RETINOBLASTOMA
A
3-in-1
Medical
Reference
A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES
RETINOBLASTOMA A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS
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. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 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., 1960Retinoblastoma: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11286-8 1. Retinoblastoma-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:
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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 retinoblastoma. 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 Chaired Professor of Management Science 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. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON RETINOBLASTOMA .................................................................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Retinoblastoma? ............................................................................................................... 3 How Common Is Retinoblastoma?................................................................................................. 4 What Are the Genetic Changes Related to Retinoblastoma? ......................................................... 4 Where Can I Find Additional Information about Retinoblastoma?............................................... 4 References....................................................................................................................................... 6 What Is Chromosome 13? .............................................................................................................. 7 What Chromosomal Conditions Are Related to Chromosome 13? ................................................ 7 Is There a Standard Way to Diagram Chromosome 13?................................................................ 8 References....................................................................................................................................... 8 What Is the Official Name of the RB1 Gene?................................................................................. 9 What Is the Normal Function of the RB1 Gene? ........................................................................... 9 What Conditions Are Related to the RB1 Gene? ........................................................................... 9 Where Is the RB1 Gene Located? ................................................................................................. 10 References..................................................................................................................................... 11 Federally Funded Research on Retinoblastoma............................................................................ 12 The National Library of Medicine: PubMed ................................................................................ 74 CHAPTER 2. ALTERNATIVE MEDICINE AND RETINOBLASTOMA .................................................. 117 Overview.................................................................................................................................... 117 National Center for Complementary and Alternative Medicine................................................ 117 Additional Web Resources ......................................................................................................... 139 General References ..................................................................................................................... 139 CHAPTER 3. BOOKS ON RETINOBLASTOMA .................................................................................. 140 Overview.................................................................................................................................... 140 Book Summaries: Online Booksellers......................................................................................... 140 The National Library of Medicine Book Index ........................................................................... 141 CHAPTER 4. MULTIMEDIA ON RETINOBLASTOMA ....................................................................... 143 Overview.................................................................................................................................... 143 Bibliography: Multimedia on Retinoblastoma ........................................................................... 143 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 145 Overview.................................................................................................................................... 145 The Basics: Genes and How They Work..................................................................................... 145 Genetic Mutations and Health................................................................................................... 156 Inheriting Genetic Conditions ................................................................................................... 162 Genetic Consultation ................................................................................................................. 170 Genetic Testing .......................................................................................................................... 172 Gene Therapy ............................................................................................................................. 178 The Human Genome Project and Genomic Research................................................................. 181 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 184 Overview.................................................................................................................................... 184 NIH Guidelines.......................................................................................................................... 184 NIH Databases........................................................................................................................... 185 Other Commercial Databases..................................................................................................... 188 The Genome Project and Retinoblastoma................................................................................... 188 APPENDIX C. PATIENT RESOURCES .............................................................................................. 192 Overview.................................................................................................................................... 192 Patient Guideline Sources.......................................................................................................... 192 Finding Associations.................................................................................................................. 194
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Resources for Patients and Families........................................................................................... 195 ONLINE GLOSSARIES................................................................................................................ 196 Online Dictionary Directories ................................................................................................... 197 RETINOBLASTOMA DICTIONARY........................................................................................ 198 INDEX .............................................................................................................................................. 269
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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 retinoblastoma 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 retinoblastoma, 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 retinoblastoma, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of retinoblastoma. 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 retinoblastoma. 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 retinoblastoma, 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. We hope these resources will prove useful to the widest possible audience seeking information on retinoblastoma. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.
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CHAPTER 1. STUDIES ON RETINOBLASTOMA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on retinoblastoma. For those interested in basic information about retinoblastoma, we begin with a condition summary published by the National Library of Medicine.
Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on retinoblastoma that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to retinoblastoma is provided.2 The Genetics Home Reference has recently published the following summary for retinoblastoma:
What Is Retinoblastoma?3 Retinoblastoma is a rare type of eye cancer that develops in the retina, the part of the eye that detects light and color. Although this disorder can occur at any age, it usually develops in young children. Most cases of retinoblastoma occur in only one eye, but both eyes can be affected. The most common sign of this disorder is a visible whiteness in the normally black pupil (the opening through which light enters the eye). This unusual whiteness is particularly noticeable in photographs taken with a flash, and is called "cat's eye reflex" or leukocoria. Other signs and 2 3
This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=retinoblastoma.
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Retinoblastoma
symptoms of retinoblastoma include crossed eyes or eyes that do not point in the same direction (strabismus); persistent eye pain, redness, or irritation; and blindness or poor vision in the affected eye. People with the hereditary form of retinoblastoma may also develop a tumor in the brain called pinealoma. Pinealoma develops in the pineal gland, which is located at the base of the skull. The presence of retinoblastoma and pinealoma together is called trilateral retinoblastoma. Later in life, people with hereditary retinoblastoma also have an increased risk of developing bone cancer (osteosarcoma), soft tissue cancers, a form of skin cancer called melanoma, and other types of cancer.
How Common Is Retinoblastoma? Retinoblastoma affects an estimated 1 in 15,000 to 20,000 live births. This disease is diagnosed in about 250 children per year in the United States. It accounts for about 3 percent of all cancers in children younger than 15 years.
What Are the Genetic Changes Related to Retinoblastoma? Retinoblastoma is a chromosomal condition related to chromosome 13 (http://ghr.nlm.nih.gov/chromosome=13). Variations of the RB1 (http://ghr.nlm.nih.gov/gene=rb1) gene increase the risk of developing retinoblastoma. Mutations in the RB1 gene are responsible for most cases of retinoblastoma. RB1 is a tumor suppressor gene, which means it normally keeps cells from growing and dividing too rapidly or in an uncontrolled way. Most mutations in the RB1 gene prevent it from making any functional protein, so it is unable to effectively regulate cell division. As a result, cells divide uncontrollably and form a tumor. A small percentage of retinoblastoma cases are caused by a deletion in the region of chromosome 13 that contains the RB1 gene. Geneticists refer to this region as 13q14. Children with these chromosomal deletions may also have mental retardation, slow growth, and characteristic facial features (such as prominent eyebrows, a short nose with a broad nasal bridge, and ear abnormalities).
Where Can I Find Additional Information about Retinoblastoma? You may find the following resources about retinoblastoma helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •
National Cancer Institute: http://www.cancer.gov/CancerInformation/CancerType/retinoblastoma
Studies
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National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gn d.section.129 MedlinePlus - Health Information
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Encyclopedia: Retinoblastoma: http://www.nlm.nih.gov/medlineplus/ency/article/001030.htm
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Health Topic: Eye Cancer: http://www.nlm.nih.gov/medlineplus/eyecancer.html
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Health Topic: Retinal Disorders: http://www.nlm.nih.gov/medlineplus/retinaldisorders.html Educational Resources - Information Pages
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Cleveland Clinic Health Information Center: http://www.clevelandclinic.org/health/health-info/docs/3000/3076.asp?index=10706
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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=302
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New York Online Access to Health (NOAH): http://www.noah-health.org/en/cancer/types/childhood/types/retinoblastoma.html
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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=790
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Retinoblastoma (Digital Journal of Ophthalmology): http://www.djo.harvard.edu/site.php?url=/patients/pi/436#
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St. Louis Children's Hospital: http://www.stlouischildrens.org/default.aspx?tabid=88&acn=view&aid=153 Patient Support - for Patients and Families9
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American Cancer Society: http://www.cancer.org/docroot/cri/cri_2_3x.asp?dt=37
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Candlelighters Childhood Cancer Foundation: http://www.candlelighters.org
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CureSearch (the Children's Oncology Group and the National Childhood Cancer Foundation): http://www.curesearch.org/for_parents_and_families/newlydiagnosed/
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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Retinoblastoma
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Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/retinobl.html
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Retinoblastoma International: http://www.retinoblastoma.net
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Retinoblastoma
The EyeCare Foundation: http://www.eyecarefoundation.org/ Professional Resources
You may also be interested in these resources, which are designed for healthcare professionals and researchers. •
Gene Reviews - Clinical summary: http://www.genetests.org/query?dz=retinoblastoma
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Gene Tests - DNA tests ordered by healthcare professionals: http://www.genetests.org/query?testid=2161
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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22retinoblastoma%22?recruiting=false
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PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=retinoblastoma/show/PubMed;jsessionid=AC13C32 558B3C2ACE6B67FA630AA0CE1
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OMIM - Genetic disorder catalog: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180200
References These sources were used to develop the Genetics Home Reference condition summary on retinoblastoma. •
Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004 Dec;24(6):828-48. Review. No abstract available. PubMed citation
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Baud O, Cormier-Daire V, Lyonnet S, Desjardins L, Turleau C, Doz F. Dysmorphic phenotype and neurological impairment in 22 retinoblastoma patients with constitutional cytogenetic 13q deletion. Clin Genet. 1999 Jun;55(6):478-82. PubMed citation
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Gene Review
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Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet C Semin Med Genet. 2004 Aug 15;129(1):23-8. Review. PubMed citation
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National Cancer Institute
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Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p819-848. NLM Catalog
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Sippel KC, Fraioli RE, Smith GD, Schalkoff ME, Sutherland J, Gallie BL, Dryja TP. Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet. 1998 Mar;62(3):610-9. PubMed citation
Studies
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Summaries of the chromosome and gene related to retinoblastoma are provided below:
What Is Chromosome 13?4 Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 13, one copy inherited from each parent, form one of the pairs. Chromosome 13 spans about 114 million base pairs (the building blocks of DNA) and represents between 3.5 percent and 4 percent of the total DNA in cells. Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. Chromosome 13 likely contains between 300 and 700 genes. Genes on chromosome 13 are among the estimated 20,000 to 25,000 total genes in the human genome. There are many genetic conditions related to genes on chromosome 13.
What Chromosomal Conditions Are Related to Chromosome 13? The following conditions are caused by changes in the structure or number of copies of chromosome 13. Retinoblastoma A small percentage of retinoblastoma cases are caused by deletions in the region of chromosome 13 (13q14) containing the RB1 gene. Children with these chromosomal deletions may also have mental retardation, slow growth, and characteristic facial features (such as prominent eyebrows, a broad nasal bridge, a short nose, and ear abnormalities). Researchers have not determined which other genes are located in the deleted region, but a loss of several genes is likely responsible for these developmental problems. Trisomy 13 Trisomy 13 occurs when each cell in the body has three copies of chromosome 13 instead of the usual two copies. Trisomy 13 can also result from an extra copy of chromosome 13 in only some of the body's cells (mosaic trisomy 13). Other Chromosomal Conditions Partial monosomy 13q is a rare chromosomal disorder that results when a piece of the long arm (q) of chromosome 13 is missing (monosomic). Infants born with partial monosomy 13q 4
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/chromosome=13;jsessionid=AC13C32558B3C2ACE6B67FA630AA0CE1.
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may exhibit low birth weight, malformations of the head and face (craniofacial region), skeletal abnormalities (especially of the hands and feet), and other physical abnormalities. Mental retardation is characteristic of this condition. The mortality rate during infancy is high among individuals born with this disorder. Almost all cases of partial monosomy 13q occur randomly for no apparent reason (sporadic).
Is There a Standard Way to Diagram Chromosome 13? Geneticists use diagrams called ideograms as a standard representation for chromosomes. Ideograms show a chromosome's relative size and its banding pattern. A banding pattern is the characteristic pattern of dark and light bands that appears when a chromosome is stained with a chemical solution and then viewed under a microscope. These bands are used to describe the location of genes on each chromosome.
You may find the following resources about chromosome 13 helpful. These materials are written for the general public. You may also be interested in these resources, which are designed for genetics professionals and researchers.
References These sources were used to develop the Genetics Home Reference chromosome summary on chromosome 13. •
Baud O, Cormier-Daire V, Lyonnet S, Desjardins L, Turleau C, Doz F. Dysmorphic phenotype and neurological impairment in 22 retinoblastoma patients with constitutional cytogenetic 13q deletion. Clin Genet. 1999 Jun;55(6):478-82. PubMed citation
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Dunham A, Matthews LH, Burton J, Ashurst JL, Howe KL, Ashcroft KJ, Beare DM, Burford DC, Hunt SE, Griffiths-Jones S, Jones MC, Keenan SJ, Oliver K, Scott CE, Ainscough R, Almeida JP, Ambrose KD, Andrews DT, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Bannerjee R, Barlow KF, Bates K, Beasley H, Bird CP, Bray-Allen S, Brown AJ, Brown JY, Burrill W, Carder C, Carter NP, Chapman JC, Clamp ME, Clark SY, Clarke G, Clee CM, Clegg SC, Cobley V, Collins JE, Corby N, Coville GJ, Deloukas P, Dhami P, Dunham I, Dunn M, Earthrowl ME, Ellington AG, Faulkner L, Frankish AG, Frankland J, French L, Garner P, Garnett J, Gilbert JG, Gilson CJ, Ghori J, Grafham DV, Gribble SM, Griffiths C, Hall RE, Hammond S, Harley JL, Hart EA, Heath PD, Howden PJ, Huckle EJ, Hunt PJ, Hunt AR, Johnson C, Johnson D, Kay M, Kimberley AM, King A, Laird GK, Langford CJ, Lawlor S, Leongamornlert DA, Lloyd DM, Lloyd C, Loveland
Studies
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JE, Lovell J, Martin S, Mashreghi-Mohammadi M, McLaren SJ, McMurray A, Milne S, Moore MJ, Nickerson T, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter KM, Rice CM, Searle S, Sehra HK, Shownkeen R, Skuce CD, Smith M, Steward CA, Sycamore N, Tester J, Thomas DW, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, Whitehead SL, Willey DL, Wilming L, Wray PW, Wright MW, Young L, Coulson A, Durbin R, Hubbard T, Sulston JE, Beck S, Bentley DR, Rogers J, Ross MT. The DNA sequence and analysis of human chromosome 13. Nature. 2004 Apr 1;428(6982):522-8. PubMed citation •
Ensembl Human Map View: Chromosome 13
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Gilbert F. Chromosome 13. Genet Test. 2000;4(1):85-94. No abstract available. PubMed citation
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Kivela T, Tuppurainen K, Riikonen P, Vapalahti M. Retinoblastoma associated with chromosomal 13q14 deletion mosaicism. Ophthalmology. 2003 Oct;110(10):1983-8. Review. PubMed citation
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Map Viewer: Genes on Sequence
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UCSC Genome Browser: Statistics from NCBI Build 34, July 2003
What Is the Official Name of the RB1 Gene?5 The official name of this gene is “retinoblastoma 1 (including osteosarcoma).” RB1 is the gene's official symbol. The RB1 gene is also known by other names, listed below.
What Is the Normal Function of the RB1 Gene? The RB1 gene provides instructions for making a protein that has several critical functions within cells. The RB1 protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. It is located in the nucleus of cells throughout the body, where it interacts with many other proteins. Under certain conditions, the RB1 protein stops other proteins from triggering the process by which DNA makes a copy of itself (DNA replication). Because DNA replication must occur before a cell can divide, tight regulation of this process controls cell division and helps prevent the growth of cancerous tumors. Additionally, the RB1 protein may play a role in cell survival, controlled cell death (apoptosis), and the process by which cells mature to carry out special functions (differentiation).
What Conditions Are Related to the RB1 Gene? Retinoblastoma - Increased Risk from Variations of the RB1 Gene More than 400 mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that typically affects young children. In familial 5
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=rb1.
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Retinoblastoma
cases of retinoblastoma, a person inherits an altered copy of the RB1 gene from one parent. This mutated gene is present in all of the body's cells. For retinoblastoma to develop, the second copy of the RB1 gene must be mutated or lost in cells of the retina. This second mutation usually occurs early in life. Cells with two inactive copies of this gene produce no functional RB1 protein and are unable to regulate cell division effectively. As a result, retinal cells lacking functional RB1 protein can divide uncontrollably to form a cancerous tumor. Bladder Cancer - Associated with the RB1 Gene More than 400 mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that typically affects young children. In familial cases of retinoblastoma, a person inherits an altered copy of the RB1 gene from one parent. This mutated gene is present in all of the body's cells. For retinoblastoma to develop, the second copy of the RB1 gene must be mutated or lost in cells of the retina. This second mutation usually occurs early in life. Cells with two inactive copies of this gene produce no functional RB1 protein and are unable to regulate cell division effectively. As a result, retinal cells lacking functional RB1 protein can divide uncontrollably to form a cancerous tumor. Other Cancers - Associated with the RB1 Gene Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations that inactivate the RB1 gene have been reported in some cases of bladder cancer. Mutations in RB1 are thought to contribute to the development of bladder cancer, and may help predict whether tumors will grow rapidly and spread to other tissues.
Where Is the RB1 Gene Located? Cytogenetic Location: 13q14.2 Molecular Location on chromosome 13: base pairs 47,775,911 to 47,954,022
The RB1 gene is located on the long (q) arm of chromosome 13 at position 14.2. More precisely, the RB1 gene is located from base pair 47,775,911 to base pair 47,954,022 on chromosome 13.
Studies
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References These sources were used to develop the Genetics Home Reference gene summary on the RB1 gene. •
Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer. 2002 Dec;2(12):910-7. Review. PubMed citation
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de Andrade AF, da Hora Barbosa R, Vargas FR, Ferman S, Eisenberg AL, Fernandes L, Bonvicino CR. A molecular study of first and second RB1 mutational hits in retinoblastoma patients. Cancer Genet Cytogenet. 2006 May;167(1):43-6. PubMed citation
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Gene Review: Retinoblastoma
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Goodrich DW. The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene. 2006 Aug 28;25(38):5233-43. Review. PubMed citation
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Herwig S, Strauss M. The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. Eur J Biochem. 1997 Jun 15;246(3):581-601. Review. PubMed citation
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Korabiowska M, Ruschenburg I, Betke H, Stachura J, Schlott T, Cardo CC, Brinck U. Downregulation of the retinoblastoma gene expression in the progression of malignant melanoma. Pathobiology. 2001;69(5):274-80. PubMed citation
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Liu H, Dibling B, Spike B, Dirlam A, Macleod K. New roles for the RB tumor suppressor protein. Curr Opin Genet Dev. 2004 Feb;14(1):55-64. Review. PubMed citation
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Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet C Semin Med Genet. 2004 Aug 15;129(1):23-8. Review. PubMed citation
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Richter S, Vandezande K, Chen N, Zhang K, Sutherland J, Anderson J, Han L, Panton R, Branco P, Gallie B. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet. 2003 Feb;72(2):253-69. Epub 2002 Dec 18. PubMed citation
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Sampieri K, Hadjistilianou T, Mari F, Speciale C, Mencarelli MA, Cetta F, Manoukian S, Peissel B, Giachino D, Pasini B, Acquaviva A, Caporossi A, Frezzotti R, Renieri A, Bruttini M. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations. J Hum Genet. 2006;51(3):209-16. Epub 2006 Feb 4. PubMed citation
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Wolff EM, Liang G, Jones PA. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol. 2005 Oct;2(10):502-10. Review. PubMed citation
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Retinoblastoma
Federally Funded Research on Retinoblastoma The U.S. Government supports a variety of research studies relating to retinoblastoma. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.6 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP 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 retinoblastoma. 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 retinoblastoma. The following is typical of the type of information found when searching the CRISP database for retinoblastoma: •
Project Title: AH RECEPTOR ANATOMY: IMPLICATIONS FOR DIOXIN TOXICITY Principal Investigator & Institution: Elferink, Cornelis Johan.; Associate Professor; Pharmacology and Toxicology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2005; Project Start 01-MAR-1996; Project End 31-JUL-2007 Summary: (provided by applicant): Toxin and virus induced liver injury resulting in the loss of hepatic tissue, triggers a regenerative response o restore liver cell mass. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. The AhR ligand 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) is he prototype for a class of compounds responsible for a range of toxic or adaptive endpoints. The underlying mechanism responsible for TCDD toxicity remains poorly defined, but appears to reflect disruptions in normal cell proliferation and differentiation. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and to identify the molecular basis for TCDD toxicity. We have identified a component critical for AhR function: the Retinoblastoma tumor suppressor protein (pRb). Our evidence suggests that pRb may be a coactivator in AhR signaling during TCDD induced G1 phase cell cycle arrest in cultured liver cells. We hypothesize that the AhR plays an important role in liver homeostasis, in part by regulating cell proliferation via a process dependent on the AhR-pRb interaction. The goal of this proposal is to functionally characterize the AhR-pRb interaction, and to examine the AhR's role in liver regeneration in vivo. Aim 1 will determine whether TCDD induced cell cycle arrest requires a transcriptionally competent A1IR complex comprising the AhR/Arnt protein dimer, by testing the effect of targeted mutations on AhR mediated G1 arrest. Aim 2 will functionally characterize the AhR-pRb interaction. Studies will examine the importance of AhR coactivation by
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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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pRb and related proteins, the precise nature of the AhR-pRb interaction, and the effect of pRb phosphorylation on AhR activity. Aim 3 will examine how the AhR contributes to cell cycle control in vivo during liver regeneration induced by partial hepatectomy. Studies will investigate the effects of TCDD and AhR mutations using adenovirusmediated gene transfer, on in vivo liver regeneration in AhR, p27Kipl and p21Cip1 nullizygous mice, and the congenic wild-type mice. •
Project Title: ALPHA-SYNUCLEIN MRNA IS A PUTATIVE MICRORNA TARGET Principal Investigator & Institution: Nelson, Peter T.; Pathology and Lab Medicine; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 01-MAY-2005; Project End 31-MAR-2006 Summary: Small regulatory RNAs participate in many eukaryotic cell functions, microRNAs (miRNAs), the major subclass of small regulatory RNAs in animal species, regulate gene expression post-transcriptionally by destabilizing and/or reducing the translation of specific 'target' mRNAs. Post-transcriptional gene regulation has revolutionary implications, yet very little is known of the roles played by miRNAs in neurons or neurodegenerative disease. AIM 1: CHARACTERIZE THE POLYRIBOSOMAL miRNP IN NEURON-LIKE CELLS. miRNA-related biochemistry is poorly understood. We hypothesize that miRNA-containing polyribosomal ribonucleoprotein complexes (miRNPs) represent the biochemical substrate for miRNA:mRNA regulation. We will partially purify the polyribosomal miRNP from Weri retinoblastoma cells, to characterize the biochemical properties and the protein components of this important particle. AiM 2: IDENTIFY AND CHARACTERIZE miRNA:mRNA PAIRS. Although hundreds of human miRNAs are known, most mRNA targets are unknown. We discerned "rules" that govern miRNA:target mRNA interaction. Using these guidelines our bioinformatician collaborators predict mRNA targets regulated by human miRNAs. We will use cell biological tools to verify hypothesized miRNA-mRNA partners relevant to human neurological diseases. AIM 3: CHARACTERIZE A miRNA INTERACTION THAT MAY REGULATE THE EXPRESSION OF ALPHA-SYNUCLEIN (A-SN). On the basis of preliminary evidence, we hypothesize that an evolutionarily conserved sequence element in the 3'untranslated region of A-SN mRNA is recognized by a specific miRNA (miR-93). A-SN protein plays a central role in some neurodegenerative diseases and its regulation by a miRNA would have important implications in neurobiology, neurodegenerative disease, and RNA biology. We will study this interaction using neuronal cell lines, as a prototype of miRNA:mRNA validation. We will also extend the analyses to human brain tissue in health and disease.
