels. Patients will also undergo various eye examinations before grafting and at scheduled follow-up visits. These tests may include electrophysiologic (ERG) testing, fundus photographs, scanning laser ophthalmoscope, visual field test, fluorescein angiogram, visual acuity, and manifest reaction. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001735 •

Gene Therapy in HIV-Positive Patients with Non-Hodgkin's Lymphoma Condition(s): Lymphoma, Non-Hodgkin; HIV Infections Study Status: This study is completed. Sponsor(s): RibozyoMen Purpose - Excerpt: The purpose of this study is to see if it is safe and effective to use gene therapy to treat non-Hodgkin's lymphoma (NHL) in HIV-positive patients. Stem cell transplantation is a procedure used to treat NHL. Stem cells are very immature cells that develop to create all of the different types of blood cells. In this study, some of your stem cells will be treated with gene therapy, meaning the cells are treated with a virus that does not cause disease. Some cells will receive a virus that contains ribozymes, enzymes that may help fight HIV. Other cells will be treated with a virus that does not

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contain ribozymes to see how the virus works alone. Some cells will not be treated at all. Doctors would like to see whether giving patients stem cells with ribozymes can treat NHL and stop HIV from growing at the same time. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002221 •

Gene Therapy in Treating Patients With Advanced Bladder Cancer Condition(s): stage III bladder cancer; stage II bladder cancer; transitional cell carcinoma of the bladder; stage I bladder cancer; recurrent bladder cancer; stage IV bladder cancer Study Status: This study is completed. Sponsor(s): National Cancer Institute (NCI); M.D. Anderson Cancer Center Purpose - Excerpt: RATIONALE: Inserting the p53 gene into a person's bladder cancer cells may improve the body's ability to fight cancer. PURPOSE: Phase I trial to study the effectiveness of gene therapy in treating patients with advanced bladder cancer. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00003167

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Phase I Pilot Study of Liver-Directed Gene Therapy for Partial Ornithine Transcarbamylase Deficiency Condition(s): Ornithine Transcarbamylase Deficiency Disease Study Status: This study is terminated. Sponsor(s): National Institute of Child Health and Human Development (NICHD); Children's National Medical Center Purpose - Excerpt: Objectives: Evaluate the safety and feasibility of administering recombinant adenovirus containing the ornithine transcarbamylase gene to adults with partial ornithine transcarbamylase deficiency. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004386

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Phase I Study of Hypercholesterolemia

Ex

Vivo

Liver-Directed

Gene

Therapy

for

Familial

Condition(s): Familial Hypercholesterolemia Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of Pennsylvania

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Purpose - Excerpt: Objectives: I. Develop an approach for treating patients with homozygous familial hypercholesterolemia using gene therapy with autologous hepatocytes transduced with a normal low-density lipoprotein receptor gene. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004809 •

Setting up a Blood Bank for Gene Therapy in HIV-Infected Infants Condition(s): HIV Infections; Pregnancy Study Status: This study is terminated. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to set up a blood bank for infants who have HIV-positive mothers. This blood may be used in the future to treat the child if he/she turns out to be HIV-positive. Blood from the umbilical cord contains a certain kind of cell called a stem cell. Stem cells eventually turn into one of the many types of blood cells. If HIV infection can be prevented in these stem cells, then, when these stem cells are injected back into the infant, the new cells that develop will also be protected from HIV. This study will provide the blood needed to test whether this type of gene therapy is safe and effective. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000917

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Twins Study of Gene Therapy for HIV Infection Condition(s): Acquired Immunodeficiency Syndrome; HIV Infection; Kaposi's Sarcoma Study Status: This study is completed. Sponsor(s): National Human Genome Research Institute (NHGRI) Purpose - Excerpt: This study will test the safety and effectiveness of genetically altered T lymphocytes (white blood cells of the immune system) in reducing viral load in patients infected with the human immunodeficiency virus (HIV). The lymphocytes will have two genes inserted into them; a laboratory-manufactured anti-HIV gene designed to inhibit HIV reproduction (either the RevTD or Rev-TD-antiTAR gene), and a "marker" gene that will show whether or not the inserted genes have gotten into the cells. Identical twin pairs 18 years of age and older- one of whom is HIV-positive (infected with the human immunodeficiency virus) and the other HIV-negative (not infected) may be eligible for this study. All participants will have a complete medical history and physical examination, blood tests and a tetanus booster shot, if indicated. The non HIVinfected twin will then undergo lymphapheresis to collect lymphocytes. In this procedure, whole blood is collected through a needle placed in an arm vein. The blood circulates through a machine that separates it into its components. The lymphocytes are then removed, and the red cells and plasma are returned to the donor, either through the same needle or through a second needle placed in the other arm. The donor cells are grown in the laboratory for a few days, and then the new genes are inserted into them. The genetically altered cells are grown in the laboratory for several days until their numbers increase approximately a thousand-fold. They are then infused intravenously

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(through a vein) into the infected twin. These procedures-lymphapheresis, gene modification and infusion-will be repeated at approximately 2-month intervals up to four times. Each lymphocyte infusion takes about 60 minutes. The patient's vital signs (temperature, pulse, blood pressure and breathing) are monitored frequently during the infusion and hourly for 4 hours after the infusion. Blood samples are taken the day of the infusion, 3 days later, and then weekly to monitor the gene-modified cells, immune status, viral activity, and other factors. These tests may be done less often as the study progresses and more is learned about the safety of the infusions. The infusions are done on an outpatient basis unless side effects require that they be done in the hospital with post-infusion monitoring for at least 24 hours. Patients will be followed for long-term effects of treatment monthly for the first 3 months, once a month for the next 9 months and yearly from then on. This study will contribute information about the use and side effects of gene therapy in HIV infection that may lead to new treatment strategies. A potential direct benefit to HIV-infected individuals participating in this study is reduced viral load; in laboratory studies, the RevTD and Rev-TD-antiTAR genes have inhibited HIV spread in the test tube. However, this is an early phase of study, and the likelihood of receiving this benefit is unknown. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001535

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “gene therapy” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON GENE THERAPY 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.9 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 “gene therapy” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on gene therapy, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Gene Therapy By performing a patent search focusing on gene therapy, 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 9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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example of the type of information that you can expect to obtain from a patent search on gene therapy: •

AAV vectors for gene therapy Inventor(s): Kyostio; Sirkka (Ashland, MA), Piraino; Susan (Framingham, MA), Vincent; Karen (Arlington, MA), Wadsworth; Samuel C. (Shrewsbury, MA) Assignee(s): Genzyme Corporation (Cambridge, MA) Patent Number: 6,632,670 Date filed: November 16, 1998 Abstract: The present invention is directed to methods for generating high titer, contaminant free, recombinant AAV vectors, methods and genetic constructs for producing recombinant AAV vectors conveniently and in large quantities, methods for the delivery of all essential viral proteins required in trans for high yields of recombinant AAV, recombinant AAV vectors for use in gene therapy, novel packaging cell lines which obviate the need for cotransfection of vector and helper plasmids, helper plasmids and vector plasmid backbone constructs, a reporter assay for determining AAV vector yield. Further provided are recombinant AAV vectors in a pharmaceutically acceptable carrier, methods of delivering a transgene of interest to a cell, compositions and methods for delivering a DNA sequence encoding a desired polypeptide to a cell, and transgenic non-human mammals that express a human chromosome 19 AAV integration locus. Excerpt(s): Adeno-associated virus (AAV) is a parvovirus having a single-stranded DNA genome of about 4.6 kb. Unlike other viruses, AAV is naturally defective, requiring coinfection with a helper virus (e.g. adenovirus or herpes virus) to establish a productive infection. No human disease has been found to be associated with AAV infection (Blacklow et al., 1968). The host range of AAV is broad; unlike retroviruses, AAV can infect both quiescent and dividing cells in vitro and in vivo (Flotte et al., 1993; Kaplitt et al., 1994; Podsakoff et al., 1994; Russell et al., 1994) as well as cells originating from different species and tissue types in vitro (Lebkowski et al., 1988; McLaughlin et al., 1988). When infection occurs in the absence of a helper virus, wild-type AAV can integrate into the cellular genome as a provirus, until it is rescued by superinfection with adenovirus. (Handa et al., 1977; Cheung et al., 1980; Laughlin et al., 1986). The AAV genome is relatively simple, containing two open reading frames (ORFs) flanked by short inverted terminal repeats (ITRs). The ITRs contain, inter alia, cis-acting sequences required for virus replication, rescue, packaging and integration. The integration function of the ITR permits the AAV genome to integrate into a cellular chromosome after infection. The nonstructural or replication (Rep) and the capsid (Cap) proteins are encoded by the 5' and 3' ORFs, respectively. Four related proteins are expressed from the rep gene; Rep78 and Rep68 are transcribed from the p5 promoter while a downstream promoter, p19, directs the expression of Rep52 and Rep40. The larger Rep proteins (Rep78/68) are directly involved in AAV replication as well as regulation of viral gene expression (for review, see Muzyczka, 1992). The cap gene is transcribed from a third viral promoter, p40. The capsid is composed of three proteins of overlapping sequence; the smallest (VP-3) is the most abundant. Because the inverted terminal repeats are the only AAV sequences required in cis for replication, packaging, and integration (Samulski et al., 1989), most AAV vectors dispense with the viral genes encoding the Rep and Cap proteins and contain only the foreign gene inserted between the terminal repeats.

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Web site: http://www.delphion.com/details?pn=US06632670__ •

Adenoviral vectors encoding erythropoietin and their use in gene therapy Inventor(s): Ciliberto; Gennaro (Pomezia, IT), La Monica; Nicola (Pomezia, IT), Savino; Rocco (Pomezia, IT) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 6,641,807 Date filed: April 23, 2001 Abstract: Helper dependent adenoviral vectors encoding erythropoietin (epo) provide high levels of epo to achieve a long-term therapeutically effective dosage, and allow for repeat administration to patients with disorders such as anaemia of Chronic Renal Failure (CFR), anaemias due to beta-thalassaemia, and sickle cell anaemia (SCA). Excerpt(s): The present invention relates to the delivery of erythropoietin (EPO) to a mammal. More particularly, the present invention relates to provision of EPO in a mammal by means of expression from encoding nucleic acid included in an expression vector, that is by means of gene therapy. The present invention is based on the inventors' experimental demonstration that therapeutic levels of EPO can be achieved using helper-dependent adenoviral (Hd-Ad) vectors, which levels are far beyond any levels previously attained using a variety of vectors, including adenoviral (Ad) vectors (i.e. non-helper-dependent). Erythropoietin (EPO) is a protein of great interest because of its therapeutic usefulness in a variety of diseases. As is well known, the gene for human EPO was cloned by Amgen (see e.g. WO85/02610, EP-A-0148605) and recombinantly produced EPO (rEPO) has attained a huge market (in excess of 2.9 billion dollars). Currently, rEPO is administered to patients in protein form. Despite its success, there is a number of problems with delivery of rEPO resulting in various unmet clinical needs, primarily because of the prohibitive cost of providing sufficient rEPO to achieve a long-term therapeutically effective dosage. Sufferers include individuals with anaemia of Chronic Renal Failure (CRF), anaemias due to beta-thalassaemia, and sickle cell anaemia (SCA). Large numbers of such individuals go untreated despite the fact that good therapeutic results can be achieved as long as enough EPO is provided. Web site: http://www.delphion.com/details?pn=US06641807__

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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

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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 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__ •

Agent for gene therapy of dilated cardiomyopathy Inventor(s): Toyo-Oka; Teruhiko (23-3, Kamiogi 3-chome, Suginami-ku, Tokyo 167-0043, JP) Assignee(s): none reported Patent Number: 6,589,523 Date filed: January 25, 2001 Abstract: According to the present invention, there is provided a gene expression vector which is obtained by inserting a gene encoding sarcoglycan into an adeno-associated virus (AAV) vector. By administering the gene expression vector of the present invention to a living body in vivo, a sarcoglycan can be continuously expressed in the living body, so that the restoration of.alpha.-,.beta.-,.gamma.- and.delta.-sarcoglycan components can be accompanied and the heart function of the patient of dilated cardiomyopathy can be improved. Excerpt(s): The present invention relates to an agent for gene therapy of dilated cardiomyopathy, more particularly, a gene expression vector which is obtained by inserting a gene encoding a sarcoglycan into an adeno-associated virus vector. Cardiomyopathy is one of the heart diseases which shows contraction dysfunction and electrophysiological dysfunction as symptoms, and includes a group of heart diseases which lead to a sever heart failure and a sudden death. Cardiomyopathy is classified into dilated cardiomyopathy and hypertrophied cardiomyopathy, and the study for revealing the causes of each cardiomyopathy has been made. In the case of dilated cardiomyopathy (DCM), in spite of progress in the therapy, the prognosis of the patients is still poor and cardiac transplantation is necessary in the deteriorated cases (V. V. Michels, et al., New Engl.J.Med. 326, 77 (1992); E. K. Kasper, et al., J.Am.Coll.Cardiol. 23, 586 (1994); M. Packer, et al., New Engl.J.Med. 334, 1349 (1996); M. Packer, et al. New Engl.J.Med. 335,1107 (1996); R. M. Graham, W. A. Owens, N.Engl.J.Med. 341, 1759 (1999)). Therefore, it is necessary to develop a novel method for therapy which can improve the patient's mortality and morbidity. Animal model is useful for developing such a novel method for therapy. Gene transfer will be promising for the therapy of some type of DCM which is caused by the gene deletion. It has been demonstrated that the deletion of.delta.-sarcoglycan (.delta.-SG) gene is the cause of DCM in hamsters (A.

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Sakamoto, et al., Proc.Natl.Sci.Acad.U.S.A. 94, 13873 (1997); V. Nigro, et al., Hum.Mol.Genet. 6, 601 (1997)). Also, it has been found that the breakpoint of.delta.-SG gene in TO-2 hamster which is a model animal of DCM is present in the first intron, and large region including its promoter and the first exon is deleted in TO-2 hamster (A. Sakamoto, et al., Proc.Natl.Sci.Acad.U.S.A. 94, 13873 (1997)). Furthermore, dystrophinassociated glycoprotein complex (DAGC) links intracellular contractile machinery with extracellular matrix (G. F. Cox, L. M. Kunkel, Curr.Opin.Cardiol. 12, 329 (1997); K. H. Holt, et al., Mol. Cell 1, 841 (1998); M. D. Henry, K. P. Campbell, Curr.Opin.Cell Biol. 11, 602 (1999)). Web site: http://www.delphion.com/details?pn=US06589523__ •

Capsid-modified recombinant adenovirus and methods of use Inventor(s): Curiel; David T. (Birmingham, AL) Assignee(s): UAB Research Foundation (Birmingham, AL) Patent Number: 6,555,368 Date filed: September 22, 2000 Abstract: The present invention describes a recombinant adenoviral vector in which a single-chain antibody has been introduced into the minor capsid proteins, pIIha or pIX, so that the adenoviral vector can be targeted to a particular cell type. Additionally disclosed is a method of using the recombinant adenoviral vector in targeted gene therapy. Excerpt(s): The present invention relates generally to adenoviral gene therapy vectors. More specifically, the present invention relates to adenoviral gene therapy vectors in which the adenoviral tropism has been genetically modified. 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, cell-specific manner. Thus, for the many gene therapy applications where such cell-specific transduction is required, current adenoviral vectors have limited utility. To address the issue of efficient, cell-specific gene delivery, a variety of strategies have been developed to alter adenoviral tropism. These approaches have included direct chemical modifications of the adenoviral capsid proteins, bi-specific complexes (e.g., a capsid protein and a targeting moiety), and genetic capsid modifications (e.g., genetic replacement/insertion). Whereas the former two strategies have established the feasibility of adenoviral re-targeting, practical production issues as well as regulatory approval considerations have placed the utmost importance on the approach in which modifications to the adenoviral tropism are introduced genetically. Web site: http://www.delphion.com/details?pn=US06555368__

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Catheter for drug injection in cardiovascular system Inventor(s): Holmes; David R. (Rochester, MN), Schwartz; Robert S. (Rochester, MN), VanTassel; Robert A. (Excelsior, MN) Assignee(s): Tricardia, L.L.C. (Excelsior, MN) Patent Number: 6,605,061 Date filed: June 13, 2001 Abstract: A catheter for injecting medicants into the endocardium, myocardium or other portions of the cardiovascular system is presented where the catheter has apertures therein for ejection and retraction of a needle. The catheter is designed for the apertures in the catheter to press against the tissue to be injected in the heart while the heart is beating. A needle for inserting a prescribed dose of a medicant is ejected through the aperture and a plunger, pump, or diaphragm is moved to deliver a dose of the medicant to tissue adjacent the aperture. By use of the catheter gene therapy, wherein a small does of a gene are injected into the endocardium of the right or left ventricle, can be used to grow new blood vessels in the injected area of a damaged heart. The apertures in the catheter can be spaced at a prescribed distance for the dosage of medicant to form a precise pattern of injections in the area to be treated. The catheters may be used for any treatments of a human or animal patient where injections are required in the heart, veins or arteries of the cardiovascular system. Excerpt(s): This invention relates to catheters and more particularly to a catheter for injecting an agent at specified positions of the heart muscle (myocardium). In the past devices have been used for minimally invasive techniques to access the heart, veins and arteries immediately adjacent by inserting catheters into the larger veins and arteries of the neck, arm and leg. These devices are used for balloon angioplasty, laser surgery, to make endoscopic observations of valves, plaque buildup and other cardiac conditions, or to take pressure and temperature readings in various chambers of the heart and in the nearby veins and arteries. Even microsurgery can be performed by these minimally invasive techniques. Dyes, radioactive materials, radiopaque contrast materials or other substances can be added to the heart by such devices to aid in x-rays, CAT scans or other observations and measurements of the heart. However there is no currently available means for accurate patterned delivery of gene injection therapies or other injections into the myocardium of the various chambers of the heart or into the veins and arteries nearby. The invention is for minimally invasive delivery of agents for the treatment of medical conditions in the heart or adjacent veins and arteries where precision injection of genes or other agents is required in the treatment of the patient. Web site: http://www.delphion.com/details?pn=US06605061__

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Cell-based gene therapy Inventor(s): Stewart; Duncan John (3 Blythwood Crescent, Toronto, Ontario, CA M4P 2K2) Assignee(s): none reported Patent Number: 6,592,864 Date filed: March 26, 1999 Abstract: Cell-based gene transfer is effected by administering transfected cells containing an expressible transgene into the pulmonary system of a patient, where the

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cells express and secrete expression products of the transgene directly into the pulmonary system. Also provided is the use of angiogenic factors in treatment of pulmonary hypertension. Excerpt(s): This invention relates to medical treatments and composition and procedures useful therein. More specifically, it relates to cell-based gene transfer systems for administration to the pulmonary system of a mammalian patient. Cell-based gene transfer is a known, albeit relatively new and experimental, technique for conducting gene therapy on a patient. In this procedure, DNA sequences containing the genes which it is desired to introduce into the patient's body (the trans-gene) are prepared extracellularly, e.g. by using enzymatic cleavage and subsequent recombination of DNA from the patient's cells with insert DNA sequences. Mammalian cells such as the patient's own cells are then cultured in vitro and treated so as to take up the transgene in an expressible form. The trans-genes may be foreign to the mammalian cell, or additional copies of genes already present in the cell, to increase the amount of expression product of the gene. Then the cells containing the trans-gene are introduced into the patient, so that the gene may express the required gene products in the body, for therapeutic purposes. The take-up of the foreign gene by the cells in culture may be accomplished by genetic engineering techniques, e.g. by causing transfection of the cells with a virus containing the DNA of the gene to be transferred, by cell fusion with cells containing the required gene, by lipofection, by electroporation, or by other accepted means to obtain transfected cells. This is sometimes followed by selective culturing of the cells which have successfully taken up the transgene in an expressible form, so that administration of the cells to the patient can be limited to the transfected cells expressing the trans-gene. In other cases, all of the cells subjected to the take-up process are administered. Web site: http://www.delphion.com/details?pn=US06592864__ •

Chimeric viral packaging signal without gag gene sequences Inventor(s): Hodgson; Clague (Lincoln, NE), Xu; Guoping (Lincoln, NE), Zink; Mary Ann (Lincoln, NE) Assignee(s): Nature Technology Corporation (Lincoln, NE) Patent Number: 6,573,091 Date filed: September 18, 2000 Abstract: A chimeric viral packaging signal is described for the transmission of genetic materials via retrovirus. The packaging signal contains an essential packaging nucleic acid sequence and a non-essential nucleic acid sequence. The packaging signal lacks gag gene sequences, and has approximately one order of magnitude greater infectivity than retrovirus-derived packaging signals without gag gene sequences. The packaging signal of the invention can be used to transmit genetic material for gene therapy, cell therapy, or other biotechnological applications. Excerpt(s): The employment of retrovirus derived vectors in biotechnological applications has been standard practice for many years. For example, early retrovirusderived vectors are described in Wei et al., J. Virol., 39:935-44 (1980) and Shimotohno et al., Cell, 26:67-77 (1981). Retroviruses are single-stranded RNA viruses. During an infection process in a host subject, such as a human, the RNA viruses are reverse transcribed into double stranded DNA. The double stranded DNA is subsequently integrated into the host cell DNA, and the virus becomes a permanent part of the host

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cell DNA. Once integrated, the virus is capable of expression of more viral RNA as well as the proteins that make up the virion. As retroviruses are usually not lytic, the retrovirus can continue to produce virus particles that bud from the surface of the cell. Typically, modern retroviral vectoring systems consist of (1) RNA molecule(s) bearing cis-acting vector sequences needed for transcription, reverse-transcription, integration, translation and packaging of viral RNA into the viral particles, and (2) helper virus particles, budding from vector producer cells (VPCs), which express the trans-acting retroviral gene sequences (as proteins) needed for production of virus particles. By separating the cis- and trans-acting vector sequences completely, the virus is unable to maintain replication for more than one cycle of infection. The trans-acting vector sequences make empty virions (viral particles), whereas cis-acting vector sequences are capable of perpetuation or duration, only in the presence of the helper particles. Thus, cis-acting vector sequences and retroviral helper cells are the two essential components of modern retroviral vectoring systems. Retrovirus-derived vectors (RVs) have been used in the majority of gene therapy clinical trials for a variety of reasons. For example, RVs can permanently integrate and express foreign genes, thus overcoming the problem of transient (short-term) expression, which is a significant problem of DNA transfection. Retroviruses, however, also suffer from several significant drawbacks. For example, retroviruses usually infect only dividing cells, and have a lower titer than some DNA viruses, such as adenovirus 5-derived vectors having titers of >10.sup.11 transducing units/milliliter (TU)/ml. In addition, genetic recombination or "cross-over" can occur during replication (or at the DNA level), which can lead to outbreaks of replication competent retrovirus ("RCR"). RCRs occur as a result of regenerating the complete viral genome by genetic recombination. There are at least two different mechanisms by which this can occur. First, similar or identical overlapping nucleic acid sequences present on two separate DNA molecules (i.e., vector and helper sequences) can genetically recombine. Second, two separate RNA strands can serve as templates for cDNA synthesis during replication of the vector/virus, and genetic recombination can occur during DNA synthesis, leading to RCR. An additional confounding factor are the endogenous retroviral gene sequences that are present in the genome of the cells in which the virus is replicating. These retroviral gene sequences provide an additional source for generating RCR. Thus, it is important to separate the cis- and trans-acting sequences completely (i.e., no sequence overlap), and to provide a host cell genome that is devoid of closely related endogenous viral genes. Web site: http://www.delphion.com/details?pn=US06573091__ •

Diminishing viral gene expression by promoter replacement Inventor(s): Fang; Bingliang (Houston, TX), Roth; Jack A. (Houston, TX) Assignee(s): Texas Systems, University of the Board of Regents (Austin, TX) Patent Number: 6,630,344 Date filed: August 29, 2000 Abstract: The present invention provides viral vectors that have been engineered to contain a synthetic promoter that controls at least one essential gene. The synthetic promoter is induced by a specific gene product not normally produced in the cells in which the viral vector is to be transferred. The vectors are propagated in producer or helper cells that express the inducing factor, thereby permitting the virus to replicate to high titer. The lack of the inducing factor in the target cells precludes viral replication, however, meaning that no vector toxicity or immunogenicity arises. Where the virus

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carries a gene of interest, this should provide for higher level expression for longer periods of time than with current vectors. Methods for making the vectors, helper cells, and their use in protein production, vaccines and gene therapy are disclosed. Excerpt(s): The present invention relates generally to the field of viral vectors, packaging cell lines, and the use of such viral vectors to express foreign DNA in mammalian cells. The invention also relates to the field of gene therapy, and more specifically to the use of viral vectors to transport genetic material into cells in vivo for therapeutic purposes. More particularly, it concerns viral promoter replacement in order to reduce the expression levels of viral genes in host cells. Gene therapy is an area that offers an attractive approach for the treatment of many diseases and disorders. Many diseases are the result of genetic abnormalities such as gene mutations or deletions, and thus the prospect of replacing a damaged or missing gene with a fully functional gene is provocative. Throughout the last decade, studies of oncogenes and tumor suppressor genes have revealed increasing amounts of evidence that cancer is a disease caused by multiple genetic changes (Chiao et al., 1990; Levine, 1990; Weinberg, 1991; Sugimara et al., 1992). Based on this concept of carcinogenesis, new strategies of therapy have evolved rapidly as alternatives to conventional therapies such as chemo- and radiotherapy (Renan, 1990; Lotze et al., 1992; Pardoll, 1992). One of these strategies is gene therapy, in which tumor suppressor genes, antisense oligonucleotides, and other related genes are used to suppress the growth of malignant cells. Gene therapy has also been contemplated for transfer of other therapeutically important genes into cells to correct genetic defects. Such genetic defects include deficiencies of adenosine deaminase that result in severe combined immunodeficiency, human blood clotting factor IX in hemophilia B, the dystrophin gene in Duchenne muscular dystrophy, and the cystic fibrosis transmembrane receptor in cystic fibrosis. Gene transfer in these situations requires long term expression of the transgene, and the ability to transfer large DNA fragments, such as the dystrophin cDNA, which is about 14 kB in size. Web site: http://www.delphion.com/details?pn=US06630344__ •

DNA vectors without a selection marker gene Inventor(s): Ruger; Rudiger (Huglfing, DE), Seeber; Stefan (Penzberg, DE) Assignee(s): Roche Diagnostics GmbH (Penzberg, DE) Patent Number: 6,573,100 Date filed: February 27, 2001 Abstract: The use of a circular vector DNA to produce a pharmaceutical agent for the treatment of mammals or humans by gene therapy wherein the vector DNA contains a selection marker gene and a DNA sequence that is heterologous for the vector which causes a modulation, correction or activation of the expression of an endogenous gene or the expression of a gene introduced into the cells of the mammal or the human by the vector DNA which is characterized in that the vector nucleic acida) is amplified under selection pressure and cleaved in such a way that the said selection marker gene and the said heterologous DNA are present on separate DNA fragments,b) the DNA fragment which contains the heterologous DNA or both fragments are recircularized to form vectors,c) the DNA fragments are separated before or after the recircularizationd) the recircularized DNA fragment which contains the heterologous DNA is isolated ande) the recircularized DNA fragment obtained in this manner is used to produce the pharmaceutical agent.

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Excerpt(s): The invention concerns the use of vector DNA without a selection marker gene in gene therapy as well as the use of these vectors for the production of pharmaceutical agents for gene therapy. The gene therapy of somatic cells can be carried out for example using retroviral vectors, other viral vectors or by non-viral gene transfer (for review cf. T. Friedmann (1989)(1), Morgan (1993)(2)). Delivery systems that are suitable for gene therapy are for example retroviruses (Mulligan, R. C. (1991)(3)), adeno associated virus (McLughlin (1988)(4)), vaccinia virus, (Moss et al. (1987)(5)), bovine papilloma virus, (Rasmussen et al. (1987)(6)) or viruses from the herpes virus group such as the Epstein Barr virus (Margolskee et al. (1988)(7)) or herpes simplex virus. Web site: http://www.delphion.com/details?pn=US06573100__ •

EST's and encoded human proteins Inventor(s): Edwards; Jean-Baptiste Dumas Milne (Paris, FR), Giordano; Jean-Yves (Paris, FR), Jobert; Severin (Paris, FR) Assignee(s): Genset S.A. (FR) Patent Number: 6,639,063 Date filed: July 21, 2000 Abstract: The sequences of 5' ESTs and consensus contigated 5' ESTs derived from mRNAs encoding secreted proteins are disclosed. The 5' ESTs and consensus contigated 5' ESTs may be used to obtain cDNAs and genomic DNAs corresponding to the 5' ESTs and consensus contigated 5' ESTs. The 5' ESTs and consensus contigated 5' ESTs may also be used in diagnostic, forensic, gene therapy, and chromosome mapping procedures. Upstream regulatory sequences may also be obtained using the 5' ESTs and consensus contigated ESTs. The 5' ESTs and consensus contigated 5' ESTs may also be used to design expression vectors and secretion vectors. Excerpt(s): The estimated 50,000-100,000 genes scattered along the human chromosomes offer tremendous promise for the understanding, diagnosis, and treatment of human diseases. In addition, probes capable of specifically hybridizing to loci distributed throughout the human genome find applications in the construction of high resolution chromosome maps and in the identification of individuals. In the past, the characterization of even a single human gene was a painstaking process, requiring years of effort. Recent developments in the areas of cloning vectors, DNA sequencing, and computer technology have merged to greatly accelerate the rate at which human genes can be isolated, sequenced, mapped, and characterized. Currently, two different approaches are being pursued for identifying and characterizing the genes distributed along the human genome. In one approach, large fragments of genomic DNA are isolated, cloned, and sequenced. Potential open reading frames in these genomic sequences are identified using bioinformatics software. However, this approach entails sequencing large stretches of human DNA which do not encode proteins in order to find the protein encoding sequences scattered throughout the genome. In addition to requiring extensive sequencing, the bioinformatics software may mischaracterize the genomic sequences obtained, i.e., labeling non-coding DNA as coding DNA and vice versa. Web site: http://www.delphion.com/details?pn=US06639063__

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Gene therapy by secretory gland expression Inventor(s): German; Michael (San Francisco, CA), Goldfine; Ira D. (Kentfield, CA), Rothman; Stephen S. (Berkeley, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,566,342 Date filed: January 4, 2001 Abstract: Secretory gland cells, particularly pancreatic and salivary gland cells, are genetically altered to operatively incorporate a gene which expresses a protein which has a desired therapeutic effect on a mammalian subject. The expressed protein is secreted directly into the gastrointestinal tract and/or blood stream to obtain therapeutic blood levels of the protein thereby treating the patient in need of the protein. The transformed secretory gland cells provide long term therapeutic cures for diseases associated with a deficiency in a particular protein or which are amenable to treatment by overexpression of a protein. Excerpt(s): This invention relates generally to the field of gene therapy and more particularly to the application of gene therapy to the cells of a secretory gland. Although gene therapy and specifically human gene therapy has been widely discussed only over the last five years, the basic idea first became a reality in 1944 when Avery et al. carried out research on the chemical nature of substances inducing transformation of pneumococcal types. (Avery et al., J. Exp. Med. 79:137-158, 1944). The work carried out by Avery et al., did not involve the actual insertion of genetic material into cells in order to carry out gene therapy. The insertion of new genetic material into cells in order to permanently affect the genetic makeup of the cells is the methodology now generally referred to as gene therapy. Current gene therapy is carried out in a variety of ways but involves two general protocols. In the first method, referred to as ex vivo gene therapy, cells are extracted from an organism such as a human and subsequently subjected to genetic manipulation by a variety of different means. After genetic material has been properly inserted into the cells, the cells are implanted back into the body from which they were removed. Thus the process involves cell removal, transformation of the cells in vitro, and subsequent reintroduction of the modified cells into the patient. Persistent, in vivo expression of the newly implanted genetic material after transplantation of the transformed cells has been successful (see Morgan et al., Science 237:1476 (1987); and Gerrard et al., Nat. Genet. 3:180 (1993)). Web site: http://www.delphion.com/details?pn=US06566342__

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Generating replicating molecules in vivo Inventor(s): Leblois-Prehaud; Helene (1 rue Ernest Lavisse, 782280 Guyancourt, FR), Perricaudet; Michel (31 rue de Chartres, 28320 Ecrosnes, FR), Yeh; Patrice (11 Bis rue Lacepede, 75005 Paris, FR) Assignee(s): none reported Patent Number: 6,630,322 Date filed: December 7, 1998 Abstract: The invention discloses circular and replicating DNA molecules, useful in gene therapy, as well as a particularly efficient method for generating them in situ from a viral vector.

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Excerpt(s): The present invention relates to circular and replicative DNA molecules which can be used in gene therapy. The invention also describes a particularly efficient method for their generation in situ from a corresponding viral vector. Gene therapy consists in correcting a deficiency or an abnormality (mutation, aberrant expression and the like) by the introduction of genetic information into the affected organ or cell. 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, various techniques exist, among which are different transfection techniques involving vectors of different types. They may be naturally occurring or synthetic chemical and/or biochemical vectors, on the one hand, or viral vectors on the other. As examples of viral vectors, there may be mentioned especially the 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), of DNA and lipids (Felgner et al., PNAS 84 (1987) 7413), liposomes (Fraley et al., J.Biol.Chem. 255 (1980) 10431) and the like. However, their use involves especially the possibility of producing large quantities of DNA of pharmacological purity. Web site: http://www.delphion.com/details?pn=US06630322__ •

Human p27Kip1 gene promoter Inventor(s): Fujita; Naoko (Kyoto, JP), Sakai; Toshiyuki (Kyoto, JP) Assignee(s): Chugai Seiyaku Kabushiki Kaisha (JP) Patent Number: 6,623,925 Date filed: January 27, 2000 Abstract: The promoter of the human p27.sup.Kip1 gene is provided. The promoter region is useful to screen a compound that regulates the promoter of the human p27.sup.Kip1 gene or regulates the activity of the promoter. It enables the gene therapy utilizing the promoter. Excerpt(s): The present invention relates to a promoter of human p27.sup.Kip1 gene and to a method of screening a compound capable of regulating activity of the promoter. In the eukaryotic cell cycle, several positive and negative factors control the cell cycle progression. Among the positive factors, the protein kinase family plays an important role. Each member of the family comprises a regulatory subunit, or cyclin, and a catalytic subunit named cyclin-dependent kinase (cdk). A number of reports have suggested that cyclin D-cdk4, cyclin D-cdk6, and cyclin E-cdk2 play important roles in promoting the transition from the G1 phase to the S phase by the phosphorylation of retinoblastoma protein (pRB). Recently, one further level of control has become apparent, namely the expression of cdk inhibitors (Sherr, C. J. and Roberts, J. M. (1995) Genes & Dev. 9:1149-1163). Two families of cdk inhibitor with different modes of action have already been identified in mammalian cells. One group, comprised of related proteins known as p21.sup.Cip1, p27.sup.Kip1, and p57.sup.Kip2, appears to function as specific inhibitors of the cyclin/cdk complexes (Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. and Elledge, S. J. (1993) Cell 75: 805-816; Polyak, K., Lee, M. H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., and Massague, J. (1994) Cell 78: 59-66; Toyoshima, H. and Hunter, T. (1994) Cell 78: 67-74; Matsuoka, S., Edwards, M. C., Bai, C., Parker, S., Zhang, P., Baldini, A., Harper, J. W., and Elledge, S. J. (1995) Genes & Dev. 9: 650-662). The second family of the cdk inhibitors is called INK4 family proteins. The four members of this family, called p15, p16, p18, and p19, bind directly to cdk4 and cdk6, and are therefore specific inhibitors of the cyclin D-dependent kinases

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(Hannon, G. J. and Beach, D. (1994) Nature 371: 257-261; Serrano, M., Hannon, G. J., and Beach, D. (1993) Nature 366: 704-707, Hirai, H., Roussel, M. F., Kato, J., Ashmun, R. A., and Sherr, C. J. (1995) Mol. Cell. Biol. 15: 2672-2681). Although the precise roles of p27.sup.Kip1 are far from clear, its level decreases when cells are stimulated to enter the cell cycle, and increases when cells are arrested by either the change in TGF-.beta. concentration or contact inhibition (Polyak, K., Kato, J., Solomon, M. J., Sherr, C. J., Massague, J., Roberts, J. M., and Koff, A. (1994) Genes & Dev. 8: 9-22). p27.sup.Kip1 was cloned as a binding protein with cyclin E-cdk2 (Polyak, K., Lee, M.-H., ErdjumentBromage, H., Koff, A., Roberts, J. M., Tempst, P., and Massague, J. (1994) Cell 78: 59-66) or cyclin D-cdk4 (Toyoshima, H. and Hunter, T. (1994) Cell 78: 67-74). p27.sup.Kip1 inhibits the activity of most cyclin-cdk complexes and can inhibit the phosphorylation of cyclin-cdk complexes by CAK (cdk-activation kinases) (Kato. J.,Matsuoka,M., Polyak, K., Massague, J., and Sherr, C. J. (1994) Cell 79: 487-496). Therefore, p27.sup.Kip1 functions as a negative regulator of the G1/S progression. Web site: http://www.delphion.com/details?pn=US06623925__ •

Human PEA3 is a tumor suppressor for cancer cells Inventor(s): Hung; Mien-Chie (Houston, TX), Xing; Xiangming (Sugar Land, TX) Assignee(s): Board of Regents, The University of Texas System (Austin, TX) Patent Number: 6,582,725 Date filed: June 18, 2001 Abstract: The present invention relates generally to the fields of cancer therapy and gene therapy. More particularly, it demonstrates that PEA3, as exemplified by mPEA3 and hPEA3, is a tumor suppressor and may be used to treat various forms of cancer, for example neu- or ras-mediated cancers. Excerpt(s): The present invention relates generally to the fields of cancer therapy and gene therapy. More particularly, it concerns the use of PEA3, including but not limited to human PEA3 (hPEA3), to prevent and treat various transformation events. It is well established that a variety of cancers are caused, at least in part, by genetic abnormalities that result in either the over-expression of one or more genes, or the expression of an abnormal or mutant gene or genes. For example, in many cases, the expression of oncogenes is known to result in the development of cancer. "Oncogenes" are genetically altered genes whose mutated expression product somehow disrupts normal cellular function or control (Spandidos et al., 1989). Most oncogenes studied to date have been found to be "activated" as the result of a mutation, often a point mutation, in the coding region of a normal cellular gene, i.e., a "proto-oncogene", that results in amino acid substitutions in the expressed protein product. This altered expression product exhibits an abnormal biological function that takes part in the neoplastic process (Travali et al., 1990). The underlying mutations can arise by various means, such as by chemical mutagenesis or ionizing radiation. A number of oncogenes and oncogene families, including ras, myc, neu, raf, erb, src, fms, jun and abl, have now been identified and characterized to varying degrees (Travali et al., 1990; Bishop, 1987). Web site: http://www.delphion.com/details?pn=US06582725__

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Hybrid vectors for gene therapy Inventor(s): Higo; Collin (Reno, NV), Kasahara; Noriyuki (Los Angeles, CA), Mitani; Kohnosuke (Los Angeles, CA), Soifer; Harris (West Hills, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,576,463 Date filed: January 18, 2000 Abstract: The invention discloses hybrid vectors for delivering genes or other nucleic acids into mammalian cells. The hybrid vectors of the invention contain both a helper dependent adenoviral portion and a second portion derived from either a replication incompetent retrovirus or from a transposon. Such vectors provide efficient transduction of quiescent cells and provide for stable integration of the gene to be delivered. Excerpt(s): The invention relates to the field of medicine and in particular to vectors for delivery of nucleic acids into cells and to vectors useful for gene therapy. One of the foremost obstacles to the practical implementation of human gene therapy is the lack of an optimal method for the direct delivery of therapeutic genes to quiescent tissues in vivo. A number of vector systems based on viral components have been developed; however, of these individual virus vector systems, none is optimal and each system displays significant drawbacks. Retroviruses as vehicles for the delivery of genes into eukaryotic cells have several advantages (Hwang and Gilboa, 1984; Varmus, 1988): 1) gene transfer is relatively efficient; 2) stable integration into the host cell DNA is a natural part of the retroviral life cycle, and therefore the integrated provirus is passed on to all daughter cells, and continues to direct the nonlytic production of its encoded products; and 3) replication-defective vectors can be created by deletion of essential viral genes, which renders the vectors incapable of secondary infection (Mann et al., 1983; Markowitz et al., 1988; Miller and Buttimore, 1986). In spite of these advantages, retroviral gene transfer in its current form has several drawbacks. Most retroviral vectors in current use are traditionally based on Moloney murine leukemia virus (MLV), which requires cell division during infection so that the nucleocapsid complex can gain access to the host cell genome, and hence cannot infect non-dividing cells (Mulligan, 1993; Varmus, 1988). Many cell types are considered to be largely quiescent in vivo, and furthermore, most retroviral vectors are produced from packaging cells at titers on the order of only 10.sup.6-7 colony-forming units (cfu) per ml, which is barely adequate for transduction in vivo. Therefore, retroviral gene transfer in vivo is inefficient, and the traditional approach which has been adopted for retroviral vectors has been to transduce primary cells in culture by the ex vivo method, followed by re-implantation of the transduced cells. This approach requires surgical acquisition, isolation, and culture of autologous cells, and thus is labor-intensive and invasive, and limits the scope of ex vivo retroviral gene transfer to those cell types that can be readily accessed, maintained and manipulated in culture, and reimplanted, e.g., hematopoietic cells, skin fibroblasts, and hepatocytes. Web site: http://www.delphion.com/details?pn=US06576463__

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Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood Inventor(s): Boyse; Edward A. (Tucson, AZ), Broxmeyer; Hal E. (Indianapolis, IN), Douglas; Gordon W. (New York, NY) Assignee(s): PharmaStem Therapeutics, Inc. (Del Mar, CA) Patent Number: 6,569,427 Date filed: May 16, 1995 Abstract: The present invention relates to hematopoietic stem and progenitor cells of neonatal or fetal blood that are cryopreserved, and the therapeutic uses of such stem and progenitor cells upon thawing. In particular, the present invention relates to the therapeutic use of fetal or neonatal stem cells for hematopoietic (or immune) reconstitution. Hematopoietic reconstitution with the cells of the invention can be valuable in the treatment or prevention of various diseases and disorders such as anemias, malignancies, autoimmune disorders, and various immune dysfunctions and deficiencies. In another embodiment, fetal or neonatal hematopoietic stem and progenitor cells which contain a heterologous gene sequence can be used for hematopoietic reconstitution in gene therapy. In a preferred embodiment of the invention, neonatal or fetal blood cells that have been cryopreserved and thawed can be used for autologous (self) reconstitution. Excerpt(s): 1. Introduction. 2. Background of the Invention. 2.1. Hematopoietic Stem and Progenitor Cells. Web site: http://www.delphion.com/details?pn=US06569427__

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Lentiviral nucleic acids and uses thereof Inventor(s): Looney; David J. (Encinitas, CA), Poeschla; Eric M. (San Diego, CA), WongStaal; Flossie (San Diego, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,555,107 Date filed: April 17, 2001 Abstract: The invention provides non-primate lentiviral vectors, packaging cells and packaging plasmids based, for example, on feline and ungulate retroviruses. In particular, the packaging plasmids are designed for expression in human cells (which are also used as packaging cells). The vectors of the invention transduce human cells, including difficult to target non-dividing cells of the hematopoietic and nervous system, in vitro and in vivo. The vectors are suitable for general gene transfer to these cells and for gene therapy to treat conditions mediated by these non-dividing cells including cancer and HIV infection. Excerpt(s): Gene therapy provides methods for combating chronic infectious diseases (e.g., HIV infection), as well as non-infectious diseases including cancer and some forms of congenital defects such as enzyme deficiencies. Several approaches for introducing nucleic acids into cells in vivo, ex vivo and in vitro have been used. These include liposome based gene delivery (Debs and Zhu (1993) WO 93/24640 and U.S. Pat. No. 5,641,662); Mannino and Gould-Fogerite (1988) BioTechniques 6(7): 682-691; Rose U.S. Pat No. 5,279,833; Brigham (1991) WO 91/06309; and Felgner et al. (1987) Proc. Natl. Acad. Sci. USA 84: 7413-7414) and adenoviral vector mediated gene delivery, e.g., to