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Project Title: ALTERATION OF RB IN HTLV-1 TRANSFORMED CELLS Principal Investigator & Institution: Kashanchi, Fatah; Co-Director; Biochem and Molecular Biology; George Washington University Office of Research Services Washington, Dc 20052 Timing: Fiscal Year 2005; Project Start 15-JUN-2004; Project End 31-MAY-2007 Summary: (provided by applicant): Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL). ATL is a complex and multi-faceted disease that evolves initially from viral-induced carcinogenic events and leads to multiple chromosomal abnormalities that are associated with the aggressive subtypes of ATL. Tax, the viral oncoprotein encoded within the pX region of the viral genome, is considered a major contributor to cell cycle deregulation in HTLV-I transformed cells by targeting such cellular factors as cyclin D2, p21/waf1, p16/INK4a, and p53. This
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concerted deregulation, especially at the G1 phase of the cell cycle, ensures continuous cellular progression via the loss of checkpoint control and insensitivity to anti-mitogens. The long-term goal of our research is to understand how Tax-dependent perturbation of restriction point regulators leads to leukemogenesis. A significant regulator of the G1 restriction point in eukaryotic cells is the tumor suppressor protein retinoblastoma (Rb). Rb, with p107 and p130, are part of a family of proteins involved in quiescence, cellular division, differentiation, senescence, and apoptosis. We have recently found that within both HTLV-I transformed cells and ATL patients there are a decrease of Rb protein as compared to uninfected controls. Specifically, this decrease is dependent on Tax expression and regulated at the posttranslational level. We have found that Tax is able to bind to Rb within the B domain through either a LXCXE or PENF homology motif within the C terminus of Tax. We further show, through in vitro degradation assays, that Rb degradation is dependent on Tax's ability to associate with the 26S proteasome. The proteasome degradation of Rb appears to be restricted to the hypophosphorylated (or active) Rb species, since the predominant Rb species remaining in HTLV-I transformed cells is the inactive form of Rb. Therefore, loss of the active species of Rb has led us to speculate that this results in a phenotype that is similar to cells that have lost Rb activity due to genetic/epigenetic alterations. Our hypothesis is that Rb degradation by Tax contributes to the immortalization of HTLV-I infected cells. Our rationale for these studies is based on data that shows the HTLV-I viral protein Tax destabilizes the Rb protein by targeting this protein to the 26S proteasome for degradation. We believe this mechanism is analogous to HPV's E7-dependent destabilization of Rb that results in the loss of the active form of Rb. Rb deregulation within the p16/INK4a/cyclin D pathway is an early event in HPV-16 immortalization by promoting cell cycle entry and proliferation of senescent primary cells. These phenotypes are also observed in HTLV-I transformed cells as shown by our preliminary data and may contribute to ATL malignancy. The following specific aims will address our hypothesis: (I) what is the mechanism of Tax-dependent proteolysis of Rb in HTLV-I transformed cells? (II) Is degradation of Rb an early event that contributes to Taxdependent immortalization? Data obtained from these studies will shed light on how Tax and Rb interaction leads to the immortalization of HTLV-I infected ATL cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALTERATIONS OF THE HUMAN SWI/SNF COMPLEX IN LUNG CANCER Principal Investigator & Institution: Reisman, David N.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 24-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Candidate: The candidate is an Oncology fellow whose career goal is to become a translational researcher focusing on the molecular growth inhibitory pathways in lung cancer and the development of assays to detect neoplastic aberrance in these pathways both in vitro and in vivo. Research Plan: Lung cancer is the leading cause of cancer deaths in the United States. A reduction in the mortality will require the development of prognostic markers based on the understanding of growth inhibitory pathways. The SWI/SNF complex is a candidate to fill this critical need since it is likely required for function of the tumor suppressors, retinoblastoma (RB) and p130 (RB2). To understand how alterations in SWI/SNF may affect RB and p130 function, this proposal will determine the mechanisms for the downregulation of BRG and BRM (AIM 1), to clarify the role of BRG1 in RB mediated growth inhibition (AIM 2), to determine if BRG1 and BRM are lost or mutated in primary lung
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cancers (AIM 3), and to determine if BRG1 and BRM are important for p130 function (AIM 4). It is the goal of this training period to provide an intense research experience whereby expertise in molecular biology is gained leading to a career as a dually trained independent researcher. Environment: The excellent research environment at the Lineberger Comprehensive Cancer Center will promote the accomplishment of these specific aims. The candidate?s training and development will be directed by the dedicated mentorship and guidance of a senior and accomplished scientist, Dr. Bernard Weissman. Dr. Beverly Mitchell, who has many years? experience in mentoring successful physician/scientists, will provide protected research time and translational research guidance. Thus, this K08 funding period will allow the acquisition of new skills resulting in a series of publications leading to an independent cancer research career. •
Project Title: ARF MDM2 P53 TUMOR SUPPRESSION PATHWAY Principal Investigator & Institution: Zhang, Yanping; Radiation Oncology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2005; Project Start 01-AUG-2000; Project End 31-MAR-2006 Summary: p53 and Rb mediate two major tumor suppression pathways that are believed to be functionally inactivated inmost, if not all, human cancers. Understanding how these two pathways are regulated has become a major goal of contemporary cancer cell biology. Along withp53, the ARF-INK4a locus is one of the two most frequently altered loci in human cancer. Functionally, p16INK4a inhibits the activity of cyclin Ddependent kinases (CDK4 and CDK6), thereby maintaining the retinoblastoma protein (Rb) in its growth suppressive state. ARF, on the other hand, mediates an oncogeneactivated hyperproliferative checkpoint pathway through binding to and antagonizing the nuclear export of MDM2, thereby preventing cytoplasmic degradation of p53. With a focus on the connection between ARF and p53, I have tried to contribute to our understanding of these two major pathways and thereby cancer development. I had previously discovered that ARF stabilizes p53 through binding to and antagonizing the activity of MDM2-a negative regulator of p53, and thus revealed an ARF-MDM2-p53 tumor suppression pathway. Subsequently, I further elucidated the mechanism of ARFs p53 stabilization: ARF forms nuclear bodies in the nucleoplasm with MDM2 and p53, thereby blocking nuclear export of p53 and preventing its cytoplasmic degradation. I also demonstrated that frequently occurring tumor-derived mutations in the human ARF protein impair its function in blocking p53 nuclear export. More recently, I obtained new evidence showing that: (a) Association of MDM2 with ribosomal protein L5 is necessary for MDM2 nuclear export and this regulation is disrupted by frequent cancer-derived mutations in MDM2. (b) Ribosomal protein L5- binding deficient MDM2 failed to promote p53 degradation but retains its ability to suppress p53's transactivation activity. (c) ARF participates in a multipeptide complex, and (d) MDM2 is efficiently degraded by proteolysis. My current and future studies are aimed at several issues concerning the regulation of ARF-MDM2-p53 pathway: (a) Elucidate the mechanism of p53 and MDM2 nucleo-cytoplasmic shuttling controlled by ribosomal protein L5 and/or ARF. (b) Define the function of ARF-MDM2-p53 nuclear bodies by purifying the ARF complex, and (c) as a long-term goal to identify the mechanism and regulation of MDM2 ubiquitination and degradation. Together these experiments should advance understanding of the regulation of the ARF-MDM2-p53 pathway and the functional consequences of its alterations in human cancer.
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Project Title: BLADDER-SPECIFIC KNOCKOUT AND GENE EXPRESSION Principal Investigator & Institution: Wu, Xue-Ru; Professor; Urology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-MAY-2010 Summary: (provided by applicant): Bladder epithelium or urothelium is involved in major urinary tract diseases including bladder cancer, urinary tract infection and interstitial cystitis. However, research into the molecular bases of urothelial diseases has been hampered by the lack of effective model systems. Utilizing uroplakin II (UPII) gene promoter, we have succeeded over the last several years in targeting gene expression specifically into the urothelium of transgenic mice. The existing system, however, does not allow gene expression and inactivation to occur in a temporally controlled fashion, thus precluding many biological questions from being addressed. The overall goals of the current project are to develop and validate the second-generation transgenic systems that will allow urothelium-specific and inducible gene expression as well as knockout; and to utilize these novel systems to study the in vivo roles of several critical genes in urothelial growth, differentiation and tumorigenesis. Toward these goals, we plan to carry out two series of studies. In the first, we will generate transgenic lines in which the UPII promoter drives the urothelium-specific expression of a reverse tetracycline transactivator (UPll/rtTA). We will then test the feasibility and parameters of urothelium-specific and inducible gene expression by crossing UPll/rtTA mice with TRE/LacZ reporter mice so that LacZ expression is under the control of tetracycline response elements (TRE) and only occurs upon doxycycline treatment. In addition, we will establish a urothelium-specific and inducible knockout system, by crossing the UPll/rtTA mice with TRE/Cre mice. We will then test the functionality of this system by crossing the UPll/rtTA-TRE/Cre bi-transgenic mice with Rosa26 reporter mice in which the reporter genes are transcriptionally activated upon Cre expression. This system will allow inducible knockout of any genes of interest in the urothelium. In the second series of studies, we will inducibly express an activated fibroblast growth factor receptor as well as inducibly delete the retinoblastoma gene in the urothelium and test the hypothesis that the two genetic alterations induce low-grade superficial papillary tumors and high-grade invasive tumors, respectively. We will also examine the signaling pathways that these genetic alterations exploit in transforming the urothelium. These studies will generate powerful experimental tools for studying bladder biology and diseases and offer molecular insights regarding urothelial growth and tumorigenesis.
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Project Title: BRG1/BRM: ROLE IN RB TUMOR SUPPRESSOR SIGNALING Principal Investigator & Institution: Knudsen, Erik S.; Associate Professor; Cell Biol, Neurobiol/Anatomy; University of Cincinnati Sponsored Research Services Cincinnati, Oh 45221 Timing: Fiscal Year 2005; Project Start 01-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): The retinoblastoma tumor suppressor, RB, is inactivated in-the majority of human cancers, resulting in growth advantage. While the underlying basis of inactivation encompasses a variety of mechanisms (e.g. deregulated phosphorylation, direct oncoprotein binding, point mutation) all of these result in the disruption of RB assembled complexes. When active, RB is hypophosphorylated and assembles transcriptional repressor complexes to facilitate repression of critical cell cycle genes. Mitogenic signaling cascades or oncogenic lesions stimulate the phosphorylation of RB, thereby disrupting the transcriptional repressor complexes and enabling cell cycle progression. In contrast, anti-mitogenic signals (e.g. DNA-damage) will prevent
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phosphorylation and maintain RB-repressor complexes to inhibit cellular proliferation. Therefore, understanding RB-mediated transcriptional repression is germane both to regulated cell cycle progression (i.e. the interplay of mitogenic and anti-mitogenic signaling) and tumorigenesis. RB mediates transcriptional repression by recruiting corepressors to target promoters. These co-repressors have specific affects on chrornatin leading to direct modification of histories (e.g. methylation or deacetylation). Since transcriptional repression is critical for RB function, loss of co-repressors could represent a means through which RB is functionally inactivated in cancer. Of the RB associated corepressors, SWI/SNF proteins have been implicated as a tumor suppressor through a combination of genetic studies in cell lines, mouse models and expression analysis in primary human tumors. Consistent with the idea that loss of this co-repressor complexes compromise RB signaling, we have found that loss of the core SWI/SNF ATPases (BRG1 and BRM) bypass RB-mediated transcriptional repression and cell cycle inhibition. Therefore, we will test the hypothesis that BRG1/BRM plays a specific role in mediating RB-dependent transcriptional repression to suppress uncontrolled proliferation and tumorigenesis. Specifically, we will (I) determine the mechanism through which BRG1/BRM facilitate the action of RB in transcriptional repression, (11) define the targets of specific RB co-repressor complexes, and (111)specifically elucidate the role of BRG1/BRM and transcriptional repression in RB-dependent tumor suppression. •
Project Title: C/EBP ALPHA IN AGING LIVER Principal Investigator & Institution: Timchenko, Nikolai A.; Associate Professor; Pathology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-AUG-2010 Summary: (provided by applicant): An aging liver loses the ability to proliferate after partial hepatic resections leading to a higher mortality in the elderly. Our laboratory' investigates molecular mechanisms that control liver proliferation. Liver specific protein, CCAAT/Enhancer Binding Protein alpha (C/EBPalpha), is a strong inhibitor of liver proliferation. C/EBPalpha inhibits proliferation of young livers through direct interactions with cyclin dependent kinases 2 and 4. In adipose tissues, C/EBPalpha causes growth arrest via repression of E2F transcription. We have recently found that aging switches C/EBPalpha in liver from inhibition of cdks to repression of E2F, the pathway that normally operates in adipose tissues. In old livers, C/EBPalpha is observed in a high MW complex C/EBPalpha-Rb-E2F4-Brm. This complex occupies E2F-dependent promoters and blocks activation of genes whose expression is required for liver proliferation. A failure to diminish this complex after partial hepatectomy seems to be a major cause for the reduced proliferative response in old livers. Three components of the complex, Rb, C/EBPalpha and E2F4, are differentially phosphorylated in old livers. Phosphorylation of C/EBPalpha at Serl93 is a key event in the formation of the age-specific complex. We have recently identified cdk4 and PP2A as enzymes that regulate phosphorylation-dephosphorylation of Serl93 of C/EBPalpha. In this application, we propose to examine the effects of aging on these signal transduction pathways and determine their roles -in the appearance of the C/EBPalpha-Rb-E2F4-Brm complex and in the reduction of the proliferative response. Our working hypotheses are that: 1) Phosphorylation of C/EBPalpha, E2F4, and Rb promotes the formation of the age related complex, 2) Phosphorylation of Serl93 of C/EBPalpha in the liver is mediated by cdk4 and is reversed by the action of the PI3K-Akt-PP2A pathway, 3) Aging liver increases the age-specific complex by diminishing the PI3K-Akt-PP2A pathway and by activation of cdk4. In Specific Aim 1, we will examine mechanisms by which aging activates cdk4 and down-regulates activity of PP2A. Specific Aim 2
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examines whether phosphorylation of Rb and E2F4 affects their ability to form the agespecific C/EBPalpha complex. In Specific Aim 3, additional proteins of the complex will be identified and their role in liver proliferation will be examined. Based on data obtained in this project, we are planning to start developing a strategy to correct liver proliferation in elderly. •
Project Title: CELL HYPERTROPHY
CYCLE
DEPENDENT
MECHANISMS
OF
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Principal Investigator & Institution: Riley, Daniel J.; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2005; Project Start 15-MAY-2002; Project End 31-JAN-2007 Summary: (Provided by applicant): Early in diabetic nephropathy glomerular mesangium and renal tubules hypertrophy. Mesangial hypertrophy is an important, perhaps reversible, step preceding glomeruloscierosis and overt nephropathy. Using unique transgenic mice overexpressing retinoblastoma protein (Rb) and mesangial cells expressing Rb from a tetracycline-confrollable promoter system, we have discovered that renal and glomerular mesangial cell hypertrophy occur with both diabetes mellitus and with over expression of hypophosphorylated Rb. Preliminary data has shown that when Rh is over expressed, neither kidneys nor mesangial cells hypertrophy further in diabetic conditions. Our hypothesis to explain these observations is that excess glucose results in specific, cyclin-dependent phosphorylation of Rb protein during early Gi phase, and that Rb is involved distally in a pathway of glomerular mesangial cell hypertrophy. To test this hypothesis, three Specific Aims are proposed: (1) Determine whether renal and glomerular hypertrophy caused by diabetes mellitus in vivo and mesangial cell hypertrophy caused by high glucose concentrations ex vivo are dependent on activation of specific C1 phase cyclin-cdk complexes and specific phosphorylations of Rb protein. (2) Determine how high glucose regulates cdk4-cyclin Dl activity and Rb phosphorylation in mesangial cells by examining patterns of gene regulation including transcription of the cyclin D1 gene itself and of events controlled by relevant transcription factors including AP-1. (3) Test the requirement for Cl cyclin dependent kinase activation and specific cdk4-dependent phosphorylations of Rb protein for diabetic renal hypertrophy in vivo and mesangial cell hypertrophy in culture. Transgenic mice with strategic phosphorylation sites in Rb inactivated by sitedirected mutagenesis will be generated and the effects of type 1 diabetes mellitus will be examined in them. Primary mesangial cells will also be cultured from the mice and more detailed studies on hypertrophy and GI cell cycle regulation by cdks and Rb conducted in vitro. •
Project Title: CHARACTERIZATION OF NOVEL MODIFIERS OF DE2F/RBF FUNCTION Principal Investigator & Institution: Frolov, Maxim; Biochemistry and Molecular Genetics; University of Illinois at Chicago 310 Aob, M/C 672 Chicago, Il 60612 Timing: Fiscal Year 2007; Project Start 01-APR-2007; Project End 31-MAR-2012 Summary: (provided by applicant): The retinoblastoma protein (pRB) is an important tumor suppressor that functions as a negative regulator of cell proliferation by restraining the activity of the E2F transcription factor. The E2F transcription factor is a critical regulator of the G1 to S transition and its activity is rate-limiting for S phase entry. In most tumor cells, the pRB pathway is believed to be functionally inactivated; this highlights the significance of pRB and E2F in the regulation of mammalian cell proliferation. While the critical role of pRB and E2F is well established, how precisely
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these proteins regulate cell cycle progression, what these proteins do, and why their activities are " so important, is not completely understood. Adding to the problem, there is an increasing number of proteins which have been shown to interact with pRB. Currently, the field faces a major challenge to identify the interactions which are functionally significant for pRB function. The proposed research aims to take advantage of Drosophila as a model organism to identify important regulators of endogenous E2F/RBF represser activity. In Drosophila, there are two E2F genes. dE2F1 is a strong activator of transcription and positive regulator of cell proliferation. During larval development, its activity is counterbalanced by the represser dE2F2. Our approach is based on our previous finding, that the strong block in cell proliferation in de2f1 mutants is due to the unchecked activity of the dE2F2/RBF represser complex. We propose to perform a genetic screen for mutations which suppress the de2f1 mutant phenotype. These mutations may be in genes whose products are functionally important for dE2F2/RBF to block cell cycle in vivo. Two specific aims are proposed: (1) To perform a full scale screen for suppressors of the de2f1 mutant phenotype on the right arm of chromosome 3, and to develop strategies for and to initiate screening of, other autosomal arms. (2) To carry out a detailed phenotypic analysis and mapping of suppressors of the de2f1 mutant phenotype. Our goal is to identify functional partners of the dE2F2/RBF represser complex which are critical for dE2F2/RBF- dependent block in cell proliferation in vivo. Given the pivotal role of pRB in tumor suppression, an understanding of how the function of the Drosophila homologues dE2F2/RBF is regulated will provide crucial clues in understanding the regulation of mammalian cell growth and the ways in which such controls may go wrong in human cancer. •
Project Title: CONDITIONAL REPLICATING ADENOVIRUS FOR GLIOMA TREATMENT Principal Investigator & Institution: Fueyo, Juan; Assistant Professor; Neuro-Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2005; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Due to lack of effective therapy, primary brain tumors are the focus of intense investigation of novel experimental approaches that use vectors and recombinant viruses. Therapeutic approaches have been both indirect, whereby vectors are used, or direct to allow for direct cell killing by the introduced virus. Promising therapies can be designed by targeting fundamental molecular defects of the glioma cells. The function of p16-Rb-E2F pathway is abnormal in most malignant gliomas and therefore constitutes a suitable target for anti-cancer therapies. We have previously generated a conditional replicating adenovirus, D24, unable to bind to and inactivate the retinoblastoma protein (Rb). This tumor-selective adenovirus is able to replicate in glioma cells but not in normal cells. Although, the adenovirus induces a potent cytopathic effect in vitro, its anti-cancer effect in vivo is less dramatic. In this project, we propose a series of modifications in the D24 adenovirus in order to render the oncolytic virus more efficient infecting and killing glioma cells in vivo. In addition, experiments will be designed to introduce the necessary modifications in the D24 adenovirus to increase its specificity and to control pharmacologically its replication and spread. In vivo cancer gene therapy approaches for gliomas based on adenoviral vectormediated gene delivery and oncolytic adenoviruses can be limited by the suboptimal efficacy of adenoviruses to infect tumor cells. This issue is mainly due to deficiency of the primary adenoviral receptor on the tumor targets. To circumvent this deficiency, we propose the construction of a tumor-selective adenoviral targeted to a tumor cell marker. In this regard, RGD-related integrins are frequently overexpressed in gliomas. Furthermore, these integrins recognize the RGD peptide motif. On this basis, we will
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construct an adenoviral vector genetically modified to contain such a peptide within the HI loop of the fiber protein as a means to alter viral tropism. This RGD-D24 adenovirus should infect glioma cells in vivo with extraordinary efficiency, increasing dramatically the oncolytic power of the D24. In Specific Aim 1. We propose to characterize the anticancer effect of D24-RGD in vitro in comparison with D24. In Specific Aim 2, the D24-RGD construct will be characterized in vivo using an orthotopic glioma animal model. In addition, we will examine the correlation between the anti-cancer effect of the D24-RGD ant its spread throughout the tumor. The experiments will require pathological examination of the tumors, viral protein expression, as well as examination of spread of the virus throughout the tumor. We will asses the replication of the virus within the tumor and titer the viral production in vivo. Finally, we will analyze how the administration of anti-adenoviral drugs influence the growth of D24-RGD-infected tumors. In Specific Aim 3, we will combine a high-effective oncolytic adenovirus with a regulatory system that can be used to control viral replication in vivo in a selected site and at a desired time. The D24-RGD construct will be genetically modified to include drug response elements sensitive to the effect of tetracycline. To obtain tissue-specific expression of the target gene, we will coupled the regulator to a cancer specific (E2F-1) promoter to drive the early viral genes. The combination of an inducible system and a tissue-specific promoter will allow the development of an innovative oncolytic system, which is able to kill cancer cells and spread within the tumor in a cell type-specific and time- and level-controllable fashion. •
Project Title: CONTROL OF SKELETAL GROWTH BY ATF-2 Principal Investigator & Institution: Luvalle, Phyllis A.; Associate Professor; Anatomy and Cell Biology; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2005; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Control of growth plate chondrocyte progression is essential for proper bone and marrow formation. Disruptions in several genes such as those for the PTHrP receptor, FGFR3 receptor, TGF beta receptor type II, vitamin D receptor, and thyroid hormone receptor result in disorganization of the growth plate and abnormal endochondral ossification in mice. Multiple human genetic and acquired skeletal disorders result from the perturbation of the balance between chondrocyte proliferation and maturation in the growth plate, including chondrodysplasias, overgrowth diseases like Beckwith Wiedernann syndrome, osteochondromas and other cartilage neoplasms, and some forms of osteoarthritis. Activating transcription factor 2 (ATF-2) targets the cyclic AMP response element (CRE) in many different genes and results in the activation of gene transcription. A mutation in the ATF-2 gene in mice results in the absence fo ATF-2 in growth plate chondrocytes and defects in endochondral ossification resembling human hypochondroplasia, a dwarfism due to activating mutations in the FGFR3 receptor. ATF-2-deficient mice have a substantially reduced survival rate, and display a growth plate phenotype that encompasses reductions in both the proliferative and hypertrophic zones. The overall goal of this proposal is to define the roles of ATF-2 in control of chondrocyte proliferation and growth plate progression. The proposal is focused on eight gene targets of ATF-2: those for cyclin D1, cyclin A, c-Fos, c-Jun, the retinoblastoma protein (pRb), p107, p130,and Bcl-2. All but Bcl-2 are directly involved in cell cycle progression, and therefore are regulators of chondrocyte proliferation. Bcl-2 plays a role in the control of apoptosis, which occurs in the terminal chondrocytes of the hypertrophic zone in the growth plate. This proposal exploits the growth plates of ATF-2-deficient mice for molecular analyses of 1) the direct and indirect effects of ATF-2 on target genes; 2) the consequences of reductions in expression of the target genes in the absence of ATF-2; and 3) the
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definition of signaling pathways that result in normal I or abberant growth plate chondrocyte proliferation and progression. •
Project Title: CRX DEGENERATIONS
AND
ITS
REGULATORY
NETWORK
IN
RETINAL
Principal Investigator & Institution: Chen, Shiming; Associate Professor; Ophthalmology and Visual Sci; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2005; Project Start 01-MAR-2000; Project End 31-JUL-2008 Summary: (provided by applicant): The development and maintenance of photoreceptor cell function require precisely regulated expression of photoreceptor-specific genes. The long-term goal of our research is to determine the molecular mechanisms regulating the transcription of photoreceptor genes and the role of transcription dysregulation in photoreceptor diseases. Regulation of transcription involves interactions among network transcription factors and their target genes. We are studying a photoreceptorspecific transcription factor, cone-rod homeobox (Crx) that is essential for the transcription of many photoreceptor genes and is associated with photoreceptor degenerative diseases. We have identified ten Crx interacting proteins (CIPs) that are expressed either ubiquitously in many cells or specifically (preferentially) in photoreceptors. We hypothesize that the interactions of Crx and these CIPs regulate transcription of target genes in specific types of photoreceptors. In this renewal application, we propose to test this hypothesis using both in vivo and in vitro approaches. In Aim #1, we will focus on two specific CIPs, the nuclear receptor Nr2e3 and the zinc-finger transcription factor Sp4 and characterize their interactions with Crx in vivo using co-immunoprecipitation and coexpression studies in the mouse retina. We will also use cell transfections to determine if these interactions have functional significance on the transcription of rod- or cone-specific genes, such as opsins and the gene products identified in Aim #2. In Aim #2, we will use chromatin immunoprecipitation assays (ChIP) to identify a variety of in vivo targets that are regulated by Crx and CIPs and that are important for the function and survival of photoreceptors. Candidate photoreceptor gene targets will be detected using PCR with primers corresponding to the regulatory regions of specific genes, while novel targets will be identified by screening genomic arrays (ChIP-Array) or by cloning (ChIPCloning). Aim #3 is based on our recent findings that histones on the regulatory regions of several photoreceptor genes are hyper-acetylated (a chromatin modification that activates transcription) and that Crx interacts with ataxin-7 or CBP/p300, ubiquitous CIPs associated with co-activator complexes that catalyze histone acetylation. Thus, we hypothesize that hyper-acetylation of histones is important for activating transcription of the photoreceptor genes and is promoted by Crx interacting with ubiquitous CIPs. We will determine if the degree of histone acetylation affects photoreceptor gene expression by modifying the factors regulating this process. For example, histone deacetylase inhibitors should increase histone acetylation and therefore photoreceptor gene transcription in retinoblastoma cells, and Crx or ataxin-7 mutations should decrease histone acetylation and transcription of photoreceptor genes in the retina of Crx-/- or SCA7 mice. We will also determine if Crx recruits the co-activator complexes involved in histone acetylation in vivo. In each of the three aims, we will use mouse models of photoreceptor diseases to investigate how disease-causing mutations in Crx and its associated factors, alter the normal functions of these regulatory proteins in vivo. These studies will lead to a new level of understanding of the molecular mechanisms that regulate photoreceptor-specific gene expression in vivo and will provide new approaches for designing treatments for photoreceptor diseases.