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treat cancer (see, e.g., Chen et al. (1994) Proc. Nat'l. Acad. Sci. USA 91: 3054-3057; Tong et al. (1996) Gynecol. Oncol. 61: 175-179; Clayman et al. (1995) Cancer Res. 5: 1-6; O'Malley et al. (1995) Cancer Res. 55: 1080-1085; Hwang et al. (1995) Am. J. Respir. Cell Mol. Biol. 13: 7-16; Haddada et al. (1995) Curr. Top. Microbiol. Immunol. 199 (Pt. 3): 297306; Addison et al. (1995) Proc. Nat'l. Acad. Sci. USA 92: 8522-8526; Colak et al. (1995) Brain Res. 691: 76-82; Crystal (1995) Science 270: 404-410; Elshami et al. (1996) Human Gene Ther. 7: 141-148; Vincent et al. (1996) J. Neurosurg. 85: 648-654). Replicationdefective retroviral vectors harboring a therapeutic polynucleotide sequence as part of the retroviral genome have also been used, particularly with regard to simple MuLV vectors. See, e.g., Miller et al. (1990) Mol. Cell. Biol. 10:4239 (1990); Kolberg (1992) J. NIH Res. 4:43, and Cornetta et al. Hum. Gene Ther. 2:215 (1991)). One of the most attractive targets for gene therapy is HIV infection. The pandemic spread of HIV has driven an intense world-wide effort to unravel the molecular mechanisms and life cycle of these viruses. It is now clear that the life cycle of HIVs provide many potential targets for inhibition by gene therapy, including cellular expression of transdominant mutant gag and env nucleic acids to interfere with virus entry, TAR (the binding site for tat, which is typically required for transactivation) decoys to inhibit transcription and trans activation, and RRE (the binding site for Rev; i.e., the Rev Response Element) decoys and transdominant Rev mutants to inhibit RNA processing. See, Rosenburg and Fauci (1993) in Fundamental Immunology, Third Edition Paul (ed) Raven Press, Ltd., New York and the references therein for an overview of HIV infection and the HIV life cycle. Gene therapy vectors encoding ribozymes, antisense molecules, decoy genes, transdominant genes and suicide genes, including retroviruses are described in Yu et al., Gene Therapy (1994) 1:13-26. Antisense and ribozyme therapeutic agents are of increasing importance in the treatment and prevention of HIV infection. Despite the various gene therapeutic approaches now underway for treating cancer, HIV and the like, there are a variety of limitations of the delivery systems currently used in gene therapy. For instance, with regard to HIV treatment, the extensively used murine retroviral vectors transduce (transfer nucleic acids into) human peripheral blood lymphocytes poorly, and fail to transduce non-dividing cells such as monocytes/macrophages, which are known to be reservoirs for HIV. New safer vectors for the delivery of viral inhibitors, particularly to non-dividing hematopoietic stem cells for the treatment of HIV infection, are desirable. Web site: http://www.delphion.com/details?pn=US06555107__ •

Ligand/lytic peptide compositions and methods of use Inventor(s): Elzer; Philip H. (Baton Rouge, LA), Enright; Frederick M. (Baton Rouge, LA), Foil; Lane D. (Baton Rouge, LA), Hansel; William (Baton Rouge, LA), Jaynes; Jesse M. (Baton Rouge, LA), Koonce; Kenneth L. (Baton Rouge, LA), McCann; Samuel M. (Baton Rouge, LA), Melrose; Patricia A. (Baton Rouge, LA), Yu; Wen H. (Baton Rouge, LA) Assignee(s): Board of Supervisors of Louisiana State University and Agricultural and (Baton Rouge, LA) Patent Number: 6,635,740 Date filed: September 24, 1999 Abstract: Amphipathic lytic peptides are ideally suited to use in a ligand/cytotoxin combination to specifically inhibit cells that are driven by or are dependent upon a specific ligand interaction; for example, to induce sterility or long-term contraception, or

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to attack tumor cells, or to selectively lyse virally-infected cells, or to attack lymphocytes responsible for autoimmune diseases. The peptides act directly on cell membranes, and need not be internalized. Administering a combination of gonadotropin-releasing hormone (GnRH) (or a GnRH agonist) and a membrane-active lytic peptide produces long-term contraception or sterilization in animals in vivo. Administering in vivo a combination of a ligand and a membrane-active lytic peptide kills cells with a receptor for the ligand. The compounds are relatively small, and are not antigenic. Lysis of gonadotropes has been observed to be very rapid (on the order of ten minutes.) Lysis of tumor cells is rapid. The two components--the ligand and the lytic peptide--may optionally be administered as a fusion peptide, or they may be administered separately, with the ligand administered slightly before the lytic peptide, to activate cells with receptors for the ligand, and thereby make those cells susceptible to lysis by the lytic peptide. The compounds may be used in gene therapy to treat malignant or nonmalignant tumors, and other diseases caused by clones or populations of "normal" host cells bearing specific receptors (such as lymphocytes), because genes encoding a lytic peptide or encoding a lytic peptide/peptide hormone fusion may readily be inserted into hematopoietic stem cells or myeloid precursor cells. Excerpt(s): This invention pertains to compositions and methods for specifically inhibiting cells that are driven by or are dependent on specific ligand interactions. Examples are compositions and methods for long-term contraception or sterilization; compositions and methods for inhibiting or killing malignant and non-malignant, hormone-dependent tumors; compositions and methods for selectively killing virally infected cells; and compositions and methods for selectively destroying lymphocytes responsible for autoimmune disorders. Compositions that have sometimes been used for long-term contraception include those based upon natural or synthetic steroidal hormones to "trick" the female reproductive tract into a "false pregnancy." These steroidal hormones must be administered repeatedly to prevent completion of the estrous cycle and conception. Steroids have side effects that can be potentially dangerous. P. Olson et al., "New Developments in Small Animal Population Control," JAVMA, vol. 202, pp. 904-909 (1993) gives an overview of methods for preventing or terminating unwanted pregnancies in small animals. The following discussion appears at page 905: "Tissue-specific cytotoxins--Permanent contraception in females and males might be achieved by administration of a cytotoxin that is linked to gonadotropinreleasing hormone (GnRH) and that selectively destroys gonadotropin-secreting pituitary cells. Similarly, a cytotoxin linked to antibodies against gonadotropin receptors could be targeted to alter gonadal function. Toxins would need to be carefully targeted to specific cells, yet be safe for all other body tissues." (citation omitted). Web site: http://www.delphion.com/details?pn=US06635740__ •

Materials and methods for intracellular delivery of biologically active molecules Inventor(s): Hughes; Jeffrey Allen (Gainesville, FL), Lasch; Jurgen (Halle, DE), Rowe; Thomas Cardon (Gainesville, FL), Weissig; Volkmar (Allston, MA) Assignee(s): University of Florida Research Foundation, Inc. (Gainesville, FL) Patent Number: 6,627,618 Date filed: January 5, 2001 Abstract: The subject invention finds utility in the area of gene therapy of diseases. More specifically, the invention concerns the making of a novel non-viral vector which can bind to desired DNA to form a combination useful to transfect diseased

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mitochondria of human or animal cells. The non-viral vector comprises a dequalinium salt subjected to standard liposome production procedures to obtain the vector named DQAsomes. Excerpt(s): Since the first demonstration in 1988 that mitochondrial DNA (mtDNA) base substitution and deletion mutations are linked to human disease, a variety of degenerative diseases have been associated with mtDNA mutations (reviewed in Wallace, D. C. [1994] J. Bioenergetics and Biomembranes 26:241-250). For example, certain deleterious base substitutions can cause familial deafness and some cases of Alzheimer's disease and Parkinson's disease. Other nucleotide substitutions have been associated with Leber's Hereditary Optic Neuropathy (LHON) and myoclonic epilepsy and ragged-red fiber disease (MERF). Base substitutions can also cause pediatric diseases such as Leigh's syndrome and dystonia. Severe rearrangements involving deletions have been linked with adult-onset chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS) as well as the lethal childhood disorder Pearson's marrow/pancreas syndrome (Wallace [1994], supra). Somatic gene therapy. Three different approaches for somatic gene therapy (reviewed in Ledley, F. D. [1996] Pharmaceutical Res. 13:1996) can be distinguished based on the nature of the material that is administered to the patient: (a) cell-based approaches involving the administration to the patient of genetically engineered cells ("ex-vivo"), (b) administration to the patient of genetically engineered, attenuated, or defective viruses, and (c) plasmid-based approaches that involve pharmaceutical formulations of DNA molecules. A variety of viral and non-viral methods have been developed for introducing DNA molecules into a cell. Non-viral techniques include precipitation of DNA with calcium phosphate (Chen, C., H. Okayama [1987] Mol. Cell. Biol. 7:27452752), dextran derivatives (Sompayrac, L., K. Danna [1981] PNAS 12:7575-7584), or polybrene (Aubin, R. J., M. Weinfield, M. C. Paterson [1988] Somatic Cell Mol. Genet. 14:155-167); direct introduction of DNA using cell electroporation (Neuman, E., M. Schaefer-Ridder, Y. Wang, P. H. Hofschneider [1982] EMBO J. 1:841-845) or DNA microinjection (Capecchi, M. R. [1980] Cell 22:479-486); complexation of DNA with polycations (Kabanov, A. V., V. A. Kabanov [1995] Bioconjugate Chem. 6:7-20); and DNA incorporation in reconstructed virus coats (Schreier, H., R. Chander, V. Weissig et al. [1992] Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 19:70-71; Schreier, H., M. Ausbom, S. Gunther, V. Weissig, R. Chander [1995] J. Molecular Recog. 8:59-62). Web site: http://www.delphion.com/details?pn=US06627618__ •

Method for in vitro amplification of circular DNA Inventor(s): Chen; Zhidong (Salt Lake City, UT), Ruffner; Duane E. (Salt Lake City, UT) Assignee(s): University of Utah Research Foundation (Salt Lake City, UT) Patent Number: 6,620,597 Date filed: July 6, 2000 Abstract: A method for generating and amplifying closed circular DNA having a specific sequence in vitro in a cell-free system is disclosed. Prior to the invention of this method, closed circular DNA could only be amplified in vivo in appropriate host cells. The essence of the method is the inclusion of a thermostable DNA ligase in a PCR reaction. This procedure is referred to as ligation-during-amplification (LDA), in which the fully extended DNA strands are ligated by the DNA ligase and used as templates for subsequent amplification. Closed circular DNA having a specific sequence can be selectively amplified exponentially by the use of two sequence-specific primers in the

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LDA reaction. In addition, one or more site-specific mutations can be introduced into a closed circular DNA by the use of one or more mutagenic primers in the LDA reaction. Various thermostable DNA polymerases and thermostable ligases can be used for LDA amplification. Any primer position and orientation, either inward or outward, can be used in LDA amplification, as long as there is at least one primer complementary to each strand of the circular DNA. This method has applications in the areas of mutagenesis, cloning, DNA detection, DNA modification, gene hunting, gene therapy, and cell-free DNA production. Excerpt(s): This invention relates to a method for the in vitro amplification of closed circular DNA. More particularly, the invention relates to a process for the cell-free amplification of closed circular DNA for applications such as mutagenesis, molecular cloning, DNA detection, DNA modification, gene hunting, gene therapy, and cell-free DNA production. The polymerase chain reaction (PCR) is a powerful method for the rapid and exponential amplification of target nucleic acids. E.g., U.S. Pat. Nos. 4,683,195 and 4,683,202, hereby incorporated by reference. PCR has facilitated the development of gene characterization and molecular cloning technologies including direct sequencing of PCR-amplified DNA, the determination of allelic variation, and the detection of infectious and genetic disorders. PCR is performed by repeated cycles of heat denaturation of a DNA template containing the target sequence, annealing of opposing primers to the complementary DNA strands, and extension of the annealed primers with a DNA polymerase. Multiple PCR cycles result in the exponential amplification of the nucleotide sequence delineated by the flanking amplification primers. An important modification of the original PCR technique was the substitution of Thermus aquaticus (Taq) DNA polymerase in place of the Klenow fragment of E. coil DNA polymerase I. Saiki et al., 230 Science 1350-1354 (1988). The incorporation of a thermostable DNA polymerase into the PCR protocol obviates the need for repeated enzyme additions and permits elevated annealing and primer extension temperatures, which enhance the specificity of primer/template associations. Other thermostable DNA polymerases have also been discovered and commercialized, such as the thermostable DNA polymerase from Pyrococcus furiosus (Pfu DNA polymerase; U.S. Pat. No. 5,545,552, hereby incorporated by reference), the thermostable DNA polymerase from Thermus flavus (Tfl DNA polymerase; Epicentre Technologies), the thermostable DNA polymerase from Thermus thermophilus (Tth DNA polymerase, Epicentre Technoloigies, Madison, Wis.), a mixture of Taq DNA polymerase and Pyrococcus species GB-D thermostable DNA polymerase (ELONGASE.TM., Life Technologies, Inc., Gaithersburg, Md.), the thermostable DNA polymerase from Thermococcus litoralis (Vent.sub.R.RTM. DNA polymerase, New England Biolabs, Beverly, Mass.), and AMPLITHERM.TM. DNA polymerase (proprietary thermostable DNA polymerase, Epicentre Technologies). Thermostable DNA polymerases thus serve to increase the specificity and simplicity of PCR. PCR can be used to amplify linear DNA segments, but not closed circular DNA. Since most replicatively competent DNAs exist in closed circular form, for functional studies a PCR product needs to be subcloned into a closed circular DNA vector and then introduced into and amplified in appropriate cellular hosts. The ability to amplify circular DNA in vitro in a cell-free system would allow modification of the nucleotide composition and sequence of a circular DNA at will. This achievement would represent a significant advancement in the art and have potential applications in areas of mutagenesis, cloning, DNA detection, DNA modification, gene hunting, gene therapy, and cell-free DNA production. Web site: http://www.delphion.com/details?pn=US06620597__

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Methods and compositions for genomic modification Inventor(s): Calos; Michele P. (Woodside, CA) Assignee(s): The Board of Trustees of the Leland Stanford Junior University (Palo Alto, CA) Patent Number: 6,632,672 Date filed: August 19, 1999 Abstract: The present invention provides methods of site-specifically integrating a polynucleotide sequence of interest in a genome of a eucaryotic cell, as well as, enzymes, polypeptides, and a variety of vector constructs useful therefore. In the method, a targeting construct comprises, for example, (i) a first recombination site and a polynucleotide sequence of interest, and (ii) a site-specific recombinase, which are introduced into the cell. The genome of the cell comprises a second recombination site. Recombination between the first and second recombination sites is facilitated by the sitespecific recombinase. The invention describes compositions, vectors, and methods of use thereof, for the generation of transgenic cells, tissues, plants, and animals. The compositions, vectors, and methods of the present invention are also useful in gene therapy techniques. Excerpt(s): The present invention relates to the field of biotechnology, and more specifically to the field of genomic modification. Disclosed herein are compositions, vectors, and methods of use thereof, for the generation of transgenic cells, tissues, plants, and animals. The compositions, vectors, and methods of the present invention are also useful in gene therapy techniques. Permanent genomic modification has been a long sought after goal since the discovery that many human disorders are the result of genetic mutations that could, in theory, be corrected by providing the patient with a non-mutated gene. Permanent alterations of the genomes of cells and tissues would also be valuable for research applications, commercial products, protein production, and medical applications. Furthermore, genomic modification in the form of transgenic animals and plants has become an important approach for the analysis of gene function, the development of disease models, and the design of economically important animals and crops. A major problem with many genomic modification methods associated with gene therapy is their lack of permanence. Life-long expression of the introduced gene is required for correction of genetic diseases. Indeed, sustained gene expression is required in most applications, yet current methods often rely on vectors that provide only a limited duration of gene expression. For example, gene expression is often curtailed by shut-off of integrated retroviruses, destruction of adenovirus-infected cells by the immune system, and degradation of introduced plasmid DNA (Anderson, W F, Nature 329:25-30, 1998; Kay, et al, Proc. Natl. Acad. Sci. USA 94:12744-12746, 1997; Verma and Somia, Nature 389:239-242, 1997). Even in shorter-term applications, such as therapy designed to kill tumor cells or discourage regrowth of endothelial tissue after restenosis surgery, the short lifetime of gene expression of current methods often limits the usefulness of the technique. Web site: http://www.delphion.com/details?pn=US06632672__

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Methods and compositions for in vivo gene therapy Inventor(s): Debs; Robert J. (Mill Valley, CA), Zhu; Ning (El Cerrito, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,627,615 Date filed: August 11, 1998 Abstract: Novel methods and compositions are provided for introducing a gene capable of modulating the genotype and phenotype into two or more tissues following systemic administration. The gene can be introduced into a mammalian host by way of an expression vector either as naked DNA or associated with lipid carriers, particularly cationic lipid carriers. Multiple individual tisssues can be transfected using naked DNA. Using a DNA: lipid carrier complex. multiple tissues and cell types can be transfected. The techniques and compositions find use in the palliation or treatment of any of a variety of genetic-based disorders. Excerpt(s): The present invention relates to methods and compositions for systemic introduction of exogenous genetic material into mammalian, particularly human, cells in vivo. An ever-expanding array of genes for which abnormal expression is associated with life-threatening human diseases is being cloned and identified. The ability to express such cloned genes in humans will ultimately permit the prevention and/or cure of many important human diseases, diseases which now either are treated poorly or are untreatable by currently available therapies. As an example, in vivo expression of cholesterol-regulating genes, genes which selectively block the replication of HIV, or of tumor-suppressing genes in human patients should dramatically improve treatment of heart disease, HIV, and cancer, respectively. However, currently available gene delivery strategies have been unable to produce either a high level of or generalized transgene expression in vivo in a wide variety of tissues after systemic administration to a mammalian host. This inability has precluded the development of effective gene therapy for most human diseases. Approaches to gene therapy include both different goals and different means of achieving those goals. The goals generally include gene replacement, gene correction and gene augmentation. In gene replacement, a mutant gene sequence is specifically removed from the genome and replaced with a normal, functional gene. In gene correction, a mutant gene sequence is corrected without any additional changes in the target genome. In gene augmentation, the expression of mutant genes in defective cells is modified by introducing foreign normal genetic sequences. Web site: http://www.delphion.com/details?pn=US06627615__

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Methods and compositions for treatment of diabetes and related conditions via gene therapy Inventor(s): Boettcher; Brian R. (Morristown, NJ), Caplan; Shari L. (Sloatsburg, NY), Connelly; Sheila (Ijamsville, MD), Desai; Urvi J. (Germantown, MD), Kaleko; Michael (Rockville, MD), Slosberg; Eric D. (New York, NY) Assignee(s): Novartis AG (Basel, CH) Patent Number: 6,608,038 Date filed: March 14, 2001

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Abstract: Disclosed are methods and compositions for treatment of diabetes, obesity and diabetic-related conditions. The methods include gene therapy based administration of a therapeutically effective amount of vectors encoding the following: glucokinase regulatory protein alone or co-administered with glucokinase or with metabolism modifying proteins; glucokinase co-administered with metabolism modifying proteins; or glucokinase regulatory protein co-administered with glucokinase in combination with metabolism modifying proteins, to a diabetic patient. Wherein the metabolism modifying proteins include UCP2, UCP3, PPAR.alpha., OB-Rb, GLP-1 and GLP-1 analogs (administered via vector or directly as a peptide). Preferred examples of GLP-1 analogs include GLP-1-Gly8, Extendin-4 and the "Black Widow" chimeric GLP-1 analog. Additionally, PPAR.alpha. ligands and DPP-IV inhibitors may be co-administered with the above. Excerpt(s): There are 15.7 million people or 5.9% of the population in the United States who have diabetes. While an estimated 10.3 million have been diagnosed, unfortunately, 5.4 million people are not aware that they have the disease. Each day approximately 2,200 people are diagnosed with diabetes. About 798,000 people will be diagnosed this year. Diabetes is the seventh leading cause of death (sixth-leading cause of death by disease) in the United States. Based on death certificate data, diabetes contributed to more than 187,000 deaths in 1995. Diabetes is a chronic disease that has no cure. Many people first become aware that they have diabetes when they develop one of its lifethreatening complications. Diabetes is the leading cause of new cases of blindness in people ages 20-74. Each year, from 12,000 to 24,000 people lose their sight because of diabetes. Diabetes is the leading cause of end-stage renal disease, accounting for about 40% of new cases. In 1995, approximately 27,900 people initiated treatment for end stage renal disease (kidney failure) because of diabetes. About 60-70 percent of people with diabetes have mild to severe forms of diabetic nerve damage, which, in severe forms, can lead to lower limb amputations. In fact, diabetes is the most frequent cause of nontraumatic lower limb amputations. The risk of a leg amputation is 1540 times greater for a person with diabetes. Each year, more than 56,000 amputations are performed among people with diabetes. People with diabetes are 2 to 4 times more likely to have heart disease which is present in 75 percent of diabetes-related deaths (more than 77,000 deaths due to heart disease annually). They are also 2 to 4 times more likely to suffer a stroke. Web site: http://www.delphion.com/details?pn=US06608038__ •

Methods and compositions to induce antitumor response Inventor(s): LaFace; Drake M. (San Diego, CA) Assignee(s): Canji, Inc. (San Diego, CA) Patent Number: 6,649,158 Date filed: October 13, 1999 Abstract: The present invention provides compositions which are engineered to induce killing of tumor cells and concomitantly mobilize differentiate, activate and attract dendritic cells through the expression of cytokines and dendritic cell chemoattractants. The present invention invention is induces multiple stages of dendritic cell differentiation, activation and migration in vivo using gene therapy delivery systems. Moreover, this invention describes the rational design of utilizing viral vectors (preferred vector is rAd) for multiple administrations of targeted delivery to dendritic cells which can promote differentiation and activation of the transduced dendritic cells

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(thus augmenting in vivo stimulation of T cells, NK cells and B cells. The present invention provides a method to induce an antitumor immune response through the use of such compositions. Excerpt(s): The immune system has evolved to process and recognize intracellular antigens via a class I MHC mediated antigen presentation pathway. Class I MHC restricted antigens are targeted by CD8 positive T cells largely consisting of cytotoxic T cells (CTL). An essential property of tumor antigen recognition by CD8 positive CTL cells is the requirement of the TCR to engage class I MHC/peptide complexes. Class I MHC restricted peptides are customarily derived from intracellular proteins. Thus, stimulation of immunity following in vivo administration of recombinant proteins preferentially stimulates antibody responses and only weak CTL responses. Based on these fundamentals of CTL recognition, several methods have traditionally been utilized to stimulate CTL responses. Peptides with conanical sequences optimized for MHC class I binding can displace non-covalently bound peptide on cell surface MHC class I in a concentration dependent manner. Peptides have successfully been utilized to stimulate CTL responses in vivo but generally require the use of adjuvants such as IFA. Alternatively, genetic approaches such as viral vectors or naked DNA have been utilized to introduce gene sequences directly into cells to expression intracellularly to deliver antigen directly into the endogenous class MHC antigen processing machinery. However, a limitation to targeting specific antigens limited to a relatively small subset of tumors is that mutations or overexpression of specific tumor associated antigens must be determined and applied on an individual basis. An optimal immunotherapeutic strategy would allow treatment of a broad spectrum of human malignancies with a common pharmaceutical product. Stimulating immune responses to tumors with p53 mutations may enable treatment of a broad spectrum of tumors as approximately 50% of tumors have mutations in the p53 tumor suppresser gene. The p53 tumor associated antigen is characterized as a mutant TAA. Initially, strategies were designed to elicit CTL responses to "unique peptide antigens" generated by the p53 mutant sequences. This strategy was based on the premise that tumor specific CTL recognize peptides, derived from endogenously synthesized cellular proteins, presented by class I major histocompatibility complex (MHC) molecules. However, targeting such tissue-specific antigens may restrict immunotherapies to a very limited set of tumors as the mutations occur in many different loci within the p53 gene. Web site: http://www.delphion.com/details?pn=US06649158__ •

Methods of in vivo gene transfer using a sleeping beauty transposon system Inventor(s): Kay; Mark A. (Los Altos, CA), Yant; Steve (Menlo Park, CA) Assignee(s): The Board of Trustees of the Leland Stanford Junior University (Palo Alto, CA) Patent Number: 6,613,752 Date filed: August 10, 2001 Abstract: Methods and compositions for introducing a nucleic acid into the genome of at least one cell of a multicellular organism are provided. In the subject methods, a Sleeping Beauty transposon that includes the nucleic acid is administered to the multicellular organism along with a source of a Sleeping Beauty transposase activity. Administration of the transposon and transposase results in integration of the transposon, as well as the nucleic acid present therein, into the genome of at least one cell of the multicellular organism The subject methods find use in a variety of different

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applications, including the in vivo transfer of genes for use in, among other applications, gene therapy applications. Excerpt(s): The field of this transformation. The introduction of an exogenous nucleic acid sequence (e.g. DNA) into a cell, a process known as "transformation," plays a major role in a variety of biotechnology and related applications, including research, synthetic and therapeutic applications. Research applications in which transformation plays a critical role include the production of transgenic cells and animals. Synthetic applications in which transformation plays a critical role include the production of peptides and proteins. Therapeutic applications in which transformation plays a key role include gene therapy applications. Because of the prevalent role transformation plays in the above and other applications, a variety of different transformation protocols have been developed. In many transformation applications, it is desirable to introduce the exogenous DNA in a manner such that it is incorporated into a target cell's genome. One means of providing for genome integration is to employ a vector that is capable of homologous recombination. Techniques that rely on homologous recombination can be disadvantageous in that the necessary homologies may not always exist; the recombination events may be slow, etc. As such, homologous recombination based protocols are not entirely satisfactory. Web site: http://www.delphion.com/details?pn=US06613752__ •

Methods to enhance wound healing and enhanced wound coverage material Inventor(s): Barrow; Robert E. (Galveston, TX), Herndon; David N. (Galveston, TX), Perez-Polo; Jose R. (Galveston, TX) Assignee(s): Research Development Foundation (Carson City, NV) Patent Number: 6,576,618 Date filed: June 22, 2000 Abstract: The present invention describes the incorporation of liposomal gene constructs directly into a wound to further improve wound repair, or into wound coverage and/or closure materials to enhance the functionality of the material. The present invention further describes the use of human fetal membranes (e.g., amnion) enhanced with the liposomal gene therapy as a wound coverage material in full-thickness wound repair. The enhanced fetal membranes or enhanced cadaver skin have advantages over currently used materials lacking the liposomal gene construct and are an efficient and safe approach to improve clinical outcome in patients with burn injuries. Excerpt(s): The present invention relates generally to the field of trauma medicine and wounds. More specifically the present invention relates to methods of enhancing wound healing and enhanced wound coverage materials. Burn injuries represent one of the most severe forms of trauma. The larger the burn injury, the more severe the consequences and the higher the chance of poor extended outcomes and death. There are over 2 million burn patients annually, and costs for treatment exceed one billion dollars a year. Fire and burn injuries are the third leading cause of injuries and death in children aged 1 to 18 years. The number of mortalities from burns has decreased over the last decade, primarily due to early and adequate fluid resuscitation, early and aggressive nutritional support, improved infection control, improved wound care/would healing, and hormonal modulation. Wound healing is of major importance in the recovery of burn patients, and therefore, their clinical outcome. It has been shown that early wound excision and tissue grafting improved the hypermetabolic response

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and survival after burn injury. Autologous skin can be used to graft the excised wound (donor-site), however, this is not an effective treatment in patients with especially large burns. In these cases, synthetic skin materials or cadaver skin have been used. Web site: http://www.delphion.com/details?pn=US06576618__ •

Molecular chemotherapy enhancement of radiotherapy Inventor(s): Buchsbaum; Donald J. (Birmingham, AL), Curiel; David T. (Birmingham, AL), Pederson; Lee C. (Birmingham, AL), Stackhouse; Murray A. (Birmingham, AL) Assignee(s): UAB Research Foundation (Birmingham, AL) Patent Number: 6,599,909 Date filed: September 29, 1999 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 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. Also provided is a noninvasive method for continuous in vivo monitoring of 5-fluorouracil production via magnetic resonance spectroscopy. 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, which was 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.alpha. 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 b e targeted with radiolabeled peptides (18-21).

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Web site: http://www.delphion.com/details?pn=US06599909__ •

Mutated steroid hormone receptors, methods for their use and molecular switch for gene therapy Inventor(s): McDonnell; Donald P. (San Diego, CA), O'Malley; Bert W. (Houston, TX), Schrader; William T. (San Diego, CA), Tsai; Ming-Jer (Houston, TX), Vegeto; Elisabetta (Houston, TX) Assignee(s): Baylor College of Medicine (Houston, TX) Patent Number: 6,599,698 Date filed: December 9, 1998 Abstract: The present invention provides mutant proteins of steroid hormone receptors. These mutant proteins are useful in methods of distinguishing a steroid hormone receptor antagonist from a steroid hormone receptor agonist. The present invention also provides plasmids containing mutated steroid hormone receptor proteins and cells transfected with those plasmids. In addition, the present invention provides methods for determining whether a compound is a steroid hormone receptor antagonist or agonist. Also, the present invention provides methods of determining endogenous ligands for steroid hormone receptors. The invention further provides a molecular switch for regulating expression in gene therapy and methods of employing the molecular switch in humans, animals, transgenic animals and plants. Excerpt(s): The present invention relates generally to the fields of molecular endocrinology and receptor pharmacology. It further relates to molecular switches for gene therapy. More specifically, the present invention relates to a novel in vivo method for the identification of steroid hormone receptor agonists and antagonists and to a molecular switch involving a modified steroid receptor for up-regulating and downregulating the synthesis of heterologous nucleic acid sequences which have been inserted into cells. Steroid receptors are responsible for the regulation of complex cellular events, including transcription. The ovarian hormones, estrogen and progesterone, are responsible, in part, for the regulation of the complex cellular events associated with differentiation, growth and functioning of female reproductive tissues. These hormones play also important roles in development and progression of malignancies of the reproductive endocrine system. The biological activity of steroid hormones is mediated directly by a hormone and tissue-specific intracellular receptor. The physiologically inactive form of the receptor may exist as an oligomeric complex with proteins, such as heat-shock protein (hsp) 90, hsp70 and hsp56. Upon binding its cognate ligand, the receptor changes conformation and dissociates from the inhibitory heteroligomeric complex. Subsequent dimerization allows the receptor to bind to specific DNA sites in the regulatory region of target gene promoters. Following binding of the receptor to DNA, the hormone is responsible for mediating a second function that allows the receptor to interact specifically with the transcription apparatus. Displacement of additional inhibitory proteins and DNA-dependent phosphorylation may constitute the final steps in this activation pathway. Web site: http://www.delphion.com/details?pn=US06599698__

Patents 189

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Nucleic acid constructs containing hybrid promoters Inventor(s): Mueller; Rolf (Marburg, DE), Sedlacek; Hans-Harald (Marburg, DE), Seifart; Klaus-Heinrich (Marburg, DE) Assignee(s): Aventis Pharma Deutschland GmbH (Frankfurt am Main, DE) Patent Number: 6,576,758 Date filed: September 24, 1997 Abstract: Nucleic acid constructs containing hybrid promoters for use in gene therapy and genetic manipulation. The invention relates to a nucleic acid construct for the precise, regulated expression of genes in host cells, which construct exhibits at least one mutation which inhibits the proper expression of the expressed gene and exhibits at least one additional second mutation which relieves the inhibition due to the first mutation, to an isolated cell which harbors the nucleic acid construct, and to the use of the nucleic acid construct for preparing pharmaceuticals and for treating diseases with excessive cell proliferation. Excerpt(s): The present application relates to nucleic acid constructs which can be used in genetic manipulation and in particular in the prophylaxis or therapy of diseases (termed gene therapy in that which follows). In gene therapy, genes which are to be expressed in an organism are introduced into the organism. The regulation of the expression of these genes is of significance for the prophylactic or therapeutic effect of the gene therapy. Regulators of the expression of a gene are described in Patent Applications PCT/GB95/02000, PCT/EP95/03370, PCT/EP95/03371, PCT/EP95/03368 and PCT/EP95/03339. These regulators comprise an activator sequence whose function is, for example, the cell-specific or virus-specific activation of basal transcription. The DNA sequence of this activator sequence is linked by its 3' end to the 5' end of a promoter module. The structural gene is in turn linked by its 5' end to the 3' end of the promoter module. The promoter module is composed of nucleic acid sequences for binding the transcription factors of the CDF and CHF families or of the E2F and CHF families. In the G0 and G1 phases of the cell cycle, this binding leads to inhibition of the upstream activator sequence and consequently to inhibition or transcription of the structural gene which is located downstream (i.e. in the direction of transcription). Web site: http://www.delphion.com/details?pn=US06576758__

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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

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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 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__ •

RECOMBINANT DNA COMPRISING DNA CODING FOR MYOSIN HEAVY CHAIN SM1 ISO-FORM PROTEIN INSERTED INTO VECTOR DNA MICROORGANISM CARRYING THE RECOMBINANT DNA, AND AN AGENT FOR TREATMENT OF ARTERIOSCLEROSIS COMPRISING THE RECOMBINANT DNA Inventor(s): Arakawa; Emi (Tokyo, JP), Hasegawa; Kazuhide (Tokyo, JP), Ishiyama; Haruo (Kanagawa, JP), Matsuda; Yuzuru (Tokyo, JP), Oda; Shoji (Kanagawa, JP), Sugahara; Michihiro (Shizuoka, JP), Takahashi; Katsuhito (Osaka, JP) Assignee(s): Osaka Prefectual Government (Osaka, JP), Vessell Research Laboratory Co. Ltd. (Tokyo, JP) Patent Number: 6,593,304 Date filed: July 25, 1997 Abstract: The present invention relates to recombinant DNA comprising DNA coding for smooth-muscle-type myosin heavy chain SM1 isoform protein inserted into vector DNA, a microorganism carrying the recombinant DNA, and an agent for treatment of arteriosclerosis comprising the recombinant DNA. The recombinant DNA of the present invention can be used effectively as an agent for gene therapy of restenosis after PTCA treatment. Excerpt(s): The present invention relates to recombinant DNA comprising DNA coding for myosin heavy chain SM1 isoform protein inserted into vector DNA, a microorganism carrying the recombinant DNA and an agent for treatment of arteriosclerosis comprising the recombinant DNA which are used in gene therapy. Smooth muscle-type myosin heavy chain SM1 isoform protein is responsible for contraction and relaxation of smooth muscles, and is one of the myosin heavy chain isoform proteins expressed specifically in smooth muscle cells. As the DNA coding for the protein, the nucleotide sequence of cDNA coding for rabbit SM1 isoform is known

Patents 191

(P. Babij et al.: Proc. Natl. Acad. Sci. USA, 88, 10676 (1991)), but there is not known any homology among nucleotide sequences for such DNAs. Further, there is not known any recombinant DNA comprising DNA coding for smooth muscle-type myosin heavy chain SM1 isoform protein inserted into vector DNA which recombinant DNA can be injected into animal cells. It has been reported that when cDNA coding for a protein called calponin which is a protein existing in smooth muscle cells is introduced and expressed in a vascular smooth muscle cell line derived from rat pulmonary arteries, the time required for doubling the cells is prolonged by about 4 hours (Takahashi et al.: Circulation, 88, I-174 (1993)) and that when cDNA for human calponin is injected into a rabbit topically at a site where the carotid artery has been abraded with a balloon, thickening of the intima is inhibited (Takahashi et al.: Circulation, 88, I-656 (1993)). It is not known that recombinant DNA comprising DNA coding for myosin heavy chain SM1 isoform protein inserted into vector DNA has pharmacological effect and is used for in gene therapy. Web site: http://www.delphion.com/details?pn=US06593304__ •

Recombinant vector for use in gene therapy for insulin-dependent diabetes mellitus and therapeutic composition thereof Inventor(s): Suh; Dongsang (Department Genetic Engineering, Sungkyunkwan University, Chunchun-dong, Jangan-ku, Suwon, Kyonggi-do, KR 440-746) Assignee(s): none reported Patent Number: 6,596,515 Date filed: February 5, 2001 Abstract: Disclosed are a recombinant vector for use in gene therapy for insulindependent diabetes mellitus and a therapeutic composition thereof. Following the injection of a.beta.-galactosidase expression vector having a K14 promoter gene, along with a Drosophola's P transposase expression helper vector, into murine skin in a liposome-mediated manner, the.beta.-galactosidase gene is expressed in the keratinocyte layer from 24 hours to 20 weeks after injection as measured by X-gal staining. With the enhancement effect and tissue specificity, the K14 promoter is applied for the expression of a human insulin gene in keratinocytes, thereby suggesting a new gene therapy method for treating insulin-dependent diabetes mellitus. When, in combination with the P-element expression helper vector, a human insulin expression vector with the K14 promoter is injected into the skin of diabetic mice, which lack insulin-producing.beta.cells of the pancreas, their blood glucose levels are maintained in a normal range. Excerpt(s): The present invention relates to a recombinant vector suitable for use in gene therapy for insulin-dependent diabetes mellitus and a pharmaceutical composition comprising the recombinant vector as an effective ingredient. More particularly, the present invention relates to a gene therapy system for effectively and safely treating insulin-dependent diabetes mellitus by taking advantage of the gene delivery capacity of Drosophila's P-transposon and the tissue specificity and expression enhancement of a K14 promoter. Gene therapy offers a new paradigm for curing human diseases. Rather than altering disease phenotypes by using agents that interact with gene products or are themselves gene products, gene therapy theoretically can modify specific genes, which results in a cure following a single administration. Initially, gene therapy was envisioned for the treatment of genetic disorders, but is currently studied for a broad spectrum of diseases, including cancer, peripheral vascular disease, arthritis, neurodegenerative disorders and other acquired diseases. Further, in combination with the

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Human Genome Project, gene therapy is expected to make a great progress in the treatment of far more diseases. With gene therapy, the delivery of genes into cells and their expression therein can be artificially regulated, so that the mutated genes of patients can be corrected by genetic recombination. There are disclosed patents regarding gene therapy. For instance, PCT publication No. 1997-27310 claims a retrovirus vector which can be used in gene therapy and PCT publication No. 199734009 discloses a recombinant adenovirus vector for gene therapy for human tumors. Virus vectors are, however, limited to only the treatment of hereditary diseases, owing to safety concerns and highly complex procedures. Also, the gene therapy utilizing virus vectors, as in such patents, suffers from the disadvantage of requiring much time and high expense. In prior arts, non-viral insulin vectors have been disclosed nowhere yet. Web site: http://www.delphion.com/details?pn=US06596515__ •

Recombinant, active caspases and uses thereof Inventor(s): Alnemri; Emad S. (Ambler, PA) Assignee(s): Thomas Jefferson University (Philadelphia, PA) Patent Number: 6,610,541 Date filed: September 14, 2001 Abstract: Rev-caspases comprising a primary product in which the small subunit is Nterminal to the large subunit are provided. Rev-caspases are used for screening and identifying caspase inhibitors and enhancers. Rev-caspase genes can be delivered to cells for gene therapy. Excerpt(s): The present invention relates generally to regulating apoptosis, and more particularly to the novel aspartate-specific cysteine proteases known as caspases, their coding regions, mutant forms thereof, and their use in screening assays and as pharmaceutical compositions for the controlled death of targeted cells to treat human disease. Tissue homeostasis is maintained by the process of apoptosis--that is, the normal physiological process of programmed cell death. Changes to the apoptotic pathway that prevent or delay normal cell turnover can be just as important in the pathogenesis of diseases as are abnormalities in the regulation of the cell cycle. Like cell division, which is controlled through complex interactions between cell cycle regulatory proteins, apoptosis is similarly regulated under normal circumstances by the interaction of gene products that either prevent or induce cell death. Since apoptosis functions in maintaining tissue homeostasis in a range of physiological processes such as embryonic development, immune cell regulation and normal cellular turnover, the dysfunction or loss of regulated apoptosis can lead to a variety of pathological disease states. For example, the loss of apoptosis can lead to the pathological accumulation of self-reactive lymphocytes that occurs with many autoimmune diseases. Inappropriate loss or inhibition of apoptosis can also lead to the accumulation of virally infected cells and of hyperproliferative cells such as neoplastic or tumor cells. Similarly, the inappropriate activation of apoptosis can also contribute to a variety of pathological disease states including, for example, acquired immunodeficiency syndrome (AIDS), neurodegenerative diseases and ischemic injury. Treatments which are specifically designed to modulate the apoptotic pathways in these and other pathological conditions can alter the natural progression of many of these diseases. Web site: http://www.delphion.com/details?pn=US06610541__

Patents 193

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Retroviral hybrid vectors pseudotyped with LCMV Inventor(s): Beyer; Winfried (Hamburg, DE), Von Laer; Meike-Dorothee (Hamburg, DE) Assignee(s): Heinrich-Pette-Institute (Hamburg, DE) Patent Number: 6,589,763 Date filed: November 22, 2000 Excerpt(s): The present invention relates in general to the pseudotyping of retroviruses with lymphocytic choriomeningitis virus. In particular, the invention relates to pseudotyping in MLV packaging cells which are optionally env-deleted, or in packaging cells derived from lentiviruses. Preferably, pseudotyping is carried out by infection with LCMV or a preferably env-deleted mutant, or by transfection with an expression plasmid containing the gp-gene of LCMV or a part thereof and optionally, in addition, the np-, the 1- and/or the z-gene of LCMV. The invention also relates to the use of such pseudotypes for the infection of cells, particularly the use in gene therapy. Retroviral vectors are increasingly being used in the state of the art, for example, for gene transfer in genetic engineering and medical research or in gene therapy approaches (cf. e.g. C. Baum et al. in Seminars in Oncology: Gene Therapy of Cancer: Translational approaches from preclinical studies to clinical implementations., eds. Gerson & Lattime, Academic Press, 1998). The retroviral vectors are mostly derived from murine leukaemia viruses (MLV) and contain all the sequences of the LTR regions required for integration and the.psi.-element responsible for packaging. The regions coding for the virus proteins are replaced by foreign genes and the control sequences thereof which it would be desirable to introduce into human cells. The vectors are expressed in so-called helper cell lines (packaging cell lines) which contain a copy of a complete retrovirus genome. It synthesises all the proteins required for replication and infection, but is unable to package its genomic virus-RNA into particles because it has a defect in the.psi.sequences. If the retroviral vectors are inserted into these helper cells and transcribed, the transgenic mRNA formed is able, by means of the.psi.-region which is characteristic of it, to interact with the structure proteins of the helper virus and be packaged to particles. The recombinant virions, which possess no genetic information at all for virus components, adsorb on cells by way of their surface proteins, the capsids are taken up in the cytoplasm, and the transgenic RNA is converted to double-stranded DNA and integrated into the host cell genome. The advantage of this system is the stable integration of the foreign genes which are passed on to the daughter cells on division. The non-specific integration at arbitrary sites of the cell genome, which is characteristic of retroviruses, is a disadvantage. Retroviral vectors impart a stable colinear integration (i.e. without recombinations and rearrangement of the coding sequences in the vector genome) and thereby a long-term expression of the transgene. Long-term gene expression has otherwise been possible hitherto only by means of the episomal herpes virus vectors or the adeno-associated virus vectors (AAV vectors). The packaging systems (packaging cell lines) have not yet, however, been optimised for the latter vector systems. Moreover, AAV vectors have a lower packaging capacity (about 5 kb for AAV compared with about 10-12 kb for retroviral vectors). Web site: http://www.delphion.com/details?pn=US06589763__

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Screening methods for identifying viral proteins with interferon antagonizing functions and potential antiviral agents Inventor(s): Basler; Christopher (New York, NY), Garcia-Sastre; Adolfo (New York, NY), Palese; Peter M. (Leonia, NJ) Assignee(s): Mount Sinai School of Medicine of New York University (New York, NY) Patent Number: 6,635,416 Date filed: April 10, 2001 Abstract: The present invention relates, in general, to a screening method for identifying novel viral proteins with interferon antagonizing function using a transfection-based assay, and the use of such proteins in isolating various types of attenuated viruses for the development of vaccine and pharmaceutical formulations. The invention also relates to the use of viral interferon antagonists in screening assays to identify potential antiviral agents. The invention further relates to protocols utilizing interferon antagonists, e.g., NS1, to enhance gene therapy or DNA vaccination based on their ability to increase gene expression. Excerpt(s): The present invention relates, in general, to a screening method for identifying novel viral proteins with interferon antagonizing function, and the use of such proteins in isolating various types of attenuated viruses for the development of vaccine and pharmaceutical formulations. The invention also relates to the use of viral interferon antagonists in screening assays to identify potential anti-viral agents. The invention further relates to protocols utilizing interferon antagonists, e.g., NS1, to enhance gene therapy or DNA vaccination based on their ability to increase gene expression. One important component of the host antiviral response is the type I IFN system. Type I IFN is synthesized in response to viral infection. Double stranded RNA (dsRNA) or viral infection activate latent transcription factors, including IRF-3 and NF.sub.k B, resulting in transcriptional up-regulation of type I IFN, IFN-.alpha., and IFN.beta. genes. Secreted type I IFNs signal through a common receptor, activating the JAK/STAT signaling pathway. This signaling stimulates transcription of IFN-sensitive genes, including a number of that encode antiviral proteins, and leads to the induction of an antiviral state. Among the antiviral proteins induced in response to type I IFN are dsRNA-dependent protein kinase R (PKR). 2',5'-oligoadenylate synthetase (OSA), and the Mx proteins (Clemens et al., 1997 Interferon Cytokine Res. 17:503-524; Floyd-Smith et al., 1981 Science 212:1030-1032; Haller et al., 1998 Rev. Sci Tech 17:220-230; Stark et al., Annu Rev. Biochem 67:227-264). Many viruses have evolved mechanisms to subvert the host IFN response. For example, the herpes simplex virus counteracts the PKR-mediated phosphorylation of translation initiation factor cIF-2.alpha., preventing the establishment of an IFN-induced block in protein synthesis (Garcia-Sastre et al. 1998 Virology 252 (2):324-30). In the negative-strand RNA viruses, several different anti-IFN mechanisms have been identified (Garcia-Sastre et al., 1998 Virology 252:324-330). Web site: http://www.delphion.com/details?pn=US06635416__

Patents 195

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Single-chain insulin analog and a polynucleotide sequence encoding the analog Inventor(s): Kim; Kyung Sup (Yongdeungpogu Yeoyeedodong Samik, Apt. B-202, Seoul, KR), Kim; Su-Jin (Dukyanggu Haengsindong 938 Haibit 1819-1304, Goyangsi, KR), Lee; Hyun Chul (Seodaemungu Hongeundong 268, Dongdo-academyhouse A-402, Seoul, KR), Shin; Hang-Cheol (Seochogu Wonjidong 401-37, Seoul, KR), Yoon; Ji-Won (206 Edgeview Drive, N.W., Calgary, Alberta, CA T3A 4X5) Assignee(s): none reported Patent Number: 6,630,348 Date filed: November 7, 2000 Abstract: The subject matter of the invention is directed to a single-chain insulin analog that is used to treat diabetes by gene therapy methods. Excerpt(s): The present invention relates to a method of introducing at least one singlechain insulin analog protein or a gene encoding a single-chain insulin analog (SIA) into at least one mammalian tissue for use in treating diabetes in the mammalian host. The present invention also relates to the single-chain insulin analog and a recombinant vector construct comprising the gene encoding SIA. The cure of diabetes has long been sought using several different approaches, including islet transplantation, regeneration of.beta. cells and insulin gene therapy (Levine, F. & Leibowitz, G. Towards gene therapy of diabetes mellitus. Mol. Med. Today 5, 165-171 (1999)). However, the permanent remission of type 1 diabetes has not yet been satisfactorily achieved. There remains a very real and substantial need for a method of introducing at least one gene encoding a single-chain insulin analog to at least one cell of a mammalian host in vitro or in vivo, for use in treating the mammalian host suffering from diabetes. Web site: http://www.delphion.com/details?pn=US06630348__

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Skin and muscle-targeted gene therapy by pulsed electrical field Inventor(s): Dev; Nagendu B. (San Diego, CA), Hofmann; Gunter A. (San Diego, CA), Nolan; Edward (San Diego, CA), Rabussay; Dietmar P. (San Diego, CA), Tonnessen; Arnt (El Cajon, CA), Widera; Georg (Del Mar, CA), Zhang; Lei (San Diego, CA) Assignee(s): Genetronics, Inc. (San Diego, CA) Patent Number: 6,654,636 Date filed: July 26, 2000 Abstract: The present invention describes an in vivo method, using pulsed electric field to deliver therapeutic agents into cells of the skin and muscle for local and systemic treatments. In particular, therapeutic agents include naked or formulated nucleic acid, polypeptides and chemotherapeutic agents. Excerpt(s): The present invention relates generally to the use of electric pulses to increase the permeability of cells, and more specifically to a method and apparatus for the application of controlled electric fields for in vivo delivery of pharmaceutical compounds and genes into cells by electroporation therapy (EPT), also known as cell poration therapy (CPT) and electrochemotherapy (ECT). The skin is an especially attractive target for gene therapy. In particular, the ability to target genes to the epidermis of the skin could be used to correct skin-specific disorders as well as for the production of proteins secreted into the skin to correct certain systemic diseases. For example, genes expressing cytokines, interferons or other biologically active molecules

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could be used to treat skin tumors or other lesions. In addition, keratinocytes and fibroblasts in the skin can secrete protein factors which circulate to treat systemic conditions such as hemophilia. Despite the clear potential in using skin as a target for gene therapy, the major technical problem of an in vivo method of gene delivery remains largely unresolved. Since the stratum corneum (SC) acts as a significant physical barrier to gene transfer into the skin, the technical problem of how to deliver genes through this layer persists. Similarly, muscle cells are also useful targets for gene therapy due to their ubiquity. Nonetheless, as with skin, there exists a need for a method to reliably introduce exogenous therapeutic material into muscle cells. Web site: http://www.delphion.com/details?pn=US06654636__ •

Somatic cell gene therapy Inventor(s): St. Louis; Daniel Claude (Gaithersburg, MD), Verma; Inder Mohan (Solana Beach, CA) Assignee(s): The Salk Institute for Biological Studies (La Jolla, CA) Patent Number: 6,645,942 Date filed: April 22, 1994 Abstract: The present invention is a somatic cell gene therapy method that is especially useful for the treatment of certain diseases that are caused by gene defects. According to the invention, fibroblast cells are transduced so that they express a "replacement" gene of interest. These transduced fibroblasts are preferably fixed in vitro in an extracellular matrix, and then implanted in the loose connective tissue of the skin of an individual or animal to be treated. Because the fibroblasts are implanted in a highly vascularized compartment of the skin i.e., loose connective tissue of the dermis, the transduced cells, and thus their "replacement" gene products, have direct access to the circulatory system. As a result the needed replacement gene products can easily and efficiently be distributed to other parts of the body. When the gene therapy is no longer needed, the implanted fibroblasts can be conveniently removed. Excerpt(s): The present invention relates generally to gene therapy. More specifically, the present invention relates to somatic cell gene therapy in humans and animals. Genetic defects in the human genome account for more than 4500 identified diseases. The resulting diseases are caused by single or multiple defects in a given gene. It is possible that many of these diseases can be alleviated, at least in part, if the deficient function can be supplied. The concept of human gene therapy involves the introduction of a functionally active "replacement" gene into somatic cells of an affected subject to correct the gene defect. Retroviral vectors, because of their unique structure, modes of replication, and ability to infect a wide variety of cells, including stem cells, are ideally suited to transfer genetic material into somatic cells (Verma, 1985). Web site: http://www.delphion.com/details?pn=US06645942__

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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 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__

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Uncoupling protein homologue: UCP 3 Inventor(s): Boss; Olivier (Boston, MA), Giacobino; Jean-Paul (Geneve, CH), Muzzin; Patrick (Gland, CH) Assignee(s): Novartis AG (Basel, CH) Patent Number: 6,620,594 Date filed: November 4, 1999 Abstract: The present invention relates to the cloned genes which code for uncoupling proteins controlling thermogenesis in human skeletal muscle and heart. A further aspect

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of the present invention relates to the use of the said genes for correcting dysfunctions of thermogenesis in human skeletal muscle and heart.The present invention makes it possible to exploit novel therapeutic (or preventive) methods for disorders such as obesity or cachexia. As a result of the identification and isolation of the genes coding for UCP3.sub.L and UCP3.sub.S, it is, in effect, possible to develop medicaments which act on the basis of a correction, by gene therapy or by antisense oligonucleotides relating to the sequence of the gene in question or to one of its fragments, of a lack or an excess of UCP3. Excerpt(s): This application is the National Stage of International Application No. PCT/EP98/02645, filed on May 5, 1998. The present invention relates to a cloned gene which codes for an uncoupling protein (UCP3.sub.L) which controls thermogenesis in human skeletal muscle and heart. The present invention also relates to a cloned gene which codes for an uncoupling protein (UCP3.sub.S), also controlling thermogenesis in human skeletal muscle and heart. Web site: http://www.delphion.com/details?pn=US06620594__ •

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.

Patents 199

Web site: http://www.delphion.com/details?pn=US06599744__ •

Viral vectors with modified tropism Inventor(s): Baird; Andrew (San Diego, CA), Curiel; David T. (Birmingham, AL), Douglas; Joanne T. (Huntsville, AL), Pierce; Glenn F. (Rancho Santa Fe, CA), Rogers; Buck E. (Birmingham, AL), Sosnowski; Barbara A. (Coronado, CA) Assignee(s): Selective Gentics, Inc. (San Diego, CA), UAB Research Foundation (Birmingham, AL) Patent Number: 6,613,563 Date filed: March 13, 1998 Abstract: The present invention relates to gene therapy. In particular, therapeutic agents, therapeutic gene products, and compositions are disclosed. Various systems and methods useful in targeting and delivering non-native nucleotide sequences to specific cells are disclosed, wherein virus-antibody-ligand conjugates are used to facilitate targeting and delivery. Excerpt(s): The present invention relates to gene therapy. In particular, therapeutic agents and methods useful in targeting and delivering genes more efficiently to particular cells are disclosed, wherein re-targeted, tropism-modified viral vectors presenting ligand on the surface and including a nucleotide sequence encoding a therapeutic gene product are used to facilitate targeting and delivery. The primary impediment to the transfer of non-native or foreign DNA into mammalian cells is that the genetic material must be transported across multiple cellular barriers before it enters the host cell nucleus and initiates gene expression. Previously established methods have utilized artificial means to introduce DNA into the cell although these methods are associated with significant cell toxicity (Graham et al., Virology 52:456-467 (1973); Felgner et al, PNAS USA 84:7413-7417 (1987)). More recently, enhanced transfer of DNA conjugates into cells has been achieved with adenovirus, a human DNA virus which readily infects various cell types (Horwitz, Adenoviridae and their replication, in Virology, Fields and Knipe, eds., Raven Press, NY (1990) pp. 1679-1740). Since adenovirus efficiently disrupts the membranes of endocytic vesicles, co-internalization of the virus with the DNA conjugate allows rapid transfer of the conjugate into the cell cytoplasm before it can be subjected to lysosomal degradation. The fact that adenovirus exhibits selective tropism has also been exploited to reconstitute these cells in vivo with the human cystic fibrosis transmembrane conductance regulator (CFTR) (Rosenfeld et at., Cell 68:143-155 (1992)) and the alpha 1-antitrypsin genes (Rosenfeld et al., Science 252:431-434 (1991)). Web site: http://www.delphion.com/details?pn=US06613563__

Patent Applications on Gene Therapy As of December 2000, U.S. patent applications are open to public viewing.10 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 gene therapy: 10

This has been a common practice outside the United States prior to December 2000.

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Alteration of cell membrane for new functions Inventor(s): Shirwan, Haval; (Louisville, KY) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20030219419 Date filed: May 16, 2003 Abstract: Methods and compositions are provided for the persistent modification of cell membranes with exogenous proteins so as to alter the function of the cell to achieve effects similar to those of gene therapy, without the introduction of exogenous DNA. DNA sequences, the proteins and polypeptides embodying these sequences are disclosed for modulating the immune system. The modulations include downregulation, up-regulation and apoptosis. Excerpt(s): This invention relates to the persistent modification of cell membranes so as to alter the function of the cells. The compositions and methods of this invention achieve effects similar to those of gene therapy without the introduction of exogenous DNA. A useful alteration of cell function is the induction of apoptosis. It has long been the goal of experimental biology and medicine to induce cells to behave in predictable ways and to alter the behavior of cells in ways that are beneficial to a subject. For example, if undesired cells could be induced to alter their behavior to undergo apoptosis while normal cells retain normal function, subjects with a disease caused by proliferation of undesired cells would obtain relief from the disease. Similarly, if tissue-rejecting cells can be eliminated or their behavior changed, transplantation with tissues foreign to the subject can be successful. Gene therapy has been proposed for selected diseases in order to correct or modify pathological or physiological processes. In gene therapy as it is generally termed, specific DNA is introduced into a tissue and organ, where it is produces various proteins that will correct or ameliorate the condition. It is an unpredictable therapy, depending on potentially dangerous expression vectors and the uncertain efficiency of delivery, which is often low. Moreover, gene therapy is considered to have dangerous side effects, such as sustained expression in desired cells or tissues past the desired duration of therapy, or the introduction of genetic modifications in undesired tissues or cells. Because of such adverse effects, as discovered in human clinical trials, much caution is advised before gene therapy is put in practice. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Complementary DNAs encoding proteins with signal peptides Inventor(s): Bougueleret, Lydie; (Petit Laney, FR), Jobert, Severin; (Paris, FR), Milne Edwards, Jean-Baptiste Dumas; (Paris, FR) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20030203377 Date filed: December 9, 2002 Abstract: The sequences of cDNAs encoding secreted proteins are disclosed. The cDNAs can be used to express secreted proteins or fragments thereof or to obtain antibodies capable of specifically binding to the secreted proteins. The cDNAs may also be used in

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diagnostic, forensic, gene therapy, and chromosome mapping procedures. The cDNAs may also be used to design expression vectors and secretion vectors. Excerpt(s): The disclosures of all references cited throughout this application are incorporated herein in their entireties. The estimated 50,000-100,000 genes scattered along the human chromosomes offer tremendous promise for the understanding, diagnosis, and treatment of human diseases. In addition, probes capable of specifically hybridizing to loci distributed throughout the human genome find applications in the construction of high resolution chromosome maps and in the identification of individuals. In the past, the characterization of even a single human gene was a painstaking process, requiring years of effort. Recent developments in the areas of cloning vectors, DNA sequencing, and computer technology have merged to greatly accelerate the rate at which human genes can be isolated, sequenced, mapped, and characterized. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Complementing cell lines Inventor(s): Havenga, Menzo Jans Emco; (Alphen a/d Rijn, NL), Mehtali, Majid; (Plobsheim, FR), Vogels, Ronald; (Linschoten, NL) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20030185801 Date filed: November 15, 2001 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 (e.g., primary human retinoblasts, primary human embryonic kidney cells and primary human amniocytes) which are transformed by adenovirus E1 sequences either operatively linked on one DNA molecule or located on two separate DNA molecules, the sequences being operatively linked to regulatory sequences enabling transcription and translation of encoded proteins. Also disclosed is a cell line derived from PER.C6 (ECACC deposit number 96022940), which cell expresses functional Ad35 E1B sequences. The Ad35-E1B sequences are driven by the E1B promoter or a heterologous promoter and terminated by a heterologous poly-adenylation signal. The new cell lines are useful for producing recombinant adenoviruses designed for gene therapy and vaccination. The cell lines can also be used for producing human recombinant therapeutic proteins such as human growth factors and human antibodies. In addition, the cell lines are useful for producing human viruses other than adenovirus such as influenza virus, herpes simplex virus, rotavirus, measles virus. Excerpt(s): This application is a continuation-in-part of application Ser. No. 09/713,678, filed Nov. 15, 2000, pending. The invention relates to the field of biotechnology generally and, more specifically, to adenoviral-based complementing cell lines. Typically, vector and packaging cells have to be adapted to one another so that they have all the necessary elements, but they do not have overlapping elements that 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, nonhuman adenoviruses, other viruses like, but not limited to, SV40, hepatitis B virus (HBV), Rous Sarcoma Virus (RSV), cytomegalovirus (CMV), etc. or from higher

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eukaryotes such as mammals. In general, these sequences include a promoter, enhancer and poly-adenylation sequences. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition and imaging methods for pharmacokinetic and pharmacodynamic evaluation of therapeutic delivery system Inventor(s): Hallahan, Dennis E.; (Nashville, TN) Correspondence: Jenkins & Wilson, PA; 3100 Tower Blvd; Suite 1400; Durham; NC; 27707; US Patent Application Number: 20030216337 Date filed: January 15, 2003 Abstract: A halogen-labeled gene therapy construct that includes halogen-labeled nucleic acids, methods for preparing a halogenated gene therapy construct, and methods for in vivo imaging of the same. Also provided are methods for non-invasive drug detection in a subject using a labeled antibody that recognizes a heterologous antigen conjugated to, encoded by, or otherwise associated with the drug. Excerpt(s): This application is based on and claims priority to U.S. Provisional Application Serial No. 60/348,945, filed Jan. 15, 2002, herein incorporated by reference in its entirety. The present invention generally relates to in vivo imaging of drug biodistribution. More particularly, the present invention relates to methods for drug labeling such that drug can be detected non-invasively following administration to a subject. A limitation of current therapeutic methods is that drug biodistribution following administration to a subject can be non-specific or non-homogenous. For example, local injection of a gene therapy construct can result in a non-homogeneous distribution of an encoded gene product along the injection track. Systemic administration of a gene therapy construct can improve the distribution of an encoded gene product, although the construct dose achieved at a target tissue is unpredictable. In addition, systemic toxicity can result from vector delivery to non-target tissues. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions and methods relating to ovarian specific genes and proteins Inventor(s): Cafferkey, Robert; (South San Francisco, CA), Hu, Ping; (San Ramon, CA), Karra, Kalpana; (San Jose, CA), Liu, Chenghua; (San Jose, CA), Macina, Roberto A.; (San Jose, CA), Recipon, Herve E.; (San Francisco, CA), Salceda, Susana; (San Jose, CA), Sun, Yongming; (Redwood City, CA) Correspondence: Licatla & Tyrrell P.C.; 66 E. Main Street; Marlton; NJ; 08053; US Patent Application Number: 20030180726 Date filed: February 13, 2002 Abstract: The present invention relates to newly identified nucleic acids and polypeptides present in normal and neoplastic ovary cells, including fragments, variants and derivatives of the nucleic acids and polypeptides. The present invention also relates to antibodies to the polypeptides of the invention, as well as agonists and antagonists of the polypeptides of the invention. The invention also relates to compositions comprising the nucleic acids, polypeptides, antibodies, variants, derivatives, agonists and

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antagonists of the invention and methods for the use of these compositions. These uses include identifying, diagnosing, monitoring, staging, imaging and treating ovarian cancer and non-cancerous disease states in ovary tissue, identifying ovary tissue, monitoring and identifying and/or designing agonists and antagonists of polypeptides of the invention. The uses also include gene therapy, production of transgenic animals and cells, and production of engineered ovary tissue for treatment and research. Excerpt(s): This application claims the benefit of priority from U.S. Provisional Application Serial No. 60/268,290 filed Feb. 13, 2001, and U.S. Provisional Application Serial No. 60/268,834 filed Feb. 15, 2001, which are herein incorporated by reference in their entirety. The present invention relates to newly identified nucleic acid molecules and polypeptides present in normal and neoplastic ovary cells, including fragments, variants and derivatives of the nucleic acids and polypeptides. The present invention also relates to antibodies to the polypeptides of the invention, as well as agonists and antagonists of the polypeptides of the invention. The invention also relates to compositions comprising the nucleic acids, polypeptides, antibodies, variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. These uses include identifying, diagnosing, monitoring, staging, imaging and treating ovarian cancer and non-cancerous disease states in ovary tissue, identifying ovary tissue and monitoring and identifying and/or designing agonists and antagonists of polypeptides of the invention. The uses also include gene therapy, production of transgenic animals and cells, and production of engineered ovary tissue for treatment and research. Cancer of the ovaries is the fourth-most cause of cancer death in women in the United States, with more than 23,000 new cases and roughly 14,000 deaths predicted for the year 2001. Shridhar, V. et al., Cancer Res. 61(15): 5895-904 (2001); Memarzadeh, S. & Berek, J. S., J. Reprod. Med. 46(7): 621-29 (2001). The incidence of ovarian cancer is of serious concern worldwide, with an estimated 191,000 new cases predicted anually. Runnebaum, I. B. & Stickeler, E., J. Cancer Res. Clin. Oncol. 127(2): 73-79 (2001). Because women with ovarian cancer are typically asypmtomatic until the disease has metastasized, and because effective screening for ovarian cancer is not available, roughly 70% of women present with an advanced stage of the cancer, with a five-year survival rate of.about.25-30% at that stage. Memarzadeh, S. & Berek, J. S., supra; Nunns, D. et al., Obstet. Gynecol. Surv. 55(12): 746-51. Conversely, women diagnosed with early stage ovarian cancer enjoy considerably higher survival rates. Werness, B. A. & Eltabbakh, G. H., Int'l. J. Gynecol. Pathol. 20(1): 48-63 (2001). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Diagnostic and therapeutic compositions and methods related to GPCR 38, a G protein-coupled receptor (GPCR) Inventor(s): Brown, Joseph P.; (Seattle, WA), Burmer, Glenna C.; (Seattle, WA), Kulander, Bruce G.; (Seattle, WA), Roush, Christine L.; (Seattle, WA) Correspondence: Joshua King; Graybeal Jackson Haley Llp; Suite 350; 155-108th Avenue N.E.; Bellevue; WA; 98004-5901; US Patent Application Number: 20030186336 Date filed: July 26, 2002 Abstract: The present invention comprises systems, methods, compositions and the like, such as diagnostics, medicaments and therapeutics, relating to GPR 38 and Alzheimer's disease and Parkinson's disease, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, Hodgkin's disease, glioblastoma and carcinomas including

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breast, colon, lung (small cell and adenocarcinoma) pancreatic (small cell and adenocarcinoma), ovarian, and prostate. Such diagnostics and therapeutics include peptide, protein, antibody and nucleic acid based compositions, including agonists, antagonists, probes, antisense and gene therapy compositions. Excerpt(s): The present application claims priority from PCT patent application PCT/US01/45219, filed Nov. 29, 2001, which application claims priority from U.S. provisional patent application Ser. No. 60/250,251, filed Nov. 29, 2000, and U.S. provisional patent application Ser. No. 60/250,452, filed Nov. 30, 2000, both of which are presently pending. G protein-coupled receptors (GPCRs) are a large group of proteins that transmit signals across cell membranes. In general terms, GPCRs function somewhat like doorbells. When a molecule outside the cell contacts the GPCR (pushes the doorbell), the GPCR changes its shape and activates "G proteins" inside the cell (similar to the doorbell causing the bell to ring inside the house, which in turn causes people inside to answer the door). In addition, GPCRs are like high-security doorbells because each GPCR responds to only one specific kind of signaling molecule (called its "endogenous ligand"). Part of the GPCR is located outside the cell (the "extracellular domain"), part spans the cell's membrane (the "transmembrane domain"), and part is located inside the cell (the "intracellular domain"). GPCRs are embedded in the outer membrane of a cell and recognize and bind certain types of signaling molecules that are present in the spaces surrounding the cell. GPCRs are used by cells to keep an eye on the cells' own activity and environment. In organisms having many cells, the cells use GPCRs to talk to each other. GPCRs are of great interest to the pharmaceutical industry and other industries. For example, many drugs act by binding to specific GPCRs and initiating their intracellular actions, and diagnostics and therapeutics based on GPCRs are becoming increasingly important. Databases, such as LifeSpan BioScience's GPCR Database, help researchers to compare and contrast different GPCRs so that various GPCR functions can be investigated and established. With greater knowledge about the distribution of GPCRs in human tissues and their involvement in disease processes, researchers can design more diagnostics and more effective drugs with fewer side effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Emulsion and micellar formulations for the delivery of biologically active substances to cells Inventor(s): Huang, Leaf; (Wexford, PA), Liu, Dexi; (Pittsburgh, PA), Liu, Feng; (Pittsburgh, PA), Yang, Jing-Ping; (Pittsburgh, PA) Correspondence: Morrison & Foerster Llp; 755 Page Mill RD; Palo Alto; CA; 94304-1018; US Patent Application Number: 20030211143 Date filed: May 12, 2003 Abstract: New emulsion and micelle formulations are described as are complexes of these formulations with biologically active substances. The novel formulations are different from cationic lipid vectors such as cationic liposomes in that the complexes formed between biologically active substances and the emulsion and micellar formulations of this invention are physically stable and their transfection activity is resistant to the presence of serum. These novel formulations are disclosed to be useful in areas such as gene therapy or vaccine delivery.

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Excerpt(s): The present invention relates to the use of lipid dispersions to deliver biologically active substances to cells. In particular, the present invention relates to emulsion and micellar formulations and to the ability of these formulations to form stable complexes with biologically active substances and thereby facilitate the delivery of these substances to cells. Cationic liposomes are of interest as a non-viral vehicle for the delivery of biologically active substances such as drugs, hormones, enzymes, nucleic acids and antigens, including viruses, to cells both in vitro and in vivo. Indeed, cationic liposomes have been demonstrated to deliver genes in vivo (Nabel, E. G., et al. (1990) Science, 249: 1285-1288), (Brigham, K. L., et al. (1989) Am. J. Respir. Cell Mol. Biol., 195200, Stribling, R., et al. (1992) Proc. Natl. Acad. Sci. U.S.A., 89: 11277-11281), (Plautz, G. E., et al. (1993) Proc. Natl. Acad. Sci. U.S.A., 90: 4645-4649, Stewart, M. J., et al. (1992) Hum. Gene Ther., 3: 267-275). However, the inhibition by serum components of the transfer of nucleic acids by cationic liposomes limits the application of liposomes as a vector for nucleic acids in vivo to regional administrations which avoid exposure to serum. In addition, stability is a major problem limiting the use of liposomes, both in terms of shelf life and after administration in vivo. Thus, it is desirable to explore the use of other types of lipid dispersions as delivery systems utility for biologically active substances. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Eukaryotic genes involved in adult lifespan regulation Inventor(s): Apfeld, Javier; (San Francisco, CA), Dillin, Andrew; (Oakland, CA), Garigan, Delia; (San Francisco, CA), Hsu, Ao-Lin A.; (Albany, CA), Kenyon, Cynthia; (San Francisco, CA), Lehrer-Graiwer, Josh; (San Francisco, CA), Murphy, Coleen; (San Francisco, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030190312 Date filed: June 24, 2002 Abstract: The present invention relates to regulation of adult lifespan in eukaryotes. More particularly, the present invention is directed to methods of assaying for genes, gene products, and genes in pathways controlled by such genes and gene products, using RNAi and microarray analysis, that regulate lifespan (e.g., extend or truncate adult lifespan) in eukaryotes such as invertebrates (e.g., C. elegans), plants, and mammals, e.g., humans. For example, the present invention is directed to genes encoding components of the mitochondrial respiratory chain and genes encoding glycolysis enzymes, which are involved in lifespan regulation, and genes and gene products in pathways controlled by such genes. Other genes and gene products identified as regulating aging and aging pathways include a gene encoding a GTPase; a transcriptional activator; novel genes: llw-1, llw-2, llw-3, and llw-4; genes encoding cytochrome P450 proteins (involved in steroid biosynthesis); a melatonin synthesis gene; genes encoding insulin and insulin-like peptides; genes encoding heat shock factors; genes encoding catalases; stress-response genes; and metabolic genes. The invention further relates to methods for identifying and using agents, including small molecule chemical compositions, antibodies, antisense nucleic acids, and ribozymes, that regulate, e.g., enhance, adult lifespan via modulation of aging associated proteins; as well as to the use of expression profiles, markers, and compositions in diagnosis and therapy

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related to lifespan extension, life expectancy, and aging. The present invention also relates to gene therapy involving lifespan associated genes. Excerpt(s): The present application is related to U.S. Serial No. 60/300,577, filed Jun. 22, 2001, U.S. Serial No. 60/301,052, filed Jun. 25, 2001, and U.S. Serial No. 60/373,975, filed Apr. 18, 2002, each herein incorporated by reference in their entirety. The present invention relates to regulation of lifespan in eukaryotes. More particularly, one aspect of the present invention is directed to methods of assaying for genes, gene products, and genes in pathways controlled by such genes and gene products, using RNAi and microarray analysis, that regulate lifespan (e.g., extend or truncate adult lifespan) in eukaryotes such as invertebrates (e.g., C. elegans), plants, and mammals, e.g., humans. For example, one aspect of the present invention is directed to genes, in particular human genes, encoding components of the mitochondrial respiratory chain and genes encoding glycolysis enzymes, which are involved in lifespan regulation, and genes and gene products in pathways controlled by such genes. Other genes and gene products identified as regulating aging and aging pathways include a gene encoding a GTPase; a transcriptional activator; novel genes: llw-1, llw-2, llw-3, and llw-4; genes encoding cytochrome P450 proteins (involved in steroid biosynthesis); a melatonin synthesis gene; genes encoding insulin and insulin-like peptides; genes encoding heat shock factors; genes encoding catalases; stress-response genes; and metabolic genes. The invention further relates to methods for identifying and using agents, including small molecule chemical compositions, antibodies, antisense nucleic acids, and ribozymes, that regulate, e.g., enhance, adult lifespan via modulation of aging associated proteins; as well as to the use of expression profiles, markers, and compositions in diagnosis and therapy related to lifespan extension, life expectancy, and aging. The present invention also relates to gene therapy involving lifespan associated genes. Previously, classic genetic screens have been used to identify genes involved in the C. elegans development. In one example, inhibition of mitochondrial respiratory chain genes such as NADH ubiquinone oxidoreductase and ATP synthase in C. elegans larva was found to impair larval development and cause arrest in the third larval stage (see, e.g., Tsang et al., JBC 276:33240-33246 (2001)). In other examples, classical genetic screens have been used to identify C. elegans genes involved in a variety of processes, including dauer formation, and embryonic development. Some of these genes, for example the daf-2 and daf-16 genes, have been implicated in the regulation of lifespan see, e.g., Kenyon et al., Nature 366:461-464 (1993); Morris et al., Nature 382:536-539 (1996); Kimura et al., Science 277:942-946 (1997); Paradis et al., Genes Dev. 12:2488-2498 (1998); Paradis et al., Genes Dev. 13:1438-1452 (1999); Off & Ruvkun, Mol. Cell 2:886-893 (1998); Guarente & Kenyon, Nature 408:255-262 (2000); Ogg et al., Nature 389:994-999 (1997); and Lin et al., Science 278:1319-1322 (1997)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Fusion protein for use as vector Inventor(s): Hwu, Paul L.; (Taipei, TW) Correspondence: A. Blair Hughes; Mcdonnell Boehnen Hulbert & Berghoff; 32nd Floor; 300 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030211590 Date filed: May 13, 2002 Abstract: The present invention provides a fusion protein comprising a fusion protein for delivery of a desired molecule into cells or nuclei, comprising i) a cold shock domain

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and the homologue or the functional equivalent derivatives thereof and ii) a membrane translocation sequence or the functional equivalent peptides and/or derivatives thereof. The fusion protein is used as a vector for nucleic acids delivery in vitro and particularly in vivo for gene therapy and the production of transgenic animal. Excerpt(s): The present invention relates to a fusion protein referred as a novel vector for delivering molecules into cells. The transfer of genetic material into cells in mammals is of increasing therapeutic and commercial importance. For instance, gene therapy procedures are used to correct acquired and inherited genetic defects, cancer, and viral infection. The ability to express artificial genes in humans facilitates the prevention and/or cure of many major human diseases, including many diseases that are not amenable to treatment by other therapies. However, biological membranes are natural barriers central to compartmentalization in living systems. Therefore, the polypeptides and oligonucleotides are generally considered to be of limited therapeutic value. Many studies have been conducted to overcome the problem of delivering such polypeptides and oligonucleotides. Most of the initial work focused on the use of retroviral vectors to transform these cells. However, numerous difficulties with retroviruses have been reported. For example, it is hard to infect certain cell types. Retroviruses typically enter cells via receptors and if such receptors are not present in the cell, or are not present in large numbers, the infection is not possible or efficient. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Gene sequences associated with neural plasticity and methods related thereto Inventor(s): Cynader, Max; (West Vancouver, CA), Prasad, Shiv; (Vancouver, CA) Correspondence: Davis Wright Tremaine, Llp; 2600 Century Square; 1501 Fourth Avenue; Seattle; WA; 98101-1688; US Patent Application Number: 20030216339 Date filed: January 31, 2003 Abstract: The disclosed invention generally relates to newly identified polynucleotide sequences capable of conferring neural plasticity to neurons. Additionally, this application encompasses the complete gene sequences, the polypeptides associated therewith, and methods of using. These methods include the use of the sequences for gene therapy, including the treatment or cure of genetic diseases, for the treatment of degenerative disorders, for the treatment of neuron damage, and for the treatment of learning disorders. Additionally, these sequences are useful to enhance memory and learning capacity. Excerpt(s): The present invention relates to newly-identified polynucleotide sequences capable of conferring neural plasticity, and to the complete gene sequences and polypeptides associated therewith and to uses thereof. Identification and sequencing of genes is a major goal of modern scientific research. By identifying genes and determining their sequences, scientists have, for example, been able to make large quantities of valuable human "gene products." These include human insulin, interferon, Factor VIII, tumor necrosis factor, human growth hormone, tissue plasminogen activator, and numerous other compounds. Additionally, knowledge of gene sequences of the central and peripheral nervous systems can provide the key to treatment or cure of genetic diseases, degenerative disorders, neural damage or regrowth and learning disorders. Genes are the basic units of inheritance. Each gene is a string of connected bases called nucleotides. Most genes are formed of deoxyribonucleic acid, DNA. (Some

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viruses contain genes of ribonucleic acid, RNA.) The genetic information resides in the particular sequence in which the bases are arranged. A sequence of nucleotides is often called a polynucleotide or an oligonucleotide. A triplet of nucleotides, called a "codon," in DNA codes for each amino acid or signals the beginning or end of the message, called an "anticodon." The term codon is also used for the corresponding (and complementary) sequences of three nucleotides in the mRNA into which the original DNA sequence is transcribed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Gene therapy approaches to supply apolipoprotein A-I agonists and their use to treat dyslipidemic disorders Inventor(s): Buttner, Klaus; (Epfenbach, DE), Cornut, Isabelle; (Edingen-Neckarhausen, DE), Dasseux, Jean-Louis; (Mannheim, DE), Dufourcq, Jean; (Pessac, FR), Metz, Gunther; (Edingen-Neckarhausen, DE), Sekul, Renate; (Ladenburg, DE) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20030208059 Date filed: October 29, 2002 Abstract: The invention relates to genetic approaches to supply nucleotide sequences encoding modified forms of the native forms of apolipoprotein A-I (ApoA-I): mature ApoA-I, preproApoA-I and proApoA-I; including native ApoA-I modified to contain ApoA-I agonists, peptides which mimic the activity of ApoA-I; ApoA-I superagonists, peptides which exceed the activity of native ApoA-I; and modified native ApoA-I having one or more amphipathic helices replaced by the nucleotide sequences of one or more ApoA-I agonists; for the treatment of disorders associated with dyslipoproteinemia, including cardiovascular disease, atherosclerosis, restenosis, hyperlipidemia, and other disorders such as septic shock. Excerpt(s): The invention relates to gene therapy approaches to supply nucleotide sequences encoding modified forms of the native forms of apolipoprotein A-I (ApoA-I) i.e., mature ApoA-I, preproApoA-I and proApoA-I; ApoA-I peptides; ApoA-I agonists and superagonists, peptides which mimic or exceed the activity of native ApoA-I; and the native ApoA-I gene for the treatment of disorders associated with dyslipoproteinemia, including cardiovascular disease, atherosclerosis, restenosis, hyperlipidemia, and other disorders such as septic shock. Circulating cholesterol is carried by plasma lipoproteins--particles of complex lipid and protein composition that transport lipids in the blood. Low density lipoproteins (LDL), and high density lipoproteins (HDL) are the major cholesterol carriers. LDL are believed to be responsible for the delivery of cholesterol from the liver (where it is synthesized or obtained from dietary sources) to extrahepatic tissues in the body. The term "reverse cholesterol transport" describes the transport of cholesterol from extrahepatic tissues to the liver where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol. The evidence linking elevated serum cholesterol to coronary heart disease is overwhelming. For example, atherosclerosis is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the concept that lipids deposited in atherosclerotic lesions are derived primarily from plasma LDL; thus, LDLs have popularly become known as the "bad" cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart

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disease--indeed, high serum levels of HDL are regarded as a negative risk factor. It is hypothesized that high levels of plasma HDL are not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaques (e.g., see Badimon et al., 1992, Circulation 86 (Suppl. III):86-94). Thus, HDL have popularly become known as the "good" cholesterol. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Gene therapy for effector cell regulation Inventor(s): Dow, Steve W.; (Denver, CO), Elmslie, Robyn E.; (Denver, CO), Potter, Terence A.; (Denver, CO) Correspondence: Sheridan Ross PC; 1560 Broadway; Suite 1200; Denver; CO; 80202 Patent Application Number: 20030202962 Date filed: January 29, 2003 Abstract: The present invention provides a nucleic acid-based therapeutic composition to treat an animal with disease by controlling the activity of effector cells, including T cells, macrophages, monocytes and/or natural killer cells, in the animal. Therapeutic compositions of the present invention include superantigen-encoding nucleic acid molecules, either in the presence or absence of a cytokine-encoding nucleic acid molecule and/or chemokine-encoding nucleic acid molecules, depending upon the disease being treated. The present invention also relates to an adjuvant for use with nucleic acid-based vaccines. Adjuvant compositions of the present invention include an immunogen combined with superantigen-encoding nucleic acid molecules, either in the presence or absence of a cytokine-encoding nucleic acid molecule and/or chemokineencoding nucleic acid molecules. Excerpt(s): The present application is a continuation-in-part of U.S. patent application Ser. No. 08/446,918 for "Gene Therapy for T Cell Regulation", filed May 18, 1995, incorporated herein by this reference in its entirety. The present application is also a continuation-in-part of U.S. patent application Ser. No. 08/484,169 for "Mycobacterium Peptides, Nucleic Acid Molecules, and Uses Thereof", filed Jun. 7, 1995, incorporated herein by this reference in its entirety. The present invention relates to a product and process for regulating T cell activity by providing a superantigen gene, in the presence or absence of a cytokine and/or chemokine gene. The present invention also relates to a product and process for regulating T cell activity by providing a peptide and a superantigen gene, in the presence or absence of a cytokine and/or chemokine gene. In particular, the present invention relates to a product and process for controlling tumor development, immune responses to infectious diseases and diseases caused by immunological disorders. Two major causes of disease include infectious agents and malfunctions of normal biological functions of an animal. Examples of infectious agents include viruses, bacteria, parasites, yeast and other fungi. Examples of abnormal biological function include uncontrolled cell growth, abnormal immune responses and abnormal inflammatory responses. Traditional reagents used attempt to protect an animal from disease include reagents that destroy infectious agents or cells involved in deregulated biological functions. Such reagents, however, can result in unwanted side effects. For example, anti-viral drugs that disrupt the replication of viral DNA also often disrupt DNA replication in normal cells in the treated patient. Other treatments with chemotherapeutic reagents to destroy cancer cells typically leads to side effects, such as bleeding, vomiting, diarrhea, ulcers, hair loss and increased susceptibility to secondary cancers and infections.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Gene therapy for obesity Inventor(s): Caskey, C. Thomas; (Houston, TX), Gu, Ming Cheng; (Lansdale, PA), Kochanek, Stephan; (Cologne, DE), Morsy, Manal A.; (Blue Bell, PA), Zhoa, Jing; (Lansdale, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030215423 Date filed: April 21, 2003 Abstract: Gene therapy can treat obesity in mammals. An obesity regulating gene is delivered to a mammal. Preferably, the gene encodes leptin or a leptin receptor. The protein which is delivered and expressed in vivo is more effective than protein which is injected into the animal. Excerpt(s): This invention relates to methods of gene therapy by vector-assisted delivery of a peptide hormone, and to transgenic non-human mammals so produced. This invention also related to gene therapy for obesity. This invention also relates to vectors useful in this gene therapy. There are numerous potentially therapeutic hormones which are peptides or proteins, including leptin, insulin, calcitonin, erythropoietin, (EPO), growth hormone, interferons, interleukin-2, hemophilia factors, vascular endothelial growth factors such as VEGF, granulocyte-macrophage colony stimulating factor, alpha 1 anti-trypsin, and others. Many have been purified, extensively studied, and even produced recombinantly and administered in a clinical setting. One problem with peptide and/or proteins as therapeutic agents, however, is that they cannot be made into conventional oral dosage forms, as contact with gastric juices will destroy the peptide. Instead, they have to be delivered by injection, intravenously, intranasally or other non-oral routes which are often not convenient for chronic usage, and may add to the expense of the drug therapy. In addition, protein injection is frequently of short duration of action and requires repetitive dosing. Mice which are homozygous for the ob gene (ob/ob) are obese, perhaps due to leptin deficiency. When ob/ob mice are given daily injections of recombinant protein, their food intake was markedly inhibited and they experienced a reduction in body weight and fat. In lean (i.e. wild-type) mice, daily injections of leptin lead to modest decreases of food intake and body weight. The results for body fat have been confirmatory to the effect of leptin on fat metabolism. (Pelleymounter et al., 1995, Science 269:540-543; Halaas et al., 1995 Science 269: 543-546; and Campfield et al., 1995 Science 269:546-549). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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GENE THERAPY FOR PROLIFERATIVE VITREORETINOPATHY Inventor(s): ANDERSON, W. FRENCH; (SAN MARINO, CA), HINTON, DAVID; (VENICE, CA), RYAN, STEPHEN J.; (SAN MARINO, CA) Correspondence: Scott C. Harris; Fish & Richardson P.C.; 4350 LA Jolla Village Drive, Suite 500; San Diego; CA; 92122; US Patent Application Number: 20030191072 Date filed: October 16, 1998