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Retinoblastoma
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYCLIN D1-PRAD1 IN MAMMARY NEOPLASIA Principal Investigator & Institution: Arnold, Andrew; Center for Molecular Medicine; University of Connecticut Sch of Med/Dnt 263 Farmington Avenue Farmington, Ct 060302806 Timing: Fiscal Year 2005; Project Start 01-FEB-1992; Project End 31-MAR-2007 Summary: Cyclin D1 (PRAD1) has emerged as a major oncogene involved in a variety of human tumors including up to 50 percent of breast cancers. Numerous studies, generally employing in vitro systems, have led to the widely accepted paradigm that cyclin D1 functions in a biochemical pathway with cyclin- dependent kinase (cdk) 4 or 6, which it activates, the pl6 inhibitor of cdk4/6, and the retinoblastoma oncosuppressor protein pRB, thought to be the primary substrate of cyclin D1- activated cdk. These molecules have tremendous significance to cancer, being targeted by mutation or regulatory derangements in most or perhaps even all cancers. Current concepts of cyclin D1 function, however, may not fully reflect its true role when overexpressed in the complex in vivo process of tumorigenesis. Recent data, in fact, indicate that cyclin D1 may contribute to oncogenesis through mechanisms other than, or in addition to, its role in the cdk4/6 - pRB pathway, for example by activating the estrogen receptor in breast cancer cells. Our mammary cancer- prone transgenic mice with targeted overexpression of cyclin D1 constitute an especially relevant system in which to test such hypotheses. The proposed studies are designed to address the mechanisms through which cyclin D1 contributes to breast cancer using the pathophysiologically relevant experimental context of the intact animal. The studies will (a) examine whether overexpressed cyclin D1 may contribute to mammary tumorigenesis through mechanisms apart from activation of cdk4, by developing and characterizing transgenic mice with a mammarytargeted mutant cyclin D1 transgene unable to activate cdk4; (b) examine whether overexpressed cyclin D1 may contribute to mammary tumorigenesis through mechanisms that do not rely on its ability to interact with pRB, by developing and characterizing transgenic mice with a mammary-targeted mutant cyclin D1 transgene unable to interact with pRB; (c) examine whether overexpressed cyclin D1 may significantly contribute to mammary tumorigenesis through direct activation of the estrogen receptor, by developing and characterizing transgenic mice with a mammarytargeted mutant cyclin D1 transgene unable to activate the estrogen receptor. These results will carry important implications to the molecular pathogenesis of breast cancer, and may ultimately contribute to novel treatment strategies.
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Project Title: DELINEATING THE ROLE OF RB IN CELLULAR SENESCENCE Principal Investigator & Institution: Chicas, Agustin; Cold Spring Harbor Laboratory P.O. Box 100 Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2009 Summary: (provided by applicant): The goal of this proposal is to dissect the role of the Rb family of proteins in cellular senescence, identify the targets of Rb during cellular senescence and identify genes that that contribute to the stability of senescence. Because components of the senescence machinery have been shown to play important roles in aging and cancer, this approach could lead to the identification of new molecules with potential role in ageing and/or cancer. These questions will be addressed using the well characterize IMR90 human diploid fibroblast. These cells can be induced to undergo senescence by exogenous expression of oncogenic ras, etoposide, enforce expression of p16, or extensive passage. Senescent IMR90 cells display the characteristic associated
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with senescence such as irreversible cell cycle arrest, large flat morphology, senescenceassociated beta-galactosidase (SA-beta-gal) activity and heterochromatic foci. These characteristics will be used together with RNAi technology to assess the role of the different Rb family members in senescence and to identify factors that contribute to the stability of senescence. RNAi technology will also be combined with expression microarray to identify the targets of Rb during senescence. •
Project Title: DEVELOPMENTAL FUNCTION OF RB FAMILY PROTEINS Principal Investigator & Institution: Fay, David S.; Molecular Biology; University of Wyoming 1000 E. University Avenue Laramie, Wy 82071 Timing: Fiscal Year 2005; Project Start 01-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): Among the many pathways controlling cell proliferation and differentiation, genes of the retinoblastoma protein (Rb) regulatory network stand out as frequent if not obligatory targets for mutation or deregulation during tumorigenesis. Although biochemical and tissue culture studies have implicated Rb family members in a wide range of cellular activities, the bona fide functions of Rb in vivo and during normal development are not well understood. Our long-term objective is to understand the cellular, and developmental functions of Rb family proteins at the molecular level. To this end, we have devised a genetic strategy that has allowed us to identify genes and pathways that function coordinately with the C. elegans Rb homolog, lin-35, to control essential developmental processes. Using this system, we have demonstrated canonical cell cycle functions for LIN-35 as well as a novel role for this protein in organ morphogenesis. We have also uncovered a complementary pathway that acts to control organ morphogenesis through UBC-18/UbcH7, a conserved ubiquitin-conjugating enzyme involved in the targeting of proteins for degradation. The proposed experiments are designed to uncover the underlying mechanism by which LIN-35, acting in conjunction with one or more parallel pathways, regulates organ morphogenesis in C. elegans. Our main objectives fall into two categories. One broad aim is to identify additional factors that function cooperatively with LIN-35 and UBC-18 to control organogenesis. These studies will include the cloning and characterization of sir-9, a gene that, like ubc-18, functions redundantly with lin-35 to control organ morphogenesis; the execution of a two-hybrid screen to identify UBC-18-interacting proteins; and a directed RNAi feeding screen using known or putative ubiquitin pathway components. Our second objective is to identify functionally relevant downstream targets for regulation by LIN-35 and UBC-18. These studies will include genetic selections to isolate mutations that suppress the lethality of lin-35; ubc-18 double mutants; microarray analyses to identify the complete spectrum of LIN-35-regulated transcripts; and additional two-hybrid screens using co-factors of UBC-18 identified through earlier two-hybrid or RNAi-feeding screens. The successful completion of these studies will greatly enhance our general understanding of Rb family functions and will provide detailed mechanistic knowledge of this novel role for Rb proteins in morphogenesis.
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Project Title: E2F TRANSCRIPTION FACTOR AND TUMOR SUPPRESSION Principal Investigator & Institution: Chellappan, Srikumar P.; Associate Professor; H. Lee Moffitt Cancer Ctr & Research Ins 12902 Magnolia Dr Tampa, Fl 336129497 Timing: Fiscal Year 2005; Project Start 01-MAY-1994; Project End 31-JAN-2008 Summary: (provided by applicant): Mammalian cell cycle progression is regulated by a complex machinery that can respond to a wide variety of extra-cellular signals. Multiple signaling cascades modulate components of the cell cycle machinery to elicit
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Retinoblastoma
proliferation, differentiation or apoptosis. We have been studying how two major components of the cell cycle machinery, the retinoblastoma tumor suppressor protein (Rb) and its main downstream target, the E2F family of transcription factors, are regulated by signaling cascades. Our studies have shown that the signaling kinases Raf1 as well as p38 can inactivate Rb in response to proliferative or apoptotic signals. An 8amino acid peptide derived from Raf-1 disrupts the Rb-Raf-1 interaction in vitro. This peptide could bring about an inhibition of Rb phosphorylation, cell proliferation and angiogenesis when introduced into cells via a carrier molecule. In addition, the volume of a human tumor xenografted into nude mice was reduced by about 79% upon injecting the Raf-1 peptide conjugate. In this proposal we plan to study the mechanisms by which Raf-1 reverses Rb-mediated transcriptional repression. Attempts will also be made to screen a drug library (mainly the Diversity Set from DTP, NCI) for agents that can disrupt the Rb-Raf-1 interaction; such a compound could be expected to have anticancer effects. Our experiments will also address the role of cell cycle molecules, especially Rb and E2F, in angiogenesis. These experiments will be done on Human Aortic Endothelial Cells induced to form capillary tubules in matrigel by stimulating with VEGF. We had carried out a micro-array analysis to examine genes induced upon VEGF stimulation. A subset of the genes whose expression was altered appeared to have E2F binding sites in their promoter. The potential contribution of these downstream targets of E2F on the angiogenic process will be examined. Experiments are also proposed to study the regulation of Rb function by apoptotic signals. We had found that Fas stimulation of Jurkat cells leads to an inactivation of Rb by phosphorylation, mainly brought about by the p38/Hog 1 kinase; similarly, TNFalpha stimulation of Jurkat cells leads to the binding of the Apoptosis Signal-regulating Kinase (ASK1) to Rb. We plan to assess the functional role of these interactions and investigate how Rb inactivation contributes to the apoptotic process. We expect that the studies proposed here would help identify the molecular mechanisms underlying different aspects of cell proliferation, angiogenesis and apoptosis. We will also attempt to identify and evaluate the anti-cancer properties of agents that can modulate these processes. •
Project Title: E2F3 GENE LOCUS IN THE CONTROL OF CELL PROLIFERATION Principal Investigator & Institution: Leone, Gustavo W.; Assistant Professor; Molecular Virology, Immunology & Medical Genetics; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2005; Project Start 25-JAN-2001; Project End 31-DEC-2005 Summary: (from the application): Mammalian E2F is composed of a family of heterodimeric proteins encoded by six distinct genes and its important role in the control of cellular proliferation has now been demonstrated in mammals, in Drosophilia, and is thought to play a fundamental role in all other eukaryotes. Our recent findings have pointed to a role for the E2F3 gene locus as a particularly important regulator of the cell cycle by encoding two independent but overlapping transcription units that direct the synthesis of two distinct proteins, E2F3a and E2F3b. In contrast to E2F3a activity which is cell cycle regulated, peaking at every G1/S transition, the novel E2F3b protein is expressed in quiescent cells and specifically associates with Rb, representing the predominant E2F-Rb complex in non-proliferating cells. In view that the tumor suppressor function of Rb is intimately related to its ability to interact with E2F and repress the transcription of E2F target genes, we view the E2F3b protein as having a potentially important role in regulating cell cycle entry/exit by its virtue of forming a transcriptional repressor with Rb. The proposed studies will aim to elucidate the role and mechanism of action of the E2F3 gene locus in the regulation of the cell cycle. We will take advantage of Cre-lox technologies to generate mice with conditional
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null alleles for each of the two E2F gene products to study their function in vivo. Moreover, this approach will allow us to execute sophisticated cell cycle studies in cells lacking multiple members of the E2F family. These studies will involve three specific aims: 1. To generate mice deficient for E2F3a, E2F3b, or both E2F3a and E2F3b. 2. To evaluate the role of the E2F3 gene locus in the control of cell proliferation and tumorigenesis in vivo. 3. To investigate the roles of E2F3a and E2F3b in the control of the cell cycle and cell proliferation in vitro. The long term goal of these studies is to molecularly dissect how the E2F transcriptional program contributes, in concert with other signaling pathways, towards the control of cell proliferation. The Rb/E2F pathway which is key in controlling cell cycle progression and cellular proliferation is almost always sabotaged during cancer development, and it is through the molecular understanding of these processes that we hope to contribute to the development of future cancer therapy. •
Project Title: E2F4 TUMORIGENESIS
AND
RB
IN
DIFFERENTIATION
CONTROL
AND
Principal Investigator & Institution: Lees, Jacqueline A.; Center for Cancer Research; Massachusetts Institute of Technology 77 Massachusetts Ave Cambridge, Ma 02139 Timing: Fiscal Year 2006; Project Start 01-APR-1997; Project End 31-MAR-2011 Summary: (provided by applicant): The human retinoblastoma gene (RB-1) is a wellestablished tumor suppressor. Somatic RB-1 inactivation is observed in approximately one third of all human tumors. Individuals carrying germline RB-1 mutations develop retinoblastoma with near complete penetrance and they are also highly predisposed to develop osteosarcomas. The retinoblastoma protein (pRB) inhibits cellular proliferation by binding to the E2F transcription factors and thereby blocks the activation of genes encoding essential components of the cell division machinery. pRB has also been shown to bind transcription factors that are master regulators of differentiation. Together, these observations suggest that pRB acts to coordinate cell cycle arrest and terminal differentiation. The analysis of mutant mouse models and cell lines has been used to gain insight into the roles of pRB and E2F4 in vivo. First, these studies show that E2F4loss suppresses the development of pRB-deficient tumors. Molecular studies suggest a hypothesis for the underlying basis of E2F4's oncogenic activity. Experiments in aim 1 will directly test this hypothesis. Second, these studies show that pRB and E2F4 are required for the appropriate development of numerous tissues. In particular they reveal important roles for both pRB and E2F4 in the development of bone arising via either intramembranous or endochondral ossification. Experiments in aim 2 will continue to investigate the mechanisms by which pRB and E2F4 contribute to differentiation with particular emphasis on bone development. In Aim 3, we will use osteoblast-specific Rb mouse models to further investigate pRB's role in osteogenesis and osteosarcoma formation. •
Project Title: E2F-MEDIATED CONTROL OF VASCULAR GROWTH AND REMODELING Principal Investigator & Institution: Sullenger, Bruce Alan.; Professor & Vice Chair; Surgery; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Vascular smooth muscle cell (VSMC) proliferation and migration following by-pass grafting and arterial angioplasty can lead to graft failure and restenosis. This pathological process is known as intimal hyperplasia. Limiting intimal hyperplasia in grafted vessels or a vessel following angioplasty is a
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Retinoblastoma
critically important therapeutic target. A number of recent studies have attempted to limit VSMC proliferation and intimal hyperplasia by delivering inhibitors of cell cycle proteins to by-pass grafts or sites of angioplasty. One of the most promising approaches, developed by Dzau and colleagues, targets the E2F family of transcription factors for inhibition. A number of studies have shown that the growth suppression action of the retinoblastoma tumor suppressor protein (Rb) and other Rb family members is dependent on their ability to regulate the E2F family of transcription factors. It has also become increasingly clear that the E2F family of transcription factors can be divided into 2 subclasses based upon sequence homology and functional properties. The first subclass, containing E2F1, E2F2 and E2F3, are transcriptional activators that induce quiescent cells to proliferate. The second subclass, E2F4, E2F5 and E2F6 are important in the repression of E2F responsive genes and cell proliferation. Consistent with the repressor role of E2F4, we have recently determined that mice lacking E2F4 undergo accelerated intimal hyperplasia following arterial injury. Our Overall Hypothesis is that inhibition of individual (or subsets of the) E2Fs can reduce or enhance intimal hyperplasia following vessel damage or grafting and that a detailed understanding of how the various E2Fs control vascular smooth muscle cell proliferation during intimal hyperplasia will facilitate the development of more specific and potent inhibitors of this pathological process. Our Specific Aims are 1.) To determine the E2F family members that promote intimal hyperplasia and those that repress this pathological process using genetically modified mice, 2) To explore how perturbations in multiple E2F activities affect intimal hyperplasia and restenosis using genetically modified mice and 3) To develop aptamers that specifically target those E2F family that promote intimal hyperplasia and to evaluate the ability of these aptamers to limit intimal hyperplasia in animal models of vein graft failure and arterial restenosis Thus these experiments will delineate the E2F family member(s) that should be targeted for inhibition to reduce the occurrence of restenosis and vein-graft failure in humans and yield novel therapeutic compounds that may be useful in the treatment of individuals undergoing by-pass surgery or angioplasty. •
Project Title: EMBRYONIC STEM CELL RENEWAL-MYC TRANSCRIPTION FACTORS Principal Investigator & Institution: Dalton, Stephen; Professor; Animal and Dairy Science; University of Georgia (Uga) Office of Sponsored Programs Athens, Ga 306027411 Timing: Fiscal Year 2006; Project Start 01-MAY-2006; Project End 31-MAR-2011 Summary: (provided by applicant): Embryonic stem cells (ESCs) have the capacity for unlimited proliferation and differentiation into a wide range of cell types. Our long-term goals are to define the molecular mechanisms underpinning self-renewal and pluripotency of ESCs with the expectation that this information will, (i) define fundamental mechanisms of early embryonic development and, (ii) generate enabling technology that will give utility to ESCs in the area of regenerative medicine. The specific hypothesis is that Myc family transcription factors are important regulators of ESC self-renewal and pluripotency. This is supported by well defined roles for Myc transcription factors in immortalization of tumor cells and roles for the Myc regulatory pathway in early embryonic development. Using both murine and human ESCs, we will determine mechanisms of stem cell self-renewal using biochemical and genetic approaches. The outcomes of this work wil have important implications for general health sciences since ESCs can potentially be used to cure a wide range of degenerative diseases and for repairing chronic injury. Moreover, they are a valuable tool for understanding human embryonic development. The Specific Aims are to: 1. define
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mechanism(s) by which Myc maintains ESCs in a self-renewing, pluripotent state. This Specific Aim will identify mechanisms of Myc function in self-renewal by characterizing its role in cell cycle control and through the identification of transcriptional targets. This will help elucidate the genetic program underpinning self-renewal and stem cell identity. 2. investigate the relationship between Myc and regulation of self-renewal by the cell cycle machinery. 3. establish mechanisms of self-renewal in human ESCs and to evaluate the role of Myc. Although distinct differences exist between murine and human ESCs, it is likely that common modes of self-renewal regulation will exist. To understand self-renewal of hESCs, we will use information obtained from the mouse ESC model system (Specific Aims 1,2). This information will be crucial for our understanding of human ESC biology and in harnessing their therapeutic potential. The following hESC lines from the NIH Human Embryonic Stem Cell Registry will be used in these studies; BG01, TEO3 and WAO1. •
Project Title: EVOLUTION OF SEXUALLY DIMORPHIC GERM CELLS IN VOLVOX CARTERI Principal Investigator & Institution: Umen, James G.; Salk Institute for Biological Studies 10010 N Torrey Pines Rd La Jolla, Ca 920371099 Timing: Fiscal Year 2006; Project Start 27-JUN-2006; Project End 31-MAY-2011 Summary: (provided by applicant): SUMMARY. The long-term goal of this work is to understand the molecular genetic mechanisms that underlie developmental complexity. Multicellularity has evolved multiple times in the history of life and has led to an explosion of eukaryotic diversity, including novel reproductive strategies. Sexual dimorphism and multicellularity have coevolved in several lineages, but the mechanisms that led to their co-evolution in animals and plants lie in the distant past and are unknown. Volvox carteri is a multicellular green alga that shares recent common ancestry with its closest unicellular relative, Chlamydomonas reinhardtii. From a single-celled Chlamydomonas ancestor V. carteri has evolved many metazoan-like features including complete germ-soma separation and sexually dimorphic development. During sexual differentiation V. carteri females produce eggs and males produce sperm, a trait that is controlled by a mating type (mt) locus with two alleles, mtf (female) and mtm (male). The genomic region that encodes V. carteri mt has been identified and partially characterized, leading to the following Aims: (i) Clone and sequence both alleles of mt; (ii) Use annotation and transcriptional profiling to identify key regulators of sex determination; (iii) Characterize the genes that are responsible for sexually dimorphic development including vMATS, a mt-linked retinoblastoma (RB) tumor suppressor homolog that is highly polymorphic between V. carteri males and females; (iv) Directly test the role of female and male vMATS isoforms and other potential sex determining genes in regulating sexual differentiation by using ectopic expression and genetic inactivation experiments. The discovery of the V. carteri mating locus provides an unprecedented opportunity to dissect the molecular genetic changes that underlie the evolution of sexual dimorphism and to understand how sex chromosomes evolve to influence developmental programming. RELEVANCE. Germ cells are critical for human reproductive health and are also associated with some forms of human cancer, but their biology is poorly understood. The work proposed here is expected to reveal the underlying genetic architecture that leads to the production of eggs and sperm in a simple model system, and has already uncovered a potentially conserved link between a human tumor suppressor and germ cell formation.
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Project Title: EXPRESSION OF CLASS I SPECIFIC RECEPTORS IN NK CELLS Principal Investigator & Institution: Raulet, David H.; Professor; Molecular and Cell Biology (Mcb); University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2006; Project Start 01-APR-1996; Project End 31-MAR-2010 Summary: (provided by applicant): The NKG2D receptor expressed by NK cells and activated CDS T cells is a potent activator or costimulator of both innate immunity and T cell immunity. The Rae1 and MULT1 ligands for NKG2D are poorly expressed by normal cells but strongly upregulated in virus-infected cells and cancer cells by undefined molecular mechanisms. We have found that expression of Rae1 ligands is induced in normal cells by agents that damage DMA or impart DNA replication stress, but not by other common forms of cell stress. Agents that induce Rae1 activate the DNA damage response, a pathway that plays a central role in maintaining genomic integrity, suppressing tumors and regulating the cell cycle. DNA lesions are recognized by sensor kinases ATM and/or ATR, which activate the checkpoint kinases, Chk2 and Chk1, p53, and ultimately lead to activation of the retinoblastoma protein pRb, cell cycle arrest, and upregulation of DNA repair functions, and, when damage is extreme, apoptosis. We demonstrated that Rae1 upregulation in DNA damaged cells was inhibited by blocking ATM, ATR, or Chk1 using siRNA, conditional gene knockouts or chemical inhibitors. Recently, striking new findings in tumor biology show that human precancerous lesions upregulate the DNA damage pathway and undergo cell cycle arrest, probably triggered by replication stress due to inappropriate proliferation. Advanced tumors, which accumulate many genomic abnormalities, are thought to reactivate the DNA damage pathway. These findings suggested that stable upregulation of Rae1 that occurs in tumor cells may be due to the activity of the DNA damage response. Indeed, we found that inhibiting ATM expression in tumor cell lines with siRNA inhibited Rae1 expression. Other studies show that various viruses activate the DNA damage response when they infect cells. Our hypothesis is that disease-induced genomic insults, via the DNA damage response and Rae1 family molecules, alert the immune system to potential danger arising from the presence of infected, precancerous or cancer cells. The experiments herein are designed to uncover the detailed mechanisms whereby the DNA damage pathway activates expression of NKG2D ligands, determine whether it occurs in developing tumors in vivo, and assess its functional consequences. These data should provide deeper understanding of the role of NK receptors in fighting disease, and may provide the basis for designing potential therapeutic drugs that selectively upregulate Rae1 in diseased cells. Our aims are to: 1) define the proximal regulators of Rae1 genes in the DNA damage pathway; 2) identify elements in the Rae1 gene that regulate gene expression; 3) test the role of the DNA damage response in upregulating Rae1 ligands in developing tumors; 4) determine the functional consequences of the DNA damage pathway-induced Rae1 gene expression; and 5) examine the role of a cellular IRES sequence in regulating MULT1. These studies should advance our understanding of how the immune system surveys cells for loss of genomic integrity and may provide strategies to enhance immunity.
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Project Title: FOLATE RETINOBLASTOMA
DEFICIENCY,
METABOLISM
&
SPORADIC
Principal Investigator & Institution: Orjuela, Manuela A.; Environmental Health Sciences; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 12-SEP-2003; Project End 31-AUG-2007
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Summary: (provided by applicant): The objective of this study is to examine whether mutations in maternal and infant genes regulating folate metabolism are associated with an increased risk for the development of sporadic retinoblastoma. Environmental factors associated with poor living conditions may increase the risk of tumor formation, as the incidence of unilateral retinoblastoma is higher in several less affluent regions of the world. Mutations in the retinoblastoma gene, RB1 in germinal or dividing retinal cells result in tumor development. Most mutations occur at methylated cytosines, suggesting that abnormalities in methyl transfer may lead to mutagenesis. Folate, a regulator of methyl group transfer, is normally found in high concentrations in neural tissues and its deficiency can lead to mutagenesis through impaired methyl group transfer and pyrimidine synthesis. Risk for having a child with retinoblastoma is increased in women who do not take prenatal vitamin supplements and consume fewer folate-containing foods during pregnancy. The C677T and A1298C mutations in the methylene tetrahydrofolate reductase (MTHFR) gene and the A66G mutation in the methionine synthetase (MTRR) gene are common mutations in folate metabolizing enzymes genes which result in less functional enzymes. These act synergistically with low folate and co-balamin (B12) intake and increase the risk for neural tube defects. We hypothesize that decreased folate availability, because of poor intake, combined with less functional MTHFR and MTRR enzymes during key periods of retinal formation, in utero and in early infancy will lead to development of sporadic retinoblastoma. This molecular epidemiologic study proposes to use a case-control design, using questionnaires and blood samples, to examine two populations of mothers and children, one in central Mexico whose diet relies on foods not fortified with folate, and one in New York, where folate-fortified foods are widely consumed, in order to determine whether children with sporadic unilateral retinoblastoma and their mothers have an increased frequency of these MTHFR and MTRR mutations. The study will also examine whether the increased risk varies depending on folate intake, and levels of red blood cell and plasma folate, and plasma homocysteine. If our results are as anticipated, this project may lead to the development of new preventive strategies for those populations with an elevated incidence of sporadic retinoblastoma. •
Project Title: FUNCTIONAL ANALYSIS OF THE HPV-16 E6 AND E7 ONCOGENES Principal Investigator & Institution: Lambert, Paul F.; Professor; Oncology; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2005; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues including the epidermis and epithelial linings of the upper respiratory system and anogenital tract. A subset of anogenital HPVs, the 'high risk' HPVs including HPV-16 and 18 genotypes, are associated with greater than 95% of cervical carcinomas. Two genes of the high-risk anogenital human papillomaviruses (HPV), E6 and E7, are implicated in cervical carcinogenesis owing to their selective and continued expression in those cancers. E6 and E7 proteins possess multiple biochemical activities including but not limited to their capacities to inactivate tumor suppressor genes p53 and pRB, respectively. We and others have demonstrated that the inactivation of p53 and pRB cannot account completely for E6 and E7's transforming potential in tissue culture and tumorigenic properties in animal models. The goals of this application are to identify the cellular targets of E6 and E7 that contribute to their oncogenic function. We shall use transgenic mouse models in which the E6 and E7 genes of the high risk HPV most commonly associated with human cervical cancer, HPV-16, are directed in their expression to stratified squamous epithelia. These mouse models permit us to evaluate acute and long-term effects of E6 and E7
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Retinoblastoma
expression on mouse tissue including tumorigenesis in the epidermis and cervix. The availability of mouse strains that have been altered in specific cellular genes provide us a compelling approach to defining the cellular targets of E6 and E7 that contribute to HPV-associated cancer. •
Project Title: FUNCTIONAL ANALYSIS OF THE PTEN TUMOR SUPPRESSOR PROTEIN Principal Investigator & Institution: Garraway, Levi A.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-JUN-2000; Project End 31-MAY-2010 Summary: (provided by applicant): It is clear that inactivation of PTEN is a major contributor to the evolution of hormone-refractory prostate cancer. The function of PTEN as a tumor suppressor is most closely linked to its activity as a lipid phosphatase (Maehama and Dixon, 1998) and hence its ability to attenuate signaling through the phosphoinositide 3-kinase pathway. In the initial funding period our work focused on the role of PTEN as a cell-cycle regulator. Here,we showed that the PTEN lipid phosphatase activity and regulation of Akt was essential for PTEN to arrest cells in G1 (Ramaswamy et al., 1999). Elegant genetic studies placing PTEN in the dauer pathway in C.elegans led us to ask whether human FOXO homologues of daf-16, might play a role in PTEN-mediate tumor suppression. Indeed, we found that Foxol is constitutively inactivated in PTEN null cells and its reconstitution is sufficient to reverse the transformed phenotype of PTEN-null cancer cell lines (Nakamura et al., 2000). Surprisingly, we found that this Foxol activity did not require binding to an insulinresponse element and instead was associated with the ability of FOX01 to inhibit cyclin D1 and D2 transcription (Ramaswamy et al., 2002). Preliminary data strongly suggest that FOX01 can act as a transcriptional repressor through interactions with the protooncogene SKI and that this activity is linked to its ability to induce a cell-cycle arrest and suppress tumor growth. Based on this data we propose in specific Aim 1:1. To test the hypothesis that a repressor complex mediates the cell-cycle regulatory properties of FOXO1- During the original grant period we were the first group to demonstrate that PTEN is phosphorylated on residues within the C-terminal 'tail' and that these phosphorylation events appear to regulate PTEN stability. Moreover, we showed that the unphosphorylated form of PTEN is found in a more open conformation, associates with a high molecular weight complex, and is more active in biological assays. Based on this data we proposed a model whereby the majority of cellular PTEN is phosphorylated and in a relatively inactive state, upon dephosphorylation PTEN can then enter a so-called PTEN-associated complex (PAC) (Vazquez et al., 2001). In this context PTEN is more active yet subjected to degradation. Data from other labs have been entirely consistent with this model, yet an understanding of the mechanism through which phosphorylation regulates PTEN, the localization of the unphosphorylated forms of PTEN, and the nature of the PAC remain obscure. Based on this data we propose in specific aims 2 and 3: 2. To generate antibody reagents that selectively recognizes unphosphorylated PTEN. 3. To purify and identify proteins in the PTEN associated complex (PAC).
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Project Title: FUNCTIONS OF AN E1A-ASSOCIATED CELLULAR PROTEIN Principal Investigator & Institution: Thimmapaya, Bayar; Professor; MicrobiologyImmunology; Northwestern University 750 N. Lake Shore Drive, 7Th Chicago, Il 60611 Timing: Fiscal Year 2005; Project Start 01-APR-1998; Project End 31-MAR-2009
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Summary: (provided by applicant): The N-terminal region of the adenovirus transforming protein E1A binds to several host proteins whose functions are critical for the cell cycle control. These include p400, p300 and the highly related CBP, Retinoblastoma protein (Rb), and two Rb related proteins p107 and p130. E1A interactions with these host proteins result in profound alterations in cellular growth control, p300/CBP is a coactivator and a histone acetyl transferase that links chromatin remodeling with transcription. The focus of this application is to investigate the roles played by p300 in cell cycle control and to investigate how E1A binding to p300 deregulates the cell cycle related p300 functions. Recently, this laboratory has shown that depletion of p300 in quiescent cells leads to premature G1 exit and upregulation of c-Myc. Conversely, overexpression of p300 in quiescent cells leads to downregulation of c-Myc followed by inhibition of S phase entry. Thus, p300 provides an important function in G1 control of the cell cycle by negatively regulating Myc, and preventing a premature G1 exit. These results provide a molecular basis for the previously documented need for viral oncoproteins such as E1A and SV40 large-T to inactivate the p300 functions during cell transformation. Here, studies are proposed to investigate the mechanism by which p300 negatively regulates c-Myc at the chromatin level. The specific aims include the identification of the domains and activities of p300 that are critical for the negative regulation of Myc, the Myc promoter specific transcription factors and chromatin remodeling proteins that interact with p300 during this negative regulation, and the mechanism of their interactions that results in the repression of the Myc promoter. Finally, studies are proposed to investigate the mechanism by which EIA inactivates p300 functions that leads to Myc upregulation, and how E1A binding to p300 contributes to the G1 exit. p300/CBP is a key regulator of cell proliferation with tumor suppression properties. Therefore, understanding the functions of this protein in cell cycle control, and the mechanism by which viral oncogene products interfere with its functions will be valuable in understanding the p300 mediated growth regulatory pathways. •
Project Title: FUNCTIONS OF PRB IN STRESS ERYTHROPOIESIS Principal Investigator & Institution: Macleod, Kay F.; Cancer Research Facility; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2009 Summary: (provided by applicant): The Rb tumor suppressor (pRb) plays a critical role in stress erythropoiesis. We have shown that under stress conditions, such as hemolytic anemia, bone marrow transplant or tumorigenesis, pRb is required to regulate erythroblast expansion and to coordinate cell cycle exit with enucleation. Loss of pRb resulted in aplastic anemia and depletion of stem cells and progenitors from bone marrow and spleen. However, the underlying mechanisms that explain the critical role of pRb in stress erythropoiesis are not known. We hypothesize that the Rb tumor suppressor regulates a differentiation checkpoint in erythroblasts that is sensitive to oxidative stress and levels of DNA damage. We shall determine whether oxidative stress and/or DNA damage affects the ability of erythroblasts to exit cell cycle, differentiate and mature by enucleating and whether the ability to do so is dependent on functional pRb (Aim 1). Furthermore, we shall characterize the effects of Rb loss on expression of key modulators of DNA repair and oxidative stress, including red cell antioxidants. We also propose that E2f-2 is the key E2f target of pRb in post-mitotic erythroblasts and that by understanding how E2f-2 is regulated and by identifying physiologically relevant target genes, we shall understand why pRb is critical for stress erythropoiesis. We shall identify the upstream signaling pathways that promote expression of E2f-2 and are required to induce growth arrest of erythroblasts (Aim 2).
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We shall characterize how these signaling pathways impinge upon transcriptional regulation of E2f-2 by identifying the transcription factors that bind to and activate the E2f-2 promoter. Finally, we shall identify and validate genes that are regulated by E2f-2 and/or pRb in differentiating erythroblasts that explain aspects of the role played by pRb/E2f-2 in modulating oxidative stress, DNA damage and maturation of red cells (Aim 3). Thus by examining how the ability of erythroblasts to manage oxidative stress, repair DNA damage and undergo checkpoint arrest affects their differentiation potential, and how this in turn is regulated by pRb and E2f-2, we shall shed light on how the proliferative response to anemia is attenuated following anemic stress and how aplastic anemia, myelofibrosis and other blood disorders develop in humans. •
Project Title: GENE THERAPY FOR EXTENSION OF VEIN GRAFT PATENCY Principal Investigator & Institution: Weichselbaum, Ralph R.; Professor and Chairman; Surgery; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2005; Project Start 20-FEB-2002; Project End 31-JAN-2007 Summary: Bypass grafting using autologous vein is a common and effective treatment for end-stage atherosclerosis, and over one million vein grafts are created annually in the United States. Although vein grafting is almost always initially successful, the development of neointimal hyperplasia eventually leads to stenosis and failure in 5070percent of cases over the first five years, and remains the most significant obstacle to long-term patency. Neointimal hyperplasia is the direct result of uncontrolled vascular smooth muscle cell (VSMC) proliferation, which is stimulated in vein grafts by the profoundly increased pressure and flow of the arterial environment. As pharmacologic approaches to this problem have been uniformly disappointing, therapeutic strategies employing antiproliferative gene therapy have recently been suggested. Efficient adenoviral-mediated gene transfer into animal veins and vein grafts has been demonstrated in many laboratories, including the applicant's. The early programmed transgene expression is stable and leads to a modest reduction in vein graft neointimal thickening after four weeks. However, the lack of animal models that develop truly occlusive lesions (as opposed to simple thickening), as well as the uncertain toxicity and long-term efficacy of adenoviral-mediated gene transfer has hampered translation of this approach to the clinical setting. Furthermore, while efficient in thin animal veins, adenoviral- mediated gene transfer into human saphenous veins has been more problematic, due to the thickness of the smooth muscle cell layer and the natural barrier that the endothelium provides against large particle penetration. The purpose of this project is to develop better models of vein graft VSMC proliferation and to use these models to test the toxicity and tong-term efficacy of anti proliferative gene transfer using adenoviral and herpes simplex viral (HSV) vectors. The specific aims are: (1) to develop new models of vein graft VSMC proliferation in the experimental animal in vivo and using human veins in vitro, (2) to evaluate the toxicity and long-term efficacy of adenoviral-mediated antiproliferative gene transfer using these models, and (3) to evaluate the efficiency and toxicity of vascular gene transfer using HSV, a nonintegrating DNA virus with the potential for penetration and durable programmed expression in thick-walled human veins.