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Abstract: A method of treating ocular disorders (such as, for example, proliferative vitreoretinopathy or PVR) associated with replicating ocular cells by transfecting replicating ocular cells in vivo with a polynucleotide encoding an agent which is capable of providing for the inhibition, prevention, or destruction of the growth of the replicating ocular cells upon expression of the agent. The agent may be a viral thymidine kinase, and the polynucleotide encoding the agent may be contained in a retroviral vector. Once the replicating ocular cells are transduced with the retroviral vector, the patient is given a chemotherapeutic or interaction agent, such as ganciclovir, which kills the transfected replicating ocular cells. Excerpt(s): This invention relates to gene therapy for treating ocular disorders involving intraocular cellular proliferation, such as, for example, proliferative vitreoretinopathy or PVR. More particularly, this invention relates to the treatment of ocular disorders associated with intraocular cellular proliferation, such as proliferative vitreoretinopathy, by transducing replicating ocular cells with a polynucleotide encoding an agent which is capable of providing for the inhibition, prevention, or destruction of the growth of the replicating ocular cells. The agent may be a negative selective marker, such as, for example, a viral thymidine kinase. Such transduction then may be followed by the administration of an interaction agent, such as, for example, ganciclovir or acyclovir, thereby killing the replicating ocular cells. One of the most common causes of retinal detachment is proliferative vitreoretinopathy, an intraocular, non-malignant cellular proliferation. This process results ultimately in a separation of the retina from the retinal pigment epithelium, or RPE, because of tractional forces applied directly to the inner and outer retinal surfaces. This is the major cause for failure of retinal re-attachment surgery. (Ophthalmology, Vol. 90, pgs. 121-123 (1983)). Proliferative vitreoretinopathy is characterized by the formation of contractile cellular membranes on both sides of the retina. (Clarkson, et al., Am. J. Ophthalmol., Vol. 84, pgs. 1-17 (1977); Constable, Trans. Ophthalmol. Soc. U.K., Vol. 95, pgs. 382-386 (1975); Constable, et al., Retina Congress, Pruett, et al., eds., pgs. 245-257, Appleton-Century-Crofts, New York (1972); Daicker, et al., Graefe's Arch. Klin. Exp. Ophthalmol., Vol. 210, pgs. 109-120 (1979); Fastenberg, et al., Am. J. Ophthalmol., Vol. 93, pgs. 565-572 (1982); Glaser, et al., Ophthalmology, Vol 94, pgs. 327-332 (1987); Green, et al., Trans. Ophthalmol. Soc. U.K., Vol. 99, pgs. 63-77 (1979); Kampik, et al., Arch. Ophthalmol., Vol. 99, pgs. 1445-1454 (1981); Machemer, et al., Am. J. Ophthalmol., Vol. 85, pgs. 181-191 (1978)). While the pathobiology of proliferative vitreoretinopathy is not clear, it appears that RPE cells are key to the development of these membranes. (Green, et al., 1979; Kampik, et al., 1981; Machemer, et al., 1978; Laqua, et al., Am. J. Ophthalmol., Vol. 80, pgs. 602-618 (1975); Hiscott, et al., Br. J. Ophthalmol., Vol. 68, pgs. 708-715 (1984)). A large body of evidence supports the concept that previously quiescent RPE cells, when displaced into the vitreous cavity and exposed to the appropriate combination of cytokines, will divide and differentiate. This differentiation results in cells having myofibroblastic characteristics including adhesiveness and contractility. As these membranes form tight adhesions with the retinal surfaces, tractional forces are generated and detachment ensues. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Genetic marker for spondyloepimetaphyseal dysplasia Inventor(s): Cohn, Daniel H.; (Santa Monica, CA), Faiyaz-Ul-Haque, Muhammad; (Islamabad, PK), King, Lily; (Los Angeles, CA), Krakow, Deborah; (Los Angeles, CA) Correspondence: Sidley Austin Brown & Wood; 555 West Fifth Street; Los Angeles; CA; 90013-1010; US Patent Application Number: 20030195162 Date filed: July 2, 2001 Abstract: Disclosed are isolated polynucleotides containing nucleic acid segments encoding human or murine ATP sulfurylase/APS kinase, also known as PAPS synthetase (PAPSS), particularly PAPSS2 and Papss2 proteins. Also disclosed are nucleic acid constructs, including vectors, probes, primers, and primer pairs containing novel PAPSS2 and Papss2 gene sequences. A genetically modified vertebrate cell containing a nucleic acid construct of the present invention and a non-human vertebrate comprising the cell are also disclosed. Based on the present PAPSS2-specific polynucleotides and nucleic acid constructs, are genetic testing kits and methods for diagnosing spondyloepimetaphyseal dysplasia (SEMD) in a human subject, of identifying a human carrier of an heritable allele associated with SEMD, and of gene therapy or protein therapy for treating a human subject having an osteoarthritic disorder, which is caused or aggravated by deficient enzymatic sulfation activity. Also disclosed is a protein therapy method for treating a human subject having an osteoarthritic disorder caused or aggravated by deficient enzymatic sulfation activity that employs an inventive PAPSS2 fusion protein. Also disclosed are an isolated antibody or antibody fragment that selectively binds a PAPSS2 or Papss2 protein. Excerpt(s): Throughout the application various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains. This invention relates to the medical arts. In particular, it relates to a genetic marker that is useful for diagnosing or treating spondyloepimetaphyseal dysplasia and for identifying genetic carriers of heritable alleles associated with spondyloepimetaphyseal dysplasia. Osteochondrodysplasias are a genetically heterogeneous group of disorders related to cartilage producing cells. Abnormalities in cartilage formation can cause defects in bone deposition, skeletal development, linear growth, and the continued maintenance of cartilage and bone. (Reviewed in Mundlos, S. and Olsen, B. R., Heritable diseases of the skeleton. Part II: Molecular insights into skeletal development-matrix components and their homeostasis, FASEB J. 11 (4):227-33 [1997]). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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High efficiency regulatable gene expression system Inventor(s): Lotze, Michael T; (Pittsburgh, PA), Siamak, Agha-Mohammadi; (Pittsburgh, PA) Correspondence: Kirkpatrick & Lockhart Llp; 535 Smithfield Street; Pittsburgh; PA; 15222; US Patent Application Number: 20030221203 Date filed: April 4, 2003

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Abstract: Highly efficient regulated promoters (RPs) and transactivators are provided. The RPs contain 2-8 transactivator binding domains positioned in an optimized manner with respect to each other. In a tetracycline-regulatable system, the RP displays 5- to 10fold enhanced regulation efficiency by maintaining high maximal expression while offering 5- to 10-fold reduced basal leakiness. In transient studies, these novel promoters display over 900-fold gene regulation at 1:1 ratio of transactivator to reporter plasmid. Furthermore, these promoters preserve their regulator efficienty in the context of a single positive feedback regulatory vector that presents ease of delivery of the system for many uses, including for use in vivo and in gene therapy. Finally, humanized transactivators are provided, for example a tetracycline transactivator utilizing the human transactivational domain of NF-.kappa.p65 protein fused to tetracycline repressor (terR) is provided that functions as efficiently as the tetracycline-regulated transactivator (tTA) and should reduce the potential immunogenicity of the original tTA. Excerpt(s): This application claims priority to U.S. Provisional Patent Application Serial No. 60/237,633, filed Oct. 3, 2000. Provided is a high efficiency regulatable gene expression system including a promoter and a humanized transactivator. Also provided are methods for inducing expression of a nucleic acid using the regulatable gene expression system. Certain regulatable systems, such as tetracycline-regulatable systems (TRS), offer powerful tools for regulating gene expression. For effective in vivo gene regulation, these systems often suffer from inconsistent delivery and efficiency as double vectors, low efficiency as a single vector, high basal leakiness, and potential immunogenicity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Human DNA Ligase III Inventor(s): Haseltine, William A.; (Washington, DC), Wei, Ying-Fei; (Berkeley, CA), Yu, Guo-Liang; (Berkeley, CA) Correspondence: Human Genome Sciences Inc; 9410 Key West Avenue; Rockville; MD; 20850 Patent Application Number: 20030211582 Date filed: June 19, 2003 Abstract: A human DNA Ligase III polypeptide and DNA (RNA) encoding such polypeptide and a procedure for producing such polypeptide by recombinant techniques is disclosed. Also disclosed are methods for utilizing such polypeptide via gene therapy for the treatment of disorders associated with a defect in DNA Ligase III. Antagonists against such polypeptides and their use as a therapeutic to destroy unwanted cells are also disclosed. Diagnostic assays to detect mutant DNA Ligase III genes are also disclosed. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/879,228, filed Jun. 13, 2001, which is a divisional of U.S. application Ser. No. 09/054,775, filed Apr. 3, 1998, (now U.S. Pat. No. issued 6,284,504, issued Sep. 4, 2001), which is a divisional of U.S. application Ser. No. 08/464,402, filed Jun. 5, 1995 (now U.S. Pat. No. 5,858,705, issued Jan. 12, 1999), which is a continuation-in-part of International Application No. PCT/US95/03939, filed Mar. 31, 1995. Each of the above cited patents and patent applications are incorporated by reference herein. This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the

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use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. The polypeptide of the present invention has been putatively identified as Human DNA Ligase III. The invention also relates to inhibiting the action of such polypeptides. DNA strand breaks and gaps are generated transiently during replication, repair and recombination. In mammalian cell nuclei, rejoining of such strand breaks depends on several different DNA polymerases and DNA ligase enzymes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Human monoclonal antibodies to interleukin-5 and methods and compositions comprising same Inventor(s): Corvalan, Jose; (Foster City, CA), Greenfeder, Scott; (Metuchen, NJ) Correspondence: Schering-plough Corporation; Patent Department (k-6-1, 1990); 2000 Galloping Hill Road; Kenilworth; NJ; 07033-0530; US Patent Application Number: 20030194404 Date filed: March 27, 2003 Abstract: The present invention relates to antibodies and antigen-binding portions thereof that specifically bind to interleukin 5 (IL-5), which is preferably human IL-5. The invention also relates to human anti-IL-5 antibodies, including chimeric, bispecific, derivatized, single chain antibodies or portions of fusion proteins. The invention also relates to isolated heavy and light chain immunoglobulin molecules derived from antiIL-5 antibodies and nucleic acid molecules encoding such molecules. The present invention also relates to methods of making anti-IL-5 antibodies, pharmaceutical compositions comprising these antibodies and methods of using the antibodies and compositions thereof for diagnosis and treatment. The invention also provides gene therapy methods using nucleic acid molecules encoding the heavy and/or light immunoglobulin molecules that comprise the human anti-IL-5 antibodies. The invention also relates to gene therapy methods and transgenic animals comprising nucleic acid molecules of the present invention. Excerpt(s): This application is a non-provisional application that claims priority under 35 U.S.C.sctn. 119(e) of provisional application No. 60/369,044 filed Mar. 29, 2002, the contents of which are hereby incorporated by reference in their entireties. The present invention relates to human monoclonal antibodies and antigen-binding portions thereof that specifically bind to interleukin-5 (IL-5) and methods and compositions comprising such monoclonal antibodies or antigen-binding portions thereof. Eosinophils play an important role in the pathogenesis of asthma. Both asthma severity and extent of airway hyperresponsiveness correlate with numbers of blood and sputum eosinophils. Bronchial biopsy studies show that eosinophils are a prominent component of asthmatic airway inflammation and that eosinophil granule contents are present in increased concentrations in the airway lining fluid of asthmatics. These granule contents consist of a number of proteins that have direct toxic effects on airway cells through multiple mechanisms such as epithelial cell sloughing, ciliostasis, generation of oxygen radicals and injury of airway nerve fibers. Eosinophils also produce mediators that can augment mast cell histamine release. This spectrum of activities contributes directly to chronic inflammation of the bronchial airway as manifested by swelling of the airway walls and the generation of airway mucus. By facilitating the penetration of airborne agents through the damaged airway epithelium, this inflammation can directly cause increased

Patents 215

neuronal responsiveness and smooth muscle contraction (Greenfeder et al., Respiratory Research 2:71-79, 2001). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Hyaluronic acid mediated adenoviral transduction Inventor(s): Chaudhuri, Saumya-Ray; (West Bengal, IN), Holcombe, Vien; (Houston, TX), Hurwitz, Mary Y.; (Houston, TX), Hurwitz, Richard L.; (Houston, TX), Marcus, Karen T.; (Sugarland, TX) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20030186936 Date filed: February 14, 2003 Abstract: The present invention provides methods of treatment of adenoviral mediated disease, improved methods for transducing cells with adenoviral and related vectors, and improved methods of gene therapy utilizing such methods. Excerpt(s): The present application claims the benefit of U.S. Provisional Application Serial No. 60/357,485 filed Feb. 15, 2002, the entire text of which is herein incorporated by reference. The present invention is directed to the fields of molecular biology, gene therapy, and treatment of viral disease. More specifically, the present invention relates to methods of treatment of adenoviral infection and disease, to improved methods for expressing transgenes introduced into cells with adenoviral and related vectors, and improved methods of gene therapy utilizing such methods. Wild-type adenoviruses are associated with a variety of human diseases including respiratory, ocular, and gastrointestinal infections. These infections are a major cause of school absenteeism for children and of loss of work productivity for adults. In immuno-compromised individuals, infection with adenovirus currently has no effective antiviral treatment and is frequently fatal. Adenovirus infections may thus be lethal to immunocompromised patients who have received chemotherapy, bone marrow transplants, other organ transplants, or suffer from AIDS. Pediatric bone marrow transplant patients are particularly susceptible, with 10-30% developing adenovirus infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Increasing growth factor production by cells Inventor(s): Chaum, Edward; (Germantown, TN) Correspondence: Margaret J. Mclaren, PH.D., ESQ.; Akerman Senterfitt; Suite 400; 222 Lakeview Avenue; West Palm Beach; FL; 33402-3188; US Patent Application Number: 20030186918 Date filed: March 26, 2003 Abstract: Disclosed are methods and compositions for growth factor gene therapy for conditions involving degeneration or injury of cells of the retina, including age-related macular degeneration. Included in the invention are non-viral vectors for delivery of growth factor fusion proteins, cells transduced with such vectors, and methods of treatment using these vectors.

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Excerpt(s): This application claims priority from U.S. Provisional Application Serial No. 60/367,873 filed Mar. 27, 2002. The foregoing is incorporated herein by reference. This invention relates generally to the fields of molecular biology and medicine. More particularly, the invention relates to methods of gene therapy for eye diseases using growth factors. The retinal pigment epithelium (RPE) serves many critical functions in maintaining the health of the neurosensory retina. One of these functions is the production of growth factors (also known as cytokines, neurotrophic factors, and trophic hormones), that have both paracrine and autocrine activity in the RPE (Waldbillig R J, et al. J Neurochem 1991, 57:1522-1533; Takagi H, et al., Invest Ophthalmol Vis Sci 1994, 35:916-923; Schweigerer I, et al., Biochem Biophys Res Commun 1987, 143:934-940; Martin D M et al., Brain Res Mol Brain Res 1992, 12:181186). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Interferon alpha plasmids and delivery systems, and methods of making and using the same Inventor(s): Nordstrom, Jeffrey L.; (College Station, TX), Pericle, Federica; (The Woodlands, TX), Ralston, Robert Orville II; (San Diego, CA), Rolland, Alain; (The Woodlands, TX) Correspondence: Perkins Coie Llp; Post Office Box 1208; Seattle; WA; 98111-1208; US Patent Application Number: 20030181405 Date filed: April 29, 2002 Abstract: The present invention relates to gene delivery and gene therapy, and provides novel nucleic acid constructs for expression of interferon alpha in a mammal, formulations for delivery that incorporate a nucleic acid construct for expression, and methods for preparing and using such constructs and formulations. In particular, this invention relates to plasmid constructs for delivery of therapeutic interferon alpha encoding nucleic acids to cells in order to modulate tumor activity, methods of using those constructs (including combination therapy with other agents, such as cytokines, preferably IL-12), as well as methods for preparing such constructs. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/268,135, filed Mar. 12, 1999 (Lyon & Lyon Docket No. 240/223), which relates to U.S. patent application Ser. No. 08/949,160, filed Oct. 10, 1997 and International patent application No. PCT/US97/18779, filed Oct. 10, 1997, (Lyon & Lyon Docket Nos. 226/285 US and PCT, respectively), both of which are related to U.S. patent application Serial No. 60/028,676, filed Oct. 18, 1996, (Lyon & Lyon Docket No. 222/086 US), all three of which are entitled "IL-12 GENE EXPRESSION AND DELIVERY SYSTEMS AND USES" (by Nordstrom et al.). This application is also related to U.S. patent application Ser. No. 08/798,974, filed Feb. 11, 1997, (Lyon & Lyon Docket No. 224/084 US) and International patent application No. PCT/US95/17038, filed Dec. 28, 1995, (Lyon & Lyon Docket No. 210/190 PCT), both of which are related to U.S. patent application Ser. No. 08/372,213, filed Jan. 13, 1995, (Lyon & Lyon Docket No. 210/190 US), all three of which are entitled "FORMULATED NUCLEIC ACID COMPOSITIONS AND METHODS OF ADMINISTERING THE SAME FOR GENE THERAPY" (by Mumper Rolland). Each of the above-mentioned applications are incorporated herein by reference in their entirety, including any drawings. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Ligand activated transcriptional regulator proteins Inventor(s): Barbas, Carlos F. III; (Del Mar, CA), Beerli, Roger; (San Diego, CA), Kadan, Michael Joseph; (Adams Town, MD) Correspondence: Stephanie Seidman; Heller Ehrman White & Mcauliffe Llp; 7th Floor; 4350 LA Jolla Village Drive; San Diego; CA; 92122; US Patent Application Number: 20030186841 Date filed: April 23, 2003 Abstract: Fusion proteins for use as ligand-dependent transcriptional are provided. The fusion proteins include a nucleotide binding domain operatively linked to a ligandbinding domain. They also can include a transcription regulating domain. The nucleotide binding domain is a zinc-finger peptide that binds to a targeted contiguous nucleotide sequence of from 3 to about 18 nucleotides are provided. The fusion proteins are used for gene therapy. Also provided are polynucleotides encoding the fusion proteins, expression vectors, and transfected cells. Excerpt(s): This application also is a continuation-in-part of U.S. application Ser. No. 09/433,042, filed Oct. 25, 1999, to Carlos F. Barbas III, Michael Kadan, and Roger R. Beerli, entitled "Recombinant Ligand Activated Transcriptional Regulator Polypeptides." U.S. application Ser. No. 09/433,042 is a continuation-in-part of U.S. application Ser. No. 09/586,625. The subject matter of each of U.S. application Ser. Nos. 09/433,042 and 09/586,625 is herein incorporated by reference in its entirety. The field of this invention is the regulation of gene expression. In particular, ligand-activated fusion proteins (also referred to herein as chimeric regulators) and the use thereof for regulation of gene expression are provided. The fusion polypeptides contain a DNA binding domain containing one or a plurality of zinc finger polypeptide domains and a ligand binding domain (LBD) derived from an intracellular receptor. Intracellular receptors are a superfamily of related proteins that mediate the nuclear effects of a variety of hormones and effector molecules, include steroid hormones, thyroid hormones and vitamins A and D. Members of this family of intracellular receptors are prototypical ligand activated transcription factors. These receptors contain two primary functional domains: a DNA binding domain (DBD) that contains about sixty-six amino acids and a ligand-binding domain (LBD) located in the carboxyl-terminal half of the receptor that has about 300 amino acids The receptors are inactive in the absence of hormone (ligand) by virtue of association with inactivating factors, such as heat shock proteins. Upon ligand binding, the receptors dissociate from the inactivating complex and dimerize, which renders them able to bind to DNA and modulate transcription. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Lipid-comprising drug delivery complexes and methods for their production Inventor(s): Cudmore, Sally; (Dublin, IE), Harvie, Pierrot; (Seattle, WA), O'Mahony, Daniel J.; (Dublin, IE), Paul, Ralph; (Seattle, WA) Correspondence: Gladys H. Monroy; Morrison & Foerster Llp; 755 Page Mill Road; Palo Alto; CA; 94304; US Patent Application Number: 20030203865 Date filed: April 30, 2002

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Abstract: Novel stable, concentrated, biologically active and ready-to-use lipidcomprising drug delivery complexes and methods for their production are described. The complexes of the invention comprise a drug, at least one lipid species, optionally at least one polycation, and at least one targeting factor. The at least one lipid species may comprise a pegylated lipid. The complexes of the invention may provoke lower levels of inflammatory cytokines such as tumor necrosis factor-.alpha. (TNF-.alpha.). The method described herein provides for the large scale production of lipid-comprising drug delivery systems useful for gene therapy and other applications. Excerpt(s): This application claims the benefit of U.S. Provisional Application Ser. No. 60/287,786, filed Apr. 30, 2001, the disclosure of which is incorporated herein by reference in its entirety. Not applicable. The present invention relates to lipids and their use as vehicles for the transfer of nucleic acids into cells. More specifically, this invention relates to lipid-comprising drug delivery complexes which are stable, biologically active, and capable of being concentrated, and to methods for their production. The complexes of the invention may reduce levels of inflammatory cytokines such as tumor necrosis factor-.alpha. (TNF-.alpha.). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of reducing an immune response to a recombinant virus Inventor(s): Trinchieri, Giorgio; (Wynnewood, PA), Wilson, James M.; (Gladwyne, PA), Yang, Yiping; (Philadelphia, PA) Correspondence: Howson And Howson; One Spring House Corporation Center; Box 457; 321 Norristown Road; Spring House; PA; 19477; US Patent Application Number: 20030219435 Date filed: November 27, 2001 Abstract: A method of reducing immune response during gene therapy is provided which involves co-administration of the viral vector bearing a therapeutic transgene and a selected immune modulator capable of inhibiting the formation of neutralizing antibodies and/or CTL elimination of the vectors upon repeated administration. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/407,490, filed Sep. 28, 1999, which is a continuation of U.S. patent application Ser. No. 08/894,488, filed Aug. 22, 1997, which is a 35 USC.sctn.371 of PCT/US96/03035, filed Feb. 23, 1996, which claims the benefit of the priority of U.S. patent application Ser. No. 08/585,397, filed Jan. 11, 1996, now abandoned, and U.S. patent application Ser. No. 08/394,032, filed Feb. 24, 1995, now U.S. Pat. No. 5,872,154. The present invention relates generally to gene therapy, and more specifically, to methods of administering viral vectors used in gene therapy. Recombinant adenoviruses have emerged as attractive vehicles for in vivo gene transfer to a wide variety of cell types. The first generation vectors, which are rendered replication defective by deletion of the immediate early genes E1a and E1b, are capable of highly efficient in vivo gene transfer into nondividing target cells [M. Kay et al, Proc. Natl. Acad. Sci. USA 91:2353-2357 (1994); S. Ishibashi et al, J. Clin. Invest., 92:883-893 (1993); B. Quantin et al, Proc. Natl. Acad. Sci. USA, 89:25812584 (1992); M. Rosenfeld et al, Cell, 68:143 (1992); R. Simon et al, Hum. Gene Thera., 4:771 (1993); Rosenfeld et al, Science, 252:431-434 (1991); Stratford-Perricaudet et al, Hum. Gene Ther., 1:241-256 (1990)]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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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 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

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Methods of ex-vivo expansion of hematopoeitic cells using multivariant IL-3 hematopoiesis chimera proteins Inventor(s): Abrams, Mark Allen; (St. Louis, MO), Bauer, S. Christopher; (New Haven, MO), Braford-Goldberg, Sarah Ruth; (St. Louis, MO), Caparon, Maire Helena; (Chesterfield, MO), Easton, Alan Michael; (Maryland Heights, MO), Klein, Barbara Kure; (St. Louis, MO), McKearn, John P.; (Glencoe, MO), Olins, Peter O.; (Lafayette, CO), Paik, Kumnan; (Wilmette, IL), Thomas, John W.; (Town ?amp; Country, MO) Correspondence: Carol M Nielsen; Gardere Wynne Sewell Llp; 1000 Louisianna; Suite 3400; Houston; TX; 77002-5007; US Patent Application Number: 20030185790 Date filed: February 26, 2002

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Abstract: The present invention relates to methods of ex-vivo expansion of hematopoietic cells by culturing hematopoietic cells in a growth medium comprising a chimera protein which comprises a variant of human interleukin-3 (hIL-3) which contains multiple amino acid substitutions and which may have portions of the native hIL-3 molecule deleted and a hematopoietic growth factor. The present invention also relates to the ex-vivo expansion of hematopoietic cells for gene therapy. Additionally, the present invention relates to the use of the expanded hematopoietic cells for treating patients having a hematopoietic disorder. Excerpt(s): This is a continuation-in-part of U.S. application Ser. No. 08/446,872 filed Feb. 2, 1995 which is a continuation-in-part of U.S. application Ser. No. 08/192,325 filed Feb. 4, 1994 which are incorporated herein by reference. The present invention relates to methods of ex-vivo expansion of hematopoietic cells by culturing hematopoietic cells in a medium which includes a chimera protein comprising a variant of human interleukin3 (hIL-3) joined with or without a linker to a second colony stimulating factors, cytokines, lymphokines, interleukins, hematopoietic growth factors or IL-3 variants and the use of the expanded hematopoietic cells for treating patients having a hematopoietic disorder. Colony stimulating factors, cytokines, lymphokines, interleukins or hematopoietic growth factors (herein collectively referred to as "hematopoietic growth factors") which stimulate the differentiation and/or proliferation of bone marrow cells have generated much interest because of their therapeutic potential for restoring depressed levels of hematopoietic stem cell-derived cells. Hematopoietic growth factors in both human and murine systems have been identified and distinguished according to their activities. For example, granulocyte-CSF (G-CSF) and macrophage-CSF (M-CSF) stimulate the in vitro formation of neutrophilic granulocyte and macrophage colonies, respectively while GM-CSF and interleukin-3 (IL-3) have broader activities and stimulate the formation of both macrophage, neutrophilic and eosinophilic granulocyte colonies. IL-3 also stimulates the formation of mast, megakaryocyte and pure and mixed erythroid colonies. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Microspheres for active embolization Inventor(s): Boschetti, Egisto; (Gougenot, FR), Vogel, Jean-Marie; (Boxborough, FR) Correspondence: Pennie & Edmonds Llp; 1667 K Street NW; Suite 1000; Washington; DC; 20006 Patent Application Number: 20030211165 Date filed: December 12, 2002 Abstract: The present invention relates to injectable compositions comprising biocompatible, swellable, substantially hydrophilic, non-toxic and substantially spherical polymeric material carriers which are capable of efficiently delivering bioactive therapeutic factor(s) for use in embolization drug therapy. The present invention further relates to methods of embolization gene therapy, particularly for the treatment of angiogenic and non-angiogenic-dependent diseases, using the injectable compositions. Excerpt(s): The present invention relates to compositions and methods for treating diseases including cancer and various other angiogenic-dependent diseases, and more particularly to compositions comprising bioactive therapeutic factors in association with microspheres as carriers (which have been coated with or otherwise contain such

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factors), as well as methods for using such compositions for active embolization therapy. Angiogenesis-dependent diseases (i.e., those diseases which require or induce vascular growth) represent a significant portion of all diseases for which medical treatment is sought. For example, cancer remains the second leading cause of death in the United States, and accounts for over one-fifth of the total mortality. Briefly, cancer is characterized by the uncontrolled division of a population of cells which, most typically, leads to the formation of one or more tumors. Such tumors are also characterized by the ingrowth of vasculature which provide by blood circulation various factors that permit continued tumor growth. Although cancer is generally more readily diagnosed than in the past, many forms, even if detected early, are still incurable. A variety of methods are presently utilized to treat cancer, including for example, various surgical procedures. If treated with surgery alone however, many patients (particularly those with certain types of cancer, such as breast, brain, colon and hepatic cancer) will experience recurrence of the cancer. Therefore, in addition to surgery, many cancers are also treated with a combination of therapies involving cytotoxic chemotherapeutic drugs (e.g., vincristine, doxorubicin, taxol, vinblastine, cisplatin, methotrexate, 5-FU, etc.) and/or radiation therapy. One difficulty with this approach, however, is that radiotherapeutic and chemotherapeutic agents are toxic to normal tissues, and often create lifethreatening side effects. In addition, these approaches often have extremely high failure/remission rates. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Minicell-based gene therapy Inventor(s): Berkley, Neil; (San Diego, CA), Sabbadini, Roger A.; (Lakeside, CA), Surber, Mark W.; (Coronado, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030199088 Date filed: May 28, 2002 Abstract: The invention provides compositions and methods for the production of achromosomal and anucleate cells useful for applications such as diagnositic and therapeutic uses, as well as research tools and agents for drug discovery. Excerpt(s): Ser. No. ______ (attorney docket No. 089608-0401), entitled "Methods of Making Minicells," by Surber, et al., filed May 24, 2002. All of the preceding applications are hereby incorporated in their entirety (including drawings) by reference thereto. The invention is drawn to compositions and methods for the production of achromosomal archeabacterial, eubacterial and anucleate eukaryotic cells that are used as, e.g., therapeutics and/or diagnostics, reagents in drug discovery and functional proteomics, research tools, and in other applications as well. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Minimal adenoviral vector Inventor(s): Alemany, Ramon; (Grayslake, IL), Ayares, David; (Blacksburgh, VA), Balague, Cristina; (Grayslake, IL), Dai, Yifan; (Grayslake, IL), Josephs, Steven; (Grayslake, IL), Schneiderman, Richard; (Highland Park, IL), Zhang, Wei-Wei; (Libertyville, IL) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20030192066 Date filed: May 28, 2002 Abstract: This invention is related to adenoviral (Ad) vectors and their applications in the field of genetic medicine, including gene transfer, gene therapy, and gene vaccination. More specifically, this invention is related to the Ad vectors that carry the minimal cis-element of the Ad genome (mini-Ad vector) and are capable of delivering transgenes and/or heterologous DNA up to 36 kb. The generation and propagation of the mini-Ad vectors require trans-complementation of a packaging-attenuated and replication-defective helper Ad (helper) in an Ad helper cell line.This invention further comprises a methodology for generating a mini-adenoviral (mini-Ad) vector for use in gene therapy of hemophilia and animal test systems for in vivo evaluation of the Ad vectors. More specifically, this invention describes factor VIII (FVIII) Ad vectors that only contain minimal cis-elements of the Ad genome (so called mini-Ad) and comprise a human FVIII cDNA with other supporting DNA elements up to 36 kb. The FVIII miniAd can be generated and preferentially amplified through the assistance of a packagingattenuated helper Ad and a helper cell line. This invention also reports designs and methods for producing transgenic mouse models that can be used for in vivo testing the mini-Ad. Excerpt(s): This application claims priority to U.S. application Ser. No. 08/658,961 filed on May 31, 1996 and U.S. application Ser. No. 08/791,218 filed on Jan. 31, 1997. This invention further comprises a methodology for generating a mini-adenoviral (mini-Ad) vector for use in gene therapy of hemophilia and animal test systems for in vivo evaluation of the Ad vectors. More specifically, this invention describes factor Vif (FVII) Ad vectors that only contain minimal cis-elements of the Ad genome (so called mini-Ad) and comprise a human FVIII CDNA with other supporting DNA elements up to 36 kb. The FVIH mini-Ad can be generated and preferentially amplified through the assistance of a packaging-attenuated helper Ad and a helper cell line. This invention also reports designs and methods for producing transgenic mouse models that can be used for in vivo testing the mini-Ad. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Mixed-cell gene therapy Inventor(s): Lee, Kwan Hee; (Gaithersburg, MD), Noh, Moon Jong; (Gaithersburg, MD), Song, Sun Uk; (Inchon, KR), Yi, Youngsuk; (Gaithersburg, MD) Correspondence: Jhk Law; P.O. Box 1078; LA Canada; CA; 91012-1078; US Patent Application Number: 20030185809 Date filed: March 5, 2003

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Abstract: The subject invention is directed to a mixed cell composition to generate a therapeutic protein at a target site by providing a first population of mammalian cells transfected or transduced with a gene that is sought to be expressed, and a second population of mammalian cells that have not been transfected or transduced with the gene, wherein endogenously existing forms of the second population of mammalian cells are decreased at the target site, and wherein generation of the therapeutic protein by the first population of mammalian cells at the target site stimulates the second population cells to induce a therapeutic effect. Excerpt(s): The present invention relates to using a mixture of cells for somatic cell gene therapy. The present invention also relates to a mixture of cells that include connective tissue cells transfected or transduced with a gene encoding a member of the transforming growth factor.beta. superfamily and connective tissue cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor.beta. superfamily. The present invention also relates to a method of regenerating cartilage by injecting the cell mixture to a mammalian connective tissue. In addition, the present invention relates to a method of treating osteoarthritis by injecting the cell mixture to a mammalian connective tissue. In the orthopedic field, degenerative arthritis or osteoarthritis is the most frequently encountered disease associated with cartilage damage. Almost every joint in the body, such as the knee, the hip, the shoulder, and even the wrist, is affected. The pathogenesis of this disease is the degeneration of hyaline articular cartilage (Mankin et al., J Bone Joint Surg, 52A: 460-466, 1982). The hyaline cartilage of the joint becomes deformed, fibrillated, and eventually excavated. If the degenerated cartilage could somehow be regenerated, most patients would be able to enjoy their lives without debilitating pain. Traditional routes of drug delivery, such as oral, intravenous or intramuscular administration, to carry the drug to the joint are inefficient. The half-life of drugs injected intra-articularly is generally short. Another disadvantage of intra-articular injection of drugs is that frequent repeated injections are necessary to obtain acceptable drug levels at the joint spaces for treating a chronic condition such as arthritis. Because therapeutic agents heretofore could not be selectively targeted to joints, it was necessary to expose the mammalian host to systemically high concentrations of drugs in order to achieve a sustained, intra-articular therapeutic dose. Exposure of non-target organs in this manner exacerbated the tendency of anti-arthritis drugs to produce serious side effects, such as gastrointestinal upset and changes in the hematological, cardiovascular, hepatic and renal systems of the mammalian host. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel g protein-coupled receptor proteins and dnas thereof Inventor(s): Matsui, Hideki; (Ibaraki, JP), Miwa, Masanori; (Ibaraki, JP), Shintani, Yasushi; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030191285 Date filed: November 25, 2002 Abstract: DNAs encoding human leukocyte-derived G protein-coupled receptor proteins or salts thereof are useful in: (1) determining ligands; (2) acquiring antibodies and antisera; (3) constructing a recombinant receptor protein expression system; (4) developing a receptor-bound assay system and screening candidate compounds for a

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drug using the expression system above; (5) designing drugs based on the comparison with ligand receptors having similar structures; (6) reagents in preparing probes, PCR primers, etc. for gene therapy; (7) constructing transgenic animals; (8) drugs such as gene preventives and remedies; etc. Excerpt(s): The present invention relates to novel human leukocyte-derived proteins or salts thereof and DNAs encoding the same, and the like. Many physiologically active substances like hormones, neurotransmitters, etc. regulate the functions of the body via specific receptor proteins present on cell membranes. Most of these receptor proteins are coupled to guanine nucleotide-binding proteins (hereinafter sometimes referred to as G proteins) to mediate the intracellular signal transduction through activation of the G proteins. These receptors possess a common structure comprising seven transmembrane domains and are thus referred to collectively as G protein-coupled receptor proteins or seven transmembrane receptors (7 TMR). G protein-coupled receptor proteins exist on cells of a living body and each functional cell surface of cells and organs and play very important roles as the targets of molecules, for example, hormones, neurotransmitters, physiologically active substances and the like, which molecules regulate the functions of cells and organs in vivo. These receptors mediate signal transduction in a cell by binding to physiologically active substances and various reactions such as activation or inhibition of cells are induced. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Nucleic acid constructs containing hybrid promoters for use in gene therapy Inventor(s): Mueller, Rolf; (Marburg, DE), Sedlacek, Hans-Harald; (Marburg, DE), Seifart, Klaus-Heinrich; (Marburg, DE) Correspondence: Heller Ehrman White & Mcauliffe Llp; 1666 K Street,nw; Suite 300; Washington; DC; 20006; US Patent Application Number: 20030187245 Date filed: April 7, 2003 Abstract: Nucleic acid constructs containing hybrid promoters for use in gene therapy and genetic manipulation. The invention relates to a nucleic acid construct for the precise, regulated expression of genes in host cells, which construct exhibits at least one mutation which inhibits the proper expression of the expressed gene and exhibits at least one additional second mutation which relieves the inhibition due to the first mutation, to an isolated cell which harbors the nucleic acid construct, and to the use of the nucleic acid construct for preparing pharmaceuticals and for treating diseases with excessive cell proliferation. Excerpt(s): The present application relates to nucleic acid constructs which can be used in genetic manipulation and in particular in the prophylaxis or therapy of diseases (termed gene therapy in that which follows). In gene therapy, genes which are to be expressed in an organism are introduced into the organism. The regulation of the expression of these genes is of significance for the prophylactic or therapeutic effect of the gene therapy. Regulators of the expression of a gene are described in patent applications PCT/GB95/02000, PCT/EP95/03370, PCT/EP95/03371, PCT/EP95/03368 and PCT/EP95/03339. These regulators comprise an activator sequence whose function is, for example, the cell-specific or virus-specific activation of basal transcription. The DNA sequence of this activator sequence is linked by its 3' end to the 5' end of a promoter module. The structural gene is in turn linked by its 5' end to the 3' end of the

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promoter module. The promoter module is composed of nucleic acid sequences for binding the transcription factors of the CDF and CHF families or of the E2F and CHF families. In the G0 and G1 phases of the cell cycle, this binding leads to inhibition of the upstream activator sequence and consequently to inhibition or transcription of the structural gene which is located downstream (i.e. in the direction of transcription). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical compositions and methods of use thereof comprising polyanionic polymers and amphiphilic block copolymers to improve gene expression Inventor(s): Goyette, Phillipe; (Montreal, CA), Lemieux, Pierre; (Ste-Therese, CA) Correspondence: Mathews, Collins, Shepherd & Mckay, P.A.; 100 Thanet Circle, Suite 306; Princeton; NJ; 08540; US Patent Application Number: 20030191081 Date filed: December 26, 2002 Abstract: The present invention is directed to polynucleotide compositions containing (a) a polynucleotide or derivative thereof and (b) a block copolymer having a polyether segment and a polyanion segment, compositions containing (a) a polynucleotide or its derivative thereof, (b) at least one polyanionic polymer, and (c) at least one amphiphilic block copolymer, and methods of using these compositions for gene therapy. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/344,075, filed on Dec. 28, 2001, the content of which is hereby incorporated by reference. The invention relates to the field of gene delivery, such as gene therapy and genetic vaccination. The unique features of smooth, skeletal, and cardiac muscles, have presented numerous challenges for the development and administration of effective polynucleotide compositions for intramuscular administration. Direct injection of purified plasmids ("naked DNA") in isotonic saline into muscle was found to result in DNA uptake and gene expression in smooth, skeletal, and cardiac muscles of various species. Rolland A., Critical Reviews in Therapeutic Drug Carrier Systems, Begell House, 143 (1998). It is believed that the unique cytoarchitectural features of muscle tissue are responsible for the uptake of polynucleotides because skeletal and cardiac muscle cells appear to be better suited to take-up and express injected foreign DNA vectors relative to other types of tissues. Dowty & Wolff, Gene Therapeutics: Methods and Applications of Direct Gene Transfer, Birkhuser, Boston, p. 182 (1994). The relatively low expression levels attained by this method, however, have limited its applications. See Aihara and Miyazaki, Nature Biotechnology, 16:867 (1998). Additionally, traditional gene delivery systems such as polycations, cationic liposomes, and lipids that are commonly proposed to boost gene expression in other tissues usually result in inhibition of gene expression in skeletal and cardiac muscles. Dowty & Wolff, Gene Therapeutics: Methods and Applications of Direct Gene Transfer, Birkhuser, Boston, p. 82 (1994). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Products and methods for controlling the suppression of the neoplastic phenotype Inventor(s): Huang, Huei-Jen Su; (San Diego, CA), Lee, Eva Y. H.P.; (San Diego, CA), Lee, Wen-Hwa; (San Diego, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030181403 Date filed: December 21, 2001 Abstract: A method for gene therapy for cancers wherein chromosomal location of an inactive or defective cancer suppressing gene is established, a replacement gene which is preferably cloned is then used to replace the inactive or defective cancer suppressing gene in the chromosome. In addition to its uses in therapy, the present invention provides a means for prophylactically treating individuals having a genetic predisposition to cancer and provides an animal model for testing for carcinogenicity of environmental substances. Excerpt(s): This invention relates in general to products and methods for the therapeutic and prophylactic treatment of mammals, to control the phenotypic expression of cancer, and to the production of products and methods for testing for carcinogenicity of environmental substances. This invention was made with Government support under Grant No. EY05758 with the National Institute of Health, and the University of California. The Government has certain rights in this invention. For many years, cancer in its numerous forms, has been a frightful bane to human society. In many cases, the condition is discovered when the pathological condition has advanced to the point that the patient's life cannot be saved, and the fatal progress of the disease cannot be reversed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Pseudotype retroviral vectors containing membrane proteins having hemagglutinin activity Inventor(s): Hasegawa, Mamoru; (Ibaraki, JP), Iida, Akihiro; (Ibaraki, JP), Kobayashi, Masanori; (Osaka, JP), Nakajima, Toshihiro; (Hyogo, JP), Nakamaru, Kenji; (Tokyo, JP), Sakakibara, Hiroyuki; (Ibaraki, JP), Ueda, Yasuji; (Ibaraki, JP), Yonemitsu, Yoshikazu; (Fukuoka, JP) Correspondence: Clark & Elbing Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20030203489 Date filed: November 29, 2002 Abstract: The present invention provides a retroviral vector containing a membrane protein having a hemagglutinin activity. The present inventors constructed a retroviral vector pseudotyped by the membrane protein having a hemagglutinin activity. This viral vector showed gene transfer at a high efficiency into host cells. In particular, it was established that genes can be transferred thereby at a high efficiency into cells into which genes can hardly be transferred by the conventional techniques, for example, blood cells and hematopoietic cells including hematopoietic stem cells, and mucous cells including mucosa epithelial cells. The viral vector of the present invention is highly useful as a vector for gene therapy.