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Project Title: GENETIC MODELS OF CELLULAR PROLIFERATION Principal Investigator & Institution: Haber, Daniel A.; Director, Cancer Center; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 04-SEP-2002; Project End 31-AUG-2007
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Summary: (provided by applicant): The advent of comprehensive genomic resources has led to the rapid identification of novel genes with potential roles in regulating cellular proliferation, but only limited approaches to define their role within functional pathways and their contribution to human cancer. Genome projects in multiple organisms have underscored the evolutionary conservation of cellular proliferation pathways between man and simpler organisms, and it is the goal of this P01 application to provide a bridge between studies in genetic model organisms and human cancer. The use of screens for novel genes involved in cell proliferation and cell cycle regulation based in Drosophila and C. elegans will lead to the discovery of mammalian orthologs, whose role in human cancer will be assessed by mutational studies. C. elegans and Drosophila also provide efficient tools, such as RNA interference (RNAi), for the functional analysis of novel genes identified in these screens and in mammalian genomic screens targeting homozygous deletions in mouse tumor models. Project 1 (Dyson): Identify novel modifiers of the cell cycle regulators E2F and retinoblastoma (RB) in Drosophila, isolate their mammalian orthologs, and search for mutations in human cancers. Project 2 (Hariharan): Use a recombination-driven screen in the Drosophila eye for genes whose homozygous inactivation triggers increased cellular proliferation, characterize promising candidates, including a novel gene Salvador, and determine whether it is targeted by mutations in human tumors. Project 3 (Haber): Adapt Representational Difference Analysis (RDA) to screen for homozygous genomic deletions in a mouse tumor model of cancer progression, characterize DOS, a novel gene implicated in Rho signaling that is targeted by such a deletion, use RNAi to analyze novel genes present within tumor-associated deletions. Project 4 (van den Heuvel): Use C. elegans to search for genes that modulate the function of D-type cyclins, characterize two novel negative regulators, lin-9 and lin-36, and define their contribution to human cancer. These projects will be supported by cores for Administration (Haber), Genetics (Drosophila: Artavanis-Tsakonas, and C. elegans: Hart), and Molecular Pathology (expression: Stamenkovic, and mutational analysis: Bell). Collectively, these studies provide a concerted effort to make use of powerful tools provided by genetic model systems to define the function of new genes involved in cellular proliferation and their potential roles in human cancer. •
Project Title: GENETICS OF PRADER-WILLI/ANGELMAN SYNDROME Principal Investigator & Institution: Beaudet, Arthur L.; Professor and Chair; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-JAN-1999; Project End 31-DEC-2008 Summary: The overall goals of this project are 1) to determine genotype/phenotype relationships across the chromosome 15q11-q13 imprinted domain and its mouse equivalent to include Angelman syndrome (AS), Prader-Willi syndrome (PWS), and other phenotypes; 2) to explore the molecular genetic and biochemical bases for regulation of genomic imprinting in mice and humans; 3) to expand the understanding of the role of genomic imprinting and epigenetics more generally in human disease; and 4) to explore therapeutic strategies for AS in mice and in cultured human cells as a model for epigenetic therapies. Initial gene trap experiments identified retinoblastoma binding protein 1 (Rbbp1) and Rbbp1-like-1 (Rbbp111) as having effects on imprinting; in addition, cultured cells lacking expression of the retinoblastoma (Rb) protein show altered DNA methylation and gene expression in both the Snrpn and H19 imprinted domains. The aims related to studies of regulation of genomic imprinting include the following: a) Continue genetic analysis of human chromosome 15q11-q13 and mouse 7C; b) Extend genetic screens in mice using ENU mutagenesis and perhaps sleeping beauty mutagenesis with new "yellow" Snrpn-agouti allele and in ES cells using gene-
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trap mutagenesis; c) Prepare null mutations in mice for Rbbp1 and Rbbp111 and characterize the phenotypes; d) Genetic analysis in mice using Mecp2, eed, Rbbp1, Rbbp111, Rb and other candidate genes and genes isolated in screens; and e) Biochemical and microscopy studies to include co-immunoprecipitation (IP) studies to identify protein-protein interactions, chromatin immunoprecipitation (CHIP) studies, immuno-histochemistry, immuno-FISH, and analysis of gene expression and DNA methylation. One goal is to validate whether five proteins identified by 2D gels of Purkinje cells from Ube3a mutant and wild-type mice are increased in abundance in vivo in mutant mice using immuno-histochemistry and western blots. Treatment for AS will be explored attempting to increase leaky expression of the silenced paternal allele of UBE3A. Studies will test the effect of various drugs on human cultured fibroblasts and in mice, and an ongoing clinical trial of folate and betaine will be modified based on these results. The hypothesis that intracytoplasmic sperm injection (ICSI) may cause imprinting defects will be tested in mice using a gene fusion method which allows detection of these defects based on coat color. •
Project Title: GLOBE CONSERVATION IN TRANSGENIC RETINOBLASTOMA Principal Investigator & Institution: Murray, Timothy G.; Associate Professor; Ophthalmology; University of Miami-Medical School 1507 Levante Avenue Coral Gables, Fl 33124 Timing: Fiscal Year 2005; Project Start 30-SEP-2004; Project End 31-AUG-2007 Summary: (provided by applicant): The broad long-term objective of this research is to improve treatment of children with intraocular retinoblastoma by utilizing animal modeling of current and experimental therapies to enhance tumor control while decreasing treatment related morbidity. Extensive pilot data, utilizing a unique transgenic model of intraocular retinoblastoma, has documented the reliability of this approach to model human retinoblastoma and its response to treatment. Retinoblastoma is the most common primary intraocular tumor in children. This cause of this disease is characterized on a molecular genetic level as inactivation of both copies of the retinoblastoma gene. It is now recognized that this genetic defect predisposes children to a lifelong risk of second, independent malignancies. The incidence of these malignancies is affected by the treatment chosen to cure the primary eye tumor. Over the last decade, external beam radiotherapy has virtually been eliminated as an initial treatment option in childhood retinoblastoma and has been replaced by systemically delivered chemotherapy coupled to local tumor treatment with laser ablation or cryoablation. Complications during this treatment are expected to occur in up to twothirds of treated children. Focally delivered chemotherapy (relatively easily due to the unique accessibility and anatomy of the eye and orbit) reduces complications related to systemic delivery and has been shown to be effective in pilot labora-tory studies and in early pilot treatment projects in children with retinoblastoma. Retinoblastoma is a highly vascularized tumor. Pilot data suggests that angiostatic therapy is effective in the reduction of tumor burden in a murine transgenic model of retinoblastoma. This model system will be used to evaluate the efficacy of focally delivered vascular targeting agents in the treatment of retinal tumors. Dose dependent reduction of tumor burden and blood vessel closure will be determined for two different vascular targeting agents. These individual therapies will be combined with focal/ subconjunctival Carboplatin chemotherapy. The optimal drug concentrations and delivery schedules for the combined treatment will be determined. To understand disease progression and to identify potential novel therapeutic agents, the processes of angiogenesis and tumor cell death during tumor progression and in response to treatment will be assessed. The differential expression and localization of angiogenesis promoting factors will be
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determined during tumor progression and following treatment; The spontaneous induction of tumor cell death (necrosis or apoptosis) will be determined during tumor progression and the differential induction of tumor cell death will be assessed following each treatment modality. It is likely that results from these studies will contribute immediately to the care of children with this devastating ocular malignancy. •
Project Title: GROWTH-REGULATORY TARGETS OF DROSOPHILA CYCLIN D/CDK4 Principal Investigator & Institution: Edgar, Bruce A.; Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 981091024 Timing: Fiscal Year 2005; Project Start 01-SEP-2000; Project End 31-AUG-2008 Summary: (provided by applicant): Deregulation of at least one component of the Ink4/Cyclin D1/retinoblastoma pathway is a common feature of most of human cancers, but the mechanism by which these genes contribute to tumorigenesis is poorly understood. In studies using Drosophila we discovered that Cyclin D/Cdk4 complexes, in addition to their widely appreciated function as promoters of cell cycle progression, also regulate rates of increase in cell mass (growth). CycD/Cdk4 does this via unknown targets, distinct from those in the well-studied pRb/E2F pathway. We are using Drosophila genetics to identify and characterize these novel growth-regulatory targets, which we believe may be important for understanding CycD/Cdk4 function during normal and neoplastic development. Specific aims of this project comprise: 1) Identification and characterization of growth regulatory targets of CycD/Cdk4 using proven, genome-wide screens for mutations that dominantly suppress overgrowth of the eye caused by ectopic CycD/Cdk4; 2) Identification of CycD/Cdk4 targets by gene expression profiling; 3) development of a Drosophila CycD/Cdk4 kinase assay for characterizing putative targets; 4) Characterizing the Hph/Hif-1/VHL and JAK/STAT pathways as mediators of CycD/Cdk4-driven growth; and 5) Tests to determine whether CycD/Cdk4 effects cellular growth by modulating nutrient import, protein synthesis, protein degradation, or mitochondrial function. This project aims to elucidate how CycD/Cdk4 alters cell physiology to promote growth, and should contribute to molecular paradigms explaining how cell growth and cell division are coupled. It should also allow identification of novel Cyclin D and Ink4 targets in humans, and thus help to reveal how growth of our own cells is controlled during normal and neoplastic development. Some of the identified genes could be useful targets for cancer diagnosis or anti-cancer chemotherapeutics.
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Project Title: HAIR CELL DEVELOPMENT Principal Investigator & Institution: Chen, Zheng-Yi; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2008 Summary: (provided by applicant): Millions of people suffer from irreversible hearing loss due to hair cell degeneration as a result of aging and early exposure to hazardous environment such as noise. Unlike other species such as birds, the mammalian inner ear does not replace the damaged hair cells spontaneously. Any intervention aiming at replacing damaged hair cells requires understanding the developmental controls of the hair cells, so that by manipulating the determining factors it will be possible to induce the regeneration of hair cells. The development of the hair cell is controlled by proliferation of progenitor cells, initiation of cell fate determination and the terminal differentiation. Little is known, however, about the identity of genes and associated pathways that control the cell cycle exit of progenitor cells and the maintenance of the
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quiescent post mitotic status of the hair cells and the supporting cells. In this application we propose to accomplish fours aims. First, to test our hypothesis that the retinoblastoma gene (Rb) is critically involved in the cell cycle exit of the sensory epithelium in the inner ear. This will be accomplished using the conditional Rb knockout mouse model in which Rb is abolished in the sensory epithelial cells. Furthermore two hair cell- specific Rb conditional mouse models will be studied, to understand whether Rb is required for the maintenance of post mitotic hair cells. These mouse models will also provide us with the answers to questions including whether Rb is involved in the differentiation of hair cells, or whether functional hair cells can be produced in the absence of pRb function. Second, to test our hypothesis that Rb is required for the quiescent status of mature hair cells. The proliferation potential of mature hair cells will be studied, after acute deletion of Rb in the mature lox-P Rb utricle organ culture system. The newly derived hair cells will be studied to determine if they are functional, by dye FM1-43 uptake and patch clamping. The re-entry into the cell cycle by the mature hair cells to produce the functional hair cells will have enormous potential for hair cell regeneration for future therapy. Third, using the functional genomic approach, we will identify the pathways controlled by Rb in the inner ear. Identification of critical molecules involved in the Rb pathway will offer us the possibility to fine-tune the process controlling the hair cell post mitotic status. Lastly, by taking advantage of proliferating properties of differentiated Rb-null hair cells, we will establish cell lines enriched with hair cell properties. The cell lines will be characterized for hair-cell-specific gene expression. Such cell lines will be of great value to hearing research in general. Completion of the project will provide better understanding of the mechanism involved in cell cycle control of hair cells, and help to open new avenues in hair cell regeneration. •
Project Title: HEC1 NETWORK AS MOLECULAR THERAPEUTIC TARGETS Principal Investigator & Institution: Lee, Wen-Hwa; Donald Bren Professor; Biological Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2005; Project Start 01-JUL-1991; Project End 31-JAN-2009 Summary: (provided by applicant): Genetic instability is one of the most important hallmarks of cancer. Associations of oncoproteins or tumor suppressors with the process of chromosome segregation provide possible links between carcinogenesis and chromosomal instability. Studies on the function of Rb have been centralized on its role in G1 phase but recently extended to G2/M phases of the cell cycle. Rb interacts with Heclp, through an IxCxE motif, specifically during G2/M phase. Inactivation of hsHeclp by microinjection with anti-Hecl monoclonal antibodies leads to cell death due to abnormal chromosomal segregation. Similarly, inactivation of scHEC1 in budding yeast results in lethality, which can be rescued by hsHEC 1, indicating a highly conserved function for this protein. Heclp appears to be a novel critical protein for M phase progression, and RB can increase the fidelity of chromosome segregation mediated by hsHec lp. Intriguingly, the expression of HEC 1 is highly elevated in most cancer cell lines. Based on these preliminary results, we plan to address the role of Heclp during chromosome segregation in mammalian cells and to explore the possibility of using the Heclp network as a target for developing small molecules that inactivate its function as potential therapeutic candidates. In this application, we proposed four specific aims to address these issues: Aim 1: To elucidate the biological significance of the interaction between Hec 1 and Hint 1 at kinetochores and to analyze the role of Heclp and Hintl in spindle checkpoint response. Aim 2: To elucidate the biological function of 15A2 and its interaction with Hecl at centrosomes and to analyze the role of Heclp and 15A2 in centrosome functions. Aim 3: To examine the regulatory phosphorylation of Hecl by
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identifying the responsible kinases and to determine roles of the phosphorylated Heclp during chromosome segregation; and Aim 4: To explore the Hec 1 networks for potentials as molecular therapeutic targets by identifying small molecules that disrupt the interactions between Heclp and Nek2 as therapeutic candidates. It is expected that elucidation of the function of Heclp will provide useful information in understanding the regulation of chromosome segregation. Moreover, the identified small molecules will not only be a useful tool for dissecting the mitotic machinery, but will have potentials for therapeutic application to treat cancer. •
Project Title: HORMONAL CARCINOGENESIS IN RB-KNOCKOUT MOUSE PROSTATE Principal Investigator & Institution: Hayward, Simon W.; Assistant Professor of Urologic Surgery; Surgery; Vanderbilt University Medical Center Nashville, Tn 372036869 Timing: Fiscal Year 2005; Project Start 25-SEP-2001; Project End 31-AUG-2007 Summary: The overall objective of this work is to enhance the understanding of prostate cancer initiation and progression. The main goal of the present proposal is to characterize new models of hormonal carcinogenesis in the mouse prostate. These experiments will use retinoblastoma (Rb) gene-knockout and conditionally deleted-Rb mouse prostate as a target for hormonal carcinogenesis. Experiments will examine the ontogeny and histopathology of carcinogenesis (aim 1), the precise role played by sex steroids (aim 2) and the specific epithelial cell type targeted by hormonal carcinogens (aim 3). A panel of cell strains will be derived from the tumors which are generated. Their behavior in vivo will be characterized and they will be subject to genomic analysis to identify common genetic lesions associated with prostate cancer (aim 4). Data from these studies will be used to identify candidate genes involved in prostatic carcinogenesis. The central hypothesis is that the progression from normal histology to cancer seen in mouse prostatic tissue lacking expression of the Rb tumor-suppressor gene is a good in vivo model of human prostate cancer. This project will use two new in vivo models of prostatic carcinogenesis. The first is a tissue recombination model based upon prostatic epithelium derived from the Rb-knockout mouse. The second model is a conditional deletion of Rb in the luminal epithelial cells of the prostate utilizing cre-lox technology. In both models a combination of testosterone and estradiol will be used to initiate the formation of prostate tumors. Prostate tumors will be used to generate a spectrum of cell lines representative of the stages from normal prostate to hormoneindependent prostate cancer. These cell lines will serve as a source material to examine genomic lesions associated with prostate cancer progression. The following specific aims will be pursued. Specific Aim 1 Characterization of tumor progression in Rb-deficient mouse prostate under the influence of testosterone and estradiol. Specific Aim 2 An examination of the roles of testosterone and estradiol in hormonally induced prostatic carcinogenesis in the Rb-deficient mouse prostate Specific Aim 3 Generation and Characterization of ARR2Pb-cre RbloxP/loxP mice. Hormonal Carcinogenesis in ARR2Pb-cre RbloxP/loxP mice. Specific Aim 4 Isolation, phenotypic and genomic characterization of Rb-deficient cell strains.
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Project Title: ID2 IN CELL CYCLE REGULATION AND CANCER Principal Investigator & Institution: Iavarone, Antonio; Associate Professor; Institute for Cancer Genetics; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2006; Project Start 05-APR-2000; Project End 31-JUL-2011
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Summary: (provided by applicant): The Id2 protein has been implicated in a broad spectrum of cellular processes, including differentiation, cell cycle and tumor progression. Our work discovered that genetic oncogenic changes converge on the activation of Id2 to implement multiple hallmarks of neoplasia, such as uncontrolled cell proliferation, anaplasia and neo-angiogenesis. Although some crucial proteins engaged by Id2 to carry out these functions have been identified (bHLH transcription factors and the pocket proteins Rb, p107 and p130), the mechanisms directing the Id2 activity in normal and tumor cells are still unknown. Important levels of regulation of Id2 are subcellular compartmentalization and the control of Id2 protein stability. We identified the cytoplasmic, actin- associated protein ENH (ENigma Homolog) as a new Id2 protein partner. Accumulation of ENH during neural differentiation and cell cycle arrest is required for cytoplasmic sequestration and functional inactivation of Id2. By combining an array of cell biology and mouse genetics experiments, we will determine the role of the ENH-ld2 pathway in normal development and tumorigenesis in the nervous system. We will also uncover how differentiated tumors restrain their drive towards full-blown anaplasia by retaining active ENH. Recently, we discovered that Id2 is a highly unstable protein that is targeted for ubiquitin-dependent degradation by the Anaphase Promoting Complex/Cyclosome (APC/C) and its activator Cdh1. Degradation of Id2 requires a highly conserved destruction box motif in the Id2 protein. Although several tumors accumulate aberrant amounts of Id2, whether deregulated Id2 operates as an oncogene has never been rigorously demonstrated. We will use mutants of Id2 that are resistant to APC/C-mediated degradation to explore the consequences of instigating deregulated Id2 activity for cell cycle progression, cellular transformation, genomic instability and tumor development in the mouse. By generating mouse models that conditionally express degradation-resistant Id2, we will also unravel the integration of deregulated Id2 with other tumor-inducing mutations for tumorigenesis. The proposed work will define the mechanisms underlying regulation of Id2 and enhance our understanding of the involvement of uncontrolled Id2 activity in human cancer. •
Project Title: IN VIVO ANALYSIS OF MOUSE H1 HISTONE FUNCTION Principal Investigator & Institution: Skoultchi, Arthur I.; Resnick Professor and Chair; Cell Biology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2005; Project Start 01-APR-1998; Project End 31-MAY-2008 Summary: (provided by applicant): The goals of this project are to advance our knowledge about the functions of H1 linker histones and to understand the functional significance of the diversity present in this family of chromatin proteins. H1 linker histones play a key role in the structure of chromatin and thereby affect gene expression as well as other processes requiring access to DNA. Most of our knowledge about the functions of H1 histones has been derived from in vitro experiments. Our approach is to analyze the functions of H1 histones in vivo in mice. The mouse (and other mammalian) H1 histones consist of at least 8 subtypes that differ considerably, both in their primary sequences and in their expression during development and tissue differentiation. These subtypes offer an additional, potential level of regulation of chromatin function. Our strategy for studying the function of linker histones has been to generate and characterize mice in which one or more H1 genes has been inactivated by gene targeting. We have generated a large repertoire of mouse strains consisting of 6 single H1 null mice and several compound null strains and cultured cell lines. We have used these mutants to show that, unlike in lower organisms, H1 histones are essential for mammalian development. Some of the mutants have been analyzed for their effects on gene expression. The results show that loss of individual subtypes as well as reduction in total amount of H1 causes changes in expression of specific genes. We now propose to
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use our unique set of mouse strains to: (1) study the mechanisms by which individual H1 subtypes and H1 stoichiometry affect gene transcription and regulation in vivo. We will compare the chromatin structure in the vicinity of specific genes in wild-type and mutant H1-depleted cells and mice; and (2) study the role of H1 linker histones in the structure, composition and post-translational modifications of chromatin in vivo. We also propose to develop new cell lines with extremely low amounts or completely lacking H1 histones. We also propose to perform an in vivo test of specific H1 subtype function by a gene replacement strategy in mice. There is evidence that H1 histones are downstream targets of cyclin-dependent kinases regulated by the retinoblastoma protein. Thus H1 histones may be key transducers of information between cell cycle regulators and chromatin structure, gene expression and other activities of the genome in normal and malignant cells. •
Project Title: INDUCTIBLE MOUSE MODELS FOR ORAL CANCER Principal Investigator & Institution: Caulin, Carlos; Dermatology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 13-JAN-2005; Project End 31-DEC-2009 Summary: (provided by applicant): Oral cancer is the seventh most common form of cancer and causes 8,000 deaths in the United States each year and 128,000 worldwide. Similar to other tumor types, it is widely accepted that the formation of oral cancer is a multi-step process that results from the accumulation of genetic alterations. The high frequency of genetic and epigenetic alterations found in certain genes strongly suggests a causal role in the development of oral cancer. Our long-term objective is to generate transgenic mice carrying inducible genetic alterations that closely mimic some of the most common mutations found in human cancer of the oral cavity. Although a large number of genetic alterations have been reported in oral cancer patients, three different molecular pathways seem to be the major targets of mutations, namely the p53, retinoblastoma (Rb) and Epidermal Growth Factor Receptor (EGFR) signaling pathways. Accordingly, the gene alterations most frequently found in oral cancer include EGFR overexpression, p53 mutations (such as the gain-of-function p53R175H) and inactivation of the INK4a/ARF locus, which functions at least in part as a negative regulator of the Rb pathway. We hypothesize that these mutations that have a high incidence in oral cancer patients play a causal role in the development of cancer of the oral cavity. To test this hypothesis we will use an inducible system to generate mouse models that exhibit p53 mutations, EGFR overexpression or inactivation of the INK4a/ARF locus only in the oral cavity. These models have several advantages over conventional transgenic/knockout models: the mutation can be targeted to a restricted area of the tissue and the moment of tumor initiation can be chosen. Therefore, they will closely mimic the sporadic focal accumulation of somatic mutations found in human tumors. These mouse models will be useful not only to better understand the molecular mechanisms of oral cancer development, but also as preclinical models for testing therapeutic agents for prevention and intervention of oral cancer.
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Project Title: INTERFERONS MODULATE AIRWAY SMOOTH MUSCLE GROWTH Principal Investigator & Institution: Panettieri, Reynold A.; Professor; Medicine; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 05-SEP-2005; Project End 31-JUL-2009 Summary: (provided by applicant): The goal of this proposal is to define the molecular signaling processes by which interferons (IFNs) inhibit basal and mitogen-induced growth of human airway smooth muscle (ASM) cells. This question is critical to
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understanding the pathogenesis of severe asthma, which is characterized by increased ASM mass and hyperplasia, and to developing new therapeutic approaches to abrogate myocyte hyperplasia. ASM growth induced by mitogens requires activation of p21 Ras, p60Src, phosphatidylinositol 3-kinase (PI3K) and S6K1. The Pl's studies show that IFN( and IFN( profoundly inhibit ASM growth while decreasing retinoblastoma (Rb) phosphorylation and increasing IFI 16 expression, key steps in regulating cell cycle progression. In vivo studies showed ASM constitutively expresses IFN( and autocrine IFN(, which activates JAK/STAT pathways, inhibited mitogen/cytokine-induced growth in vitro. The central hypothesis of this proposal states that basal, cytokine- and mitogen-induced ASM cell proliferation is inhibited by the autocrine secretion of IFNb in a JAK/STAT-and IFI 16-dependent manner. To test these hypotheses, in Aim 1 mitogen-induced ASM growth and activation of Src, PI3K and S6K1 in the presence and absence of IFNb will determine whether inhibition of these signals mediates IFNb growth effects. Studies using ASM transfected with mutant cDNA constructs or using siRNA knockdown will define whether JAK/STAT activity or IFI 16 expression is necessary and sufficient to inhibit myocyte growth. In Aim 2, abrogation of constitutive IFNb using siRNA, mutant cDNA constructs or ASM cells derived from IFNb -/- mice will determine whether abrogating constitutive IFN( promotes ASM growth. In Aim 3, the use of novel transgenic models that express GFP, that lack IFNb or overexpress PDGF exclusively in smooth muscle will characterize whether expression of IFNb in vivo is necessary and sufficient to regulate ASM hyperplasia induced by allergen or PDGF. •
Project Title: LENS DIFFERENTIATION & CATARACT: ROLE OF FGF, RA & WNT Principal Investigator & Institution: Mcavoy, Johnston W.; University of Sydney Research Office Sydney, 2006 Timing: Fiscal Year 2005; Project Start 30-SEP-1991; Project End 31-JUL-2007 Summary: (provided by applicant): This project aims to elucidate factors that regulate differentiation and growth of the epithelial monolayer. There is growing evidence that members of the FGF, RA and Wnt families may play key roles in lens epithelial cell biology. Part one is directed at testing the hypothesis that FGF (a low dose), RA and Wnt regulate lens epithelial proliferation, adhesion and communication. The effects of these ligands on expression of lens epithelial phenotypic characteristics including key molecules, such as cadherins, integrins and connexons, will be investigated using RTPCR, in-situ hybridisation and immunohistochemistry. Part two will test the hypothesis that FGF (a low dose), RA and Wnt stimulate signalling cascades which cooperate to stimulate expression of key epithelial transcription factors. This will investigate modulation of receptor expression and identification of signaling cascades activated by these ligands. Transcription factors studied will be Pax-6, Eya-1, Six-3, maf-B, AP2a, RAR/RXR and Foxe-3. Part three will test the hypothesis that TFGbeta-induced cataractous changes involve inhibition of FGF, RA and Wnt signalling, and down regulation of expression of key epithelial transcription factors. This will investigate how TGFbeta modulates expression of FGF, RA and Wnt receptors, signalling molecules and transcription factors (see above). Part four will test the hypothesis that reduced Pax-6 expression makes lens epithelial cells more susceptible tp TGFbeta-induced cataractous changes. The small eye (Sey) mouse will be investigated to determine if epithelial cells from this mutant are more sensitive to TGFbeta and, if so, the mechanism(s) involved. Understanding the molecular interactions that determine the lens epithelial phenotype is central to understanding the molecular basis of cataracts involving aberrant epithelial growth, including PCO.
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Project Title: LIGAND-RECEPTOR SUPERFAMILY
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Principal Investigator & Institution: Hinck, Andrew P.; Associate Professor; Biochemistry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2006; Project Start 01-SEP-1999; Project End 31-AUG-2010 Summary: (provided by applicant): TGFp isoforms ((31, (32, and p3) are 25 kDa disulfide-linked homodimers that regulate cell proliferation, cell differentiation, and expression of extracellular matrix proteins. TGFps are best known for their tumor suppressor activity, and while loss of this activity leads to certain hereditary forms of colon and pancreatic cancer, in most cancers, including those of the breast, the TGFp signaling pathway remains intact. This usually has adverse effects, since the tumor promoting activities of TGFp, including its ability to stimulate immune suppression and endothelial-to-mesenchymal transitions, remain intact, yet its growth inhibitory activity is lost, due to either inactivation of the retinoblastoma gene product (pRB) or expression of growth stimulatory genes, such as c-myc. The three isoforms of TGFp share 71 - 79 % sequence identity and signal through a pair of structurally similar single-pass transmembrane receptors known as TRI and TRII. The isoforms nevertheless fufill distinct roles in vivo, as shown by the non-overlapping and lethal phenotypes of the isoform specific -/- null mice, by differences in response induced by the addition of purified isoforms in tissue ex-plant assays, and by the opposing roles they play in diseases, such as breast cancer. The origins of these differences are not understood, although based on previous cell-based cross-linking and structural studies, it might be due to differences in the manner by which they bind and assemble their receptors into a signaling complex. The first major objective of this proposal is to define the molecular architecture of the extracellular component of the TRI:TRII:TGFp signaling complex. This will provide fundamental information concerning the inter-dependent nature of TGFp receptor assembly, as well as how assembly differs for the isoforms whose monomers are fixed relative to one another (TGFps 1 and 2) compared to those whose monomers are not fixed (TGFpS). The second major component of this project concerns TGFp2, which also signals by binding and bringing together TRI and TRII, but which binds TRII weakly, and which is dependent upon a third cell surface TGFp binding protein, known as betaglycan, to induce its cellular responses. The objective of the proposed studies is to determine the structural basis underlying the mechanism by which the endoglin-like domain of the TGFp co-receptor betaglycan facilitates binding of TGFp2 to TRII. This will provide the first example of how one of the co-receptors in the family functions to selectively enhance the sensitivity of cells to a particular ligand isoform. The information derived from these studies will then be used to generate mutant TGFps, to test whether differences among the isoforms in their manner of receptor binding indeed underlie their differences in biological activity using two different cell-based systems. •
Project Title: MECHANISMS OF PROSTHETIC ARTERIAL GRAFT FAILURE Principal Investigator & Institution: Logerfo, Frank W.; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2005; Project Start 01-JUL-1987; Project End 31-MAY-2008 Summary: (provided by applicant): Anastomotic intimal hyperplasia (AIH) remains the most common cause of delayed prosthetic arterial graft failure, a consequence of focal, unregulated gene expression. As graft healing occurs, genes are either up or downregulated compared to a quiescent arterial wall. Our hypothesis is that this altered gene expression results in cellular proliferation, migration, and extracellular matrix
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Retinoblastoma
production by smooth muscle cells, leading to AIH. The significance and unique aspect of this work is that our group was the first to identify specific genes that are altered following prosthetic arterial grafting in vivo. This is continuing study of AIH following prosthetic arterial grafting, uses microarray analysis and quantitative real-time RT-PCR (qPCR) to define temporal gene expression at the anastomotic region compared with control artery. This proposal builds on a foundation of molecular data originally derived by our group using differential display and Northern blot analysis to understand the molecular changes that occur at the anastomoses of prosthetic arterial grafts compared with normal arterial wall. Our group was the first to identify alterations in gene expression in the proteosome-ubiquitin pathway following prosthetic arterial grafting. Cell cycle regulators including retinoblastoma susceptibility protein were found to have altered expression following prosthetic arterial grafting. These two pathways subsequently have recently been identified by other investigators as codependent in terms of cell homeostatic functions. Our continued investigation will assess gene expression at additional time points using microarray analysis and computational software techniques. Laser Capture Microdissection will be utilized as an adjunct to localize altered gene expression within the medial wall and within the neointima of the prosthetic graft. In addition, our previous time points of gene expression using qPCR will be validated. Further, downstream products will be assessed using in situ hybridization, and protein expression will be examined using immunohistochemistry. Identification of alterations in gene expression, their time course, cellular localization and computational analysis provides a valuable guide to a comprehensive understanding of anastomotic intimal hyperplasia. •
Project Title: MENTORED DEVELOPMENT AWARD
PATIENT-ORIENTED
RESEARCH
CAREER
Principal Investigator & Institution: Florell, Scott R.; Dermatology; University of Utah 75 South 2000 East Salt Lake City, Ut 84112 Timing: Fiscal Year 2005; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The goal of this project is to determine the role of p16, a tumor-suppressor gene in the retinoblastoma cell-cycle regulation pathway, in familial melanoma kindreds. Malignant melanoma is the most lethal of the skin cancers, and unlike most malignancies, often affects younger patients in their third and fourth decades. Several risk factors have been associated with melanoma, including sun exposure, genetic predisposition, total number of nevi present on an individual, and characteristics of nevi. The overall proportion of cutaneous melanoma attributable to genetic predisposition is reported to be about 10- 15%, but evaluation of cancer incidence data from the Utah Population Database suggests that the fraction of melanoma occurring in a familial setting may be as high as 30%. The applicant proposes to re-examine members of Utah melanoma kindreds, first studied 15 years ago at the UUSM, that helped establish the presence of a melanoma susceptibility locus on 9p21 and later confirm the association of p16 mutations with familial melanoma. A five-year mentored program is proposed to investigate the global hypothesis that carriage of a germline p16 mutation results in measurable clinical, histologic, and cellular changes that lead to familial susceptibility to melanoma. This program will incorporate both didactic and research training and will be guided by a research oversight committee composed of four established scientists at the UUSM and the Huntsman Cancer Institute. Three specific aims are proposed. First, clinical differences between carriers and non-carriers of a p16 mutation will be examined in the Familial Melanoma Research Clinic (FMRC) at the Huntsman Cancer Institute. Kindred members studied 15 years ago will be re-examined to measure differences in photodamage, number of nevi, size of
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nevi, characteristics of nevi, and distribution of nevi among p16 carrier and noncarrier kindred members. Second, I will determine whether p16 mutation carriage results in decreased senescence or apoptosis of nevus cells utilizing B-galactosidase levels and TUNEL staining, respectively. Third, I will determine whether nevi and melanomas from p16 mutation carriers have acquired additional mutations that could lead to increased risk of malignant transformation. •
Project Title: MIT TRANSCRIPTION FACTOR FAMILY IN PEDIATRIC SOLID TUMOR Principal Investigator & Institution: Davis, Ian J.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 30-SEP-2004; Project End 31-AUG-2009 Summary: (provided by applicant): The identification of chromosomal translocations in solid tumors of children and adults has led to the discovery of genes important for normal and tumor growth. Clear cell sarcoma, a metastatic soft tissue tumor of children and young adults with an overall 5-year mortality rate of 50%, is associated with a specific chromosomal translocation that fuses EWS with ATF1. This fusion oncoprotein transcriptionally activates the microphthalmia transcription factor (MITF), a master regulator of melanocyte differentiation, proliferation and survival. MITF, together with TFEB, TFEC and TFE3, comprise the MiT family of basic helix-loop-helix leucine zipper transcription factors. We have shown that the aberrant expression of MITF in clear cell sarcoma results in the melanocytic differentiation of this tumor and plays a key role in its proliferation and/or survival. Furthermore, we have discovered the involvement of a unique TFEB translocation in a subset of pediatric papillary renal cell carcinomas. Taken together, these results suggest that dysregulated MiT activity serves a critical oncogenic function in these tumors. This project mechanistically examines the role of the MiT family in these tumors. To understand the possible role of transcriptional dysregulation, the normal pattern of MiT expression will be determined then compared to tumor cell expression, validating these results with similar analyses of primary tumor specimens. The role of MiT posttranslational modification in oncogenesis will also be examined. An interaction between the retinoblastoma pathway and the MiT family will be explored. MiT family members, along with the transcription factor MYC, activate overlapping target genes through an E-box promoter element. Specific MiT targets expressed by these tumors will be identified employing a candidate gene based approach followed by comprehensive microarray hybridization-based gene expression profiling. The identification of putative target genes will be followed by biological validation with emphasis on therapeutically relevant targets. One such example is the receptor tyrosine kinase MET. Intriguingly, MET is both mutated in familial and some sporadic papillary renal cell carcinomas and a target of MITF in melanocytes. This connection and its therapeutic implications will be explored. By examining both MiT function and downstream targets, a mechanistic understanding of the role of the MiT family in clear cell sarcoma and papillary renal cell carcinoma will emerge with implications for these and other MiT-associated tumors such as melanoma.
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Project Title: MOLECULAR ANALYSIS OF METALLOPROTEASE DISINTEGRIN ADAM12 Principal Investigator & Institution: Zolkiewska, Anna; Biochemistry; Kansas State University 2 Fairchild Hall Manhattan, Ks 665061103 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2008
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Summary: (provided by applicant): ADAMs, a family of cell surface proteins containing a disintegrin and metalloprotease domains, play important roles in many biological processes involving cell surface proteolysis, cell-cell, or cell-matrix interactions. Our long-term goal is to understand the function of ADAM proteins and to dissect their roles in transmembrane signaling. Currently, we focus our studies on ADAM12, an ADAM family member that is involved in skeletal muscle development and/or regeneration. Our preliminary results suggest that ADAM12 plays a role in the induction of GO phase (quiescence) during myoblast differentiation in vitro. Quiescent, undifferentiated cells formed during myogenic differentiation in vitro share several characteristics with muscle satellite cells in vivo. Satellite cells play a pivotal role during muscle regeneration, muscle hypertrophy, and post-natal muscle growth, but the mechanism of self-renewal of the satellite cell compartment in skeletal muscle is poorly understood. The goal of this proposal is to understand the role of ADAM12 during GO entry in muscle cells. We hypothesize that the mechanism by which ADAM12 induces the entry into quiescence involves down-regulation of PI3K activity and depends on ADAM12mediated cell-cell interactions. To test our hypothesis, we will perform a series of studies that will pursue the following Specific Aims. In Aim 1, we will characterize the molecular events associated with cell cycle arrest and the sequence of events leading to up-regulation of quiescent cell markers (retinoblastoma-related protein p130 and cell cycle inhibitor p27) by ADAM12 in myoblastic cell lines and in primary myoblasts. In Aim 2, we will perform a comprehensive analysis of the effect of ADAM12 binding on the activity of PI3K in cultured myoblasts. In Aim 3, we will examine the role of the extracellular sub-domains of ADAM12: disintegrin, cysteine-rich, and EGF-like region, in ADAM12-induced cell cycle arrest and up-regulation of p130 and p27. The results of our studies may help understand the biology of satellite cells and their role in muscle growth and repair. •
Project Title: MOLECULAR MECHANISMS OF PML MEDIATED GROWTH CONTROL Principal Investigator & Institution: Borden, Katherine L B.; Associate Professr; University of Montreal 5160 Decarie Blvd. Montreal, Pq H3x 2H9 Timing: Fiscal Year 2005; Project Start 05-JAN-2001; Project End 31-DEC-2006 Summary: (Adapted from the investigator's abstract) The promyelocytic leukemia protein PML is ascribed roles in growth control, transformation suppression and cell death but its mechanism of action remains enigmatic. These actions are closely tied to the subcellular localization of the protein. In normal cells, the majority of PML forms nuclear bodies, which are modulated by stress. PML nuclear bodies are heterogeneous multiprotein complexes that are found in all normal cell types studies suggesting that they play a basic role in mammalian cells. The t(15;17) disrupts PML in acute promyelocytic leukemia (APL) resulting in loss of PML nuclear bodies. Subsequent disruptions of PML's growth control and apoptotic action are thought to contribute to leukemogenesis. PML is disrupted in other pathogenic conditions such as spinocerebellar ataxia, and by several viruses including papilloma and Herpes. To determine a molecular function for PML, Dr. Borden identified nuclear body components likely to be of physiological relevance. These components include eukaryotic translation initiation factor (4E (eKF-4E) and the proline-rich homeodomain protein PRH. In addition, PRH and eIF-4E interact. Her data suggest that PML acts in the regulation of transport of selected mRNAs. This action is modulated through an interaction between PML and eIF-4E, a protein with established functions in RNA transport. She has shown that transport of cyclin D1 mRNA is preferentially suppressed by PML presenting a possible mechanism for PML's growth suppression activity. EIF-4E
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is mitrogenic and induces oncogenic transformation suggesting that association of this protein with PML in the nucleus may be related to PML's growth control functions. PRH is required for myeloid development. Thus, the PRH-PML interaction may represent a link between growth control and differentiation. She hypothesizes that PML executes its growth suppression actions through association with other cellular partners, e.g. eIF-4E and PRH, by regulating RNA transport selectively. She proposes to: (1) Investigate the RNA transport activities of PML, and ascertain whether this function is related to its growth suppression action, (2) Determine whether PRH modulates RNA transport actions mediated by PML and PML's growth suppression action, and (3) Investigate the PML/PRH interaction using high-resolution NMR method to elucidate the basis of this interaction. •
Project Title: MOUSE MODELS FOR PRB GROWTH CONTROL VIA E2F/DP ACTION Principal Investigator & Institution: Yamasaki, Lili; Biological Sciences; Columbia Univ New York Morningside Research Administration New York, Ny 100277003 Timing: Fiscal Year 2005; Project Start 07-JAN-1999; Project End 31-MAY-2010 Summary: (provided by applicant): Inactivation of the retinoblastoma tumor suppressor in humans (RB) and in mice (Rb) facilitates neoplastic progression. To a large part, pRB regulates growth by repressing E2F/DP famil) complexes, a subset of which when free, stimulates cell cycle progression. Instead, pRB stimulates differentiation by regulating transcription factors responsible for specific differentiation programs (e.g., activation of MyoD, C/EBP, CBFA1). Yet, loss of pRB does not compromise the development of all tissues, and germ-line RB or Rb mutations lead to highly penetrant, tissue specific tumor predisposition. In vitro, the extent of Gl Cyclin/Cdk-mediated phosphorylation governs the ability of pRB to restrain cell cycle progression; however, the recently demonstrated dispensability of Gl Cyclins and Cdks for the normal development of most tissues; raises the question of what is the "wiring" that normally regulates the pRB/E2F/DP pathway in vivo. It is likely that the unique tumor suppressive function of pRB (among pRB family numbers) stems from its ability to coordinate growth inhibition with specific lineage commitment. Only by identifying the signals operating in vivo can we understand how loss of Rb disrupts the development of key tissues and facilitates tumorigenesis at specific sites. First, using our novel series of wildtype and mutant Rb promoter transgenics and a new Rb promoter knock-in allele, we will identify the activators and repressors that normally regulate the neuronal-specific expression of Rb and test the functional consequences of deregulating Rb expression in vitro and vivo (Aim 11. Second, we will define a requirement for the entire DP family and its individual family members (Dpi and Dpi) in cell cycle control and embryonic development through siRNA-mediated knockdown of DP family expression and the establishment of conditional Dpi and/or Dp2 knockout mice (Aim 2). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEW FUNCTION FOR THE SERPIN PAI-2 AS A REGULAR OF PRB Principal Investigator & Institution: Antalis, Toni M.; Professor of Physiology; Physiology; University of Maryland Balt Prof School Professional School Baltimore, Md 21201 Timing: Fiscal Year 2005; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Proteolytic cleavage of signal transduction molecules is an important mechanism for controlling cell growth, death and
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Retinoblastoma
differentiation affecting a wide range of physiological and pathological processes. Intracellular proteolysis must be tightly regulated by endogenous inhibitors. Plasminogen activator inhibitor type 2 (PAl-2) is structurally and functionally a member of a large family of serine protease inhibitors or serpins. Serpins are key regulators of important biological processes such as complement activation, fibrinolysis, coagulation, cellular differentiation, tumor suppression, apoptosis and cell motility. PAl-2 was originally characterised as an inhibitor of the extracellular urokinase-type plasminogen activator, however PAl-2 is an inefficiently secreted serpin that exhibits a nucleocytoplasmic distribution. We have previously found that PAl-2 expression confers resistance to apoptosis and protects cells from certain cytopathic viruses in vitro. Our preliminary data identifies an intracellular activity for PAl-2 as a retinoblastoma tumor suppressor (pRb) binding protein that protects pRb from proteolytic degradation. The pRb family of proteins is ubiquitous regulators of transcription and plays a critical role in controlling cell proliferation. The central hypothesis of this application is that intracellular PAl-2 stabilizes pRb and p130, and in doing so, promotes pRb mediated activities associated with cell cycle arrest and promotion of differentiation, decreased sensitivity to E2F1 dependent apoptosis, transcriptional regulation and tumor suppression. The specific hypotheses to be tested are: 1) that PAl-2 binds pRb and the related pocket protein, p130, 2) that PAl-2 inhibits proteolytic cleavage of pRb, thereby enhancing pRb levels and pRb mediated activities, and 3) that PAl-2 promotes survival of keratinocytes and endothelial cells via pRb mediated stabilization. These hypotheses will be tested by 1) characterising the specific molecular interactions between PAl-2 and pRb utilizing mutant proteins in which specific functions have been disrupted, 2) determining the molecular mechanism by which PAl-2 stabilizes pRb and evaluating the role of calpain-like proteases in mediating proteolytic cleavage of pRb, and 3) testing the in vivo function of PAl-2 in stabilizing pRb using a PAl-2-/- mouse model. Analyses will specifically evaluate the roles of PAl-2 in keratinocyte differentiation, and endothelial cell proliferation and angiogenesis. •
Project Title: NUCLEAR LAMIN FUNCTIONS AND HUMAN DISEASE Principal Investigator & Institution: Kennedy, Brian K.; Biochemistry; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 15-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): While individual genes, regulatory factors, and events in the mammalian nucleus have been intensely studied and are beginning to be understood, the mechanisms by which the nucleus is organized and nuclear processes are coordinated remain largely unknown. Recently, the study of nuclear structure and function has taken on increased medical relevance with the discovery that A-type nuclear lamins, core constituents of the nuclear substructure, are targets for mutation in a wide variety of human diseases including dystrophic and progeroid syndromes (collectively termed laminopathies). An important question in understanding the molecular basis of the laminopathies is how mutations throughout the LMNA coding region could be associated with tissue-specific disorders. We have established a functional association between A-type lamins and the retinoblastoma protein (pRB), a known differentiation factor, regulator of cell proliferation and tumor suppressor. Lamin A/C protects pRB from proteosome-mediated degradation, pRB is required for normal differentiation of muscle and fat tissue, two of the tissues frequently affected in laminopathies. Moreover, pRB has been implicated in cellular senescence, a tissue culture model system for aging. A major focus of this proposal is to characterize the interactions between A-type lamins and pRB at a molecular and cellular level, and to determine whether lamin-dependent regulation of pRB is functionally significant in cell
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proliferation, stable tissue differentiation and the pathogenesis of laminopathies. We view the functional interaction between lamins and pRB as a prototype for how lamins coordinate nuclear regulatory proteins. Both directed and unbiased approaches will be initiated to identify novel, functionally significant lamin A/C interacting proteins. In vitro cell differentiation assays have served as important tools to identify key regulatory molecules that mediate cell specification. Given that A-type lamin expression is generally restricted to differentiating tissues and LMNA mutations cause dystrophic syndromes primarily affecting muscle and fat tissue, as a final Aim, a project has been initiated to examine the role of A-type lamins for myocyte and adipocyte differentiation. Myoblast cell lines, generated from Lmna-/- mice, exhibit differentiation defects. These defects will be studied at the molecular level to better understand how aberrant A-type lamin function leads to tissue degeneration. •
Project Title: P27KIP1 EXPRESSION, A PROGNOSTIC INDICATOR==BUT WHY? Principal Investigator & Institution: Koff, Andrew C.; Associate Member; SloanKettering Institute for Cancer Res 1275 York Ave New York, Ny 100216007 Timing: Fiscal Year 2005; Project Start 20-JAN-2001; Project End 31-DEC-2006 Summary: The goal of this proposal is to understand why the loss of p27kip1 expression is a strong prognostic indicator for tumor development in many types of human cancer. This proposal examines two alternative hypotheses: First, that the loss of p27 may accelerate cell proliferation making the cell refractory to the negative growth influences of the surrounding cells; or second, that the loss of p27 may eliminate oncogene-induced apoptosis by "desensitizing" the cell to negative growth regulatory signals. In Aim 1, these two models will be examined in the development of pituitary tumors in Rb+/- and Rb+/-;p27-/- mice. Aim 2 will investigate the relationship between p27-deficiency and p53-mdm2-Arf induced apoptosis in the pituitary tumor mouse model, and in human breast and prostate tumor samples. Aim 3 will characterize the growth, apoptosis and transformation properties of mouse embryonic fibroblasts derived from Rb-/-;p27-/embryos. A 4th Aim is proposed in the supplementary information that is based on the recent finding of Adenocarcinomas in p107+/-;p130-/-;p27-/- mice. This section will extend the analysis of Rb+/-;p27-/- mice to other pocket protein/p27 combinations to determine how loss of p27 modulates their tumor suppressor properties.