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Excerpt(s): The present invention relates to pseudotype viral vectors containing HN protein of paramyxovirus. Retroviral vectors have been used to express foreign genes in target cells for research, gene therapy, etc. Retroviral vectors can be produced with a relatively simple method, and also have some advantages, such as, to introduce foreign genes into the chromosomes of the host. Normally, viral proteins localized in the viral envelope play a crucial role in retroviral vector infection. Much effort has been expended to widen the range of host cells to which the vectors can infect or to develop viral vectors which infect only specific cells by modifying the envelope proteins of retroviral vector. For example, a system, where VSV-G protein is integrated into the retroviral vector envelope, has been developed to ensure the infectivity to a broader range of host cells (H. Yu et al., 1999, Gene Therapy, 6, 1876-1883). VSV-G is a protein expressed on the surface of envelope of vesicular stomatitis virus, which is infectious to a considerably broad range of host cells. In addition, for example, Sendai virus F protein has been used as an envelope protein by way of experiment. An F protein-pseudotyped retrovirus was found to exhibit specific infectivity to asialoglycoprotein receptorpositive cells (M. Spiegel et al., 1998, Hepatology, 28, 1429-1429; M. Spiegel et al., 1998, J. Virology, 72, 5296-5302). 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

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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 •

Tamoxifen and 4-hydroxytamoxifen-activated system for regulated production of proteins in eukaryotic cells Inventor(s): Mao, Chengjian; (Savoy, IL), Shapiro, David J.; (Urbana, IL) Correspondence: Brinks Hofer Gilson & Lione; P.O. Box 10395; Chicago; IL; 60610; US Patent Application Number: 20030199022 Date filed: March 11, 2002 Abstract: Novel tamoxifen inducible and ICI 182,780 repressible expression systems comprising mutant estrogen receptors and mutant estrogen response element are disclosed. Such systems have a wide variety of applications, including gene therapy and in vivo and in vitro expression, as well as their use in transgenic animals. Excerpt(s): As a light switch can provide instant illumination (ON) or sudden darkness (OFF), so, too, can gene expression systems provide a gene product at will. Such regulated gene expression systems, wherein specific promoters and regulatory elements that play the role of a light switch are functionally-linked to a gene of interest, are important tools that facilitate gene function studies and enable exogenous control in gene therapies. While endogenous gene expression is tightly regulated, being turned ON and OFF according to developmental state, extracellular and intracellular cues and environmental signals, exogenous gene expression has most often been accomplished by constitutive expression (the light is always ON) wherein transcription is controlled from an unregulated, strong promoter sequence. However, such expression can result in over-expression, temporal mis-expression and cell lethality; hampering gene function studies and gene therapy interventions, and even rendering them ineffective. Although today, regulated (inducible) gene expression systems are readily available, they often suffer from high basal expression (even OFF, the light still flickers), low protein synthesis (the light bulb is dimly illuminated) and over-riding cellular circuits (factors) that interfere with the intended molecular switch. In many cases, the agent that flips the switch itself often exerts pleiotropic effects, becomes ineffective over time, or the safety of its administration to an organism or cell is unknown. To obviate these and other difficulties, inducible expression systems have been developed. Such systems subjugate the gene(s) of interest under the control of an "inducible" promoter--that is, a promoter to which transcription factors, etc., can be made to bind at will, using exogenous factors such as metals, temperature, hormones, or other polypeptides provided in trans. However, most inducible systems are not completely "turned off" in the absence of the inducer--low levels of basal expression are often observed. Such basal expression reduces the advantages of an inducible expression when the gene to be induced is lethal to the target cell (Ausubel et al., 1987). Desirable characteristics of inducible gene expression systems are presented in Table 1. Common eukaryotic (or adaptable to eukarayotes) inducible expression systems, their characteristics, advantages and disadvantages are presented in Table 2. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Transport proteins and their uses Inventor(s): Elliott, Gillian Daphne; (Surrey, GB), O'Hare, Peter Francis Joseph; (Surrey, GB) Correspondence: Klarquist Sparkman, Llp; One World Trade Center, Suite 1600; 121 S.W. Salmon Street; Portland; OR; 97204; US Patent Application Number: 20030219859 Date filed: September 27, 2002 Abstract: The present invention relates to transport proteins, in particular VP22 and homologues thereof, and to methods of delivering these proteins and any associated molecules to a target population of cells. This transport protein has applications in gene therapy and methods of targeting agents to cells where targeting at high efficiency is required. Excerpt(s): The present invention relates to transport proteins, and in particular to transport proteins based on VP22, homologues of VP22 or fragments thereof, to molecules and compositions including the transport proteins, and to methods of delivering these proteins and any associated molecules to a target population of cells, typically at high efficiency. The product of the herpes simplex virus type 1 (HSV-1) UL49 gene, the structural protein VP22 (4), is a major component of the HSV tegument, a compartment of the virion located outside the capsid and inside the envelope and composed of at least 10 or more additional virus polypeptides (for a review see (6)). VP22 has a molecular weight of 32 k, is very basic and is modified by phosphorylation and nucleotidylation (1,4,8,9,11) in the infected cell. Despite being one of the major tegument proteins within the virion, together with the well characterised transcription regulatory protein VP16, little is known about the function of VP22 during the virus replicative cycle. It is not yet known if it is an essential virus protein, but it is possible that, in a manner similar to VP16, VP22 has two roles to perform during infection-initially as a functional protein during viral gene expression, and subsequently as a structural component of the virion during virus assembly. With regard to the former, some evidence exists to suggest that VF22 can bind specifically to HSV-1 DNA (2,8,10). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Treatment of cancer and neurological diseases Inventor(s): Jackson, Andrew Peter; (Leeds, GB), Markham, Alexander Fred; (Leeds, GB), Woods, Christopher Geoffrey; (Leeds, GB) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20030180750 Date filed: May 8, 2003 Abstract: The present invention relates to a nucleic acid molecule and the protein encoded thereby absence of which is associated with oral and other cancers and lack of neurogenesis. The invention also provides antibodies and the use of these products as therapeutic and/or diagnostic agents in gene therapy and/or tissue repair. Excerpt(s): The present invention relates to the isolation of a nucleic acid molecule and the protein encoded thereby; antibodies raised thereto and the use of these products as therapeutic and/or diagnostic agents particularly, but not exclusively, in gene therapy and/or tissue repair such as, without limitation enhancing neuronal

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repair/regeneration and in the treatment of cancer. Oral cancer has significant morbidity and mortality rates. In England and Wales the 5-year survival is around 50%. Globally, oral cancer is one of most common cancers and in some parts of the world it is the most prevalent of all cancer types. For example, in India and Sri Lanka oral cancer accounts for up to 40% of all diagnosed cancers. In addition to geographic "hot spots", there seems to be a rising trend in the increased incidence of oral cancers in many developed nations. Recent advances in cancer management have failed to impact significantly on the outcome of oral cancer. Surgery and radiotherapy remain the principle forms of treatment with a limited role for chemotherapy. Treatment can be mutilating and is associated with high morbidity that significantly impacts on the quality of life. Speech, swallowing and taste can be markedly impaired after treatment. New treatment modalities are required for oral cancer therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Tumor radiosensitization using gene therapy Inventor(s): McBride, William H.; (Los Angeles, CA) Correspondence: Mcdermott, Will & Emery; 7th Floor; 4370 LA Jolla Village Drive; San Diego; CA; 92122; US Patent Application Number: 20030185810 Date filed: April 21, 2003 Abstract: The invention provides a method of radiosensitizing a tumor in a subject by contacting the tumor with a cytokine or a nucleic acid molecule encoding a cytokine. The invention also provides a method of radiosensitizing a tumor in a subject by administering, at a site other than the tumor, a cell genetically modified to express a cytokine. The invention further provides a method of reducing the severity of a cancer in a subject by administering a cytokine at the site of the tumor or by immunizing the subject at a site other than the tumor with tumor cells genetically modified to express a cytokine, and treating the tumor with radiotherapy. Excerpt(s): The present invention relates generally to cancer therapy and, more particularly, to compositions and methods for sensitizing a cancer in a subject to radiation therapy. Improved methods and novel agents for treating cancer have resulted in increased survival time and survival rate for patients with various types of cancer. For example, improved surgical and radiotherapeutic procedures result in more effective removal of localized tumors. Surgical methods, however, can be limited due, for example, to the location of a tumor or to dissemination of metastatic tumor cells. Radiotherapy also can be limited by these factors, which limits the dose that can be administered. Tumors that are relatively radioresistant will not be cured at such a dose. Immunotherapeutic methods also are being examined as a means to treat a cancer by stimulating the patient's immune response against the cancer. In particular, the role of cytokines, which are cellular factors that can modulate an immune response, is an important factor to consider when planning an immunotherapeutic procedure. For example, expression of a cytokine such as interleukin-2 (IL-2) can increase the proliferation of T cells, which are involved in the cellular immune response against a cancer. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Vector for transfection of eukaryotic cells Inventor(s): Matsumoto, Kenji; (San Diego, CA), Yu, Lei; (Carlsbad, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030186916 Date filed: March 10, 2003 Abstract: Vectors comprising a nucleic acid, a nucleic acid binding polymer, a vesicle and a membrane active polypeptide are described. Preferred vectors facilitate transfection and/or reduce cytotoxicity. Methods of making the vectors and methods of using the vectors to transfect cells and/or treat a patient in need of gene therapy are described. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/363,955, filed Mar. 12, 2002, which is hereby incorporated by reference in its entirety. The present invention relates to a vector comprising a cationic polymer that efficiently condenses nucleic acid and a lipid-based functional vesicle that carries a membrane active agent, such as viral envelope proteins or membrane active peptides which enhance efficiency of transfection of nucleic acids into eukaryotic cells with reduced cytotoxicity. The present invention also relates to methods of transfecting eukaryotic cells with such vectors. Gene therapy potentially offers a means of treating currently incurable genetic and acquired diseases (Verma, I M. Gene Therapy: Beyond 2000. Mol Ther. Jun. 1, 2000 (6):493). However, in this post-genomic era, the main problem with this therapeutic approach is a lack of effective gene delivery systems (Anderson, W F. Human Gene Therapy. Nature 392:25-30 (1998)). Gene delivery systems are designed to protect and control the location of a gene within the body by affecting the distribution and access of a gene expression system to the target cell, and/or recognition by a cellsurface receptor followed by intracellular trafficking and nuclear translocation (Friedmann, T. The Development of Human Gene Therapy. Cold Spring Harbor Laboratory Press. San Diego. 1999). Generally, there are two classes of gene vector systems: viral vector systems and non-viral vector systems. Viral vector systems include retroviral vector systems, lentiviral vector systems, adenoviral vector systems, adenoassociated viral vector systems, HSV viral vector systems, and alpha viral vector systems. Generally, viral vector systems have efficient gene transfer relative to non-viral gene carrier systems, because viruses have developed efficient mechanisms to overcome the gene transfer barrier in human beings. However, viral gene carrier systems have inherent disadvantages for use in the human body, such as the risk of wild-type virus regeneration, high immunogenecity and inflammation, and tumorogenesis (Verma I M, Stevenson J. Gene Therapy--Promises, Problems and Prospects. Nature. Sep. 18, 1997;389(6648):239-42; Huang, L. and Viroonchatapan, E. Part I: Introduction in Nonviral Vectors for Gene Therapy. In L. Huang, M. C. Hung and E. Wanger (eds.). Nonviral Gene Vectors. Academic Press. (1999)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Viral vectors and line for gene therapy Inventor(s): Lusky, Monika; (Freiburg, DE), Mehtali, Majid; (Illkirch-Graffenstaden, FR), Rittner, Karola; (Strasbourg, FR) Correspondence: Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030203488 Date filed: March 19, 2001 Abstract: Novel viral vectors in which the expression of viral genes is regulated in such a way that it is functional in a complementation cell and non-functional in a host cell, as well as viral particles and host cells containing said novel vectors, are disclosed. A complementation cell including a viral gene expression regulator, and a method for preparing infectious viral particles, are also disclosed. Finally, a pharmaceutical composition containing said vectors, and the therapeutical use thereof, are disclosed. Excerpt(s): The present invention relates to new viral vectors permitting the transfer and expression of genes of interest in a host cell or body, the expression of the viral genes being regulated so as to be functional in a complementation cell and nonfunctional in the host cell or body. It also relates to the cells containing these now vectors, as well as to a method for preparing infectious viral particles intended for therapeutic use. The invention in of very special interest in relation to prospects for gene therapy, in particular in man. The possibility of treating human diseases by gene therapy has changed in a few years from the stage of theoretical considerations to that of clinical applications. The first protocol applied to man was initiated in the US in September 1990 on a patient who was genetically immunodeficient as a result of a mutation affecting the gene coding for adenine deaminase (ADA). The relative success of this first experiment encouraged the development of now gene therapy protocols for various genetic or acquired diseases (infectious diseases, and viral diseases in particular, such as AIDS, or cancers). The large majority of the protocols described hitherto employ viral vectors to transfer the therapeutic gene to the cells to be treated and to express it therein. To date, retroviral vectors are among the ones most widely used on account of the simplicity of their gene. or, &part from their restricted capacity for cloning, they present two major drawbacks which limit their systematic use: on the one hand they chiefly infect dividing cells, and on the other hand, an a result of their integration at random in the genome of the. host cell, the risk of insertional mutagenesis is not insignificant. For this reason, many scientific teams have endeavored to develop other types of vector, among which those originating from adenoviruses, adeno-associated viruses (AAV), cytomegaviruses, poxviruses and herpesviruses may be mentioned. Generally speaking, their organization and their infection cycle are amply described in the literature available to a person skilled in the art. 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 gene therapy, 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:

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Under “Issued Patents,” click “Quick Search.” Then, type “gene therapy” (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 gene therapy. You can also use this procedure to view pending patent applications concerning gene therapy. 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 7. BOOKS ON GENE THERAPY Overview This chapter provides bibliographic book references relating to gene therapy. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on gene therapy 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 “gene therapy” (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 gene therapy: •

Conquering Rheumatoid Arthritis: The Latest Breakthroughs and Treatments Source: Amherst, NY: Prometheus Books. 2001. 255 p. Contact: Available from Prometheus Books. 59 John Glenn Drive, NY 14228-2197. (716) 691-0133 or (800) 421-0351. Website: www.prometheusbooks.com. PRICE: $20.00. ISBN: 1573928860. Summary: This book for patients describes the origins, disease course, and treatment of rheumatoid arthritis (RA). Rheumatoid arthritis affects over two million Americans. It is three times more common in women than men and becomes increasingly common in people as they age. RA is an inflammatory disease of the synovium, or lining of a joint, that results in pain, stiffness, swelling, joint damage, and loss of function in the joints. Chapters discuss the body's immune system; the anatomy of the synovial joints; the system by which the body's immune system attacks these joints; the genetic origins of RA and gene therapy; stem cell research and therapy; traditional treatments for RA

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including NSAIDS, DMARDS, and steroids; new medications including etanercept, COX-1 and COX-2 enzymes, leflunomide, and infliximab; clinical trials; and potential therapies. Appendices include related websites and a glossary. 14 figures. •

Annual Review of Diabetes 2000 Source: Alexandria, VA: American Diabetes Association. 2000. 384 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $49.95 plus shipping and handling. Summary: This book serves as a compendium of diabetes research articles that appeared in American Diabetes Association journals. Articles in section one focus on the pathogenesis of diabetes. Topics include the applicability of the thrifty genotype to obesity and type 2 diabetes, the role of cow's milk in the etiology of type 1 diabetes, the preservation of beta cell function in type 1 diabetes, the regulation and possible significance of leptin in humans, the genetic aspects of type 1 diabetes, the pathology and pathogenesis of diabetic neuropathy, and the aldose reductase pathway and nonenzymatic glycation in the pathogenesis of diabetic neuropathy. Articles in section two explore options for treating diabetes in children, adolescents, the elderly, and the obese. Other articles in this section focus on insulin secretagogues, intensive insulin therapy, pancreas and islet transplantation, and gene therapy. In addition, articles examine the impact of smoking on diabetes, the use of influenza and pneumococcal vaccines in people who have diabetes, the measurement of patient well being, the assessment of diabetes specific quality of life, and the economic aspects of diabetes interventions. Articles in the final section deal with diabetic complications, including diabetic nephropathy; cardiovascular diseases; foot wounds; somatic neuropathy; gastrointestinal, genitourinary, and neurovascular disturbances; and macrosomia. Another article in this section reviews current and emerging treatments for diabetic neuropathies. Numerous figures. Numerous tables. Numerous references.

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Peripheral Arterial Disease: Diagnosis and Treatment Source: Totowa NJ: Humana Press. 2003. 368 p. Contact: Available from Humana Press. 999 Riverview Drive, Suite 208, Totowa, NJ 07512. (973) 256-1699. Fax (973) 256-8341. E-mail: [email protected]. Website: www.humanapress.com. PRICE: $89.55. ISBN: 588290522. Summary: This textbook acquaints physicians with all aspects of peripheral arterial disease (PAD), defined as narrowing (stenosis) or blockage (occlusion) within the arteries of the lower extremities. PAD is caused by both modifiable (diabetes, smoking, hypertension) and nonmodifiable (family history, age, gender) factors. Due to the limitations of medical therapy, there is now a special emphasis on prevention of PAD and a special emphasis on risk factors and their treatment. The text includes seventeen chapters: the etiology and pathogenesis of atherosclerosis, the epidemiology and natural history of PAD, clinical evaluation of intermittent claudication, hemodynamics and the vascular laboratory, vascular imaging, chronic critical limb ischemia (lack of blood flow), acute limb ischemia, exercise rehabilitation for intermittent claudication, treatment of risk factors and antiplatelet therapy, pharmacotherapy for intermittent claudication, angiogenesis and gene therapy, endovascular therapy, surgical revascularization, perioperative cardiac evaluation and management for vascular surgery, special consideration for the diabetic foot, arterial vascular disease in women, atheromatous embolism, thromboangiitis obliterans (Buerger's disease), and large-vessel

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vasculitis. Each chapter concludes with extensive references and a subject index concludes the textbook.

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 “gene therapy” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “gene therapy” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “gene therapy” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Adeno-Associated Virus (Aav) Vectors in Gene Therapy by K. I. Berns (Editor), C. Giraud (Editor); ISBN: 3540610766; http://www.amazon.com/exec/obidos/ASIN/3540610766/icongroupinterna

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Adenoviral Vectors for Gene Therapy by David Curiel (Author), et al (2002); ISBN: 0121995046; http://www.amazon.com/exec/obidos/ASIN/0121995046/icongroupinterna

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Adenoviruses: Basic Biology to Gene Therapy (Medical Intelligence Unit 15) by Prem Seth (Editor); ISBN: 1570595844; http://www.amazon.com/exec/obidos/ASIN/1570595844/icongroupinterna

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Advances in Hematopoietic Stem Cell Transplantation and Molecular Therapy: Proceedings of the Symposium "Hematopoietic Steam Cell Transplantation and Gene Therapy (Recent Results in Cancer Research, 144) by R. Haas (Editor), et al (1998); ISBN: 3540626263; http://www.amazon.com/exec/obidos/ASIN/3540626263/icongroupinterna

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Advances in Surgical Gene Therapy by Dana K. Anderson; ISBN: 0933751095; http://www.amazon.com/exec/obidos/ASIN/0933751095/icongroupinterna

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Altered Fates: Gene Therapy and the Retooling of Human Life by Jeff Lyon, Peter Gorner (Contributor) (1996); ISBN: 0393315282; http://www.amazon.com/exec/obidos/ASIN/0393315282/icongroupinterna

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An Introduction to Molecular Medicine and Gene Therapy by Thomas F. Kresina (Editor) (2000); ISBN: 0471391883; http://www.amazon.com/exec/obidos/ASIN/0471391883/icongroupinterna

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Biologic and Gene Therapy of Autoimmune Disease (Current Directions in Autoimmunity, Vol 2) by C. G. Fathman (Editor) (2000); ISBN: 3805569491; http://www.amazon.com/exec/obidos/ASIN/3805569491/icongroupinterna

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Blood Cell Biochemistrytherapy: Hematopoiesis and Gene Therapy (Blood Cell Biochemistry, 8) by Leslie J. Fairbairn (Editor), Nydia G. Testa (Editor) (1999); ISBN: 0306459620; http://www.amazon.com/exec/obidos/ASIN/0306459620/icongroupinterna

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Cancer Gene Therapy by David T. Curiel (Editor), Joanne, Ph.D. Douglas (Editor) (2004); ISBN: 1588292134; http://www.amazon.com/exec/obidos/ASIN/1588292134/icongroupinterna

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Cancer Gene Therapy: Past Achievements and Future Challenges by Nagy A. Habib (Editor); ISBN: 0306461919; http://www.amazon.com/exec/obidos/ASIN/0306461919/icongroupinterna

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Cell Therapy : Stem Cell Transplantation, Gene Therapy, and Cellular Immunotherapy by George Morstyn (Editor), et al (1996); ISBN: 0521473152; http://www.amazon.com/exec/obidos/ASIN/0521473152/icongroupinterna

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Concepts in Gene Therapy by Michael Strauss (Editor), John A. Barranger (Editor) (1997); ISBN: 3110149842; http://www.amazon.com/exec/obidos/ASIN/3110149842/icongroupinterna

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Cytokine-Induced Tumor Immunogenicity : From Exogenous Molecules to Gene Therapy by Guido Forni (Author), et al (1994); ISBN: 0122615204; http://www.amazon.com/exec/obidos/ASIN/0122615204/icongroupinterna

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Development and Applications of Vaccines and Gene Therapy in AIDS (Antibiotics and Chemotherapy, Vol. 48) by G. Giraldo (Editor) (1996); ISBN: 380556256X; http://www.amazon.com/exec/obidos/ASIN/380556256X/icongroupinterna

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Ethical Aspects of Research on Human Gene Therapy by National Health and Medical Research Cou (1987); ISBN: 0644066237; http://www.amazon.com/exec/obidos/ASIN/0644066237/icongroupinterna

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Extracellular Matrix and The Liver: Approach to Gene Therapy by Isao Okazaki (Author), et al (2003); ISBN: 012525251X; http://www.amazon.com/exec/obidos/ASIN/012525251X/icongroupinterna

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Forum 1996 gene therapy : development and evaluation of phase I products : vector development (SuDoc HE 20.4802:G 28) by U.S. Dept of Health and Human Services; ISBN: B00010W15Q; http://www.amazon.com/exec/obidos/ASIN/B00010W15Q/icongroupinterna

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From Genetics to Gene Therapy: The Molecular Pathology of Human Disease (Ucl Molecular Pathology) by David S. Latchman (Editor) (1994); ISBN: 1872748368; http://www.amazon.com/exec/obidos/ASIN/1872748368/icongroupinterna

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Frontiers in Human Genetics: Diseases and Technologies. Expanded and Updated Proceedings of the International Symposium on Human Genetics and Gene Therapy Held in Singapore 1999 by E. Yap (Editor), et al (2001); ISBN: 9810244584; http://www.amazon.com/exec/obidos/ASIN/9810244584/icongroupinterna

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Gene Technology and Gene Therapy in Dermatology (Supplement Issue: Cells Tissues Organs 2002) by U. R. Hengge (Editor) (2002); ISBN: 3805574940; http://www.amazon.com/exec/obidos/ASIN/3805574940/icongroupinterna

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Gene Therapy by Clay Farris Naff (Editor) (2005); ISBN: 0737719672; http://www.amazon.com/exec/obidos/ASIN/0737719672/icongroupinterna

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Gene Therapy by Linda George (2003); ISBN: 1567117864; http://www.amazon.com/exec/obidos/ASIN/1567117864/icongroupinterna

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Gene Therapy by Robert E. Sobol (Editor), et al (1998); ISBN: 3540650733; http://www.amazon.com/exec/obidos/ASIN/3540650733/icongroupinterna

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Gene Therapy by J. Thomas August (Editor), M. W. Anders (Editor) (1997); ISBN: 0120329417; http://www.amazon.com/exec/obidos/ASIN/0120329417/icongroupinterna

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Gene Therapy by Maurise Lever, et al; ISBN: 0443053332; http://www.amazon.com/exec/obidos/ASIN/0443053332/icongroupinterna

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Gene Therapy; ISBN: 0879692154; http://www.amazon.com/exec/obidos/ASIN/0879692154/icongroupinterna

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Gene Therapy by Paul Evers; ISBN: 185334818X; http://www.amazon.com/exec/obidos/ASIN/185334818X/icongroupinterna

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Gene Therapy by Helen Watt; ISBN: 1860821316; http://www.amazon.com/exec/obidos/ASIN/1860821316/icongroupinterna

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Gene Therapy (Great Medical Discoveries) by Lisa Yount (2002); ISBN: 1560069287; http://www.amazon.com/exec/obidos/ASIN/1560069287/icongroupinterna

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Gene Therapy (Human Molecular Genetics Ser.)) by N. Lemoine, D. N. Cooper (1996); ISBN: 185996205X; http://www.amazon.com/exec/obidos/ASIN/185996205X/icongroupinterna

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Gene Therapy (NATO Asi Series. Series H, Cell Biology, Vol 105) by Kleanthis G. Xanthopoulos (Editor), et al (1998); ISBN: 3540641122; http://www.amazon.com/exec/obidos/ASIN/3540641122/icongroupinterna

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Gene therapy : are patients any safer? : hearing before the Subcommittee on Public Health of the Committee on Health, Education, Labor, and Pensions, United States Senate, One Hundred Sixth Congress, second session. May 25, 2000 (SuDoc Y 4.L 11/4:S.HRG.106-640); ISBN: 0160611555; http://www.amazon.com/exec/obidos/ASIN/0160611555/icongroupinterna

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Gene Therapy and Ethics (Acta Universitatis Upsaliensis: Studies in Bioethics & Research Ethics, 4) by Anders Nordgren (Editor) (1999); ISBN: 915544640X; http://www.amazon.com/exec/obidos/ASIN/915544640X/icongroupinterna

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Gene Therapy and Molecular Biology by Teni Boulikas (Editor); ISBN: 1892245000; http://www.amazon.com/exec/obidos/ASIN/1892245000/icongroupinterna

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Gene Therapy and Therapeutic Interventions in the Auditory System: A Series of Synopses Arising from the Auditory Function and Dysfunction Satellite Symposium of the 34th Iups Congress (Special Issue: Audiology and Neuro-Otology 2002, 3) by Gary D. Housley (Editor), et al (2002); ISBN: 3805574584; http://www.amazon.com/exec/obidos/ASIN/3805574584/icongroupinterna

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Gene Therapy for Acute and Acquired Diseases by Phillip H. Factor (Editor) (2001); ISBN: 0792372689; http://www.amazon.com/exec/obidos/ASIN/0792372689/icongroupinterna

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Gene Therapy for Cancer by Prem Seth (2002); ISBN: 1587060485; http://www.amazon.com/exec/obidos/ASIN/1587060485/icongroupinterna

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Gene Therapy for Cancer : A Scientific American article [DOWNLOAD: PDF] by R. Michael Blaese (Author); ISBN: B00006BNMW; http://www.amazon.com/exec/obidos/ASIN/B00006BNMW/icongroupinterna

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Gene Therapy for Diseases of the Lung by Kenneth L. Brigham (Editor); ISBN: 0824700600; http://www.amazon.com/exec/obidos/ASIN/0824700600/icongroupinterna

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Gene Therapy for HIV Infection by Clay Smith (Editor) (1998); ISBN: 3540647139; http://www.amazon.com/exec/obidos/ASIN/3540647139/icongroupinterna

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Gene therapy for human patients : information for the general public (SuDoc HE 20.3002:G 28/3) by U.S. Dept of Health and Human Services; ISBN: B000103HOU; http://www.amazon.com/exec/obidos/ASIN/B000103HOU/icongroupinterna

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Gene Therapy for Neoplastic Diseases (Annals of the New York Academy of Sciences: Vol 716) by Brian Edward Huber, John S. Lazo (Editor) (1994); ISBN: 0897668502; http://www.amazon.com/exec/obidos/ASIN/0897668502/icongroupinterna

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Gene Therapy for Neurological Disorders & Brain Tumors by E. Antonio, Md. Chiocca (Editor), Xandra O., Ph.D. Breakefield (Editor); ISBN: 0896035077; http://www.amazon.com/exec/obidos/ASIN/0896035077/icongroupinterna

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Gene Therapy for the Nervous System : A Scientific American article [DOWNLOAD: PDF] by Dora Y. Ho (Author), Robert M. Sapolsky (Author); ISBN: B00006BNMX; http://www.amazon.com/exec/obidos/ASIN/B00006BNMX/icongroupinterna

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Gene Therapy in Cancer by Malcolm K. Brenner (Editor), Robert C. Moen (Editor) (1996); ISBN: 0824794818; http://www.amazon.com/exec/obidos/ASIN/0824794818/icongroupinterna

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Gene Therapy in Inflammatory Diseases by Christopher H. Evans (Editor), Paul D. Robbins (Editor); ISBN: 3764358556; http://www.amazon.com/exec/obidos/ASIN/3764358556/icongroupinterna

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Gene Therapy in Lung Disease by Steven M. Albelda (Editor), James C. Dobbins (2002); ISBN: 0824708202; http://www.amazon.com/exec/obidos/ASIN/0824708202/icongroupinterna

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Gene Therapy in the Treatment of Cancer : Progress and Prospects by Brian E. Huber (Editor), et al (1998); ISBN: 0521444365; http://www.amazon.com/exec/obidos/ASIN/0521444365/icongroupinterna

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Gene Therapy of Cancer (Advances in Experimental Medicine and Biology, 451) by Peter Walden (Editor), et al (1998); ISBN: 0306460270; http://www.amazon.com/exec/obidos/ASIN/0306460270/icongroupinterna

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Gene Therapy of Cancer: Methods and Protocols (Methods in Molecular Medicine, 35) by Wolfgang Walther (Editor), Ulrike Stein (Editor) (2000); ISBN: 0896037142; http://www.amazon.com/exec/obidos/ASIN/0896037142/icongroupinterna

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Gene Therapy of Cancer: Translational Approaches From Preclinical Studies to Clinical Implementation (1st Edition) by Edmund C. Lattime (Editor), Stanton L. Gerson (Editor); ISBN: 0124371906; http://www.amazon.com/exec/obidos/ASIN/0124371906/icongroupinterna

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Gene Therapy Players by Beata Langlands; ISBN: 1853347442; http://www.amazon.com/exec/obidos/ASIN/1853347442/icongroupinterna

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Gene Therapy Protocols by Paul D. Robbins (Editor) (1997); ISBN: 0896034844; http://www.amazon.com/exec/obidos/ASIN/0896034844/icongroupinterna

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Gene Therapy Protocols by Jeffrey R. Morgan (Editor); ISBN: 0896037231; http://www.amazon.com/exec/obidos/ASIN/0896037231/icongroupinterna

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Gene Therapy Technologies, Applications and Regulations: From Laboratory to Clinic by Anthony Meager (Editor); ISBN: 0471967092; http://www.amazon.com/exec/obidos/ASIN/0471967092/icongroupinterna

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Gene Therapy: A Handbook for Physicians by Kenneth W. Culver; ISBN: 0913113638; http://www.amazon.com/exec/obidos/ASIN/0913113638/icongroupinterna

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Gene Therapy: Application of Molecular Biology by James W. Larrick, Kathy L. Burck; ISBN: 0838531040; http://www.amazon.com/exec/obidos/ASIN/0838531040/icongroupinterna

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Gene Therapy: Bogdanovic Gene Therapy by S Bogdanovic, B Langlands; ISBN: 1860674380; http://www.amazon.com/exec/obidos/ASIN/1860674380/icongroupinterna

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Gene Therapy: Fact and Fiction in Biology's New Approaches to Disease by Theodore Friedmann (Editor), Friedman (1994); ISBN: 0879694467; http://www.amazon.com/exec/obidos/ASIN/0879694467/icongroupinterna

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Gene Therapy: From Laboratory to the Clinic by Kam M. Hui (1994); ISBN: 9810216556; http://www.amazon.com/exec/obidos/ASIN/9810216556/icongroupinterna

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Gene Therapy: Present Status and Future Prospects by Paul Evers; ISBN: 1853343110; http://www.amazon.com/exec/obidos/ASIN/1853343110/icongroupinterna

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Gene Therapy: Principles and Applications by Thomas Blankenstein (Editor) (1999); ISBN: 3764359722; http://www.amazon.com/exec/obidos/ASIN/3764359722/icongroupinterna

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Gene Therapy: The Use of DNA as a Drug by Pharmaceutical Press, Gavin Brooks; ISBN: 0853694559; http://www.amazon.com/exec/obidos/ASIN/0853694559/icongroupinterna

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Gene Therapy: Therapeutic Mechanisms and Strategies by Nancy Smyth Templeton (Editor), Danilo D. Lasic (Editor); ISBN: 0824776658; http://www.amazon.com/exec/obidos/ASIN/0824776658/icongroupinterna

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Gene Transfer and Gene Therapy: Proceedings of an E.I. Du Pont De Menours-UCLA Symposium Held at Tamarron, Colorado February 6-12, 1988 by Arthur L. Beaudet, et al; ISBN: 0845126865; http://www.amazon.com/exec/obidos/ASIN/0845126865/icongroupinterna

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Genetic intervention : gene transfer, gene therapy and gene modification (SuDoc HE 20.3173/3:OB-89/03) by Martin J. Cline; ISBN: 0160183294; http://www.amazon.com/exec/obidos/ASIN/0160183294/icongroupinterna

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Genetics, Ethics and Human Values: Human Genome Mapping, Genetic Screening and Gene Therapy: Human Genome Mapping, Genetic Screening and Gene Therapy by Z. Bankowski (Editor), A.M. Capron (Editor); ISBN: 9290360461; http://www.amazon.com/exec/obidos/ASIN/9290360461/icongroupinterna

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Human Gene Therapy by Eve K. Nichols, Institute of Medicine (1988); ISBN: 0674414802; http://www.amazon.com/exec/obidos/ASIN/0674414802/icongroupinterna

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Human gene therapy : technology analysis and market forecast; ISBN: 1569653895; http://www.amazon.com/exec/obidos/ASIN/1569653895/icongroupinterna

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Human Gene Therapy: A Background Paper by 52003009838; ISBN: 9999724868; http://www.amazon.com/exec/obidos/ASIN/9999724868/icongroupinterna

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Human Gene Therapy: Current Opportunities and Future Trends by G. M. Rubanyi (Editor), S. Yla-Herttuala (Editor) (2003); ISBN: 3540004130; http://www.amazon.com/exec/obidos/ASIN/3540004130/icongroupinterna

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Human Germline Gene Therapy: Scientific, Moral and Political Issues by David B., PhD Resnik, et al (1999); ISBN: 1570595860; http://www.amazon.com/exec/obidos/ASIN/1570595860/icongroupinterna

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Human radiation experimentation, ethics, and gene therapy : hearing before the Subcommittee on Energy of the Committee on Science, Space, and Technology, U.S. House of Representatives, One Hundred Third Congress, second session, February 10, 1994 (SuDoc Y 4.SCI 2:103/108); ISBN: 0160444292; http://www.amazon.com/exec/obidos/ASIN/0160444292/icongroupinterna

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Interdisciplinary Approaches to Gene Therapy: Legal, Ethical and Scientific Aspects by Stefan Muller (Editor), et al (1997); ISBN: 3540630562; http://www.amazon.com/exec/obidos/ASIN/3540630562/icongroupinterna

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Intrabodies: Basic Research and Clinical Gene Therapy Applications (Molecular Biology Intelligence Unit) by Wayne A. Marasco (Editor) (1998); ISBN: 3540641513; http://www.amazon.com/exec/obidos/ASIN/3540641513/icongroupinterna

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Market For Gene Therapy and Antisense Drugs [DOWNLOAD: PDF] by Kalorama Information (Author); ISBN: B00005TV7H; http://www.amazon.com/exec/obidos/ASIN/B00005TV7H/icongroupinterna

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Methods in Enzymology, Volume 346: Gene Therapy Methods by M. Ian Phillips (Editor), Ian Phillips (Editor) (2002); ISBN: 0121822478; http://www.amazon.com/exec/obidos/ASIN/0121822478/icongroupinterna

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Molecular Diagnosis and Gene Therapy: Proceedings of the 88th Falk Symposium (Part III of the Basel Liver Week), Held in Basel, Switzerland, October 22-23, 1995 (Falk Symposium, Vol 88) by H. E. Blum (Editor), et al (1996); ISBN: 0792387023; http://www.amazon.com/exec/obidos/ASIN/0792387023/icongroupinterna

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Molecular Genetics and Gene Therapy of Cardiovascular Disease by Stephen C. Mockrin (Editor); ISBN: 0824794087; http://www.amazon.com/exec/obidos/ASIN/0824794087/icongroupinterna

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Myoblast Transfer: Gene Therapy for Muscular Dystrophy (Medical Intelligence Unit) by Peter K. Law; ISBN: 1879702762; http://www.amazon.com/exec/obidos/ASIN/1879702762/icongroupinterna

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New Vistas in Therapeutics/Drug-Resistant Tuberculosis: From Drug Design to Gene Therapy: From Molecules to Macro-Economics (Annals of the New York Academy of Sciences, Vol 953A&B) by Paul Velletri (Editor), et al (2002); ISBN: 1573313351; http://www.amazon.com/exec/obidos/ASIN/1573313351/icongroupinterna

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Nonviral Vectors for Gene Therapy by Mien-Chie Hung (Author), et al; ISBN: 0123584655; http://www.amazon.com/exec/obidos/ASIN/0123584655/icongroupinterna

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Potential of Gene Therapy in Cancer (Natural Immunity, Vol 13, No 2-3) by E. Lotzova (Editor) (1994); ISBN: 3805559569; http://www.amazon.com/exec/obidos/ASIN/3805559569/icongroupinterna

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President's Cancer Panel : National Cancer Program : Human gene therapy (SuDoc HE 20.3152:P 92/5/990-4) by U.S. Dept of Health and Human Services; ISBN:

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B00010ALY4; http://www.amazon.com/exec/obidos/ASIN/B00010ALY4/icongroupinterna •

Progress in Gene Therapy: Basic & Clinical Frontiers by R. Bertolotti (Editor), et al; ISBN: 9067643289; http://www.amazon.com/exec/obidos/ASIN/9067643289/icongroupinterna

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Progress in Gene Therapy: Pioneering Stem Cell/Gene Therapy Trials (2003); ISBN: 9067643947; http://www.amazon.com/exec/obidos/ASIN/9067643947/icongroupinterna

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Protocols for Gene Transfer in Neuroscience: Towards Gene Therapy of Neurological Disorders by P. R. Lowenstein (Editor), L. W. Enquist (Editor); ISBN: 0471957666; http://www.amazon.com/exec/obidos/ASIN/0471957666/icongroupinterna

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Report of the Committee on the Ethics of Gene Therapy (Cm.: 1788) by Cecil Clothier (1992); ISBN: 0101178824; http://www.amazon.com/exec/obidos/ASIN/0101178824/icongroupinterna

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Retinal Dystrophies - No 255 : Functional Genomics to Gene Therapy by Novartis Foundation Symposium (Author) (2004); ISBN: 0470853573; http://www.amazon.com/exec/obidos/ASIN/0470853573/icongroupinterna

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Retro-Vectors for Human Gene Therapy (Medical Intelligence Unit) by Clague P. Hodgson (1996); ISBN: 0412102412; http://www.amazon.com/exec/obidos/ASIN/0412102412/icongroupinterna

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Ribozymes in Gene Therapy of Cancer: Biotechnology Intelligence Unit by K.J. Scanlon (Editor), M. Kashani-Sabet (Editor) (1998); ISBN: 354064167X; http://www.amazon.com/exec/obidos/ASIN/354064167X/icongroupinterna

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Ribozymes in the Gene Therapy of Cancer (Medical Intelligence Unit) by Kevin J. Scanlon (Editor), Mohammed Kashani-Sabet (Editor); ISBN: 1570595526; http://www.amazon.com/exec/obidos/ASIN/1570595526/icongroupinterna

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Somatic Gene Therapy by Patricia L. Chang (Editor); ISBN: 0849324408; http://www.amazon.com/exec/obidos/ASIN/0849324408/icongroupinterna

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Special Report on Gene Therapy Companies by K. K. Jain (Author); ISBN: 0471492906; http://www.amazon.com/exec/obidos/ASIN/0471492906/icongroupinterna

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Stem Cell Biology and Gene Therapy by Peter J. Quesenberry (Editor), et al (1998); ISBN: 0471146560; http://www.amazon.com/exec/obidos/ASIN/0471146560/icongroupinterna

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Stem Cells from Cord Blood, in Utero Stem Cells Development and Transplantation Inclusive Gene Therapy by Wolfgang Holgreve (Editor), et al; ISBN: 3540677011; http://www.amazon.com/exec/obidos/ASIN/3540677011/icongroupinterna

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Suicide Gene Therapy: Structure and Function by Caroline J. Springer (Editor) (2004); ISBN: 0896039714; http://www.amazon.com/exec/obidos/ASIN/0896039714/icongroupinterna

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Textbook of Gene Therapy by Kewal K. Jain (1998); ISBN: 0889371903; http://www.amazon.com/exec/obidos/ASIN/0889371903/icongroupinterna

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The Basis for Gene Therapy by Walter J., A.B., A.M., Ph.D., M.D. Burdette; ISBN: 0398071594; http://www.amazon.com/exec/obidos/ASIN/0398071594/icongroupinterna

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The Competitive Landscape of Cancer Gene Therapy (2nd issue) [DOWNLOAD: PDF] by BioSeeker Group AB (Author); ISBN: B00006AB50; http://www.amazon.com/exec/obidos/ASIN/B00006AB50/icongroupinterna

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The Development of Gene Therapy in Europe and the US: a Comparative Analysis (STEEP Special Reports) by Paul Martin, Sandy Thomas; ISBN: 0903622785; http://www.amazon.com/exec/obidos/ASIN/0903622785/icongroupinterna

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The Development of Human Gene Therapy (Cold Spring Harbor Monograph Series, 36) by Theodore Friedmann (Editor); ISBN: 0879695285; http://www.amazon.com/exec/obidos/ASIN/0879695285/icongroupinterna

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The Ethics of Human Gene Therapy by Leroy Walters, et al (1996); ISBN: 0195059557; http://www.amazon.com/exec/obidos/ASIN/0195059557/icongroupinterna

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The Genome Project and Gene Therapy by Sheila A.M. McLean (Editor) (2003); ISBN: 0754620557; http://www.amazon.com/exec/obidos/ASIN/0754620557/icongroupinterna

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The Internet Book of Gene Therapy: Cancer Therapeutics by Robert E. Sobol (Editor), Kevin J. Scanlon (Editor) (1996); ISBN: 0838531016; http://www.amazon.com/exec/obidos/ASIN/0838531016/icongroupinterna

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The Skin and Gene Therapy by Ulrich R. Hengge (Editor), Beatrix Volc-Platzer (Editor) (2000); ISBN: 3540667601; http://www.amazon.com/exec/obidos/ASIN/3540667601/icongroupinterna

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Therapeutic Applications of Suicide Gene Therapy by Scott M. S. Freeman (2002); ISBN: 1587060280; http://www.amazon.com/exec/obidos/ASIN/1587060280/icongroupinterna

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Tissue-engineered skeletal muscle organoids for reversible gene therapy brief report (SuDoc NAS 1.26:207803) by NASA; ISBN: B00010ZW1G; http://www.amazon.com/exec/obidos/ASIN/B00010ZW1G/icongroupinterna

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Understanding Gene Therapy by Nicholas R. Lemoine (Editor), Richard G. Vile (Editor) (2000); ISBN: 0387915125; http://www.amazon.com/exec/obidos/ASIN/0387915125/icongroupinterna

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Vascular Disease: Molecular Biology and Gene Therapy Protocols (Methods in Molecular Medicine, 30) by Andrew H. Baker (Editor) (1999); ISBN: 0896037312; http://www.amazon.com/exec/obidos/ASIN/0896037312/icongroupinterna

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Viral Vectors : Gene Therapy and Neuroscience Applications by Michael Kaplitt (Author), Arthur Loewy (Author) (1995); ISBN: 0123975719; http://www.amazon.com/exec/obidos/ASIN/0123975719/icongroupinterna

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Viral Vectors for Gene Therapy: Methods and Protocols (Methods in Molecular Medicine, 76) by Curtis A. MacHida (Editor), Jules G. Constant (2002); ISBN: 1588290190; http://www.amazon.com/exec/obidos/ASIN/1588290190/icongroupinterna

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Viral Vectors: Basic Science and Gene Therapy by Angel Cid-Arregui (Editor), Alejandro Garcia-Carranca (Editor); ISBN: 188129935X; http://www.amazon.com/exec/obidos/ASIN/188129935X/icongroupinterna

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Viruses in Human Gene Therapy by Jean-Michel H. Vos, J. Vos; ISBN: 0412631601; http://www.amazon.com/exec/obidos/ASIN/0412631601/icongroupinterna

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W. French Anderson: Father of Gene Therapy by Bob Burke, Barry Epperson; ISBN: 1885596251; http://www.amazon.com/exec/obidos/ASIN/1885596251/icongroupinterna

Chapters on Gene Therapy In order to find chapters that specifically relate to gene therapy, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and gene therapy 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 “gene therapy” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on gene therapy: •

Gene Therapy for Metabolic Disease Source: in LeRoith, D.; Taylor, S.I.; Olefsky, J.M., eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, PA: Lippincott-Raven Publishers. 1996. p. 432-438. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740-5184. (800) 777-2295. Fax (301) 824-7390. PRICE: $199.00. ISBN: 0397514565. Summary: Somatic gene therapy refers to the introduction of genetic material into a specific organ or tissue in order to treat an inherited or acquired disease. This chapter, from a medical textbook on diabetes, presents an overview of the current status of somatic gene therapy for metabolic disease. The authors focus on liver-directed gene transfer for the purpose of illustration and uses homozygous familial hypercholesterolemia as a model. A final section of the chapter covers some of the issues related to somatic gene therapy for Type 1 diabetes mellitus (insulin-dependent or IDDM). The authors note that most of the issues relating to the successful development of gene therapy for diabetes mellitus are technical issues similar to those encountered in other diseases: targeting of the transgene to the appropriate tissue and achieving stable, regulated expression of the transgene. Another important issue for diabetes mellitus is the choice of gene for gene transfer. For most patients with IDDM, the insulin gene would appear to be the appropriate therapeutic gene for transfer. Another approach would be to transduce immunomodulatory cytokines into the pancreatic islets to prevent the autoimmune destruction that causes Type 1 diabetes. 1 figure. 2 tables. 66 references.