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Project Title: PATERNAL RETINOBLASTOMA
EXPOSURE
AND
SPORADIC
BILATERAL
Principal Investigator & Institution: Bunin, Greta R.; Research Associate Professor; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 06-APR-2001; Project End 31-MAR-2008 Summary: We propose to conduct a molecular epidemiologic study of sporadic heritable retinoblastoma (RBL), a cancer of the embryonal retina that occurs in infants and young children. Our knowledge of the molecular events leading to sporadic heritable RBL and certain features of the disease together provide a unique opportunity for this study. In the proposed study, we will investigate sporadic heritable RBL in its own right and as a model for new germline mutation. Sporadic heritable RBL results from a new germline mutation in the RBL gene, which occurs on the father's gene in over 90 percent of cases. The study's major objectives are to investigate the role of paternal occupational, dietary, x-ray and tobacco exposures before the child's conception. Since the RBL gene is well characterized, we will do molecular genetic analyses to identify the mutation in all of the cases. The mutation data will be used with the exposure data to test hypotheses that
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ionizing radiation and older paternal age are risk factors for specific types of mutation. The study will use a matched case-control design with 250pairs. Cases will be ascertained through seven centers that treat most of the RBL patients in the U.S. and Canada. Controls will be identified by random-digit dialing and matched to cases on birth date, race, and geographic area. Telephone interviews will be conducted with parents of cases and controls. Blood samples will be obtained from cases and case parents, so that DNA can be isolated for mutation analysis. The proposed molecular epidemiologic study will provide new information about the etiology of sporadic heritable retinoblastoma. The study will also contribute to our knowledge of new germline mutation generally, about which very little is known. Sporadic heritable RBL is a childhood cancer worth studying in its own right and an ideal model for the investigation of new germline mutation. •
Project Title: PATTERNS OF SOMATIC GENE ALTERATIONS IN ORAL CANCER Principal Investigator & Institution: Kelsey, Karl T.; Professor; Genetics and Complex Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): We propose a case-only study of Head and Neck Squamous Cell Cancer (HNSCC) with the goal of defining the carcinogen-induced patterns of somatic inactivation of genes in the Retinoblastoma pathway. HNSCC occurs in over 42,000 men and women annually in the United States, resulting in over 13,000 deaths per year. Recent developments in the molecular pathology of this disease have delineated the important critical genes that are altered in the genesis of HNSCC. Further, as these genes have been identified and pathologists have begun to understand their relationship with disease, groups of genes have become identified as members of multiple components, critical pathways in cellular regulation. Indeed, it is now known that somatic cell inactivation can occur in multiple ways; gene mutation has long been realized as a critical type of alteration, but homozygous gene loss and epigenetic silencing have also recently been recognized as common and important mechanisms of somatic gene alteration in HNSCC. Most molecular pathology has considered only frequency of gene inactivation as important, rather than examining the type of alteration and the possible consequences of the precise nature of somatic alteration. We have developed a novel hypothesis based upon our observation of a strong, significant association of smoking with the precise nature of inactivation of the p161NK4A gene in the PRB pathway. Our new working model for the mechanism of action of carcinogens predicts the characteristics of susceptible individuals. In essence, we hypothesize that homozygous deletion events commonly occur in, and therefore define, susceptible individuals. Epigenetic inactivation of p161NK4A is more often found in patients with relatively longer smoking histories and these patients then are relatively "resistant" to the effects of tobacco carcinogens. We propose to confirm, extend and further develop this model of HNSCC susceptibility using the resources of the Pl.'s already funded, independent, case series that is derived from a population-based case control study currently in its fourth year of enrolling cases.
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Project Title: PELP1, A NOVEL REGULATOR OF ESTROGEN RECEPTOR Principal Investigator & Institution: Vadlamudi, Ratna K.; Genetics; Louisiana State Univ Hsc New Orleans 433 Bolivar St New Orleans, La 70112 Timing: Fiscal Year 2005; Project Start 01-SEP-2003; Project End 31-DEC-2005
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Summary: (provided by applicant): Breast cancer is the leading type of cancer among women. Steroid hormone 17 beta-estradiol (E2) plays an important role in controlling the expression of genes involved in a wide variety of biological processes, including development, homeostasis and breast tumor progression. The biological effects of estrogen are mediated by its binding to estrogen receptor (ER). Approximately 70% of breast cancer cells express ER. Many ER-positive tumors that initially responded to antiestrogens later acquire resistance and exhibit mixed/agonist responses. Recent evidence suggests that the relevant action of estrogen and or antiestrogens in a given cell or tumor depends on the concentration of different coactivators or corepressors that modulate ER activity. In spite of these developments, our understanding of direct causeand effect relationship between coactivators (as a critical regulators of ER) and ER signaling, and its impact on the pathobiology of breast cancer remains poorly understood. This proposal is intended to establish the role of a newly discovered coactivator (PELP1, see below) in the molecular progression of breast cancer using novel in vitro and in vivo mammary epithelial model systems. Recently, I cloned a novel ER alpha regulatory protein, Proline Glutamic acid and Leucine rich Protein (PELP1), that is abundantly expressed in the mammary gland. PELP1 is novel as it has no homology with existing coactivators, its expression is developmentally regulated in the mammary gland and upregulated ERalpha-driven transcription. In addition, PELP1 interacts with the retinoblastoma protein and promotes its hyperphosphorylation. Furthermore, PELP1 may be over expressed in human breast tumors compared to adjacent paired normal mammary gland tissues. My working hypothesis is that upregulation of PELP1 expression and functions may confer a growth advantage to breast epithelial cells and result in malignant progression by hyperstimulating ER pathway. The overall goals of this proposal are to (1) characterize the molecular events that mediate PELP1 regulation of ER pathways by domain analysis and by creating dominant negative mutants; (2) characterize the molecular mechanism of action of PELP1 by studying the nuclear function of PELP1 including, intrinsic/associated enzymatic activities, chromatin modification, and correlation with coactivation function; (3) characterize the role of PELP1 in cell proliferation by using cell lines expressing PELP1 under an inducible promoter, and studying the role of overexpression on the growth-rate, cell cycle progression and (4) characterize the role of PELP1 in tumorigenesis. The proposed studies will allow us to understand the functions of newly cloned PELP1, its role in ER signaling and provide a molecular explanation for the widely recognized differential responses of estrogen and antiestrogens. This proposal is novel because of the presence of unique structural motifs with diverse cellular functions in PELP1 and the fact that it is upregulated in breast tumors. •
Project Title: PROTEOMIC STUDIES OF THE HUTCHISON-GILFORD PROGERIA Principal Investigator & Institution: Djabali, Karima; Dermatology; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-AUG-2009 Summary: (provided by applicant): Hutchinson-Gilford Progeria syndrome (HGPS, OMIM 176670) is a rare disorder that is characterized by accelerated aging and early death, frequently from coronary artery disease. Mutations in the LMNA gene are responsible for this syndrome; as such HGPS belongs to the super-family of laminopathies. The most common HGPS mutation corresponds to G608G (GGC>GGT), within exon11 of LMNA, which elicits a deletion of 50 amino acids at the carboxylterminal tail domain of prelamin A; the resulting product is denoted progerin. The lamins are structural nuclear proteins that bind to many important nuclear regulators, and therefore, may play a role in regulating the accessibility of those regulators to fulfill
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their function. The progerin mutation exhibits a tissue specific pattern of alterations, involving primary tissues with renewal potency: muscle, skin, and bone. In our preliminary studies, we succeeded in generating a polyclonal antibody that specifically recognizes progerin. This is the first such tool in the field; it detects the truncated lamin A product progerin in HGPS G608G fibroblasts. Indirect immunofluorescence studies also revealed that the progerin protein accumulates gradually within the nuclear compartment reaching an expression level that induces a dramatic disruption of the nuclear lamin network. Based on these observations, we hypothesize that progerin products accumulate in the nucleus in an age-dependent manner and acts as a dominant negative mutant by altering the nuclear lamin networks; this ultimately affects cellular functions such as cell-cycle progression. To test this hypothesis we propose three specific aims: (1) Combine biochemical and morphological analysis to determine how progerin acts in a spatio-temporal manner on the organization and function of the nucleus; (2) Identify and characterize proteins that interact with lamin A but not with progerin and link them to functional pathway(s); (3) Determine whether cellular, nuclear and functional alterations identified in HGPS G608G fibroblasts are also altered in a similar manner in other lamin A-associated premature aging disorders, such as atypical and adult progeroid syndromes. •
Project Title: PROTON RADIATION THERAPY RESEARCH Principal Investigator & Institution: Delaney, Thomas F.; Lecture; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 31-AUG-1995; Project End 31-MAR-2007 Summary: (Applicant's Description) It is estimated that between 20-80 percent of patients treated for locally advanced epithelial or mesenchymal tumors will die secondary to the failure of photon therapy and/or surgery to achieve local control. Furthermore, these aggressive local therapies are themselves often associated with significant acute and late morbidity. There are other tumors, particularly pediatric tumors, for which local control is often satisfactory but treatment-related late effects are high. It is the primary aim of this Program Project to exploit the superior dose distributions of proton beams to improve clinical outcomes for patients with a variety of solid tumors both in terms of cancer control and treatment-related morbidity. We have treated over 5,000 cancer patients with proton therapy at the Harvard Cyclotron Laboratory since 1974. We have achieved significant gains in clinical outcomes for a number of disease sites including chondrosarcomas and chordomas of the skull base and cervical spine (95 percent and 50 percent local control, respectively), paranasal sinus tumors (87 percent local control), and ocular melanomas (97 percent local control). We propose to carry out clinical trials using proton beams in additional tumor sites where photon therapy has provided suboptimal treatment outcomes. The two basic hypotheses for this Program Project are that, using the superior dose distributions of proton beams, we can (in subproject 5) escalate tumor dose and improve local control without increasing damage to non-target normal tissues and (in subproject 6) maintain high rates of local control while decreasing treatment related morbidity. We will assess clinical gains in terms of five endpoints: 1) local control, 2) distant metastasis-free survival, 3) overall survival, 4) treatment-related morbidity, and 5) quality-of-life (QOL) We also hypothesize that proton irradiation will decrease the comorbidity between radiation therapy and chemotherapy thus improving compliance and intensity of treatment. We will use well-designed prospective phase I/II/III trials to test these hypotheses. The proposed research program consists of three closely related projects. In subproject 5 we will carry out phase I/II/III dose escalation studies for prostate, lung, paranasal sinus, nasopharynx and hepatocellular cancers. The goals of these trials are to improve local
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control and survival. In subproject 6 we will carry out phase II/III studies designed to reduce treatment-related morbidity for pediatric cancers including medulloblastoma, retinoblastoma, and soft tissue sarcomas, and adult tumors including rectal carcinoma and choroidal melanoma. In the prostate clinical trial we will collaborate with the Loma Linda University Medical Center in protocol design and patient accrual. In subproject 4 we will develop treatment delivery and planning systems, and design and carry out dosimetry and quality assurance programs to support the proposed clinical trials. The Northeast Proton Therapy Center (NPTC), jointly funded by the NCI and the MGH, has been built on the MGH campus. The NPTC will provide the increased capacity and new technologies needed to conduct the clinical trials proposed in this application. With our experience in conducting proton clinical trials, and the resources offered by the NPTC, we have unique capabilities to carry out the proposed research. It is our expectation that these clinical trials will show improved cancer control rates, reduced treatment morbidity and improved QOL. •
Project Title: RAS INDUCED SENESCENCE AND TUMOR PROGRESSION Principal Investigator & Institution: Lowe, Scott W.; Professor; Cold Spring Harbor Laboratory P.O. Box 100 Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2005; Project Start 01-JUL-1999; Project End 31-JUL-2009 Summary: (provided by applicant): Senescence was initially defined as the stable cell cycle arrest that accompanies replicative exhaustion of human fibroblasts in culture, and may be important in tumor suppression and aging. In addition to telomere malfunction, which induces replicative senescence, a phenotypically identical endpoint can be induced acutely in young cells by a variety of stresses. For example, we have shown that 'premature' cellular senescence (or STASIS) can be induced acutely in various cell types by misexpression of oncogenic ras or DNA damaging agents such as chemotherapeutic drugs. Given these observations, we proposed that senescence parallels apoptosis as a cellular response to stress, and plays similar roles in suppressing tumorigenesis and modulating chemotherapy. Over the course of the previous funding period, we developed a better understanding of the senescence program and how the process is controlled as part of a complex tumor suppressor network. Our work has evolved from identifying upstream signaling pathways that trigger senescence (e.g. MAPK signaling and ARF) to characterizing genes and processes that act further downstream to produce the senescence endpoint (e.g. PML, Rb, and SAHFs). In our renewal application, the effector mechanisms of senescence (i.e. the senescence machinery) will receive the most attention, in part, because very little is known about these processes and because they are controlled by genes with established roles in tumor suppression. Specifically, we will further dissect the role of p53 and Rb in cellular senescence, explore the effector mechanisms of senescence that contribute to its stability, and identify genes that can reverse or bypass the program. Our approach will continue to apply genetic principles to the analysis of cellular senescence in primary fibroblasts and epithelial cells, but will also incorporate expression array, genome wide RNA interference, and proteomics technology to understand the senescence machinery. These studies will provide new insights into the nature of the senescence program and, as such, will further assemble an important tumor suppressor network that provides an important brake to cancer development and may also contribute to age-related diseases. Our studies also may identify new 'biomarkers' of senescence that can eventually be used to study the process in vivo.
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Project Title: RB,P53, BCL-2 PROTEINS IN APOPTOSIS Principal Investigator & Institution: Weintraub, Steven J.; Assistant Professor; Surgery; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2005; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. We recently found that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-xL, and we found that deamidation of these asparagines imparts susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, we found that Bcl-xL deamidation is actively suppressed in fibroblasts, and that suppression of deamidation is an essential component of their resistance to DNA damage-induced apoptosis. Finally, we found that at least in some cells, the retinoblastoma protein mediates the suppression of Bcl-xL deamidation. We have begun to define the mechanism by which deamidation of Bcl-XL is regulated. Our data provides evidence that deamidation of Bcl-xL is induced by an upward shift in the cytosolic pH that is induced by cisplatin treatment and that the retinoblastoma protein suppresses Bcl-xL deamidation because it suppresses the increase in pH. Importantly, our data strongly suggests that the increase in pH does not directly cause deamidation of Bcl-xL. Instead, our findings support a mechanism in which the cytosolic pH increase induces deamidation of Bcl-xL by activating an autocatalytic "deamidase" function of Bcl-xL. We propose that this mechanism affords the cell tighter control of Bcl-xL deamidation and allows deamidation to occur at a lower pH and more rapidly than if deamidation were regulated directly by pH. We speculate that a similar mechanism has an important role in the regulation of other proteins. We now propose to (1) characterize the autocatalytic deamidase activity by performing a structure-function analysis of Bcl-xL with respect to this activity; (2) delineate signal transduction pathways that mediate cisplatin-induced cytosolic alkalinization; and (3) examine the potential role of dysregulation of cisplatininduced cytosolic alkalinization and Bcl-xL deamidation in tumor cell resistance to cisplatin. These studies may lead to the identification of cellular targets that allow for the development of more efficacious and less toxic antineoplastic therapies.
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Project Title: RB4 INTRAVESICAL GENE THERAPY: MECHANISMS OF CELL DEATH Principal Investigator & Institution: Benedict, William F.; Professor; Gas Med Oncology & Digest Dis; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): A modified retinoblastoma gene construct utilizes the second start codon of the RB gene and encodes for a 94 KD protein (pRB94. It is a markedly more potent tumor suppressor and cytotoxic agent than the wild-type RB protein and has been effective against all tumor types tested to date irrespective of tissue type, RB or other gene status, except for that of telomerase. A long-term objective of this project is to understand the cellular and molecular pRB94 interactions that cause such potent effects. Preliminary results suggest that a key mechanism of pRB94 specific induced tumor cell death may involve the production of rapid telomere attrition and chromosomal crisis. These results make the mechanism(s) of RB94 cell kill and tumor suppression potentially unique from all other agents or modalities examined to date and has occurred in all telomerase positive tumors or immortalized cells but not in tumor or
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immortalized cells containing an ALT pathway, i.e. telomerase negative cells. RB94 also has been found not to be cytotoxic or growth inhibitory to normal human cells, including urothelial cells, which are also telomerase negative. One approach will therefore be to determine if interference with the normal telomere complex plays a key role in RB94 produced telomere attrition, with subsequent chromosomal instability and cell death. The role of centrosomes and changes in STK15 kinase activity will also be studied in depth. Techniques will be include the use of microarrays, confocal laser scanning, analysis of chromosomal and telomere status, examination of RB94 specific protein interactions by Western blotting and immunochemical staining as well as immunoprecipitation with sequencing of putative RB94-specific related proteins. Studies will be expanded to examine RB94 cell kill in additional telomerase positive or negative tumor cells and genetically altered, non-tumorigenic immortalized cells. Whether or not these changes are caspase dependent will also be studied. Another specific aim is to optimize intravesical gene therapy and determine the effect of AdRB94 on superficial bladder cancer. An intravesical human bladder cancer model developed by us using GFP expressing cells will be utilized for this purpose. To increase adenovirus-mediated transfer the reagent, Syn3, will be used. Syn3 has been found to markedly increase adenoviralmediated gene transfer without being toxic itself. If these studies are successful, it could have a significant influence in developing a new modality of treatment for recurrent superficial bladder cancer and potentially for other tumor types as well as provide the molecular basis for the unique properties of RB94. •
Project Title: RB-ID2 TUMORIGENESIS
PATHWAY
IN
MOUSE
DEVELOPMENT
AND
Principal Investigator & Institution: Lasorella, Anna; Institute for Cancer Genetics; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): In mammalian cells, the Retinoblastoma (Rb) tumor suppressor protein is essential to execute terminal cell cycle withdrawal, complete differentiation and secure cell survival. In the absence of Rb, mouse development is impaired and Rb-mutant embryos die at mid-gestation with severe defects in erythropoiesis and neurogenesis. The helix-loop helix protein Inhibitor of differentiation 2 (Id2) coordinates proliferation and differentiation. Id2 binds Rb and antagonizes its antiproliferative function. We have recently reported that ablation of the mouse Id2 gene rescues the phenotypic abnormalities and lethality of Rb-mutant embryos. These results have identified Id2 as a relevant target of tumor suppressor proteins, whose function must be restrained by Rb during development. The long-term goal of this work is to understand the role of Rb-Id2 complexes in proliferation, differentiation and tumorigenesis using genetically modified mouse models. We have found that Rb is essential for differentiation of the macrophage/dendritic cell lineage, a cell type required to support erythropoiesis in the fetal liver. This is an exciting novel finding that will allow us to dissect the most relevant Rb-null defect, in order to trace the molecular events directed by the Rb-Id2 pathway in erythropoiesis. We will also determine the target specificity of Id2 in cell proliferation and differentiation by discriminating Id2 and E2F functions in the absence of Rb. Finally, to establish the role of Id2 in tumorigenesis initiated by inactivation of Rb, we will use a mouse model in which mutation of Rb predisposes to pituitary cancer. These experiments will increase our understanding of the mechanisms by which Rb promotes cell cycle arrest and differentiation in normal cells and the perturbation of these mechanisms in cellular transformation.
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Project Title: RB-RELATED PROTEINS IN SV40 T TRANSFORMATION Principal Investigator & Institution: Decaprio, James A.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 02-MAY-1994; Project End 31-MAY-2008 Summary: (provided by applicant): SV40 large T antigen (T Ag) is capable of transforming a wide variety of cell types. T Ag transformation is dependent in part upon its interaction with several tumor suppressors including p53, Rb and the Rbrelated proteins p107 and p130. T Ag's LxCxE motif binds directly to pRb family members. The N-terminal DnaJ homology domain of T Ag cooperates with the LxCxE motif to disrupt the interaction between pRb and E2F transcription factors. A bipartite C-terminal domain of T Ag binds to p53 and also contributes to binding to the transcriptional co-activators p300 and CBP (CREB binding protein. While mutations of p300 and CBP have been observed in human cancers, it is not known if T Ag binding to CBP and p300 contributes to the transformed phenotype. Furthermore, little information is available that distinguishes the normal or oncogenic activities of the p300 and CBP. Preliminary data from this laboratory has demonstrated that T Ag is specifically acetylated in a CBP dependent manner. In addition, loss of p300 activity and not CBP contributes to T Ag's ability to form tumors. These observations support the hypothesis that interaction between T Ag and p300/CBP contributes to the T Ag transforming mechanism. We propose that T Ag selectively inactivates p300 while preserving at least some CBP function. This application seeks to test this hypothesis by the following specific aims: 1. Define the role of p53 in SV40 T Ag binding to p300 and CBP. We will determine if T Ag binding to p300/CBP is direct or mediated through p53. We will define the domains of T Ag, p53, and p300/CBP required for this interaction. We will also determine whether specific post-translational modification of p53 and T Ag affects the interaction between T Ag and p300/CBP. 2. Determine the effect of T Ag on p300 and CBP function. p300 and CBP are transcriptional co-activators capable of binding to many transcription factors. p300 and CBP have intrinsic histone acetyl transferase (HAT) activity. We will determine whether T Ag binding to p300/CBP affects the ability of p300/CBP to bind to sequence-specific transcription factors, affects their HAT activity, and perturbs their role as transcriptional co-activators. 3. Determine the contribution of p300 and CBP to T Ag transformation. We will determine whether T Ag interaction with p300 and CBP is required for cellular transformation in MEFs derived from p300 and CBP knockout strains. Using a variety of genetic, biochemical, and molecular approaches, we will focus on determining the specific contribution of p300 and CBP to T Ag transformation.