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to gene therapy have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:11 11 You will need to limit your search to “Directory” and “gene therapy” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.”

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•

Educational Programs for Deaf Students Source: American Annals of the Deaf. 147 (2): 83-176. Summary: This article reviews controversial issues in the prevention, treatment, and accommodation of deafness in America's educational institutions. The narrative examines topics that have ethical implications for professionals, such as genetic counseling, gene therapy, a parent's right to have a deaf child, cochlear implants, and the increasing federal emphasis on educational outcomes that are not relevant to deaf students. Trends in research and public awareness about deafness are highlighted. A directory provides contact information for special schools and local programs in the United States and Canada. Specific services and communication methods used by the schools are identified in a matrix format. A list of postsecondary programs is also included.

Select your preferred language and the format option “Directory.” Type “gene therapy” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

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CHAPTER 8. MULTIMEDIA ON GENE THERAPY Overview In this chapter, we show you how to keep current on multimedia sources of information on gene therapy. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on gene therapy is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “gene therapy” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, 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 “Videorecording (videotape, videocassette, etc.).” Type “gene therapy” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on gene therapy: •

48 Hours: A Search for A Cure Contact: Columbia Broadcasting System News, 555 W 57th St, New York, NY, 10019, (212) 975-4321. Summary: This videotape follows three HIV-positive persons as they participate in a clinical drug trial for a gene therapy treatment. They were among 25 patients in the trial receiving injections of a genetically-engineered HIV virus, a treatment theoretically able to give T-cells a "better radar" for fighting the HIV infection. Interviews with the three -a single mother, a hemophiliac father of three teenagers, and a young gay man -- reveal their philosophies and fears about the illness, as well as their hopes for the treatment and their own futures. Their physician, who treats over one thousand HIV patients in his practice, discusses the clinical trial selection process, his anxious optimism about the drug as he watches others with AIDS dying daily, and his personal experiences living with polio. The correspondent also interviews representatives from Viagene, the biotech firm that developed the drug and analyses the ongoing test results of the trial participants. The show concludes with a one- year update on the trial: two of patients

248 Gene Therapy

are significantly holding their infection at bay; one is failing to be carefully monitored and may be applying for other trials; and Viagene reports on the results to date at the Tenth Annual AIDS Conference.

Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, 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 “Sound Recordings.” Type “gene therapy” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on gene therapy: •

AIDS/HIV Update 1 & 2: 15th National Lesbian & Gay Health Conference & 11th Annual AIDS/HIV Forum; Houston, TX, July 20-25, 1993 Contact: Encore Cassettes, PO Box 231340, San Diego, CA, 92194, (619) 596-8402. Summary: These sound recordings contain the transcript of a medical update on the status of HIV and AIDS testing, research, and treatment. The first speaker discusses the use of CD4 cell counts as "surrogate" markers for the amount of virus to chart the progression of HIV disease. The point is made that CD4 counts are a percentage of cells, and are not a good choice to quantify disease remission as a result of treatment. The speaker continues with a discussion of viral burden, methods of virologic detection, and the development of laboratory markers for long-term survivors. The formation of syncytia in virus culture is seen as a significant development in determining long-term survival. The presentation continues with a review on the progression of HIV and AIDS in women, a history of HIV disease, current clinical trial directions, antiviral treatments, new drug development, and research on gene therapy. Current standards and future directions for cytomegalovirus (CMV) therapy are explored. The last speaker of the session discusses other opportunistic infections, including chronic sinusitis; conditions that clinicians should look for in immunocompromised individuals; and the occurrence of increasingly difficult to diagnose infections.

Bibliography: Multimedia on Gene Therapy The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in gene therapy (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on gene therapy: •

Challenges in human gene therapy [videorecording] Source: a presentation of BioConferences International, Inc. and Mentor Media, Inc., in cooperation with PBS Adult Learning Satellite Service; Year: 1994; Format: Videorecording; Bethesda, MD: BioConferences International, c1994

•

Colorectal cancer [videorecording]: emerging therapeutics, gene therapy, practical issues in genetic testing Source: Society of Surgical Oncology & the World Federation

Multimedia 249

of Surgical Oncology Societies' Cancer Symposium, March 26-29, 1998, San Diego, CA; Year: 1998; Format: Videorecording; Chicago: Teach 'em, [1998] •

Functional analyses of the rep proteins of adeno-associated virus type 2 [videorecording]: implications for human gene therapy Source: Medical Arts and Photography Branch; Year: 1996; Format: Videorecording; [Bethesda, Md.: National Institutes of Health, 1996]

•

Gene therapy [videorecording] Source: [presented by] Children's Hospital, Boston; Year: 1994; Format: Videorecording; Boynton Beach, FL: Distributed by Universal Health Communications, [1994]

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Gene therapy [videorecording]: medicine of the future Source: a production of Clinical Center Communications and Medical Arts & Photography Branch; Year: 1992; Format: Videorecording; [Bethesda, Md.]: National Institutes of Health, 1992

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Gene therapy for inherited diseases of metabolism [videorecording] Source: John A. Barranger; Year: 1996; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1996

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Gene therapy protocols [videorecording]: review & analysis. Year: 1993; Format: Videorecording; Bethesda, MD: BioConferences International, c1993

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Gene therapy. Year: 9999; Houndmills, Basingstoke, Hampshire, UK: Macmillan Press Ltd., c1994-

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Human gene therapy [videorecording] Source: BioEast '92; sponsored by Genetic engineering news, IBEX, BioConferences Intl., Inc; Year: 1992; Format: Videorecording; Potomac, MD: BioConferences International, c1992

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Human gene therapy [videorecording]: clinical IND and practical considerations Source: BioEast '91; sponsored by BioConferences International, Inc., Genetic Engineering News, IBEX; co-sponsored by the Penn State University, Biotechnology and Bioprocessing Re; Year: 1991; Format: Videorecording; Bethesda, MD: BioConferences International, c1991

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International Conference on Gene Therapy & Vaccines for Cancer [videorecording]. Source: International Conference on Gene Therapy & Vaccines for Cancer (1994: Washington, D.C.); Year: 1994; Format: Videorecording; Bethesda, Md.: BioConferences International, c1994

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Molecular miracles [videorecording]: human gene therapy and the future of modern medicine Source: a presentation of Films for the Humanities & Sciences; a production of Carolina Teleproductions; a presentation of Carolina Biological Supply Company; Year: 1995; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c1995

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New delivery systems for gene therapy [videorecording]. Year: 1993; Format: Videorecording; Bethesda, MD: BioConferences International, c1993

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The Human Genome Project [electronic resource]: science, law, and social change in the 21st century Source: Whitehead Policy Symposium; Year: 1998; Format: Electronic resource; [Cambridge, Mass.]: Whitehead Institute for Biomedical Research; [Boston, Mass.]: American Society of Law, Medicine & Ethics, c1998

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CHAPTER 9. PERIODICALS AND NEWS ON GENE THERAPY Overview In this chapter, we suggest a number of news sources and present various periodicals that cover gene therapy.

News Services and Press Releases One of the simplest ways of tracking press releases on gene therapy 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 “gene therapy” (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 gene therapy. 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 “gene therapy” (or synonyms). The following was recently listed in this archive for gene therapy: •

Therapeutic angiogenesis with gene therapy improves myocardial perfusion Source: Reuters Medical News Date: November 05, 2003

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Gene therapy improves blood flow in heart Source: Reuters Health eLine Date: November 05, 2003

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Gene therapy prevents obesity in mice: study Source: Reuters Health eLine Date: November 04, 2003

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Plasmid-based gene therapy for muscular dystrophy succeeds in preclinical study Source: Reuters Medical News Date: October 20, 2003

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Oncogene activation to blame for leukemia with SCID-X1 gene therapy Source: Reuters Medical News Date: October 16, 2003

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Gene therapy did cause cancer in boys, study shows Source: Reuters Health eLine Date: October 16, 2003

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Avigen to resume gene therapy trial for hemophilia B Source: Reuters Medical News Date: September 09, 2003

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Severe angina responded to VEGF-2 gene therapy Source: Reuters Medical News Date: September 04, 2003

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First Parkinson's gene therapy patient optimistic Source: Reuters Medical News Date: August 20, 2003

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Gene therapy delays Lou Gehrig disease in mice Source: Reuters Health eLine Date: August 07, 2003

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Adeno-associated virus is safe vector for cystic fibrosis gene therapy Source: Reuters Industry Breifing Date: July 24, 2003

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Gene therapy attenuates focal seizure disorder in rats Source: Reuters Medical News Date: July 14, 2003

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Parvoviruses may be effective as cancer gene therapy vectors Source: Reuters Medical News Date: July 04, 2003

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IL-2 gene therapy plus radiation generates potent antitumor response Source: Reuters Industry Breifing Date: June 23, 2003

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Molecular imaging opens door to new gene therapy techniques for cancer Source: Reuters Industry Breifing Date: June 19, 2003

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Enzo says hold on gene therapy trial lifted, posts lower fiscal Q3 earnings Source: Reuters Industry Breifing Date: June 16, 2003

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Italy partly lifts gene therapy ban Source: Reuters Health eLine Date: June 13, 2003

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Modified Ebola virus protein may help target cystic fibrosis gene therapy Source: Reuters Medical News Date: June 12, 2003

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MLV retroviral gene therapy vector may pose higher risk than previously thought Source: Reuters Medical News Date: June 12, 2003

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Gene therapy technique may pose harm: study Source: Reuters Health eLine Date: June 12, 2003

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Gene therapy trial for epidermolysis bullosa underway Source: Reuters Industry Breifing Date: June 06, 2003

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Adeno-associated virus gene therapy vector integrates into mouse genes Source: Reuters Industry Breifing Date: June 02, 2003

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Genetronics, Genteric to study new gene therapy delivery Source: Reuters Industry Breifing Date: May 22, 2003

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Gene therapy may boost success of angioplasty Source: Reuters Health eLine Date: May 22, 2003

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VEGF gene therapy during angioplasty and stenting can improve myocardial blood flow Source: Reuters Industry Breifing Date: May 19, 2003

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UK watchdog backs gene therapy for X-SCID despite French leukaemia cases Source: Reuters Industry Breifing Date: May 12, 2003

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Gene therapy may hold key to treating hepatitis B Source: Reuters Health eLine Date: May 12, 2003

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Post-prostatectomy impotence may eventually be treated with gene therapy Source: Reuters Medical News Date: April 28, 2003

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Gene therapy helps counter impotence in rats Source: Reuters Health eLine Date: April 28, 2003

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New gene therapy cures diabetes in mice Source: Reuters Health eLine Date: April 21, 2003

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Gene therapy reverses diabetes in mouse model Source: Reuters Medical News Date: April 21, 2003

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Gene therapy vector linked to lung injury in mice Source: Reuters Medical News Date: April 15, 2003

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Gene therapy trials continue to show benefit in heart failure Source: Reuters Industry Breifing Date: April 01, 2003

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Gene therapy may ease Alzheimer's in mice Source: Reuters Health eLine Date: March 28, 2003

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Genzyme Biosurgery, Excigen in gene therapy alliance Source: Reuters Industry Breifing Date: March 25, 2003

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Tumor susceptibility to gene therapy varies with expression of vector receptor Source: Reuters Medical News Date: March 14, 2003

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G-CSF-mobilized cells can be safely used for retroviral gene therapy Source: Reuters Industry Breifing Date: March 13, 2003

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VEGF-C gene therapy induces therapeutic lymphangiogenesis Source: Reuters Medical News Date: March 06, 2003

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Lack of integrin hinders gene therapy for aging heart Source: Reuters Medical News Date: March 03, 2003

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FDA advisors say most gene therapy studies can proceed Source: Reuters Industry Breifing Date: February 28, 2003

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FDA advisers: Most gene therapy studies can proceed Source: Reuters Health eLine Date: February 28, 2003

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FDA advisers say most gene therapy studies can proceed Source: Reuters Medical News Date: February 28, 2003

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Microbubble delivery may aid gene therapy effect Source: Reuters Health eLine Date: February 24, 2003

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Transgene phase I gene therapy trials yield positive data Source: Reuters Industry Breifing Date: February 10, 2003

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Italy extends gene therapy ban Source: Reuters Industry Breifing Date: February 06, 2003

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Italy extends ban on gene therapy trials Source: Reuters Health eLine Date: February 06, 2003

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Cell Genesys to drop gene therapy program, lays off 17 Source: Reuters Industry Breifing Date: February 04, 2003

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FDA grants gene therapy orphan drug status for A1AD Source: Reuters Industry Breifing Date: January 31, 2003

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CORRECTION: Gene therapy safe in patients with severe vascular disease Source: Reuters Medical News Date: January 30, 2003

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Parents agonize over move to halt gene therapy Source: Reuters Health eLine Date: January 16, 2003

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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 “gene therapy” (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 “gene therapy” (or synonyms). If you know the name of a company that is relevant to gene therapy, 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/.

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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 “gene therapy” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “gene therapy” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on gene therapy: •

Gene Therapy Holds Promise for Sjogrens Source: Moisture Seekers Newsletter. 13(7-8): 1. July-August 1995. Contact: Available from Sjogren's Syndrome Foundation, Inc. 8120 Woodmont Avenue, Suite 530, Bethesda MD 20814-1437. (301) 718-0300 or (800) 475-6473. Fax (301) 718-0322. Website: www.sjogrens.org. Summary: This brief newsletter article reports on recent research in the use of gene therapy to protect or repair salivary glands destroyed by radiation or disease, such as Sjogren's syndrome. The article describes how the gene therapy works and briefly notes the researchers involved in this area. The article interviews one of the researchers on the techniques currently under study as well as on when readers can expect to see clinical trials of these methods. One sidebar presents general information about Sjogren's syndrome and its symptoms.

Academic Periodicals covering Gene Therapy Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to gene therapy. In addition to these sources, you can search for articles covering gene therapy 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 Institute12: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

12

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

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

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/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

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

•

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

•

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

•

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

•

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.13 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:14 •

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

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

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

•

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/

•

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

•

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/

•

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

•

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

13

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). 14 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

•

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 Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “gene therapy” using the “Detailed Search” option. Go directly to the following hyperlink: 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 the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “gene therapy” (or synonyms) into the “For these words:” box. The following is a sample result: •

A Town Forum on AIDS: Latest Advances in HIV/AIDS Vaccines and Treatments Contact: Institute for Advanced Studies in Aging and Geriatric Medicine, 1819 Pennsylvania Ave NW Ste 400, Washington, DC, 20006-3603, (202) 333-8845, http://www.iasia.org. Summary: An education outreach of the Institute for Advanced Studies in Immunology and Aging, This public forum consists of five scientific presentations, an advocate and journalist discussion panel, and an audience question period. The presentation covers the following topics: presence and replication of HIV in the lymph nodes from the onset of infection, antisense gene therapy which targets viral nucleic acids; antiviral drug therapy coupled with immunomodulators; therapeutic AIDS vaccines in development, and information exchange between doctors and patients. The panel discussion covers the importance of CD4 cells as markers and the functioning rather than their actual number of them which is useful as a marker. In addition, lack of data on gynecological symptoms in AIDS emphasizes the need to recruit women into drug trials. The audience consists of 70 minority students in health care curricula whose concerns are the effects of mental health on the immune system and the idea that vaccine development may be hindered because the current social environment discourages people from being tested.

•

Report From the IX International Conference on AIDS; Berlin, Germany, July 1993: A Monograph for People Who Manage HIV Infection Contact: Caremark Rx Incorporated, 625 Barclay Blvd, Lincolnshire, IL, 60069, (847) 6347900, http://www.caremark.com. Summary: This report provides clinicians with information on key findings presented at the 1993 IX International Conference on AIDS. The report consists of synopses of recent developments concerning management of the HIV-positive patient from the disciplines of clinical medicine, epidemiology, immunology, molecular biology, psychology, and virology. The topics covered include: pathogenesis of HIV infection; mechanisms of pathogenesis and long-term survival with HIV/AIDS; HIV, cofactors, and AIDS; molecular targets for interference with viral replication; markers of nonprogression; new data on and resistance to antiretroviral agents; experimental and new antiretroviral compounds; gene therapy; immunotherapeutics; and cytokines. Discussions related to

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opportunistic infections and manifestations of HIV covered: tuberculosis; Kaposi's sarcoma; bacterial and viral infections; lymphoma; cervical and other neoplasias; and neuropsychiatric, pulmonary, hematologic, and dermatologic manifestations.

The NLM Gateway15 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.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “gene therapy” (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 22760 1062 833 152 5 24812

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 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.19 Simply search by “gene therapy” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

15

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

16

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). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19

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 Biologists20 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.21 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.22 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/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

20 Adapted 21

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. 22 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 gene therapy 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 gene therapy. 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 gene therapy. 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 “gene therapy”:

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•

Other guides Cloning http://www.nlm.nih.gov/medlineplus/cloning.html Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html Genes and Gene Therapy http://www.nlm.nih.gov/medlineplus/genesandgenetherapy.html Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Genetic Testing/Counseling http://www.nlm.nih.gov/medlineplus/genetictestingcounseling.html Huntington's Disease http://www.nlm.nih.gov/medlineplus/huntingtonsdisease.html

Within the health topic page dedicated to gene therapy, the following was listed: •

General/Overviews Gene Therapy Source: Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/medicine/genetherapy.ht ml Introduction to Genetics and Genetic Testing Source: Nemours Foundation http://kidshealth.org/parent/system/medical/genetics.html JAMA Patient Page: Genetics Source: American Medical Association http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZZCI25TTC&s ub_cat=202

•

Specific Conditions/Aspects Cloning Source: Dept. of Energy http://www.ornl.gov/sci/techresources/Human_Genome/elsi/cloning.shtml Genes and Populations Source: National Institute of General Medical Sciences http://www.nigms.nih.gov/news/science_ed/genepop/faq.html Human Gene Therapy: Harsh Lessons, High Hopes Source: Food and Drug Administration http://www.fda.gov/fdac/features/2000/500_gene.html Medicine and the New Genetics: Gene Testing, Pharmacogenomics, and Gene Therapy Source: Dept. of Energy, Human Genome Project http://www.ornl.gov/TechResources/Human_Genome/publicat/primer2001/6.ht ml

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Your Genes, Your Choices: Exploring the Issues Raised by Genetic Research Source: American Association for the Advancement of Science, Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/publicat/genechoice/ind ex.html •

Children Gene Therapy and Your Child Source: Nemours Foundation http://kidshealth.org/parent/system/medical/gene_therapy.html What is a Gene? Source: Nemours Foundation http://kidshealth.org/kid/talk/qa/what_is_gene.html You and Your Genes: Making It in a Tough Environment Source: National Institute of Environmental Health Sciences http://www.niehs.nih.gov/oc/factsheets/genes/home.htm

•

From the National Institutes of Health Frequently Asked Questions about Genetics Source: National Human Genome Research Institute http://www.genome.gov/page.cfm?pageID=10001191 Genetics Home Reference Source: National Library of Medicine http://ghr.nlm.nih.gov/ Human Genome Project Source: National Human Genome Research Institute http://www.genome.gov/page.cfm?pageID=10001694 Questions and Answers about Gene Therapy Source: National Cancer Institute http://cis.nci.nih.gov/fact/7_18.htm

•

Journals/Newsletter Genomics Weekly Update Source: Centers for Disease Control and Prevention http://www.cdc.gov/genomics/update/current.htm

•

Latest News Ally in AIDS Fight: Smallpox Source: 11/19/2003, United Press International http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14751 .html Beyond Genes: Scientists Venture Deeper Into the Human Genome Source: 10/09/2003, National Human Genome Research Institute http://www.nih.gov/news/pr/oct2003/nhgri-09.htm

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'Clock' Genes Steer Cancer Growth in Mice Source: 11/18/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14726 .html More News on Genes and Gene Therapy http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/alphanews_g.html#G enesandGeneTherapy Study Links Genetic, Non-inherited Breast Cancer Source: 11/25/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14834 .html •

Law and Policy Genetics Privacy and Legislation Source: Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/elsi/legislat.html Human Gene Therapy and the Role of the Food and Drug Administration Source: Food and Drug Administration http://www.fda.gov/cber/infosheets/genezn.htm Issues in Genetics and Health Source: National Human Genome Research Institute http://www.genome.gov/page.cfm?pageID=10001740

•

Organizations GeneTests Source: Children's Health Care System, Seattle http://www.genetests.org/ Human Genome Project Information Source: Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/home.html National Human Genome Research Institute http://www.genome.gov/ National Reference Center for Bioethics Literature http://www.georgetown.edu/research/nrcbl/nrc/

•

Research Beyond Genes: Scientists Venture Deeper Into the Human Genome Source: National Human Genome Research Institute http://www.nih.gov/news/pr/oct2003/nhgri-09.htm Facts about Genome Sequencing Source: Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/faq/seqfacts.html Functional and Comparative Genomics Source: Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/faq/compgen.html

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Gene Therapy to Treat Angina Appears Safe Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3000956 Mouse Genome and the Measure of Man Source: National Human Genome Research Institute http://www.genome.gov/page.cfm?pageID=10005831 Mutations in DNA Mismatch Repair Genes Source: American College of Physicians http://www.annals.org/cgi/content/full/138/7/I-53 New Bioinformatics Tool Will Help Design Cancer Drugs Source: National Cancer Institute http://www.cancer.gov/newscenter/weinstein Newly Identified Tumor Suppressor Cooperates with p53 to Protect Mice against Tumors Source: National Cancer Institute http://www.nih.gov/news/pr/aug2003/nci-07.htm NHGRI Study May Help Scientists Design Safer Methods for Gene Therapy Source: National Human Genome Research Institute http://www.nih.gov/news/pr/jun2003/nhgri-12.htm Only Two Genes Needed to Form Heads in Model Organism Embryos Source: National Institute of General Medical Sciences http://www.nigms.nih.gov/news/releases/brief_solnica-krezel.html Progress Made in Sequencing of Model Organisms' Genomes Source: National Human Genome Research Institute http://www.nih.gov/news/pr/may2003/nhgri-20.htm Research Brief: A Protein to Tie Up Loose Ends Source: National Institute of General Medical Sciences http://www.nigms.nih.gov/news/releases/brief_lieber.html Researchers Discover Use of Novel Mechanism Preserves Y Chromosome Genes Source: National Human Genome Research Institute http://www.nih.gov/news/pr/jun2003/nhgri-18.htm Scientists Glimpse Cellular Machines at Work Inside Living Cells Source: National Cancer Institute http://www.cancer.gov/newscenter/pressreleases/machines SNP (Single Nucleotide Polymorphisms) Source: Dept. of Energy http://www.ornl.gov/TechResources/Human_Genome/faq/snps.html Study Finds Direction of Enzymes Affects DNA Repair Source: National Institute of Environmental Health Sciences http://www.niehs.nih.gov/oc/news/wilsdna.htm •

Teenagers Basics on Genes and Genetic Disorders Source: Nemours Foundation http://kidshealth.org/teen/your_body/health_basics/genes_genetic_disorders.ht

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ml 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 Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on gene therapy. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Usher Syndrome: Information You Need to Know Source: Owings Mill, MD: Foundation Fighting Blindness, National Retinitis Pigmentosa Foundation, Inc. 1997. 32 p. Contact: Available from Foundation Fighting Blindness. National Retinitis Pigmentosa Foundation, Inc., 11435 Cronhill Drive, Owings Mill, MD 21117-2220. (800) 683-5555 or (410) 568-0150. TDD (800) 683-5551 or (410) 363-7139. Fax (410) 363-2393. Website: www.blindness.org. PRICE: Single copy free. Summary: Printed in large type, this booklet was prepared to explain Usher syndrome to people with the condition, to their families, and to other interested individuals. There are about ten to twenty thousand people with Usher Syndrome in the United States, which is characterized by serious hearing impairment, detection at birth or in early childhood, and progressive loss of vision caused by retinitis pigmentosa (RP), a degeneration of the retina. Topics covered include the definition of Usher Syndrome and its causes, photoreceptor cells in the retina and why they deteriorate, inheriting Usher Syndrome, symptoms, diagnostic tests, progression of Usher syndrome, cataracts, legal blindness, career issues, issues of hearing loss, and present research interests, including retinal cell transplantation, gene therapy, drug therapy, and surgical techniques. The booklet addresses activities of daily living, including the use of a guide dog, hearing aids, cane, and other assistive devices and aids. The booklet also discusses the emotional and psychosocial impact of Usher syndrome. A description of the goals and activities of the Foundation Fighting Blindness is also provided. The booklet concludes with ten questions to ask the eye doctor. 2 figures.

•

Well-Connected: Osteoarthritis Source: New York, NY: Nidus Information Services, Inc. 1998. 8 p. Contact: Available from Nidus Information Services, Inc. 175 Fifth Avenue, Suite 2338, New York, NY 10010. (800) 334-WELL or (212) 260-4268. Fax (212) 529-2349. E-mail:

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[email protected]. Website: www.well-connected.com. PRICE: $5.95 plus shipping and handling. Summary: This fact sheet uses a question and answer format to provide people who have osteoarthritis with information on this degenerative joint disease. The fact sheet begins by describing the general features of osteoarthritis and the specific features of osteoarthritis of the fingers, knees, hips, and spine. This is followed by a discussion of the symptoms of osteoarthritis, focusing on pain. A few of the most common disorders that can be confused with osteoarthritis are then identified. These include rheumatoid arthritis, chondrocalcinosis, and Charcot's joints. Other topics include risk factors for osteoarthritis, including aging, obesity, heavy labor, and vitamin D deficiency, and causes of osteoarthritis, namely genetic factors, muscle weakness, anatomical abnormalities, trauma, and obesity. The fact sheet next outlines ways to prevent or slow the progression of osteoarthritis, including losing weight, exercising, undergoing hormone replacement therapy, and consuming adequate amounts of antioxidant vitamins and other important nutrients. This is followed by a discussion of the use of xrays, blood tests, and tests of the synovial fluid to confirm the diagnosis of osteoarthritis. Lifestyle measures for managing osteoarthritis are detailed: occupational changes, exercise, weight reduction, heat therapy, mechanical aids, alternative treatments, the arthritis self-help course, and cognitive behavioral therapy. Also discussed are the drug treatments for osteoarthritis: common pain relievers such as acetaminophen and nonsteroidal anti-inflammatory drugs; drugs derived from natural joint substances such as hyaluronic acid, glucosamine, and chondroitin sulfate; capsaicin; steroids; and gene therapy. Surgical treatments for osteoarthritis are also highlighted, including arthroscopy, resection arthroplasty, osteotomy, chondroplasty, arthrodesis, and joint replacement. The article concludes with comments on the emotional ramifications of osteoarthritis and a list of helpful organizations. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Gene Therapy (Journal) Summary: A monthly publication, this journal is targeted to clinicians and researchers with an interest in genetic disease and the use of genetic techniques in disease control. Source: Commercial Entity--Follow the Resource URL for More Information http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=1947

•

Gene Therapy and Cystic Fibrosis Summary: A patient education brochure that discusses gene therapy as a potentially a life-saving treatment that tackles the root cause of cystic fibrosis (CF), rather than the symptoms. Source: Cystic Fibrosis Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5032

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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 gene therapy. 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

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to gene therapy. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with gene therapy. 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 gene therapy. 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

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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 “gene therapy” (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 “gene therapy”. 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 “gene therapy” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. 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 “gene therapy” (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.23

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

23

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)24: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

24

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

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

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

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

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

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

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

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

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

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

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

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

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

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

•

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/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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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

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

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

•

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

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

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/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

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

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

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

283

GENE THERAPY DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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 Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Absenteeism: Chronic absence from work or other duty. [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] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [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] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Actin: Essential component of the cell skeleton. [NIH] Actinin: A protein factor that regulates the length of R-actin. It is chemically similar, but immunochemically distinguishable from actin. [NIH] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many

284 Gene Therapy

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] Acyclovir: Functional analog of the nucleoside guanosine. It acts as an antimetabolite, especially in viruses. It is used as an antiviral agent, especially in herpes infections. [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 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] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [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] Adjuvant Therapy: Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. [NIH]

Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases

Dictionary 285

catecholamines. [NIH] 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]

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] 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] 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 of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [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] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Akinesia: 1. Absence or poverty of movements. 2. The temporary paralysis of a muscle by the injection of procaine. [EU] 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] Alkaline: Having the reactions of an alkali. [EU]

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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]

Allantois: An embryonic diverticulum of the hindgut of reptiles, birds, and mammals; in man its blood vessels give rise to those of the umbilical cord. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allografts: A graft of tissue obtained from the body of another animal of the same species but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [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-helix: One of the secondary element of protein. [NIH] 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] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amaurosis: Partial or total blindness from any cause. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] 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

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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] 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] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [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] 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] 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] 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] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation,

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especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [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] Angiogram: An x-ray of blood vessels; the person receives an injection of dye to outline the vessels on the x-ray. [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] Angioplasty, Laser: A technique utilizing a laser coupled to a catheter which is used in the dilatation of occluded blood vessels. This includes laser thermal angioplasty where the laser energy heats up a metal tip, and direct laser angioplasty where the laser energy directly ablates the occlusion. One form of the latter approach uses an excimer laser which creates microscopically precise cuts without thermal injury. When laser angioplasty is performed in combination with balloon angioplasty it is called laser-assisted balloon angioplasty. [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] Animals, Transgenic: Animals, or the offspring of such animals, into which cloned genetic material has been experimentally transferred by microinjection of foreign DNA, either directly or into embryos or differentiated cell types. Transgenic rabbits, mice, fish, Xenopus, sheep, pigs, and chickens have been produced using genes of sea urchins, Candida, Drosophila, and mice. [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]

Anomalies: Birth defects; abnormalities. [NIH] Anterior Cruciate Ligament: A strong ligament of the knee that originates from the posteromedial portion of the lateral condyle of the femur, passes anteriorly and inferiorly between the condyles, and attaches to the depression in front of the intercondylar eminence of the tibia. [NIH] Antiangiogenesis: Prevention of the growth of new blood vessels. [NIH] Antiangiogenic: Having to do with reducing the growth of new blood vessels. [NIH] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] 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]

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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 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] Anticodon: The sequential set of three nucleotides in transfer RNA that interacts with its complement in messenger RNA, the codon, during translation in the ribosome. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] 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-infective: An agent that so acts. [EU] 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] Antimetastatic: Having to do with reducing inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [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] Antiviral Agents: Agents used in the prophylaxis or therapy of virus diseases. Some of the

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ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. [NIH] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aperture: A natural hole of perforation, especially one in a bone. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [NIH] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [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 presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arenavirus: The only genus in the family Arenaviridae. It contains two groups LCM-Lassa complex viruses and Tacaribe complex viruses, which are distinguished by antigenic relationships and geographic distribution. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [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] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH]

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Arthroscopy: Endoscopic examination, therapy and surgery of the joint. [NIH] Articular: Of or pertaining to a joint. [EU] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] 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] Aspartate: A synthetic amino acid. [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 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] Asymptomatic: Having no signs or symptoms of disease. [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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral

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afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autopsy: Postmortem examination of the body. [NIH] Avian: A plasmodial infection in birds. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [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] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [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 Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [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] Basophil: A type of white blood cell. Basophils are granulocytes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [NIH] Bilateral: Affecting both the right and left side of body. [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] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in

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the treatment of gallstones. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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] 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 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] 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] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH]

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Blood Glucose: Glucose in blood. [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] 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 scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [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] Brain Diseases: Pathologic conditions affecting the brain, which is composed of the intracranial components of the central nervous system. This includes (but is not limited to) the cerebral cortex; intracranial white matter; basal ganglia; thalamus; hypothalamus; brain stem; and cerebellum. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH]

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Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Cadaver: A dead body, usually a human body. [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 many enzymatic processes. [NIH] Cancer vaccine: A vaccine designed to prevent or treat cancer. [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] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] 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] 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] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH]

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Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] 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 blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [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] 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] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [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] 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] 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 Count: A count of the number of cells of a specific kind, usually measured per unit

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volume of sample. [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] 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 Fusion: Fusion of somatic cells in vitro or in vivo, which results in somatic cell hybridization. [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 Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [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] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] 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] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU]

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Ceroid: A naturally occurring lipid pigment with histochemical characteristics similar to lipofuscin. It accumulates in various tissues in certain experimental and pathological conditions. [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] 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] Chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. [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] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [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] 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] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [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] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]

Chorion: The outermost extraembryonic membrane. [NIH] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromaffin System: The cells of the body which stain with chromium salts. They occur along the sympathetic nerves, in the adrenal gland, and in various other organs. [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]

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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] Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome. [NIH] 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 lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic Progressive External Ophthalmoplegia: Paralysis of the extraocular muscles. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Ciliated cells: Epithelial cells with fine hair-like strands on their free borders. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [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] Claudication: Limping or lameness. [EU] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [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] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [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] 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]

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Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Implants: Electronic devices implanted beneath the skin with electrodes to the cochlear nerve to create sound sensation in persons with sensorineural deafness. [NIH] Cochlear Nerve: The cochlear part of the 8th cranial nerve (vestibulocochlear nerve). The cochlear nerve fibers originate from neurons of the spiral ganglion and project peripherally to cochlear hair cells and centrally to the cochlear nuclei (cochlear nucleus) of the brain stem. They mediate the sense of hearing. [NIH] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [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] Coliphages: Viruses whose host is Escherichia coli. [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] Colloidal: Of the nature of a colloid. [EU] 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 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

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'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] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [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] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH]

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Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [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] Contact Inhibition: Arrest of cell locomotion or cell division when two cells come into contact. [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] Contraception: Use of agents, devices, methods, or procedures which diminish the likelihood of or prevent conception. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] 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] 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] Contusion: A bruise; an injury of a part without a break in the skin. [EU] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH]

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Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [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] Corneum: The superficial layer of the epidermis containing keratinized cells. [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 Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] 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] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] 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] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] 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] Cyanogen Bromide: Cyanogen bromide (CNBr). A compound used in molecular biology to digest some proteins and as a coupling reagent for phosphoroamidate or pyrophosphate internucleotide bonds in DNA duplexes. [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]

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Cyclin: Molecule that regulates the cell cycle. [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] 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]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [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] 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] 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] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]

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Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [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] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Defective Viruses: Viruses which lack a complete genome so that they cannot completely replicate or cannot form a protein coat. Some are host-dependent defectives, meaning they can replicate only in cell systems which provide the particular genetic function which they lack. Others, called satellite viruses, are able to replicate only when their genetic defect is complemented by a helper virus. [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] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. [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]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the

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primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [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] Dequalinium: A topical bacteriostat that is available as various salts. It is used in wound dressings and mouth infections and may also have antifungal action, but may cause skin ulceration. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] 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 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] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] 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 system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [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] Dilatation: The act of dilating. [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] 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] Disease Progression: The worsening of a disease over time. This concept is most often used

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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] 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] 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] 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] 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 Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Labeling: Use of written, printed, or graphic materials upon or accompanying a drug container or wrapper. It includes contents, indications, effects, dosages, routes, methods, frequency and duration of administration, warnings, hazards, contraindications, side effects, precautions, and other relevant information. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH]

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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 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] Dyslexia: Partial alexia in which letters but not words may be read, or in which words may be read but not understood. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Dystrophin: A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as spectrin and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [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] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] 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] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is

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concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] 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] Electroporation therapy: EPT. Treatment that generates electrical pulses through an electrode placed in a tumor to enhance the ability of anticancer drugs to enter tumor cells. [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] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] 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] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [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] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord,

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often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [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] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [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 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] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of

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the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancer: Transcriptional element in the virus genome. [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]

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] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [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] 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] 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] Epidermolysis Bullosa: Group of genetically determined disorders characterized by the blistering of skin and mucosae. There are four major forms: acquired, simple, junctional, and dystrophic. Each of the latter three has several varieties. [NIH] Epidermolysis Bullosa Simplex: Form of epidermolysis bullosa characterized by autosomal dominant inheritance and by serous bullae that heal without scarring. [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]

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Epithelial carcinoma: Cancer that begins in the cells that line an organ. [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]

Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [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] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excimer laser: An ultraviolet laser used in refractive surgery to remove corneal tissue. [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] Excrete: To get rid of waste from the body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] 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]

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Expectorant: 1. Promoting the ejection, by spitting, of mucus or other fluids from the lungs 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]

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] Extraocular: External to or outside of the eye. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [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] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [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] 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] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Ferrochelatase: An enzyme widely distributed in cells and tissues. It is located in the inner

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mitochondrial membrane and catalyzes the formation of heme from protoporphyrin IX and ferrous ions during the terminal step in the heme biosynthetic pathway. EC 4.99.1.1. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetal Membranes: Thin layers of tissue which surround the embryo or fetus and provide for its nutrition, respiration, excretion and protection; they are the yolk sac, allantois, amnion, and chorion. [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] 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] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] 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] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH]

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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 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] 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] Flushing: A transient reddening of the face that may be due to fever, certain drugs, exertion, stress, or a disease process. [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] Forearm: The part between the elbow and the wrist. [NIH] Fundus: The larger part of a hollow organ that is farthest away from the organ's opening. The bladder, gallbladder, stomach, uterus, eye, and cavity of the middle ear all have a fundus. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [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 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] 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] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the

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blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [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-modified: Cells that have been altered to contain different genetic material than they originally contained. [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 Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [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 Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [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.

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[NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] 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] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [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] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental 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] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [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 Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucuronate: Salt of glucuronic acid. [NIH]

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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] Glucuronosyltransferase: A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17. [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] 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] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [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] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp 100: Glycoprotein 100. A tumor-specific antigen used in the development of cancer vaccines. [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] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH]

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Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [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] Guanosine Triphosphate: Guanosine 5'-(tetrahydrogen triphosphate). A guanine nucleotide containing three phosphate groups esterified to the sugar moiety. [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] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]

Haematuria: Blood in the urine. [EU] Haemophilia: A haemorrhagic diathesis occurring in two main forms: 1. Haemophilia A (classic haemophilia, factor VIII deficiency), an X-linked disorder due to deficiency of coagulation factor VIII; 2. Haemophilia B (factor IX deficiency, Christmas disease), also Xlinked, due to deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but a different loci, and are characterized by subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. [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] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [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] 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; 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] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Hearing aid: A miniature, portable sound amplifier for persons with impaired hearing, consisting of a microphone, audio amplifier, earphone, and battery. [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] Heartbeat: One complete contraction of the heart. [NIH] Hematogenous: Originating in the blood or spread through the bloodstream. [NIH]

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Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [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]

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] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH]

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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] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one 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] Heterodimers: 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]

Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histamine Release: The secretion of histamine from mast cell and basophil granules by exocytosis. This can be initiated by a number of factors, all of which involve binding of IgE, cross-linked by antigen, to the mast cell or basophil's Fc receptors. Once released, histamine binds to a number of different target cell receptors and exerts a wide variety of effects. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [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] 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] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also

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called endocrine therapy. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [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] Host: Any animal that receives a transplanted graft. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [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 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] 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 Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [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] 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] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH]

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Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] 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] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [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] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] 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] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Iduronidase: An enzyme that hydrolyzes iduronosidic linkages in desulfated dermatan. Deficiency of this enzyme produces Hurler's syndrome. EC 3.2.1.76. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune function: Production and action of cells that fight disease or infection. [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

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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] Immunodeficiency: The decreased ability of the body to fight infection and disease. [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] 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] Immunogen: A substance that is capable of causing antibody formation. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [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] Immunosuppressive: Describes the ability to lower immune system responses. [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] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] 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]

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Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a 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] 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]

Infection Control: Programs of disease surveillance, generally within health care facilities, designed to investigate, prevent, and control the spread of infections and their causative microorganisms. [NIH] 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] Infuse: To pour (a liquid) into something. [EU] 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] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and

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then cemented into the cavity. [NIH] Inoperable: Not suitable to be operated upon. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which 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] 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] Insulin-like: Muscular growth factor. [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] 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] Interferon-beta: One of the type I interferons produced by fibroblasts in response to stimulation by live or inactivated virus or by double-stranded RNA. It is a cytokine with antiviral, antiproliferative, and immunomodulating activity. [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]

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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 cells. It is an initiator of cell-mediated immunity. [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-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [NIH] Interleukin-5: Factor promoting eosinophil differentiation and activation in hematopoiesis. It also triggers activated B-cells for a terminal differentiation into Ig-secreting cells. [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 Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] 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] Intestinal: Having to do with the intestines. [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] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intramuscular injection: IM. Injection into a muscle. [NIH] Intraocular: Within the eye. [EU] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] 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

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and chloroplast genes. [NIH] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [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] Iodine Isotopes: Stable iodine atoms that have the same atomic number as the element iodine, but differ in atomic weight. I-127 is the only naturally occurring stable iodine isotope. [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] 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] 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] Islet: Cell producing insulin in pancreas. [NIH] 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] Isotonic: A biological term denoting a solution in which body cells can be bathed without a net flow of water across the semipermeable cell membrane. Also, denoting a solution having the same tonicity as some other solution with which it is compared, such as physiologic salt

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solution and the blood serum. [EU] Isozymes: The multiple forms of a single enzyme. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA 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] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [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] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [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]

Kinetic: Pertaining to or producing motion. [EU] 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] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large

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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] Larva: Wormlike or grublike stage, following the egg in the life cycle of insects, worms, and other metamorphosing animals. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Learning Disorders: Conditions characterized by a significant discrepancy between an individual's perceived level of intellect and their ability to acquire new language and other cognitive skills. These disorders may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. [NIH] 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] Leflunomide: An anticancer drug that works by inhibiting a cancer cell growth factor. Also called SU101. [NIH] Legal blindness: In the U.S., (1) visual acuity of 20/200 or worse in the better eye with corrective lenses (20/200 means that a person must be at 20 feet from an eye chart to see what a person with normal vision can see at 200 feet) or (2) visual field restricted to 20 d [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] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] 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]

Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils,

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and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Library Services: Services offered to the library user. They include reference and circulation. [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] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [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] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Light microscope: A microscope (device to magnify small objects) in which objects are lit directly by white light. [NIH] Linkages: 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] Lip: Either of the two fleshy, full-blooded margins of the mouth. [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] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipofuscin: A naturally occurring lipid pigment with histochemical characteristics similar to ceroid. It accumulates in various normal tissues and apparently increases in quantity with age. [NIH] Lipopolysaccharides: 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 metastases: Cancer that has spread from the original (primary) tumor to the liver. [NIH]

Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in

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the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [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] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [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] Locus Control Region: A regulatory region first identified in the human beta-globin locus but subsequently found in other loci. The region is believed to regulate transcription by opening and remodeling chromatin structure. It may also have enhancer activity. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [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] 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] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] 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] Lymphedema: Edema due to obstruction of lymph vessels or disorders of the lymph nodes. [NIH]

Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune

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system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphocytic Choriomeningitis Virus: The type species of arenavirus, part of the LCMLassa complex viruses, producing an inapparent infection in house and laboratory mice. In humans, infection with LCMV can be inapparent, or can present with an influenza-like illness, a benign aseptic meningitis, or a severe meningoencephalomyelitis. The virus can also infect monkeys, dogs, field mice, guinea pigs, and hamsters, the latter an epidemiologically important host. [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] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphoproliferative Disorders: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysosomal Storage Diseases: Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates. [NIH] Lyssavirus: A genus of the family Rhabdoviridae that includes rabies virus and other rabieslike viruses. [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] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [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 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]

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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] 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] Measles Virus: The type species of morbillivirus and the cause of the highly infectious 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] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] 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] 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 Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and

Dictionary 335

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] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] 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 Health: The state wherein the person is well adjusted. [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] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [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] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [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]

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MI: 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] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Micelle: A colloid particle formed by an aggregation of small molecules. [EU] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] 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] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

Microsurgery: Surgical procedures on the cellular level; a light microscope and miniaturized instruments are used. [NIH] 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] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [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] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] 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

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a complementary sequence by molecular hybridization. [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] 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] 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] Monogenic: A human disease caused by a mutation in a single gene. [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]

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] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucopolysaccharidoses: Group of lysosomal storage diseases each caused by an inherited deficiency of an enzyme involved in the degradation of glycosaminoglycans (mucopolysaccharides). The diseases are progressive and often display a wide spectrum of clinical severity within one enzyme deficiency. [NIH] 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] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH]

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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] 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] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Musculoskeletal System: Themuscles, bones, and cartilage of the body. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] 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] 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 Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] 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] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [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

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enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [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] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [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] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [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] Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [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] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuronal atrophy: Nerve cell death and functional loss. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon,

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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] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Neurosecretory Systems: A system of neurons that has the specialized function to produce and secrete hormones, and that constitutes, in whole or in part, an endocrine organ or system. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] 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 volume. It is a constituent of proteins and nucleic acids and found in all living cells. [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 Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [NIH]

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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] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] 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] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [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] Oncology: The study of cancer. [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]

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Ophthalmoscope: A lighted instrument used to examine the inside of the eye, including the retina and the optic nerve. [NIH] 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] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [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] Organoids: An organization of cells into an organ-like structure. Organoids can be generated in culture. They are also found in certain neoplasms. [NIH] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Oropharynx: Oral part of the pharynx. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a 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] Osteocytes: Mature osteoblasts that have become embedded in the bone matrix. They occupy a small cavity, called lacuna, in the matrix and are connected to adjacent osteocytes via protoplasmic projections called canaliculi. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteogenesis Imperfecta: A collagen disorder resulting from defective biosynthesis of type I collagen and characterized by brittle, osteoporotic, and easily fractured bones. It may also

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present with blue sclerae, loose joints, and imperfect dentin formation. There are four major types, I-IV. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteonectin: Non-collagenous, calcium-binding glycoprotein of developing bone. It links collagen to mineral in the bone matrix. In the synonym SPARC glycoprotein, the acronym stands for secreted protein, acidic and rich in cysteine. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Osteotomy: The surgical cutting of a bone. [EU] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovarian epithelial cancer: Cancer that occurs in the cells lining the ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [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]

Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] 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] 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

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gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] 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] Paralysis: Loss of ability to move all or part of the body. [NIH] Paramyxovirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have both hemagglutinin and neuraminidase activities and encode a C protein. Human parainfluenza virus 1 is the type species. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [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] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] 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] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

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] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Penile Erection: The state of the penis when the erectile tissue becomes filled with blood and causes the penis to become rigid and elevated. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third

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compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [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] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Perineal: Pertaining to the perineum. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [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] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Peripheral vision: Side vision; ability to see objects and movement outside of the direct line of vision. [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] 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

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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] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [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] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [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] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [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] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and

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teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [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] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physical Fitness: A state of well-being in which performance is optimal, often as a result of physical conditioning which may be prescribed for disease therapy. [NIH] 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 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] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [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] 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]

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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] 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: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [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-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] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Pleated: Particular three-dimensional pattern of amyloidoses. [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] Pneumococcal Vaccines: Vaccines or candidate vaccines used to prevent infections with Streptococcus pneumoniae. [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]

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Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] 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]

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] 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] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [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] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH]

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Potentiates: 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. 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] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [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] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Primary tumor: The original tumor. [NIH] 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] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [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]

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Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] 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] Prophylaxis: An attempt to prevent disease. [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 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 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] 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

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cell growth. They often have protein kinase activity. [NIH] 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] 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] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [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 Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [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]

Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [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] Rabies Virus: The type species of lyssavirus causing rabies in humans and other animals. Transmission is mostly by animal bites through saliva. The virus is neurotropic multiplying in neurons and myotubes of vertebrates. [NIH]

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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] Radar: A system using beamed and reflected radio signals to and from an object in such a way that range, bearing, and other characteristics of the object may be determined. [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] Radical prostatectomy: Surgery to remove the entire prostate. The two types of radical prostatectomy are retropubic prostatectomy and perineal prostatectomy. [NIH] Radioactive: Giving off radiation. [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] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in 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] 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]

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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] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [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] 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] 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] Renal capsule: The fibrous connective tissue that surrounds each kidney. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [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] Renovascular: Of or pertaining to the blood vessels of the kidneys. [EU] 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] 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]

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Resection: Removal of tissue or part or all of an organ by surgery. [NIH] 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 Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [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]

Restitution: The restoration to a normal state. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Reticulata: Part of substantia nigra. [NIH] Reticuloendotheliosis: Hyperplasia of reticuloendothelial tissue, in any organ or tissue. A related concept is reticulosis which is an increase in reticuloendothelial elements. [NIH] Reticuloendotheliosis Viruses: A subgenus of mammalian type C retroviruses comprising a few isolates from birds, with no known corresponding endogenous relatives. [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 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 Detachment: Separation of the inner layers of the retina (neural retina) from the pigment epithelium. Retinal detachment occurs more commonly in men than in women, in eyes with degenerative myopia, in aging and in aphakia. It may occur after an uncomplicated cataract extraction, but it is seen more often if vitreous humor has been lost during surgery. (Dorland, 27th ed; Newell, Ophthalmology: Principles and Concepts, 7th ed, p310-12). [NIH] Retinal pigment epithelium: The pigment cell layer that nourishes the retinal cells; located just outside the retina and attached to the choroid. [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]

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Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field. [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]

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] Retropubic: A potential space between the urinary bladder and the symphisis and body of the pubis. [NIH] Retropubic prostatectomy: Surgery to remove the prostate through an incision made in the abdominal wall. [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] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [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] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [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] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of

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developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rod cells: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH] Rotavirus: A genus of Reoviridae, causing acute gastroenteritis in birds and mammals, including humans. Transmission is horizontal and by environmental contamination. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Satellite Viruses: Defective viruses which can multiply only by association with a helper virus which complements the defective gene. Satellite viruses may be associated with certain plant viruses, animal viruses, or bacteriophages. They differ from satellite RNA in that satellite viruses encode their own coat protein. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Sclerae: A circular furrow between the sclerocorneal junction and the iris. [NIH] Scleroproteins: Simple proteins characterized by their insolubility and fibrous structure. Within the body, they perform a supportive or protective function. [NIH] 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] Sea Urchins: Somewhat flattened, globular echinoderms of the class Echinoidea, having thin, brittle shells of calcareous plates. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are

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the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [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] 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] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] 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] 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] 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 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] 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,

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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] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shivering: Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. [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] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [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

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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] Social Change: Social process whereby the values, attitudes, or institutions of society, such as education, family, religion, and industry become modified. It includes both the natural process and action programs initiated by members of the community. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [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 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 Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [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] 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] 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] Spectrin: A high molecular weight (220-250 kDa) water-soluble protein which can be extracted from erythrocyte ghosts in low ionic strength buffers. The protein contains no

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lipids or carbohydrates, is the predominant species of peripheral erythrocyte membrane proteins, and exists as a fibrous coating on the inner, cytoplasmic surface of the membrane. [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] 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 Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sports Medicine: The field of medicine concerned with physical fitness and the diagnosis and treatment of injuries sustained in sports activities. [NIH] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [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] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

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 cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [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

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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] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] 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] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [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] 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]

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] Striatum: A higher brain's domain thus called because of its stripes. [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] 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

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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] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [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] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [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] Synovial: Of pertaining to, or secreting synovia. [EU]

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Synovial Fluid: The clear, viscous fluid secreted by the synovial membrane. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints. [NIH] Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] 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 mammary and uterine. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [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] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [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] 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] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Thalassemia: A group of hereditary hemolytic anemias in which there is decreased

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synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [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] Thermogenesis: The generation of heat in order to maintain body temperature. The uncoupled oxidation of fatty acids contained within brown adipose tissue and shivering are examples of thermogenesis in mammals. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active 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] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] 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] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] 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] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]

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Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Plasminogen Activator: A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to plasmin. It has fibrin-binding activity and is immunologically different from urinary plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. EC 3.4.21.68. [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] Tonicity: The normal state of muscular tension. [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 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] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [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] 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]

Dictionary 367

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] 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] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [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] Transposase: An enzyme that binds to single-stranded DNA. It is thought to recognize the repetitive ends of a transposon and to participate in the cleavage of the recipient site into which the new transposon copy inserts. EC 2.7.7.-. [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 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] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Trophic: Of or pertaining to nutrition. [EU] 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]

368 Gene Therapy

Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tumor infiltrating lymphocytes: White blood cells that have left the bloodstream and migrated into a tumor. [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 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] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [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] Ubiquinone: A lipid-soluble benzoquinone which is involved in electron transport in mitochondrial preparations. The compound occurs in the majority of aerobic organisms, from bacteria to higher plants and animals. [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] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Untranslated Regions: The parts of the messenger RNA sequence that do not code for product, i.e. the 5' untranslated regions and 3' untranslated regions. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to

Dictionary 369

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 Plasminogen Activator: A proteolytic enzyme that converts plasminogen to plasmin where the preferential cleavage is between arginine and valine. It was isolated originally from human urine, but is found in most tissues of most vertebrates. EC 3.4.21.73. [NIH]

Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [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] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [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] 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] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] 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] 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]

370 Gene Therapy

Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [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 artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] 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] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] 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] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Envelope Proteins: Layers of protein which surround the capsid in animal viruses with tubular nucleocapsids. The envelope consists of an inner layer of lipids and virus specified proteins also called membrane or matrix proteins. The outer layer consists of one or more types of morphological subunits called peplomers which project from the viral envelope; this layer always consists of glycoproteins. [NIH] 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 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] Viremia: The presence of viruses in the blood. [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

Dictionary 371

called the peplos. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [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 Diseases: A general term for diseases produced by viruses. [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] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] 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] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [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] Volition: Voluntary activity without external compulsion. [NIH] Weight Gain: Increase in body weight over existing weight. [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]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [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

372 Gene Therapy

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] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zygote: The fertilized ovum. [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]

373

INDEX A Abdominal, 187, 283, 284, 296, 306, 316, 343, 345, 346, 356, 368 Abdominal Pain, 283, 316, 368 Aberrant, 32, 33, 174, 283 Ablation, 41, 49, 61, 87, 114, 283 Absenteeism, 215, 283 Acceptor, 283, 331, 343, 365 Accommodation, 246, 283, 338 Acetaminophen, 271, 283 Acetylcholine, 283, 340 Acetylgalactosamine, 283 Acetylglucosamine, 283 Acquired Immunodeficiency Syndrome, 159, 192, 283 Actin, 283, 338 Actinin, 283, 308 Activities of Daily Living, 270, 283 Acute lymphoblastic leukemia, 283 Acute lymphocytic leukemia, 117, 283 Acute myelogenous leukemia, 106, 283, 284 Acute myeloid leukemia, 284 Acute nonlymphocytic leukemia, 284 Acyclovir, 211, 284, 315 Adaptability, 284, 297 Adaptation, 284, 337, 340, 348 Adenine, 232, 284 Adenocarcinoma, 30, 75, 147, 154, 204, 284, 320, 340 Adenosine, 73, 93, 142, 171, 284, 347 Adenosine Deaminase, 73, 93, 171, 284 Adenovirus, 10, 12, 13, 23, 27, 28, 29, 39, 40, 43, 47, 49, 52, 56, 58, 60, 61, 62, 63, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 78, 81, 84, 85, 86, 88, 89, 91, 92, 101, 105, 106, 108, 111, 113, 122, 126, 127, 128, 131, 133, 135, 137, 141, 142, 143, 145, 147, 158, 164, 165, 167, 170, 182, 189, 190, 192, 197, 198, 199, 201, 215, 219, 227, 284, 356 Adenylate Cyclase, 284, 298 Adhesions, 211, 284 Adipocytes, 284, 302, 330 Adipose Tissue, 284, 365 Adjuvant, 31, 150, 209, 284 Adjuvant Therapy, 31, 284 Adrenal Cortex, 284, 303, 350

Adrenal Medulla, 284, 296, 311, 340 Adrenergic, 67, 285, 307, 311, 363 Adverse Effect, 9, 26, 55, 200, 219, 285, 359 Aerobic, 285, 336, 368 Aerosol, 9, 79, 285 Afferent, 285, 330, 347 Affinity, 13, 64, 285, 291, 335, 360, 362 Agar, 285, 347 Age of Onset, 285, 368 Agonist, 179, 188, 285, 307, 364 Airway, 8, 17, 37, 122, 144, 214, 219, 285 Akinesia, 19, 285 Albumin, 56, 285, 348, 364 Algorithms, 285, 293 Alkaline, 285, 287, 295, 346 Alkaloid, 286, 295 Alkylating Agents, 286, 368 Allantois, 286, 314 Alleles, 212, 286 Allergen, 219, 286, 358 Allografts, 17, 286, 321 Alopecia, 286, 304 Alpha 1-Antitrypsin, 199, 286 Alpha Particles, 286, 353 Alpha-1, 96, 286 Alpha-helix, 286, 329 Alternative medicine, 255, 286 Alveoli, 286, 370 Amaurosis, 29, 54, 286 Amine, 286, 321 Amino Acid Sequence, 286, 289, 312, 316 Amino Acid Substitution, 175, 220, 286, 320 Amino Acids, 217, 286, 287, 300, 316, 335, 341, 345, 349, 351, 356, 358, 366, 367, 368 Ammonia, 284, 286, 287, 318, 368 Amnion, 186, 287, 314 Amniotic Fluid, 287 Amplification, 41, 180, 181, 287 Ampulla, 287, 298, 310 Amputation, 184, 287 Anaemia, 165, 287 Anaesthesia, 287, 325 Analgesic, 283, 287 Analog, 184, 195, 284, 287, 315 Analogous, 5, 52, 287, 366 Anaphylatoxins, 287, 301 Anaplastic, 148, 287

374 Gene Therapy

Anatomical, 19, 55, 271, 287, 291, 309, 324, 357 Anemia, 26, 38, 53, 113, 154, 287, 292, 352, 365 Anesthesia, 157, 285, 287, 288, 310, 350 Anesthetics, 287, 311 Angina, 77, 97, 126, 143, 252, 269, 288 Angiogenesis, 30, 43, 49, 55, 95, 102, 118, 130, 221, 236, 251, 288, 310, 334 Angiogenesis inhibitor, 288, 310 Angiogram, 157, 288 Angioplasty, 168, 253, 288 Angioplasty, Laser, 168, 288 Animal model, 9, 11, 20, 22, 25, 28, 29, 32, 33, 39, 40, 41, 46, 54, 59, 166, 226, 288, 368 Animals, Transgenic, 188, 288 Anions, 285, 288, 328, 363 Annealing, 181, 288, 349 Anomalies, 32, 288 Anterior Cruciate Ligament, 7, 288 Antiangiogenesis, 107, 288 Antiangiogenic, 66, 67, 78, 79, 114, 288 Antiarrhythmic, 19, 288 Antibacterial, 288, 361 Antibiotic, 288, 305, 307, 361, 364 Anticoagulant, 289, 351 Anticodon, 208, 289 Antifungal, 289, 306 Antigen, 14, 33, 50, 87, 104, 133, 185, 202, 214, 219, 285, 289, 301, 305, 318, 321, 322, 323, 324, 325, 326, 334, 356, 358 Antigen-Antibody Complex, 289, 301 Antigen-presenting cell, 289, 305 Anti-infective, 289, 322, 328 Anti-inflammatory, 33, 136, 271, 283, 289 Antimetabolite, 284, 289, 305, 315 Antimetastatic, 18, 289 Antimicrobial, 77, 289, 307 Antineoplastic, 286, 289, 304, 307, 315, 322, 343, 348, 366, 370 Antioxidant, 271, 289, 343 Antiproliferative, 289, 326 Antipyretic, 283, 289 Antiserum, 23, 289 Antiviral, 42, 194, 215, 248, 262, 284, 289, 305, 326, 345 Antiviral Agents, 194, 289 Anuria, 290, 329 Anus, 290, 294, 354 Aorta, 290, 296, 370 Aperture, 168, 290

Aphakia, 290, 355 Aplastic anemia, 154, 290 Apoptosis, 6, 10, 18, 29, 49, 58, 72, 73, 78, 80, 88, 91, 96, 103, 129, 192, 200, 290, 296 Applicability, 236, 290 Aqueous, 290, 292, 304, 309, 322, 330, 331 Arenavirus, 290, 333 Arginine, 287, 290, 340, 342, 367, 369 Aromatic, 290, 335, 346 Arrhythmia, 288, 290 Arterial, 71, 133, 208, 236, 290, 296, 323, 351, 364 Arteries, 168, 191, 236, 290, 294, 296, 303, 332, 336, 338, 352, 368 Arterioles, 290, 294, 295, 338 Arteriolosclerosis, 290 Arteriosclerosis, 190, 290 Arthroplasty, 271, 290 Arthroscopy, 271, 291 Articular, 7, 223, 291, 342 Articulation, 15, 291 Asbestos, 291, 334, 335 Ascites, 14, 187, 291 Aseptic, 291, 333, 362 Aspartate, 192, 291 Assay, 42, 86, 164, 194, 223, 291, 324 Astrocytes, 48, 291, 327 Astrocytoma, 148, 291, 317 Asymptomatic, 291, 292 Atrium, 291, 370 Atrophy, 55, 156, 157, 291, 339 Attenuated, 18, 90, 107, 110, 130, 180, 194, 222, 291 Attenuation, 32, 291 Auditory, 47, 239, 291 Autoimmune disease, 5, 33, 83, 179, 192, 291 Autoimmunity, 6, 17, 237, 291 Autologous, 33, 56, 92, 159, 176, 177, 187, 291 Autologous bone marrow transplantation, 33, 56, 291 Autonomic, 283, 291, 340, 345 Autonomic Nervous System, 291, 345 Autopsy, 153, 292 Avian, 34, 292 Axonal, 137, 292 Axons, 292, 339, 342 B Bacteriophage, 58, 75, 292, 347, 366 Basal cells, 8, 292 Basal Ganglia, 19, 292, 294, 317, 323

Index 375

Base, 29, 83, 180, 284, 292, 304, 305, 306, 316, 329, 346, 349, 364 Base Sequence, 292, 316 Basement Membrane, 292, 296, 313 Basophil, 292, 321 Benign, 290, 292, 319, 333, 335, 339, 344, 353 Beta-Thalassemia, 26, 36, 53, 292 Bilateral, 292, 355 Bile, 52, 292, 293, 315, 322, 329, 331, 362 Bile Acids, 292, 362 Bile Acids and Salts, 292 Bile Pigments, 293, 329 Biliary, 293, 298 Bilirubin, 28, 285, 293, 323 Binding Sites, 293, 362 Bioassay, 10, 293 Bioavailable, 9, 293 Biochemical, 22, 37, 51, 54, 56, 81, 118, 174, 286, 289, 293, 314, 316, 329, 330, 342, 358 Biological response modifier, 293, 326 Biological therapy, 293, 319 Biopsy, 10, 150, 157, 214, 293 Biosynthesis, 205, 206, 293, 342, 358 Biotin, 64, 293, 362 Bivalent, 293, 335 Bladder, 4, 60, 78, 79, 84, 102, 107, 113, 126, 158, 293, 315, 327, 351, 354, 356, 367, 369 Blastocyst, 293, 301, 347 Blister, 59, 293 Blood Coagulation, 10, 293, 295, 365 Blood Coagulation Factors, 293 Blood Glucose, 191, 294, 320, 323, 326 Blood pressure, 160, 294, 296, 323, 337, 345, 352, 360 Blood-Brain Barrier, 48, 294 Blot, 42, 294 Body Fluids, 294, 308, 314, 341, 360 Bone Marrow, 22, 27, 33, 42, 52, 98, 106, 151, 154, 156, 215, 220, 283, 284, 290, 291, 294, 312, 324, 332, 334, 338, 360, 361, 362 Bone Marrow Cells, 52, 220, 294, 334 Bone Marrow Transplantation, 22, 28, 33, 151, 294 Bone scan, 294, 357 Bowel, 294, 306, 325, 327, 346, 368 Bowel Movement, 294, 306 Brachytherapy, 294, 327, 328, 353, 371 Bradykinin, 294, 340, 348 Brain Diseases, 94, 294

Branch, 249, 279, 294, 308, 320, 332, 344, 360, 365 Breakdown, 294, 306, 315, 342 Breeding, 44, 294 Bronchi, 295, 311, 313, 366 Bronchial, 214, 295, 321 Buccal, 295, 332, 362 Burns, 186, 295 Burns, Electric, 295 C Cachexia, 198, 295 Cadaver, 186, 187, 295 Calcification, 290, 295 Calcium, 19, 180, 291, 295, 300, 334, 342, 343, 359 Cancer vaccine, 295, 318 Capillary, 55, 61, 69, 294, 295, 370 Capsaicin, 271, 295 Capsid, 44, 164, 167, 229, 295, 341, 370 Capsules, 295, 307 Carbohydrate, 41, 295, 317, 349, 362 Carboxy, 64, 295 Carboxy-terminal, 64, 295 Carcinoembryonic Antigen, 102, 295 Carcinogenesis, 29, 171, 295 Carcinogenic, 286, 296, 325, 341, 351, 362, 368 Carcinogens, 296, 341, 371 Carcinoma, 14, 29, 30, 50, 59, 60, 66, 67, 80, 88, 91, 109, 116, 129, 143, 144, 147, 148, 296, 340 Carcinoma in Situ, 60, 296 Cardiac, 17, 20, 74, 94, 131, 166, 168, 225, 236, 288, 296, 308, 311, 338, 355, 362, 363 Cardiomyopathy, 166, 296 Cardiovascular disease, 12, 55, 67, 108, 112, 208, 236, 296 Cardiovascular System, 99, 168, 296 Carotene, 296, 355 Caspase, 127, 192, 296 Cataract, 227, 290, 296, 355 Catecholamine, 296, 307, 346 Catheterization, 45, 288, 296, 328 Catheters, 150, 168, 296, 324, 327 Causal, 37, 296, 320, 358, 364 Cause of Death, 153, 184, 221, 296 Celiac Artery, 296, 320 Cell Adhesion, 60, 296, 326 Cell Count, 248, 296 Cell Cycle, 78, 174, 189, 192, 225, 297, 299, 304, 312, 352 Cell Death, 24, 54, 192, 290, 297, 312, 339

376 Gene Therapy

Cell Differentiation, 184, 297, 359 Cell Division, 176, 192, 292, 297, 302, 312, 319, 336, 347, 358 Cell Fusion, 24, 169, 297 Cell membrane, 44, 52, 179, 200, 204, 224, 297, 306, 309, 312, 315, 328, 346, 349, 360 Cell motility, 297, 321 Cell proliferation, 105, 189, 224, 290, 297, 327, 356, 359 Cell Respiration, 297, 336, 355 Cell Size, 297, 314 Cell Survival, 297, 319 Cell Transplantation, 19, 22, 237, 238, 270, 297 Cellulose, 297, 347 Central Nervous System, 19, 20, 34, 47, 115, 283, 291, 294, 297, 315, 317, 318, 319, 342, 358 Cerebellum, 294, 297 Cerebral, 292, 294, 297, 311, 312, 317, 364 Cerebral hemispheres, 292, 297, 317, 364 Cerebrospinal, 48, 297 Cerebrospinal fluid, 48, 297 Cerebrovascular, 296, 297 Ceroid, 92, 298, 331 Cervical, 24, 58, 263, 298 Cervix, 80, 298 Character, 298, 305 Chemoprotective, 43, 298 Chemotactic Factors, 298, 301 Chimera, 219, 220, 298 Chloroplasts, 298, 367 Cholera, 37, 298, 359, 370 Cholera Toxin, 37, 298 Cholestasis, 52, 298 Cholesterol, 183, 208, 292, 298, 303, 323, 331, 332, 362, 364 Chondroitin sulfate, 187, 271, 298 Chorion, 298, 314 Chorioretinitis, 298, 355 Choroid, 298, 355 Chromaffin System, 298, 310 Chromatin, 53, 290, 298, 332 Chromosomal, 62, 226, 287, 298, 299, 316, 337, 348, 356, 357, 364 Chromosome, 23, 83, 164, 172, 201, 226, 269, 299, 302, 319, 331, 352, 357, 358, 364 Chromosome Mapping, 172, 201, 299 Chronic Disease, 73, 184, 295, 299, 330 Chronic lymphocytic leukemia, 13, 73, 103, 299

Chronic Progressive External Ophthalmoplegia, 180, 299 Chronic renal, 23, 299 Ciliated cells, 8, 299 Circadian, 54, 299 Circulatory system, 196, 299, 310 CIS, 164, 170, 222, 267, 299, 355, 367 Cisplatin, 61, 76, 145, 147, 221, 299 Claudication, 236, 299 Clinical Medicine, 262, 299, 350 Clone, 8, 45, 59, 299 Cloning, 111, 172, 181, 201, 232, 266, 293, 299, 326, 331 Coagulation, 26, 293, 299, 319, 320, 348, 365 Cochlea, 300 Cochlear, 87, 246, 300 Cochlear Implants, 246, 300 Cochlear Nerve, 300 Cod Liver Oil, 300, 309 Codon, 208, 289, 300, 316 Cofactor, 300, 351, 365 Coliphages, 292, 300 Colitis, 300 Collagen, 22, 43, 70, 112, 116, 136, 144, 292, 300, 313, 314, 334, 342, 343, 348, 351 Colloidal, 77, 285, 300, 346 Colorectal, 40, 78, 83, 130, 248, 300 Colorectal Cancer, 40, 78, 83, 300 Combination Therapy, 43, 216, 300 Combinatorial, 44, 300 Complement, 12, 21, 50, 287, 289, 300, 301, 316, 326, 333, 348, 358 Complementary and alternative medicine, 125, 139, 301 Complementary medicine, 125, 301 Complementation, 222, 232, 301 Complete remission, 301, 354 Computational Biology, 261, 301 Computed tomography, 301, 357 Computerized axial tomography, 301, 357 Conception, 179, 301, 302, 314, 362 Concomitant, 19, 24, 62, 301 Cone, 54, 301, 347 Confounding, 26, 170, 301 Congestive heart failure, 131, 301 Conjugated, 11, 72, 202, 292, 302, 304, 341 Conjugation, 302, 318 Conjunctiva, 302, 325 Connective Tissue, 22, 196, 223, 294, 300, 302, 314, 315, 332, 335, 351, 354, 356, 357, 362

Index 377

Connective Tissue Cells, 223, 302 Connexins, 302, 315 Consciousness, 287, 302, 305, 307, 355 Constitutional, 302, 355 Constriction, 302, 328, 357, 369 Contact Inhibition, 175, 302 Contamination, 302, 357 Continuous infusion, 145, 302 Contraception, 178, 179, 302 Contractility, 19, 68, 211, 302 Contraindications, ii, 302, 307 Control group, 30, 302 Contusion, 46, 302 Conventional therapy, 302, 303 Conventional treatment, 6, 302, 303 Coordination, 34, 297, 303 Cornea, 303, 318, 362 Corneum, 196, 303, 311 Coronary, 118, 131, 208, 296, 303, 336, 338 Coronary Arteriosclerosis, 303, 338 Coronary heart disease, 208, 296, 303 Coronary Thrombosis, 303, 336, 338 Corpus, 303, 344, 350 Corpus Luteum, 303, 350 Cortex, 46, 294, 303, 312 Cortical, 46, 303, 358 Cortisol, 285, 303 Cowpox, 303, 369 Cowpox Virus, 303, 369 Cranial, 90, 297, 300, 303, 319, 342, 344, 345 Crossing-over, 303, 354 Cues, 228, 303 Cultured cells, 5, 303 Curative, 38, 303, 365 Cutaneous, 132, 303, 332, 347, 369 Cyanogen Bromide, 23, 303 Cyclic, 41, 284, 303, 319, 340, 347, 349, 358 Cyclin, 136, 174, 304 Cyclophosphamide, 93, 122, 150, 304, 323 Cysteine, 192, 304, 343 Cystine, 304 Cytochrome, 84, 93, 122, 143, 205, 206, 304 Cytomegalovirus, 27, 201, 248, 304, 315 Cytomegalovirus Infections, 304, 315 Cytoplasm, 193, 199, 290, 297, 298, 304, 311, 319, 335, 338, 356 Cytosine, 63, 95, 118, 187, 304 Cytoskeletal Proteins, 304, 308 Cytoskeleton, 304, 326, 336 Cytotoxic, 18, 24, 27, 39, 84, 113, 185, 221, 295, 304, 353, 359

Cytotoxic chemotherapy, 84, 304 Cytotoxicity, 24, 27, 106, 136, 187, 231, 299, 304, 329 Cytotoxins, 179, 304 D Databases, Bibliographic, 261, 305 Daunorubicin, 305, 307 De novo, 26, 67, 305 Deamination, 305, 368 Decarboxylation, 305, 321 Defective Viruses, 119, 180, 305 Defense Mechanisms, 4, 305, 326 Degenerative, 180, 191, 207, 223, 271, 305, 320, 333, 342, 355, 356 Dehydration, 298, 305 Deletion, 66, 166, 176, 180, 218, 290, 305, 316 Dementia, 34, 283, 305 Demyelinating Diseases, 115, 305 Denaturation, 181, 305, 349 Dendrites, 305, 340 Dendritic, 24, 86, 116, 184, 305, 334 Dendritic cell, 24, 86, 116, 184, 305 Density, 55, 208, 305, 314, 331, 341, 349 Dentists, 5, 305 Deoxyglucose, 138, 305 Deoxyribonucleic, 207, 305, 356 Deoxyribonucleic acid, 207, 305, 356 Deoxyribonucleotides, 305, 306, 356 Depolarization, 306, 359 Dequalinium, 180, 306 Detoxification, 51, 306 Diabetes Mellitus, 41, 69, 191, 195, 245, 306, 317, 320 Diabetic Foot, 43, 149, 236, 306 Diagnostic procedure, 163, 255, 306 Diaphragm, 168, 306, 348 Diarrhea, 209, 306 Diastolic, 306, 323 Diathesis, 26, 306, 319 Diffusion, 306, 325 Digestion, 23, 292, 294, 306, 327, 331, 362, 369 Digestive system, 161, 306, 337 Digestive tract, 306, 360, 361, 372 Dihydrotestosterone, 306, 354 Dilatation, 288, 306, 350 Dilated cardiomyopathy, 74, 166, 306 Dimerization, 31, 188, 306 Diploid, 201, 301, 306, 347 Disease Progression, 22, 306, 370 Dissociation, 285, 307, 328

378 Gene Therapy

Distal, 23, 292, 307, 308, 329, 345, 352 Dopamine, 19, 307, 346 Dosage Forms, 210, 307 Doxorubicin, 61, 102, 221, 307 Doxycycline, 12, 307 Drive, ii, vi, 7, 8, 48, 54, 61, 121, 195, 235, 236, 270, 307 Drug Delivery Systems, 218, 307 Drug Interactions, 307 Drug Labeling, 202, 307 Drug Resistance, 55, 307, 308 Drug Tolerance, 307, 308, 366 Duct, 287, 296, 308, 312, 357 Duodenum, 292, 308, 310, 320, 362 Dyslexia, 308, 330 Dysplasia, 32, 212, 308 Dystonia, 180, 308 Dystrophic, 49, 69, 308, 311 Dystrophin, 49, 107, 143, 167, 171, 308 Dystrophy, 49, 78, 107, 143, 171, 242, 252, 308 E Ectopic, 37, 58, 308 Effector, 64, 209, 217, 283, 300, 308, 329, 340 Effector cell, 209, 308, 329, 340 Elasticity, 290, 303, 308 Elastin, 300, 308, 313 Elective, 114, 308 Electrocoagulation, 299, 308 Electrode, 308, 309 Electrolyte, 308, 314, 329, 341, 349, 360 Electrons, 289, 292, 308, 328, 333, 343, 353 Electrophysiological, 166, 308 Electroporation, 89, 169, 180, 195, 309 Electroporation therapy, 195, 309 Elementary Particles, 308, 309, 333, 340, 351 Emaciation, 283, 309 Emboli, 9, 61, 220, 221, 309 Embolism, 236, 309 Embolization, 9, 220, 221, 309 Embryo, 59, 287, 293, 297, 309, 314, 325, 342, 368, 372 Embryology, 309, 340 Emphysema, 286, 309 Empirical, 16, 309 Emulsion, 204, 205, 309, 314 Enamel, 309, 329 Encapsulated, 134, 309, 331 Encephalitis, 309, 310 Encephalomyelitis, 70, 309

Endarterectomy, 288, 310 Endemic, 298, 310, 361 Endocardium, 168, 310 Endocrine Glands, 310 Endocrine System, 188, 310, 339 Endocrinology, 79, 96, 103, 116, 188, 310 Endocytosis, 22, 28, 310 Endoscope, 310 Endoscopic, 145, 168, 291, 310 Endoscopy, 145, 310 Endostatin, 30, 64, 94, 117, 310 Endothelial cell, 30, 32, 34, 117, 133, 294, 310, 314, 365 Endothelium, 18, 30, 66, 102, 310, 340 Endothelium, Lymphatic, 310 Endothelium, Vascular, 310 Endothelium-derived, 310, 340 Endotoxic, 310, 331 Endotoxin, 310, 368 End-stage renal, 184, 299, 310 Energy balance, 311, 330 Enhancer, 20, 31, 35, 53, 69, 87, 115, 202, 311, 332, 355 Enteropeptidase, 311, 367 Environmental Exposure, 311, 341 Environmental Health, 260, 262, 267, 269, 311 Enzymatic, 28, 46, 169, 212, 295, 296, 301, 311, 321, 349, 355 Eosinophil, 214, 311, 327 Eosinophilic, 220, 311 Epidemic, 311, 361 Epidermal, 59, 64, 90, 311, 329, 334 Epidermal Growth Factor, 64, 311 Epidermis, 195, 292, 293, 303, 311, 322, 329, 350 Epidermoid carcinoma, 311, 361 Epidermolysis Bullosa, 59, 116, 253, 311 Epidermolysis Bullosa Simplex, 59, 311 Epigastric, 311, 343 Epinephrine, 41, 285, 307, 311, 340, 368 Epithelial, 18, 24, 30, 37, 41, 46, 58, 143, 155, 214, 226, 227, 284, 296, 298, 299, 311, 312, 321, 327, 344 Epithelial carcinoma, 24, 312 Epithelial Cells, 18, 37, 41, 58, 226, 227, 298, 311, 312, 321, 327 Epithelium, 8, 9, 214, 227, 292, 310, 312, 355 Epitope, 68, 101, 312 Erectile, 3, 4, 312, 344 Erection, 3, 4, 312

Index 379

Erythrocytes, 27, 287, 294, 312, 320, 354, 358 Erythropoietin, 17, 70, 165, 210, 312 Esophageal, 110, 145, 312 Esophagus, 306, 312, 346, 362 Estrogen, 188, 228, 312, 358, 364 Estrogen receptor, 228, 312 Etoposide, 136, 312 Eukaryotic Cells, 176, 221, 228, 231, 304, 312, 342 Evoke, 312, 362 Excimer laser, 288, 312 Excitation, 20, 68, 312, 314 Excrete, 290, 312, 329 Exocrine, 312, 343 Exocytosis, 312, 321 Exogenous, 5, 23, 46, 52, 183, 186, 196, 200, 228, 238, 312, 316, 318, 368 Exon, 167, 312 Expectorant, 313, 360 External-beam radiation, 313, 328, 353, 371 Extracellular Matrix, 21, 167, 196, 238, 302, 313, 314, 326, 334, 342 Extracellular Matrix Proteins, 313, 334 Extracellular Space, 313 Extraction, 290, 313, 355 Extraocular, 299, 313 Extrapyramidal, 307, 313 Eye Infections, 284, 313 F Facial, 32, 313 Family Planning, 261, 313 Fat, 68, 210, 284, 292, 294, 296, 303, 309, 313, 330, 331, 356, 360, 364 Fatal Outcome, 313, 352 Fatigue, 313, 319 Fatty acids, 285, 313, 318, 365 Feces, 295, 313 Femoral, 52, 313 Femur, 288, 313 Ferrochelatase, 27, 313 Fetal Blood, 177, 314 Fetal Membranes, 186, 314 Fetus, 11, 97, 138, 312, 314, 347, 350, 368, 369 Fibrin, 293, 314, 348, 365, 366 Fibroblast Growth Factor, 11, 314 Fibroblasts, 19, 23, 32, 33, 52, 106, 136, 176, 196, 302, 314, 326, 337 Fixation, 314, 358 Flow Cytometry, 42, 314

Fludarabine, 150, 314 Fluid Therapy, 314, 341 Fluorescence, 27, 49, 59, 94, 314, 315 Fluorescent Dyes, 314, 315 Fluorouracil, 187, 315 Flushing, 22, 315 Fold, 48, 159, 213, 315, 341 Foot Ulcer, 43, 306, 315 Foramen, 315, 346 Forearm, 294, 315 Fundus, 157, 315 Fungi, 209, 289, 302, 313, 315, 336, 372 G Gallbladder, 88, 283, 293, 306, 315, 320 Gamma Rays, 315, 353 Ganciclovir, 20, 24, 40, 65, 100, 102, 105, 115, 153, 166, 211, 315 Ganglia, 283, 315, 339, 345 Gangrenous, 315, 359 Gap Junctions, 166, 302, 315, 363 Gas, 287, 306, 315, 322, 340, 370 Gas exchange, 315, 370 Gastric, 210, 296, 307, 311, 316, 321 Gastric Juices, 210, 316 Gastrin, 316, 321 Gastroenteritis, 316, 357 Gastrointestinal, 5, 173, 215, 223, 236, 291, 294, 295, 311, 316, 359, 363, 370 Gastrointestinal tract, 173, 295, 316, 359 Gene Deletion, 166, 316 Gene Targeting, 17, 316 Gene-modified, 18, 22, 150, 160, 316 Genetic Code, 152, 316, 341 Genetic Counseling, 246, 316 Genetic Engineering, 169, 191, 193, 249, 293, 299, 316 Genetic Techniques, 271, 316 Genetic testing, 212, 248, 316, 349 Genital, 316, 369 Genitourinary, 236, 316, 369 Genomics, 243, 267, 268, 316 Genotype, 56, 183, 236, 286, 317, 346 Germ Cells, 317, 343, 360, 372 Gestation, 317, 345, 347 Gland, 173, 197, 284, 298, 317, 332, 334, 343, 344, 347, 351, 358, 362, 363, 365 Glioblastoma, 35, 100, 106, 133, 134, 148, 203, 317 Glioblastoma multiforme, 35, 148, 317 Glioma, 24, 63, 64, 67, 89, 90, 91, 105, 111, 133, 148, 165, 317 Glomerular, 317, 329, 354

380 Gene Therapy

Glomeruli, 317 Glomerulosclerosis, 12, 317 Glomerulus, 317, 329 Glucokinase, 184, 317 Glucose, 6, 37, 41, 45, 52, 131, 294, 297, 305, 306, 317, 318, 320, 326, 357 Glucose Intolerance, 306, 317 Glucose tolerance, 41, 317 Glucose Tolerance Test, 41, 317 Glucuronate, 28, 317 Glucuronic Acid, 317, 318 Glucuronosyltransferase, 28, 318 Glutamic Acid, 318, 351 Glutamine, 56, 318 Glycogen, 52, 318 Glycolysis, 205, 206, 318 Glycoprotein, 43, 64, 89, 114, 167, 286, 295, 312, 318, 343, 365, 368 Glycosaminoglycan, 298, 318 Gonad, 318 Gonadal, 179, 318, 362 Gonadotropin, 179, 318 Governing Board, 318, 350 Gp 100, 150, 318 Gp120, 318, 345 Grade, 29, 60, 317, 318 Graft, 17, 157, 187, 286, 318, 322, 324 Graft Rejection, 318, 324 Graft Survival, 17, 318 Grafting, 157, 186, 319, 324 Granule, 214, 319, 356 Granulocytes, 74, 292, 319, 330, 359, 371 Growth factors, 43, 96, 151, 201, 216, 220, 319 Guanosine Triphosphate, 19, 319 Guanylate Cyclase, 54, 319, 340 Guinea Pigs, 319, 333 H Haematuria, 319 Haemophilia, 81, 87, 97, 319 Half-Life, 223, 319 Haploid, 319, 347 Haptens, 285, 319 Headache, 319, 325 Health Status, 152, 153, 319 Hearing aid, 270, 319 Heart attack, 296, 319 Heart failure, 13, 19, 166, 254, 319 Heartbeat, 319, 363 Hematogenous, 61, 319 Hematology, 25, 36, 98, 131, 320 Hematopoiesis, 98, 111, 219, 237, 320, 327

Hematopoietic growth factors, 220, 320 Hematopoietic Stem Cells, 25, 27, 36, 38, 42, 56, 57, 87, 142, 178, 179, 226, 320 Heme, 98, 293, 304, 314, 320, 343, 349 Hemodialysis, 320, 329 Hemodynamics, 236, 320 Hemoglobin, 70, 87, 287, 292, 312, 320, 349, 365 Hemoglobin M, 320 Hemoglobinopathies, 25, 38, 53, 320 Hemolysis, 38, 320 Hemolytic, 320, 352, 364 Hemorrhage, 308, 319, 320, 362 Hemostasis, 320, 326, 359 Hepatic, 26, 28, 40, 47, 52, 55, 69, 72, 75, 221, 223, 285, 296, 317, 320, 349 Hepatic Artery, 40, 320 Hepatitis, 201, 253, 320 Hepatocellular, 74, 79, 84, 143, 320 Hepatocellular carcinoma, 74, 79, 84, 320 Hepatocyte, 26, 52, 55, 72, 98, 298, 321 Hepatocyte Growth Factor, 26, 55, 321 Hepatoma, 101, 138, 321 Hereditary, 65, 74, 180, 192, 286, 321, 339, 346, 356, 364 Heredity, 316, 321 Herpes, 9, 14, 20, 25, 29, 40, 59, 61, 63, 64, 66, 68, 72, 96, 100, 102, 110, 115, 117, 132, 134, 153, 164, 165, 172, 193, 194, 201, 229, 284, 321 Herpes virus, 153, 164, 172, 193, 321 Herpes Zoster, 321 Heterodimers, 321, 326 Heterogeneity, 71, 285, 321 Heterotrophic, 315, 321 Histamine, 214, 287, 321 Histamine Release, 214, 287, 321 Histidine, 321 Histocompatibility, 33, 321 Histology, 10, 321 Homeostasis, 192, 212, 321 Homogeneous, 202, 290, 321, 346 Homologous, 44, 186, 190, 286, 293, 302, 303, 316, 321, 358, 363 Hormonal, 49, 186, 291, 321 Hormone Replacement Therapy, 271, 321 Hormone therapy, 284, 321 Horny layer, 311, 322 Horseradish Peroxidase, 106, 322 Human growth hormone, 207, 322 Humoral, 67, 144, 318, 322 Humour, 322

Index 381

Hybrid, 56, 69, 74, 100, 108, 176, 189, 193, 224, 299, 322 Hybridization, 58, 65, 297, 322, 337, 362 Hybridomas, 309, 322 Hydrogen, 283, 286, 292, 295, 305, 313, 322, 331, 337, 340, 341, 343, 346, 351, 363 Hydrogen Peroxide, 322, 331, 363 Hydrolases, 322, 333 Hydrolysis, 284, 299, 322, 339, 346, 349, 351, 367 Hydrophilic, 220, 322 Hydroxylysine, 300, 322 Hydroxyproline, 300, 322 Hydroxyurea, 38, 100, 322 Hyperbilirubinemia, 323, 329 Hypercholesterolemia, 5, 158, 159, 245, 323 Hyperglycemia, 6, 323 Hyperlipidemia, 208, 323 Hypersensitivity, 286, 311, 323, 356, 358 Hypertension, 9, 36, 74, 236, 290, 296, 319, 323 Hyperthermia, 116, 132, 323 Hypertrophy, 13, 323 Hypoglycemia, 41, 323 Hypoglycemic, 133, 323 Hypokinesia, 323, 344 Hypoplasia, 32, 323 Hypothalamic, 37, 323 Hypothalamus, 291, 294, 323, 347 Hypoxia, 35, 38, 100, 117, 323 I Id, 123, 138, 272, 278, 280, 323 Iduronidase, 21, 323 Ifosfamide, 61, 323 Imidazole, 293, 321, 323 Immune function, 47, 48, 57, 151, 323 Immune Sera, 323, 324 Immunity, 10, 67, 71, 76, 101, 151, 185, 242, 283, 304, 323, 324, 327, 333, 366 Immunization, 64, 324, 350, 358 Immunoassay, 10, 324 Immunocompromised, 215, 248, 324 Immunodeficiency, 32, 34, 66, 72, 73, 76, 78, 96, 115, 131, 142, 151, 159, 171, 283, 324 Immunodominant Epitopes, 40, 324 Immunofluorescence, 23, 324 Immunogen, 209, 324 Immunogenic, 4, 27, 28, 30, 324, 331 Immunoglobulin, 214, 289, 324, 337 Immunologic, 298, 324, 353

Immunology, 33, 36, 52, 56, 80, 94, 101, 119, 122, 132, 133, 178, 262, 284, 285, 315, 322, 324 Immunosuppressant, 286, 315, 324 Immunosuppressive, 17, 304, 323, 324 Immunosuppressive therapy, 324 Immunotherapy, 15, 21, 80, 91, 104, 133, 238, 293, 324 Impairment, 94, 103, 122, 270, 298, 313, 324, 335 Implant radiation, 324, 327, 328, 353, 371 Implantation, 21, 176, 301, 324 Impotence, 3, 253, 312, 324 In situ, 18, 173, 174, 187, 324 Incision, 150, 324, 328, 351, 356 Incubation, 324, 325, 330 Incubation period, 325, 330 Indicative, 237, 325, 344, 369 Induction, 6, 24, 37, 43, 58, 73, 80, 91, 133, 187, 194, 200, 325 Infancy, 151, 325 Infarction, 325, 354 Infection Control, 186, 325 Infertility, 325, 369 Infiltration, 67, 325, 350 Inflammatory bowel disease, 203, 325 Influenza, 201, 236, 325, 333 Infuse, 39, 325 Infusion, 9, 150, 160, 325 Ingestion, 317, 325 Inhalation, 285, 291, 325 Initiation, 18, 41, 194, 325, 351, 366 Initiator, 325, 327 Inlay, 325, 355 Inoperable, 131, 326 Inorganic, 299, 326, 337 Inotropic, 307, 326 Insecticides, 326, 371 Insertional, 232, 326 Insight, 33, 53, 326 Insulin, 6, 21, 37, 41, 69, 71, 96, 103, 191, 195, 205, 206, 207, 210, 236, 245, 317, 326, 328, 368 Insulin-dependent diabetes mellitus, 191, 326 Insulin-like, 96, 205, 206, 326 Integrins, 10, 326 Interferon, 14, 58, 65, 72, 76, 80, 122, 148, 194, 207, 216, 326, 327, 332 Interferon-alpha, 326 Interferon-beta, 148, 326

382 Gene Therapy

Interleukin-1, 48, 66, 67, 72, 112, 141, 143, 155, 326, 327 Interleukin-12, 66, 67, 141, 143, 155, 327 Interleukin-2, 78, 96, 150, 210, 230, 326, 327 Interleukin-3, 220, 327 Interleukin-4, 70, 136, 327 Interleukin-5, 214, 327 Interleukins, 220, 327 Intermittent, 19, 236, 314, 327, 332 Internal Medicine, 12, 26, 122, 310, 320, 327, 334 Internal radiation, 327, 328, 353, 371 Interstitial, 88, 98, 294, 313, 327, 328, 354, 371 Intestinal, 41, 143, 296, 298, 311, 317, 327, 372 Intestine, 292, 294, 300, 327, 329 Intracellular Membranes, 327, 335 Intramuscular, 65, 102, 112, 223, 225, 319, 327 Intramuscular injection, 65, 327 Intraocular, 211, 327 Intrathecal, 48, 327 Intravenous, 9, 40, 56, 103, 223, 325, 327 Intravesical, 113, 327 Intrinsic, 4, 285, 292, 327 Introns, 62, 327, 367 Intubation, 296, 328 Invasive, 30, 40, 60, 104, 168, 176, 202, 323, 328, 333 Invertebrates, 205, 206, 317, 328, 367 Involuntary, 19, 328, 338, 359, 360 Iodine, 35, 45, 328, 360 Iodine Isotopes, 45, 328 Ion Channels, 291, 328, 340 Ionization, 328 Ionizing, 175, 286, 311, 328, 353 Ions, 292, 307, 308, 314, 322, 328, 349, 360 Irradiation, 63, 115, 122, 328, 372 Ischemia, 17, 55, 82, 102, 104, 236, 291, 328, 354 Islet, 21, 41, 195, 236, 328 Isoelectric, 328, 362 Isoelectric Point, 328, 362 Isotonic, 225, 328, 336 Isozymes, 329, 352 J Jaundice, 28, 323, 329 Joint, 70, 85, 223, 235, 271, 290, 291, 329, 342, 363, 364

K Kb, 31, 164, 193, 198, 222, 260, 329 Keratin, 76, 115, 329 Keratinocytes, 5, 6, 97, 103, 157, 191, 196, 329 Kidney Cortex, 329, 335 Kidney Disease, 7, 12, 156, 161, 260, 329 Kidney Failure, 184, 310, 317, 329 Kidney Failure, Acute, 329 Kidney Failure, Chronic, 329 Killer Cells, 329 Kinetic, 328, 329 L Labile, 300, 329 Laceration, 329, 364 Large Intestine, 300, 306, 327, 329, 354, 360 Larva, 206, 330 Latent, 70, 73, 103, 194, 330, 350 Learning Disorders, 207, 330 Lectin, 330, 335 Leflunomide, 236, 330 Legal blindness, 270, 330 Lens, 227, 290, 296, 330, 371 Lentivirus, 28, 29, 42, 54, 85, 104, 330 Leprosy, 315, 330 Leptin, 36, 68, 109, 210, 236, 330 Lesion, 19, 28, 30, 70, 315, 330, 332, 359 Lethal, 25, 28, 37, 49, 61, 180, 215, 228, 330 Leucocyte, 286, 311, 330, 332 Leukaemia, 92, 109, 193, 253, 330 Leukapheresis, 150, 330 Leukemia, 28, 42, 56, 73, 78, 87, 92, 97, 102, 106, 141, 154, 176, 252, 307, 330 Leukocytes, 294, 298, 319, 326, 327, 330, 337, 346, 368 Library Services, 278, 331 Life cycle, 57, 176, 178, 315, 330, 331 Life Expectancy, 206, 331 Ligament, 288, 331, 351 Ligands, 13, 34, 57, 184, 188, 223, 326, 331 Ligase, 180, 213, 214, 331 Ligation, 73, 103, 180, 331 Light microscope, 331, 336 Linkages, 320, 323, 331, 339 Lip, 147, 148, 331 Lipid, 70, 77, 133, 183, 204, 205, 208, 217, 218, 231, 290, 298, 326, 331, 343, 368 Lipid A, 208, 331 Lipid Peroxidation, 331, 343 Lipofuscin, 298, 331 Lipopolysaccharides, 331 Lipoprotein, 331, 332, 370

Index 383

Liposomal, 136, 186, 331 Liposome, 9, 23, 37, 46, 69, 77, 105, 118, 122, 156, 177, 180, 191, 331 Liver metastases, 154, 331 Liver scan, 331, 357 Liver Transplantation, 28, 332 Lobe, 322, 332, 344 Localization, 23, 53, 64, 69, 332 Localized, 19, 30, 61, 227, 230, 308, 309, 314, 325, 332, 347, 364 Locomotion, 302, 332, 347 Locoregional, 61, 332 Locus Control Region, 62, 74, 332 Long-Term Care, 12, 25, 332 Low-density lipoprotein, 159, 331, 332 Luciferase, 23, 59, 332 Lung Transplantation, 9, 332 Lupus, 102, 332 Lymph, 10, 262, 298, 299, 310, 322, 332, 362 Lymph node, 10, 262, 298, 332 Lymphatic, 111, 310, 325, 332, 335, 360, 361, 365 Lymphatic system, 332, 360, 361, 365 Lymphedema, 65, 76, 332 Lymphoblasts, 283, 332 Lymphocyte, 17, 42, 66, 151, 160, 283, 289, 329, 332, 333, 334, 337 Lymphocyte Count, 283, 333 Lymphocytic, 193, 333 Lymphocytic Choriomeningitis Virus, 193, 333 Lymphoid, 16, 289, 330, 333 Lymphokines, 220, 333 Lymphoma, 20, 149, 157, 263, 333 Lymphoproliferative, 113, 333 Lymphoproliferative Disorders, 113, 333 Lysine, 322, 333, 367 Lysosomal Storage Diseases, 33, 51, 111, 134, 333, 337 Lyssavirus, 333, 352 Lytic, 20, 170, 178, 333, 358 M Macrophage, 210, 220, 326, 333 Macula, 333 Macula Lutea, 333 Macular Degeneration, 215, 333 Magnetic Resonance Imaging, 333, 357 Magnetic Resonance Spectroscopy, 187, 333 Major Histocompatibility Complex, 85, 133, 185, 327, 333

Malignancy, 61, 334 Malignant mesothelioma, 89, 115, 334, 335 Malignant tumor, 179, 296, 334, 343, 356 Malnutrition, 285, 291, 295, 334, 338 Mammary, 58, 75, 334, 364 Manifest, 37, 157, 292, 334 Mastitis, 334, 359 Matrix metalloproteinase, 25, 334 Measles Virus, 25, 201, 334 Medial, 290, 334 Mediate, 13, 44, 64, 66, 78, 89, 119, 126, 127, 217, 224, 300, 307, 329, 334 Mediator, 4, 327, 334, 359 Medical Oncology, 334, 353 Medical Records, 153, 334 MEDLINE, 261, 334 Megakaryocytes, 294, 334 Melanin, 334, 346, 368 Melanocytes, 334 Melanoma, 58, 69, 80, 92, 115, 150, 334 Membrane Glycoproteins, 24, 334 Membrane Proteins, 25, 129, 226, 334, 361 Memory, 40, 207, 305, 335 Meninges, 297, 335 Meningitis, 333, 335 Menstrual Cycle, 335, 350 Mental Disorders, 161, 323, 335, 350, 352 Mental Health, iv, 8, 161, 260, 262, 263, 335, 350 Mental Processes, 307, 335, 352 Mental Retardation, 55, 335 Mentors, 12, 15, 25, 335 Mercury, 314, 335 Mesenchymal, 32, 81, 91, 98, 107, 118, 311, 335 Mesothelioma, 187, 334, 335 Metabolic disorder, 28, 51, 335 Metabolite, 335, 350 Metallothionein, 41, 335 Metastasis, 10, 30, 35, 61, 67, 153, 334, 335 Metastatic, 4, 9, 14, 18, 25, 30, 35, 61, 66, 91, 150, 230, 335, 358 MI, 65, 68, 198, 281, 336 Mice Minute Virus, 336, 344 Micelle, 204, 336 Microbe, 336, 366 Microorganism, 190, 300, 336, 344, 371 Microscopy, 292, 322, 336 Microspheres, 220, 336 Microsurgery, 134, 168, 336 Microtubules, 336, 343 Migration, 184, 336

384 Gene Therapy

Milliliter, 170, 336 Mineralization, 110, 336 Mitochondria, 180, 336, 342, 367 Mitochondrial Swelling, 336, 339 Mitosis, 290, 336 Mitotic, 31, 54, 312, 336, 370 Mobility, 49, 336 Modeling, 20, 107, 114, 336 Modification, 21, 31, 64, 160, 181, 182, 200, 241, 316, 336, 352 Modulator, 218, 336 Molecular Probes, 309, 336 Monitor, 41, 60, 160, 295, 337, 340 Monoclonal, 50, 51, 64, 214, 322, 328, 337, 353, 372 Monoclonal antibodies, 50, 51, 64, 214, 337 Monocyte, 127, 337 Monocyte Chemoattractant Protein-1, 127, 337 Monogenic, 20, 337 Mononuclear, 40, 337, 368 Morbillivirus, 334, 337 Morphological, 74, 309, 334, 337, 370 Morphology, 54, 60, 80, 296, 320, 337 Mosaicism, 113, 337 Mucociliary, 337, 359 Mucopolysaccharidoses, 33, 337 Mucosa, 226, 332, 337, 362, 372 Mucositis, 337, 365 Mucus, 214, 313, 337, 368 Multidrug resistance, 43, 337 Muscle Contraction, 308, 338 Muscle Fibers, 338 Muscle Relaxation, 4, 338 Muscular Atrophy, 86, 338 Muscular Dystrophies, 109, 308, 338 Musculoskeletal System, 7, 338 Mutagenesis, 51, 175, 181, 232, 338 Mutagenic, 181, 286, 338 Mutagens, 338 Myalgia, 325, 338 Myelin, 70, 305, 338 Myelogenous, 338 Myocardial infarction, 303, 336, 338 Myocardial Ischemia, 130, 338 Myocardium, 118, 168, 336, 338 Myofibrils, 308, 338 Myopia, 338, 354, 355 Myosin, 190, 338 N Nasal Mucosa, 325, 338 Natural killer cells, 209, 327, 338

Nausea, 307, 316, 339, 368 NCI, 1, 45, 147, 148, 149, 150, 153, 154, 155, 158, 160, 259, 267, 269, 299, 339 Necrosis, 29, 34, 57, 64, 290, 317, 325, 336, 338, 339, 354 Neonatal, 26, 47, 56, 72, 75, 177, 339 Neoplasia, 30, 339 Neoplasm, 153, 339, 344, 357, 368 Neoplastic, 131, 175, 192, 202, 203, 226, 240, 322, 333, 339, 341 Nephropathy, 23, 94, 236, 329, 339 Nerve Fibers, 214, 300, 339 Nervous System, 34, 177, 240, 285, 291, 297, 334, 339, 340, 345, 352, 363 Neural, 46, 99, 137, 207, 285, 322, 339, 355, 360 Neuraminidase, 337, 339, 344 Neuroblastoma, 71, 339 Neurodegenerative Diseases, 27, 192, 339 Neuroendocrine, 6, 339 Neurologic, 56, 156, 317, 339 Neuronal, 19, 20, 46, 66, 75, 92, 215, 229, 339 Neuronal atrophy, 66, 339 Neurons, 19, 27, 34, 46, 207, 300, 305, 315, 339, 340, 352, 363 Neuropathy, 180, 236, 340, 345 Neuroretinitis, 340, 355 Neurosciences, 27, 340 Neurosecretory Systems, 310, 340 Neurotransmitters, 224, 340 Neutrons, 286, 328, 340, 353 Neutrophil, 286, 340 Night Blindness, 157, 340, 356 Nitric Oxide, 4, 70, 340 Nitrogen, 56, 286, 304, 313, 314, 318, 329, 340, 367 Non-small cell lung cancer, 135, 149, 155, 340 Norepinephrine, 285, 307, 340 Nuclear Medicine, 44, 45, 126, 129, 340 Nuclear Proteins, 174, 341 Nuclei, 61, 64, 206, 214, 286, 300, 302, 308, 316, 327, 333, 336, 340, 341, 342, 351 Nucleic Acid Hybridization, 322, 341 Nucleocapsid, 176, 341 Nucleoproteins, 341 Nucleus, 19, 199, 290, 291, 298, 300, 303, 304, 309, 312, 315, 337, 340, 341, 351, 362 Nutritional Support, 186, 341 O Ocular, 95, 112, 157, 211, 215, 341

Index 385

Ointments, 307, 341 Oliguria, 329, 341 Omentum, 320, 341 Oncogene, 114, 115, 175, 252, 321, 341 Oncogenic, 326, 330, 341, 351, 352 Oncology, 45, 80, 84, 94, 101, 107, 110, 111, 113, 120, 136, 147, 149, 155, 193, 248, 341 Oncolysis, 76, 341 Oncolytic, 63, 88, 110, 341 Opacity, 296, 305, 341 Open Reading Frames, 164, 172, 198, 330, 341 Operon, 341, 351, 354 Ophthalmoscope, 157, 342 Opportunistic Infections, 248, 263, 283, 342 Opsin, 342, 355 Optic Nerve, 340, 342, 355 Oral Health, 5, 342 Organelles, 304, 334, 342 Organoids, 244, 342 Ornithine, 157, 158, 342 Oropharynx, 147, 342 Osmotic, 285, 336, 342 Ossification, 342 Osteoarthritis, 223, 270, 271, 342 Osteoblasts, 342 Osteocalcin, 9, 342 Osteocytes, 32, 342 Osteogenesis, 118, 135, 342 Osteogenesis Imperfecta, 118, 135, 342 Osteogenic sarcoma, 343 Osteonectin, 10, 343 Osteosarcoma, 61, 90, 91, 343 Osteotomy, 271, 343 Outpatient, 160, 343 Ovarian epithelial cancer, 155, 343 Ovaries, 203, 343 Ovary, 202, 203, 303, 318, 343, 362 Overexpress, 50, 343 Ovum, 303, 317, 331, 343, 350, 372 Oxidation, 283, 289, 304, 320, 331, 343, 365 Oxidative Stress, 45, 343 Oxygen Consumption, 37, 343, 355 Oxygenase, 98, 343 Oxygenation, 36, 45, 343 P P53 gene, 110, 111, 113, 120, 127, 129, 135, 136, 137, 146, 147, 148, 155, 158, 185, 343 Paclitaxel, 122, 129, 133, 343 Palate, 343, 362 Palliative, 343, 365

Pancreas, 21, 147, 180, 191, 236, 283, 293, 306, 320, 326, 328, 343, 344, 367 Pancreatic, 6, 41, 80, 83, 88, 129, 147, 173, 187, 204, 245, 344 Pancreatic cancer, 80, 83, 147, 187, 344 Papilla, 344 Papillary, 60, 344 Papilloma, 172, 344, 356 Paralysis, 285, 299, 344 Paramyxovirus, 227, 344 Paranasal Sinuses, 344, 359 Parietal, 344, 346, 348 Parkinsonism, 103, 344 Partial remission, 344, 354 Particle, 58, 331, 336, 344, 366, 371 Parvovirus, 23, 164, 336, 344 Patch, 59, 157, 344 Pathogen, 324, 344, 363 Pathogenesis, 9, 13, 18, 33, 39, 144, 192, 214, 223, 236, 262, 344 Pathologic, 9, 290, 293, 294, 303, 323, 344, 369 Pathologic Processes, 290, 344 Pathophysiology, 3, 6, 11, 15, 344 Patient Education, 270, 271, 276, 278, 281, 344 Pelvic, 344, 351 Penile Erection, 4, 344 Penis, 4, 344 Peptide T, 217, 345 Perception, 301, 345 Perforation, 290, 315, 345 Perfusion, 55, 61, 77, 126, 251, 323, 345 Perinatal, 32, 345 Perineal, 345, 353 Periodontal disease, 6, 345 Perioperative, 236, 345 Peripheral blood, 27, 40, 98, 178, 326, 345 Peripheral Nervous System, 207, 305, 339, 345, 363 Peripheral Neuropathy, 137, 345 Peripheral Vascular Disease, 118, 191, 345 Peripheral vision, 345, 371 Peritoneal, 155, 291, 345 Peritoneal Cavity, 155, 291, 345 Peritoneum, 341, 345, 346 Peroxidase, 99, 331, 346 Peroxide, 346 Petrolatum, 309, 346 PH, 48, 82, 90, 127, 134, 144, 346 Pharmaceutical Solutions, 307, 346 Pharmacodynamic, 202, 346

386 Gene Therapy

Pharmacokinetic, 202, 346 Pharmacologic, 9, 36, 39, 287, 319, 346, 366 Pharmacotherapy, 236, 346 Pharynx, 148, 325, 342, 346 Phenolphthalein, 309, 346 Phenotype, 8, 22, 26, 27, 31, 32, 37, 54, 59, 183, 226, 301, 316, 346 Phenylalanine, 346, 368 Phospholipases, 346, 359 Phospholipids, 313, 331, 346 Phosphorus, 295, 346, 347 Phosphorylated, 50, 64, 102, 166, 347 Phosphorylation, 138, 166, 174, 188, 194, 229, 347, 352 Photocoagulation, 299, 347 Photoreceptor, 54, 270, 347 Photosensitivity, 27, 347 Phototransduction, 54, 347, 357 Physical Examination, 159, 347 Physical Fitness, 347, 361 Physiologic, 9, 17, 32, 187, 285, 293, 319, 323, 328, 335, 347, 353, 359, 367 Physiology, 3, 4, 66, 85, 96, 284, 308, 310, 320, 340, 347, 363 Pigment, 293, 298, 331, 334, 347, 355 Pilot study, 49, 52, 347 Pituitary Gland, 314, 347 Placenta, 314, 347, 350, 368 Plants, 70, 182, 188, 205, 206, 286, 294, 298, 304, 317, 330, 337, 340, 347, 357, 366, 367, 368 Plaque, 168, 288, 347 Plasma cells, 289, 347 Plasma protein, 285, 310, 348 Plasmid, 9, 20, 38, 65, 72, 91, 112, 136, 164, 180, 182, 193, 213, 216, 252, 348, 369 Plasmin, 348, 366, 369 Plasminogen, 348, 366, 369 Plasticity, 111, 207, 348 Platelet Activation, 348, 359 Platelet Aggregation, 287, 340, 348 Platelet-Derived Growth Factor, 149, 348 Platelets, 154, 334, 340, 348, 359, 365 Platinum, 299, 348 Pleated, 329, 348 Pleura, 348 Pleural, 187, 348 Pneumococcal Vaccines, 236, 348 Podophyllotoxin, 312, 348 Point Mutation, 175, 349 Polyethylene, 116, 349

Polymerase, 130, 181, 198, 290, 349, 351, 354 Polymerase Chain Reaction, 181, 349 Polymers, 144, 225, 349, 351 Polypeptide, 22, 164, 213, 214, 217, 231, 286, 295, 300, 311, 322, 348, 349, 365, 372 Polyposis, 300, 349 Polysaccharide, 289, 297, 318, 349, 351 Porphyria, 7, 38, 349 Porphyrins, 349 Posterior, 297, 298, 343, 349 Postnatal, 76, 349, 361 Postoperative, 90, 349 Postsynaptic, 349, 359, 363 Potassium, 19, 349 Potassium Channels, 19, 349 Potentiates, 127, 326, 350 Potentiation, 350, 359 Practice Guidelines, 263, 350 Precancerous, 350 Precipitation, 180, 350 Preclinical, 4, 10, 15, 18, 25, 29, 38, 40, 56, 62, 63, 79, 111, 117, 127, 136, 193, 240, 252, 350 Precursor, 179, 304, 307, 308, 311, 340, 346, 348, 350, 367, 368 Predisposition, 226, 350 Premalignant, 148, 350 Prenatal, 138, 309, 350 Prevalence, 56, 350 Prickle, 329, 350 Primary Prevention, 6, 350 Primary tumor, 18, 30, 150, 350 Probe, 18, 350 Procaine, 285, 350 Prodrug, 14, 61, 62, 91, 102, 350 Progeny, 38, 42, 302, 350 Progesterone, 188, 350, 362 Progression, 9, 24, 30, 35, 49, 58, 60, 174, 188, 192, 248, 270, 271, 288, 350, 368 Progressive disease, 150, 208, 351 Projection, 305, 340, 342, 351 Proline, 300, 322, 351 Promoter, 8, 18, 24, 27, 29, 31, 35, 41, 54, 55, 59, 61, 69, 73, 76, 84, 87, 89, 91, 105, 115, 116, 134, 144, 145, 164, 167, 170, 171, 174, 187, 189, 191, 198, 201, 202, 213, 224, 227, 228, 351 Promotor, 351, 355 Prophylaxis, 189, 224, 289, 351, 369 Prostatectomy, 253, 351, 353 Protease, 286, 300, 351, 366

Index 387

Protein S, 52, 194, 198, 228, 290, 293, 316, 322, 342, 351, 356, 364 Proteinuria, 127, 317, 351 Proteoglycan, 187, 351 Proteolytic, 286, 300, 311, 348, 351, 366, 369 Protocol, 29, 30, 40, 47, 53, 62, 152, 153, 181, 232, 351 Protons, 286, 322, 328, 333, 351, 353 Proto-Oncogene Proteins, 343, 351, 352 Proto-Oncogene Proteins c-mos, 343, 352 Protozoa, 302, 336, 352 Provirus, 164, 176, 352 Proximal, 23, 307, 329, 352 Psychiatric, 95, 335, 352 Psychiatry, 95, 314, 352, 370 Psychology, 48, 262, 307, 352 Public Policy, 261, 352 Publishing, 4, 65, 352 Pulmonary, 9, 61, 100, 112, 122, 168, 169, 191, 263, 286, 294, 311, 329, 352, 370 Pulmonary Artery, 294, 352, 370 Pulmonary Edema, 329, 352 Pulmonary hypertension, 9, 100, 169, 352 Pulse, 160, 337, 352 Pyruvate Kinase, 41, 352 Q Quality of Life, 151, 230, 236, 352 Quiescent, 164, 176, 211, 352 R Rabies, 34, 333, 352 Rabies Virus, 34, 333, 352 Race, 336, 353 Radar, 247, 353 Radiation, 10, 14, 25, 35, 45, 50, 59, 61, 63, 84, 88, 90, 94, 116, 118, 122, 145, 147, 149, 153, 175, 187, 221, 230, 242, 252, 256, 284, 309, 311, 313, 315, 323, 327, 328, 353, 357, 371 Radiation Oncology, 50, 88, 90, 116, 122, 187, 353 Radiation therapy, 14, 25, 35, 145, 147, 149, 153, 187, 221, 230, 284, 313, 327, 328, 353, 371 Radical prostatectomy, 18, 353 Radioactive, 35, 45, 168, 294, 319, 322, 324, 327, 328, 331, 336, 337, 340, 341, 353, 357, 360, 368, 371 Radioimmunotherapy, 353 Radiolabeled, 187, 328, 353, 372 Radiology, 44, 45, 94, 100, 128, 134, 340, 353

Radiosensitization, 50, 187, 230, 353 Radiosensitizers, 187, 353 Radiotherapy, 50, 67, 90, 94, 171, 187, 230, 294, 328, 353, 372 Randomized, 77, 126, 146, 147, 308, 353 Reagent, 64, 303, 332, 353 Recombinant Proteins, 185, 353 Recombination, 44, 169, 170, 182, 186, 190, 192, 201, 214, 302, 316, 354 Reconstitution, 21, 29, 56, 177, 354 Rectal, 129, 354 Rectum, 290, 294, 300, 306, 315, 325, 329, 351, 354 Recur, 61, 354 Recurrence, 31, 49, 221, 354 Red blood cells, 154, 312, 320, 343, 354, 357 Reductase, 28, 41, 93, 236, 354 Refer, 1, 295, 300, 314, 315, 321, 332, 333, 340, 353, 354 Refraction, 338, 354, 361 Refractory, 6, 143, 155, 308, 354 Regeneration, 7, 90, 95, 195, 230, 231, 314, 354 Regimen, 61, 150, 308, 346, 354 Remission, 195, 221, 248, 354 Renal capsule, 30, 354 Renal failure, 23, 320, 354 Renal pelvis, 354, 367 Renovascular, 74, 354 Reperfusion, 17, 354 Reperfusion Injury, 354 Repressor, 213, 341, 354 Resection, 145, 271, 355, 367 Respiration, 314, 337, 355 Respiratory Physiology, 355, 370 Response Elements, 18, 355 Restitution, 32, 355 Restoration, 32, 64, 86, 166, 354, 355, 371 Resuscitation, 186, 355 Reticulata, 19, 355 Reticuloendotheliosis, 34, 355 Reticuloendotheliosis Viruses, 34, 355 Retina, 54, 89, 157, 211, 215, 216, 228, 270, 298, 330, 333, 338, 340, 342, 347, 355, 356, 357, 371 Retinal, 54, 157, 211, 216, 243, 270, 301, 342, 347, 355, 371 Retinal Detachment, 211, 355 Retinal pigment epithelium, 211, 216, 355 Retinitis, 54, 270, 355, 356 Retinitis Pigmentosa, 54, 270, 356

388 Gene Therapy

Retinoblastoma, 174, 356 Retinoblastoma Protein, 174, 356 Retinol, 355, 356 Retinopathy, 43, 347, 356 Retropubic, 351, 353, 356 Retropubic prostatectomy, 353, 356 Reversion, 58, 356 Rhabdomyosarcoma, 24, 356 Rheumatism, 356 Rheumatoid, 70, 235, 271, 356 Rheumatoid arthritis, 70, 235, 271, 356 Rhinitis, 356, 359 Ribonucleic acid, 208, 356 Ribonucleoside Diphosphate Reductase, 322, 356 Ribose, 130, 284, 356 Ribosome, 289, 356, 367 Rigidity, 344, 347, 356 Risk factor, 36, 209, 236, 271, 356 Rod, 54, 143, 347, 357 Rod cells, 54, 357 Rotavirus, 201, 357 S Saline, 225, 357 Saliva, 352, 357 Salivary, 5, 6, 173, 256, 304, 306, 344, 357, 363 Salivary glands, 5, 6, 256, 304, 306, 357 Saponins, 357, 362 Sarcoma, 30, 122, 126, 159, 201, 263, 357 Satellite, 239, 248, 305, 357 Satellite Viruses, 305, 357 Scans, 45, 150, 168, 357 Sclerae, 343, 357 Scleroproteins, 329, 357 Sclerosis, 122, 142, 290, 357 Screening, 29, 174, 192, 194, 203, 223, 241, 299, 357 Sea Urchins, 288, 357 Second Messenger Systems, 340, 357 Secondary tumor, 335, 358 Secretion, 6, 41, 50, 51, 52, 172, 201, 311, 321, 322, 326, 327, 337, 357, 358, 369 Secretory, 6, 50, 144, 173, 358, 363 Segmental, 317, 358 Segregation, 354, 358 Seizures, 317, 358 Selective estrogen receptor modulator, 358, 364 Self Care, 283, 358 Semen, 351, 358 Semisynthetic, 312, 358

Sensitization, 63, 100, 358 Septic, 208, 291, 358 Septicaemia, 358, 359 Sequence Homology, 345, 358 Sequencing, 172, 181, 201, 207, 268, 269, 349, 358 Serine, 352, 358, 366, 367 Serologic, 324, 358 Serotonin, 346, 358, 367 Serotypes, 31, 44, 201, 359 Serous, 310, 311, 348, 359 Serum, 51, 204, 205, 208, 285, 287, 289, 300, 318, 323, 329, 332, 342, 354, 358, 359, 368 Sharpness, 359, 371 Shedding, 86, 359 Shivering, 359, 365 Shock, 24, 188, 205, 206, 208, 217, 359, 367 Signal Transduction, 36, 37, 224, 359 Signs and Symptoms, 34, 354, 359 Sinusitis, 248, 359 Skeletal, 7, 10, 32, 50, 73, 90, 127, 197, 198, 212, 225, 244, 338, 359 Skeleton, 154, 212, 283, 313, 329, 359 Skull, 359, 364 Small cell lung cancer, 155, 360 Small intestine, 308, 321, 327, 360, 367 Smallpox, 267, 360, 369 Smooth muscle, 4, 190, 215, 287, 302, 321, 360, 363 Sneezing, 359, 360 Social Change, 249, 360 Social Environment, 262, 352, 360 Sodium, 24, 35, 79, 347, 360 Sodium Channels, 347, 360 Sodium Iodide, 24, 360 Soft tissue, 10, 294, 359, 360 Solid tumor, 72, 149, 288, 307, 310, 360 Soma, 360 Somatic cells, 172, 196, 297, 336, 360 Specialist, 272, 360 Specificity, 8, 13, 27, 29, 38, 46, 54, 57, 62, 64, 181, 191, 285, 324, 360 Spectrin, 308, 360 Spectrum, 40, 185, 191, 214, 337, 361 Sperm, 299, 361 Spinal cord, 48, 291, 297, 298, 309, 327, 335, 339, 340, 345, 361 Spinal Nerves, 345, 361 Spinous, 311, 329, 361 Spleen, 34, 57, 64, 304, 332, 361 Sporadic, 21, 339, 356, 361 Sports Medicine, 6, 7, 276, 361

Index 389

Sputum, 214, 361 Squamous, 10, 95, 141, 147, 311, 340, 361 Squamous cell carcinoma, 10, 95, 147, 311, 340, 361 Squamous cells, 361 Stabilization, 73, 361 Staging, 203, 357, 361 Statistically significant, 43, 361 Stem cell transplantation, 97, 157, 361 Sterile, 151, 291, 362 Sterility, 178, 304, 325, 362 Sterilization, 179, 362 Steroid, 188, 205, 206, 217, 292, 303, 357, 362 Stimulant, 321, 362 Stimulus, 52, 302, 307, 308, 312, 328, 362, 365 Stomach, 283, 306, 312, 315, 316, 317, 320, 321, 339, 341, 345, 346, 360, 361, 362 Stomatitis, 71, 114, 227, 362 Strand, 31, 76, 181, 194, 214, 349, 362 Streptavidin, 64, 362 Stress, 205, 206, 291, 296, 303, 315, 316, 339, 343, 350, 356, 362 Striatum, 19, 362 Stringency, 44, 362 Stroke, 36, 153, 156, 161, 184, 260, 296, 362 Stroma, 9, 362 Stromal, 22, 81, 106, 294, 362 Stromal Cells, 22, 81, 294, 362 Subacute, 325, 359, 362 Subclinical, 325, 358, 362 Subcutaneous, 29, 49, 284, 315, 319, 362 Submaxillary, 311, 362 Subspecies, 360, 363, 369 Substance P, 335, 354, 358, 363 Substrate, 20, 34, 322, 339, 363 Sudden death, 166, 363 Superinfection, 164, 363 Superoxide, 45, 122, 363 Superoxide Dismutase, 45, 122, 363 Suppression, 18, 30, 39, 58, 60, 219, 226, 363 Survival Rate, 203, 230, 363 Sympathomimetic, 307, 311, 340, 363 Symphysis, 351, 363 Symptomatic, 38, 59, 363 Synapses, 340, 363 Synaptic, 359, 363 Synergistic, 63, 75, 363 Synovial, 235, 271, 363, 364 Synovial Fluid, 271, 364

Synovial Membrane, 364 Systemic disease, 21, 23, 195, 364 Systolic, 323, 364 T Tachycardia, 20, 364 Tamoxifen, 228, 358, 364 Telencephalon, 292, 364 Telomerase, 91, 114, 116, 364 Telomere, 319, 364 Temporal, 54, 228, 333, 364 Terminator, 300, 364 Testosterone, 354, 364 Tetani, 364 Tetanic, 364 Tetanus, 159, 364 Tetracycline, 22, 27, 213, 307, 364 Thalamus, 294, 364 Thalassemia, 25, 292, 364 Therapeutics, 5, 6, 73, 99, 146, 165, 177, 203, 204, 221, 225, 242, 244, 248, 365 Thermal, 288, 291, 307, 340, 349, 365 Thermogenesis, 36, 197, 198, 365 Thigh, 157, 313, 365 Thoracic, 128, 131, 132, 187, 306, 348, 365, 371 Threonine, 345, 352, 358, 365 Threshold, 59, 323, 365 Thrombin, 314, 348, 351, 365 Thrombocytes, 348, 365 Thrombolytic, 133, 348, 365 Thrombomodulin, 351, 365 Thrombosis, 71, 133, 326, 351, 362, 365 Thrombus, 303, 325, 338, 348, 365 Thymus, 324, 332, 365 Thyroid, 35, 96, 116, 217, 328, 360, 365, 368 Thyroid Gland, 365 Thyroid Hormones, 217, 365, 368 Thyroxine, 285, 346, 365 Tin, 156, 345, 348, 366 Tissue Plasminogen Activator, 71, 207, 366 Tolerance, 17, 28, 51, 284, 317, 366 Tomography, 41, 128, 135, 301, 333, 366 Tonicity, 308, 320, 328, 366 Topical, 59, 306, 322, 346, 366 Topotecan, 122, 133, 366 Toxicity, 14, 15, 23, 26, 29, 43, 46, 53, 58, 59, 62, 145, 152, 170, 187, 199, 202, 307, 335, 366 Toxicology, 262, 366 Toxins, 179, 289, 309, 318, 325, 337, 353, 366, 370

390 Gene Therapy

Trace element, 366 Tracer, 322, 366 Trachea, 295, 313, 346, 365, 366 Transcriptase, 94, 116, 356, 364, 366 Transcription Factors, 53, 189, 194, 217, 225, 228, 355, 366 Transfection, 21, 37, 54, 80, 137, 141, 166, 169, 170, 174, 193, 194, 204, 231, 293, 309, 366 Transfer Factor, 324, 366 Transgenes, 25, 42, 62, 215, 222, 367 Transitional cell carcinoma, 60, 127, 158, 367 Translation, 25, 56, 170, 194, 201, 289, 367 Translational, 12, 63, 193, 240, 367 Translocation, 207, 231, 367 Transmitter, 283, 291, 307, 328, 334, 340, 363, 367 Transposase, 185, 191, 367 Trans-Splicing, 31, 89, 367 Transurethral, 351, 367 Transurethral Resection of Prostate, 351, 367 Trauma, 46, 97, 186, 271, 319, 339, 367 Treatment Failure, 62, 367 Tremor, 344, 367 Trophic, 216, 367 Tropism, 31, 44, 58, 167, 199, 367 Trypsin, 52, 210, 286, 311, 367 Tryptophan, 300, 358, 367 Tuberculosis, 242, 263, 332, 368 Tumor infiltrating lymphocytes, 30, 368 Tumor model, 58, 67, 136, 368 Tumor Necrosis Factor, 40, 134, 144, 147, 207, 218, 368 Tumor suppressor gene, 171, 343, 356, 368 Tumorigenic, 58, 368 Tumour, 81, 88, 129, 341, 368 Type 2 diabetes, 6, 236, 368 Tyrosine, 19, 64, 66, 101, 103, 307, 368 U Ubiquinone, 206, 368 Ulceration, 306, 368 Ulcerative colitis, 203, 325, 368 Umbilical Arteries, 368 Umbilical Cord, 159, 286, 368 Unconscious, 288, 305, 323, 368 Untranslated Regions, 62, 368 Uracil, 41, 63, 83, 95, 368 Urea, 28, 55, 329, 342, 368 Uremia, 329, 354, 368 Ureter, 354, 367, 368

Urethra, 345, 351, 367, 369 Urinary, 37, 316, 341, 351, 356, 366, 368, 369 Urinary Plasminogen Activator, 366, 369 Urinary tract, 369 Urine, 10, 73, 290, 293, 311, 319, 329, 341, 351, 354, 368, 369 Urogenital, 316, 369 Urology, 3, 4, 9, 58, 61, 107, 128, 129, 369 Uterus, 298, 303, 315, 343, 350, 369 V Vaccination, 24, 194, 201, 222, 225, 369 Vaccine, 14, 79, 86, 150, 194, 204, 262, 284, 295, 351, 369 Vaccinia, 172, 369 Vaccinia Virus, 172, 369 Vacuoles, 310, 342, 369 Vagina, 298, 369 Valves, 168, 369 Variola, 369 Vascular endothelial growth factor, 96, 97, 102, 114, 131, 210, 369 Vasculitis, 237, 369 Vasoconstriction, 311, 369 Vasodilator, 9, 294, 307, 321, 369 Vector, 8, 11, 15, 17, 18, 20, 21, 22, 23, 24, 25, 28, 29, 30, 31, 33, 34, 37, 38, 39, 40, 42, 44, 45, 46, 47, 48, 50, 52, 53, 55, 57, 58, 60, 63, 65, 66, 67, 69, 75, 76, 77, 80, 84, 85, 86, 88, 89, 90, 93, 96, 107, 108, 110, 112, 113, 118, 135, 145, 164, 165, 166, 167, 170, 171, 172, 176, 177, 180, 181, 182, 183, 184, 186, 189, 190, 191, 193, 195, 197, 201, 202, 205, 206, 207, 210, 211, 213, 219, 222, 226, 227, 231, 232, 238, 252, 253, 254, 326, 356, 366, 369 Vein, 150, 159, 327, 340, 357, 368, 369 Venoms, 304, 370 Venous, 61, 351, 370 Ventilation, 49, 370 Ventricle, 168, 323, 352, 364, 370 Venules, 294, 295, 310, 370 Vertebrae, 361, 370 Vesicular, 71, 114, 227, 321, 360, 369, 370 Veterinary Medicine, 261, 370 Vibrio, 298, 370 Vibrio cholerae, 298, 370 Vinblastine, 221, 370 Vinca Alkaloids, 370 Vincristine, 221, 370 Viral Envelope Proteins, 231, 370 Viral Load, 159, 370

Index 391

Viral vector, 13, 16, 24, 28, 29, 30, 31, 32, 36, 40, 45, 46, 49, 56, 62, 63, 97, 101, 104, 119, 136, 170, 171, 172, 173, 174, 179, 184, 185, 187, 198, 199, 215, 218, 226, 227, 231, 232, 370 Viremia, 39, 370 Virion, 170, 198, 229, 341, 370 Virulence, 17, 291, 363, 366, 371 Virus Diseases, 289, 371 Virus Replication, 42, 49, 164, 371 Viscera, 360, 371 Visual Acuity, 157, 227, 330, 371 Visual field, 157, 330, 356, 371 Vitreous Body, 298, 355, 371 Vitreous Humor, 355, 371 Vitro, 4, 8, 11, 13, 18, 20, 23, 33, 34, 35, 39, 40, 44, 50, 54, 56, 59, 60, 63, 65, 78, 84, 89, 91, 98, 99, 102, 126, 133, 142, 143, 164, 167, 169, 173, 174, 177, 180, 181, 195, 196, 205, 207, 220, 228, 297, 324, 349, 363, 371 Volition, 328, 371

W Weight Gain, 37, 371 White blood cell, 154, 159, 283, 289, 292, 299, 330, 332, 333, 337, 338, 340, 347, 368, 371 Windpipe, 346, 365, 371 Wound Healing, 43, 149, 186, 314, 326, 334, 371 X Xenobiotics, 51, 371 Xenograft, 76, 78, 129, 136, 137, 288, 368, 371 X-ray, 45, 147, 149, 150, 168, 271, 288, 301, 315, 328, 340, 353, 357, 371 X-ray therapy, 328, 371 Y Yeasts, 315, 346, 372 Yolk Sac, 314, 372 Z Zoonoses, 352, 372 Zygote, 301, 302, 337, 372 Zymogen, 351, 372

392 Gene Therapy