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Project Title: REGULATION OF CYCLIN D1 EXPRESSION Principal Investigator & Institution: Pestell, Richard G.; Director; None; Thomas Jefferson University 201 South 11Th St Philadelphia, Pa 191075587 Timing: Fiscal Year 2006; Project Start 15-MAY-1996; Project End 31-JUL-2011 Summary: (provided by applicant): The cyclin D1 gene encodes a rate-limiting component of the holoenzyme which phosphorylates and inactivates the retinoblastoma tumor suppressor gene (pRb). The abundance of cyclin D1 is increased in metastatic human tumors including breast and colon cancer. In the prior funding period we identified the molecular mechanisms by which oncogenes/growth factors regulate cyclin D1 expression and demonstrated cyclin D1 coordinated transcriptional activity through binding HDACs and histone acetylases. Using transgenic and knockout mice, we identified a molecular genetic signature regulated by cyclin D1 antisense in vivo and in mammary tumors induced by cyclin D1. These genes regulate cellular
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migration and mitochondrial function. The proposed studies will determine the mechanisms by which cyclin D1 regulates these two functions, the relationship between these two functions and the role of these cyclin D1-mediated functions in tumorigenesis. We hypothesize cyclin D1 regulates migration and invasion by affecting (1) transcriptional target genes, (2) protein-protein interactions, (3) secreted factors and (4) mitochondrial factors. In the proposed studies we will: Aim 1. Determine the role of cyclin D1-mediated gene expression in promoting cellular migration. Cyclin D1 is overexpressed in a subset of metastatic cancers. Reproduction of cyclin D1 into cyclin D1-deficient cells promotes cell migration. Cyclin D1 regulates expression of target genes governing migration (ROCKII, c-Jun). These studies will determine the functional significance of these transcriptional targets of cyclin D1 in cyclin D1-mediated migration and the mechanisms involved. Aim 2. Determine the role of cyclin D1-interacting proteins in cellular migration and invasion. We have identified a role for cyclin D1 protein interaction domains in promoting migration. We have identified cyclin D1interacting proteins (PACSIN2, cdks, pRb, p27/p21, HDACs). We will determine the role of cyclin D1- interacting proteins in promoting cellular migration and invasion. Aim 3. Determine the role of cyclin D1-mediated secretory factors and mitochondrial gene activity in cellular migration and collaborative oncogenesis. Cyclin D1 regulates the secretion of migratory factors (TSP1 (Thrombospondin-1), SCF (stem cell factor)). Cyclin D1 inhibits mitochondrial metabolism. Cyclin D1 phosphorylates and inactivates a transcription factor NRF1 that in turn regulates mitochondrial gene expression. Microarray analysis of NRF1-regulated and cyclin D1-regulated genes identified genes regulating cell migration and stem cell expansion. We will determine how cyclin D1 regulates mitochondrial metabolism and the role of this activity in cellular migration and collaborative oncogenesis. Together these three integrated Aims will determine the role of cyclin D1-regulated functions in cellular migration, invasion and tumorigenesis. •
Project Title: REGULATION OF EYE DEVELOPMENT Principal Investigator & Institution: Bohmann, Dirk; Professor; Biomedical Genetics; University of Rochester 517 Hylan Bldg., Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Organogenesis requires the ordered execution of temporally and spatially defined cell proliferation and differentiation programs. These are controlled in a major part by changes of gene expression in the partaking cells. Aberrations from the normal pattern of gene expression can cause developmental defects and other pathologies. This proposal describes experiments to study the regulation of such processes by analyzing the function of DREF/dMLF in the control of Drosophila eye development. The transcription factor DREF is a potential key regulator of proliferation-specific gene expression and the Drosophila homologue of myelodisplasia ! myeloid leukemia factor (dMLF) is a possible negative regulator of DREF and cell proliferation. The working model that guides this work can be broken up into the following hypotheses: (1) DREF regulates two important aspects of cell proliferation: cell growth and cell cycle progression. (2) DREF's transcriptional and developmental functions are negatively regulated by dMLF. (3) In the regulation of genes involved in cell cycle progression, DREF cooperates with E2F, a well characterized transcription factor of similar function that is regulated by Rb and has been implicated in the etiology of retinoblastoma. (4) Other DREF target genes such as those directing cell growth are regulated by DREF in a E2F-independent fashion. These hypotheses will be tested by examining the role of DREF, E2F, and dMLF in cell growth and division during development of the eye imaginal disc using genetic approaches paired with microscopic methods and flow cytometry. The regulatory function of DREF and E2F will
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be dissected by epistasis analyses, monitoring of target gene activation and by SAGE studies to identify common and independently regulated genetic programs. These studies will elucidate regulatory mechanisms that are critical for eye development, characterize DREF, a potentially important regulatory component of tissue growth during organogenesis, and provide insight into processes that may contribute to the control of cell proliferation in normal development and under deregulated conditions resembling neoplasia. •
Project Title: RETINOBLASTOMA DURING PLACENTAL & EMBRYONIC DEVELOPMENT Principal Investigator & Institution: Weinstein, Michael B.; Molecular Virology, Immunology & Medical Genetics; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2005; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The retinoblastoma tumor suppressor (Rb) is one of the major inhibitors of cellular proliferation that functions Iargely through its binding to basic helix-loop-helix (bHLH) transcription factors of the E2F family, which it can convert from stimulators of transcription to repressors. Rb activity is regulated during the cell cycle through its phosphorylation by Cyclin/Cyclin dependent Kinase complexes. Rb has been linked through studies of transgenic and knockout mice to many cellular and developmental processes, including proliferation, apoptosis, hematopoesis, muscle differentiation, and numerous others. Our recent experiments indicate that Rb also functions in the differentiation of an embryonic organ - the placenta. Placental defects may be responsible for many of the phenotypes seen earlier in Rb mutant embryos, because when Rb-deficient embryos gestate with a normal placenta, they survive significantly longer than when they develop with an Rb-deficient one. We therefore propose to do the following: Specific Aim 1. Carry out a mechanistic analysis of Rb functions in placentation. Rb mutant placentas evince developmental abnormalities. A histopathological analysis will be carried out to determine the molecular nature of these defects, and Rb-deficient trophoblast stem cells will be used to determine the function of Rb in the differentiation of placental cell types. Specific Aim 2. To examine the impact of Rb-mediated placental dysgenesis on the development of Rbdeficient embryos. Further placental rescue experiments must be carried out to determine the function of Rb in the development of the mammalian embryo proper, both through tetraploid rescue and genetic experiments. Wild-type embryos will be produced with Rb mutant placentas to determine whether Rb is acting in a cell autonomous fashion within the embryo, or if the Rb-associated defects seen in embryonic development are actually due to the observed placental defects. Specific Aim 3. Examine the genetic regulatory networks employed by Rb in the placenta. The bHILH factors E2F3, and 1d2 both exert functions in the placenta, and genetic deletion of either prevents the occurrence of many embryonic Rb phenotypes. Mutations in each of these genes will be bred onto an Rb mutant background, and doubly homozygous embryos will be generated. Their placentas will be examined to determine whether deletion of bHLH proteins remediates the Rb placental phenotype, in order to delineate the Rbdependent genetic circuitry of placental development.
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Project Title: ROLE OF CDC37 IN FCYR-INDUCED GROWTH ARREST IN B CELLS Principal Investigator & Institution: Chiles, Thomas C.; Professor; Biology; Boston College 140 Commonwealth Ave Chestnut Hill, Ma 02467 Timing: Fiscal Year 2005; Project Start 01-JUN-2002; Project End 31-MAY-2007
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Summary: (provided by the applicant): The long-term objective of this application is to understand how engagement of the B cell antigen receptor (BCR), simultaneously with the Ig receptor (FcgRIIB), inhibits B cell proliferation. Loss of FcgRIIB function can lead to autoantibody production and may contribute to autoimmune disease. Therefore, understanding the molecular basis that underlies growth arrest has significant implications for both humoral immune responses and pathology associated with FcgRIIB dysregulation. The D-type cyclin/cyclin-dependent kinase(cdk) 4retinoblastoma (pRb) pathway is a primary target for BCR signals and functions to regulate G1-to-S phase progression. Our results indicate that BCR-FcgRIIB co-crosslinking exerts its growth inhibitory effect, in part, by signaling the phosphorylation of Cdc37. Cdc37, along with hsp90, plays an essential role in the pathway leading to Dtype cyclin-cdk4 complex assembly. The research proposed herein will test the hypotheses that phosphorylation of Cdc37 in response to BCR-FcgRIIB coengagement prevents hsp90/Cdc37 from binding to cdk4 and in turn, disrupts assembly of cyclin D2-cdk4 complexes in mature B lymphocytes. These hypotheses will be tested, along with identification of the Cdc37 kinase, in three specific aims: 1) mass spectrometry (MS) to identify BCR-FcgRIIB-inducible phosphoacceptor sites on Cdc37, in conjunction with in vitro binding assays, to evaluate the role of phosphorylation on targeting of hsp90/Cdc37 to cdk4; 2) ectopic expression of alanine point-mutated GST-Cdc37, that cannot be phosphorylated, will be used to evaluate the role of phosphorylation on targeting of hsp90/Cdc37 to cdk4 and ectopic expression of aspartic acid substituted FLAG-Cdc37 that mimics phosphorylation will be used to force disruption of cyclin D2cdk4 complexes and promote growth arrest; and 3) GST-Cdc37 affinity purification and MS to identify the Cdc37 phosphorylating kinase. The information obtained from these experiments will serve to direct future studies aimed at therapeutic interventions in autoimmune disease. •
Project Title: ROLE OF CELL CYCLE PROTEIN IN HIV ENCEPHALITIS Principal Investigator & Institution: Jordan-Sciutto, Kelly L.; Pathology; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 01-FEB-2001; Project End 31-JAN-2009 Summary: (provided by applicant): including chemokines, cytokines, neurotrophic factors (NTF), reactive oxygen species, and viral proteins. Most of these factors stimulate changes in cell cycle regulatory machinery which determines cellular outcomes in nonneuronal systems. This has led us to propose that cell cycle proteins exhibit altered activity in neurons of patients with HIVE and this activity determines neuronal survival in response to the onslaught of macrophage secreted factors present in the extracellular milieu. We have observed increased inactivation of pRb by phosphorylation (ppRb) and increased cytoplasmic E2F1 in HIVE and SIVE. Using in vitro cultures, NTF and chemokines stimulate increased ppRb and cytoplasmic E2F1, but hydrogen peroxide does not. Because the changes in E2F1 distribution and pRb phosphorylation occur in cells responding to neurotrophic/survival signals, but not in cells responding to oxidative stress, we propose that neurons in the disease with increased ppRb and cytoplasmic E2F1 are "surviving" neurons. This has led us to hypothesize that E2F1 and ppRb determine neuronal viability dependent on their subcellular distribution and interaction partners which is determined by the prevailing signaling cues in the extracellular milieu. The following aims are proposed: 1) To determine whether cytoplasmic E2F1 provides neuroprotection from HIVE-associated toxins, 2) To determine the role of MDMx in regulating cell survival and E2F1 subcellular localization in neurons responding to neuroprotective versus neurotoxic factors, and 3) To determine if post-translational modification of pRb in response to trophic factors occurs
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on different amino acids as compared to those residues modified in response to toxic factors. These studies will elucidate the role of cell cycle proteins in determining neuronal survival in HIVE and other neurodegenerative diseases with inflammatory components. •
Project Title: SURVIVAL
ROLE
OF
GTP-BINDING/TRANSGLUTAMINASE
IN
CELL
Principal Investigator & Institution: Cerione, Richard A.; Professor; Molecular Medicine; Cornell University Ithaca 120 Day Hall Ithaca, Ny 14853 Timing: Fiscal Year 2005; Project Start 01-JUN-2000; Project End 31-MAY-2008 Summary: (provided by applicant): Tissue transglutaminase (TGase) is an approximately 80 kDa protein that exhibits GTP-binding and hydrolytic activities like signaling G proteins, as well as an enzymatic (transamidation) activity that catalyzes covalent linkages between glutamine residues and primary amino groups, leading to the formation of new protein-protein and protein-polyamine complexes. TGase has been implicated in a number of important biological responses including neuronal development and degeneration, as well as cellular differentiation and apoptosis. During the past funding period, we have found that TGase plays a key role in retinoic acid (RA)-induced differentiation by maintaining cell viability and protecting against apoptotic signals. Both the GTP-binding and transamidation activities of TGase, and its interactions with the retinoblastoma protein (Rb), all appear to be linked to its survival activity. We now propose that TGase-mediated cell survival may be an important outcome of a number of different extracellular stimuli and cell signaling pathways. The studies outlined in this renewal application will set out to directly test these ideas and further our understanding of the molecular mechanisms underlying TGase-mediated cell survival and the intricate regulation of this interesting protein. Three main experimental aims are proposed. 1.) Establish a role for the GTP-binding/GTP hydrolytic activities of TGase in cell survival. These studies will take advantage of our recently determined X-ray crystal structure for GDP-bound TGase to introduce mutations that perturb specific steps in the GTP-binding/GTP hydrolytic cycle and thus can serve as new dominant-active and dominant-negative TGase mutants in cellular studies. 2.) Establish a role for Rb in TGase-mediated survival. The importance of the stable binding of TGase to Rb, as well as the transamidation of Rb, for TGase-mediated cell survival and different cellular functions of Rb will be determined. 3,) Delineation of signaling pathways leading to the up-regulation of TGase expression. Here we will establish the general role that TGase activity plays in cell survival and in the regulation of apoptotic programs by examining the signaling pathways that lead from the nerve growth factor (NGF) receptor as well as from 13-amyloid to TGase expression in rat pheochromocytoma (PC12) cells. By better understanding the mechanisms of action and regulation of this important GTP-binding protein/acyl transferase, we expect to gain fundamental information regarding the balance between cell growth and differentiation versus apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF PRB IN OSTEOGENESIS, CELL CYCLE EXIT AND CANCER Principal Investigator & Institution: Hinds, Philip W.; Professor, Radiation Oncology; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2005; Project Start 01-FEB-2002; Project End 31-JAN-2007
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Summary: (provided by applicant): The retinoblastoma protein, pRb, controls entry into the S phase of the cell cycle and acts as a tumor suppressor in many tissues. Reintroduction of pRb into tumor cells results in growth arrest due in part to E2Fdependent transcriptional repression of S phase genes. pRb may also be involved in terminal cell cycle exit as an instigator of E2F-independent senescence or differentiation programs. The irreversibility of pRb-induced cell cycle exit is illustrated by our observation that when shifted to the nonpermissive temperature, SAOS-2 cells previously arrested by temperature-sensitive pRb (tspRb) enter S phase but do not proliferate, and instead die as a result of apoptosis. These results suggest that in addition to repressing E2F-dependent transcription and S phase entry pRb initiates an irreversible growth suppressive program. To better understand these growth inhibitory properties of pRb, we have studied the role of pRb in senescence and differentiation. First, we have found that pRb induces p27kipi post-transcriptionally independent of E2F regulation. This induction is required for pRb-mediated Gi arrest and senescence. While the mechanism of this induction is unclear, our evidence indicates that it is related to cytoskeletal changes that result from alterations in transcriptional patterns soon after pRb expression. We have uncovered a second important function of pRb in cell cycle exit that is the result of pRb's ability to interact with the transcription factor CBFA1. This factor is required for bone development and expression of late markers of osteogenesis. We find that pRb can act as a direct coactivator of CBFA1 by binding to this protein at promoter sites within certain CBFA 1-regulated genes. The physiological relevance of this interaction is illustrated by the observation that cells lacking pRb fail to achieve complete osteogenic differentiation, nor do they undergo CBFA1 dependent growth arrest, even though CBFA1 protein levels are induced normally. These multiple growth suppressive properties of pRb may explain the prevalence of pRb mutations in osteosarcoma. Our current goal is to elucidate the mechanisms of CBFA1 transcriptional activation and senescence induction by pRb and to identify genes regulated by pRb in these processes. To address these issues we will: 1) Explore the mechanism through which pRb activates CBFA 1-dependent transcription. 2) Investigate the pRb-dependent proliferation arrest in senescent cells and in cells expressing CBFA1. 3) Determine the consequences of pRb loss on osteoblast and osteocyte phenotypes in vitro and in vivo. 4) Identify novel changes in transcription patterns in cells expressing temperaturesensitive pRb. •
Project Title: ROLE OF RB FAMILY IN LUNG EPITHELIAL RESPONSE TO INJURY Principal Investigator & Institution: Wikenheiser-Brokamp, Kathryn; Pathology and Lab Medicine; University of Cincinnati Sponsored Research Services Cincinnati, Oh 45221 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-JAN-2009 Summary: (provided by applicant): Airway remodeling accompanies common pulmonary disorders including asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia and cystic fibrosis. Epithelial regeneration after injury is a key component in airway remodeling. Accordingly, cellular processes underlying the pathogenesis of lung disease include abnormalities in epithelial proliferation, differentiation and survival. The objective of the present proposal is to elucidate the role of the retinoblastoma family (Rb, p107 and p130) in lung morphogenesis and airway remodeling. The central hypothesis is that Rb family proteins act as distinct and critical regulators of epithelial proliferation, differentiation and survival both during development and in response to injury. Preliminary data demonstrate that Rb family proteins play an essential role in lung formation. In addition, Rb itself has an unexpected cell type specific function in the developing airway. Specifically, Rb is required for regulating neuroendocrine cell fate; cells known to play a central role in
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epithelial regeneration after injury. In contrast, other epithelial cell lineages are capable of compensating for loss of Rb function. This proposal is designed to 1) test the hypothesis that Rb deficiency results in deregulated epithelial regeneration after injury and subsequent development of lung disease, 2) test the hypothesis that timing of Rb inactivation in progenitor cells during development versus quiescent cells in the mature airway plays a fundamental role in determining phenotypic outcomes, and 3) elucidate the molecular mechanisms underlying cellular compensation for loss of Rb function. The studies will be performed in vivo by inducing Rb gene ablation in a temporal and lung epithelial specific manner in genetically modified mice. Effects of Rb family ablation (separately or in combination) on lung morphogenesis, cell cycle regulation and cell differentiation will be assessed. It is expected that these studies will result in a better understanding of epithelial biology and thus provide a solid foundation for development of novel therapies for lung disease. •
Project Title: ROLE DIFFERENTIATION
OF
THE
PRB
FAMILY
IN
QUIESCENCE
AND
Principal Investigator & Institution: Dynlacht, Brian D.; Professor; Pathology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2005; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): The retinoblastoma tumor suppressor protein (pRB) and the related proteins p107 and p130 (collectively termed "pocket" proteins) play an established role in suppressing cell growth through inhibition of the E2F transcription factor. A role for the pRB family in cell cycle exit and muscle differentiation has also been documented. While cellular quiescence and p16INK4a-induced growth arrest appear to require combinations of "pocket" proteins, specific pRB family members have been implicated in terminal differentiation of muscle cells. However, very few direct, physiological targets have been linked to cellular quiescence, and fewer direct targets associated with differentiation have been identified. Furthermore, pRB binding to promoters has not been widely observed in cultured fibroblasts during the cell cycle, raising interesting and important questions regarding the role of pRB in tumor suppression and suggesting that pRB's tumor suppressive function may involve a much more extensive role in promoting differentiation than previously imagined. One goal of this proposal is to identify and characterize (1) direct, physiological targets of the pRB family involved in achieving cellular quiescence and p161NK4a -mediated growth arrest and (2) those gene targets that cooperate to confer irreversible cell cycle exit and terminal differentiation of muscle. It will also attempt to distinguish between those controls involved in cell cycle withdrawal and phenotypic differentiation. This will be accomplished through large-scale analyses of "pocket" protein binding to the genome of living cells (factor location analysis) during the process of cell cycle exit and differentiation, through simultaneous analysis of gene expression profiles, and through biochemical dissection of target promoters. By examining three cell cycle exit pathways that appear to require certain pRB family members but not others, this work will have a fundamental impact on our understanding of the existence of gene regulatory networks effecting cell cycle exit in response to distinct biological cues. pRB plays a welldocumented role in growth control, and inactivation of this tumor suppressor has been associated with a large proportion of human cancers. This Proposal is therefore highly relevant to our understanding of tumor suppressive mechanisms and cancer.
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Project Title: SIGNALING DIFFERENTIATION
PATHWAYS
IN
PROLIFERATION
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AND
Principal Investigator & Institution: Ewen, Mark E.; Associate Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 10-AUG-1995; Project End 31-MAY-2010 Summary: (provided by applicant): The retinoblastoma tumor suppressor gene product, pRb, regulates cell cycle progression, and this represents one of its tumor suppressor functions. pRb is also a key participant in a number of differentiation programs; however, there is no compelling genetic or in vivo evidence that pRb's role in the control of cellular differentiation contributes to its tumor suppressor function. Like Rb, the three ras proto-oncogenes regulate differentiation and proliferation. Rb and ras function together to control differentiation in the mouse. Heterozygosity for K-ras or nullizygosity for N-ras (i) rescues many of the developmental defects that characterize Rb-deficient embryos by affecting differentiation, but not proliferation and (ii) significantly enhances the degree of differentiation of pituitary adenocarcinomas arising in Rb heterozygotes, leading to their prolonged survival. Together, these observations suggest that the ability of pRb to affect differentiation is a facet of its tumor suppressor function. Rb+/- mice also develop medullary (C-cell) thyroid adenomas. By contrast, Rb N-ras heterozygotes develop metastatic C-cell carcinomas, with a fraction of these showing loss of the remaining N-ras allele. This counterintuitive observation might be rationalized by the observations that tumors of neuroendocrine origin rarely display mutations in ras and introduction of oncogenic Ras into lines derived from such tumors promotes their differentiation. Research to be conducted examines how loss of N-ras contributes to the development of large primary thyroid tumors and their associated metastases using experimental assays. The possibility that the metastatic behavior of Ccell tumors arising in Rb N-ras mutant animals might be associated with acquisition of the normal migratory and invasive behavior C-cells possess during embryo genesis will be explored. A second line of research will address the requirement for different ras isoforms in transformation. Specifically, the role of K- and N-ras in SV40 T antigenmediated transformation of murine embryo fibroblasts will be addressed. A third line of investigation is motivated by the observation that skeletal muscle in Rb ras mutant animals continues to display evidence of ongoing proliferation, despite a rescue in differentiation. Detailed research will be focused here on the molecular mechanism by which pRb and the myogenic factor, MyoD, maintain a terminal cell cycle arrest during myogenic differentiation, with emphasis on the regulation of genes known to participate in cell cycle re-entry. •
Project Title: STRUCTURE/FUNCTION ONCOPROTEINS
OF
HUMAN
PAPILLOMAVIRUS
Principal Investigator & Institution: Marmorstein, Ronen; Professor; Wistar Institute 3601 Spruce Street Philadelphia, Pa 191044265 Timing: Fiscal Year 2005; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Viruses are often potent oncogenes and are causally linked to approximately 20 percent of human malignancies. Human papillomavirus (HPV), in particular, is considered to be the etiological agent of human cervical cancer. HPV infections are also implicated in other malignancies including cancer of the vulva, vagina, penis, anus, skin, esophagus, and oropharyngeal region. Transformation by HPV is mediated by two relatively small viral oncoproteins, E6 and E7 that mediate their activities through their interaction with host proteins, which are normally involved in controlling cell growth and division. HPV-E6 abrogates the function of the p53 tumor
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suppressor gene by cooperating with E6AP to target p53 for ubiquitin-mediated degradation, and also inhibits the transactivation properties of the global transcriptional coactivators, CBP and p300. E7 binds to the Retinoblastoma (pRb) tumor suppressor and liberates E2F transcription factors causing premature activation of genes involved in DNA synthesis during the G1 to S cell cycle transition. E7 also interacts with the AP1 family of transcription factors for transactivation of AP1-mediated transcription, with Mi2 and histone deacetylases to perturb pRb-mediated transcriptional repression, and with the p21(WAF1/CIP1) family of cyclin-dependent kinase inhibitors to perturb cell cycle regulation. The functional homologue of HPV-E7, Adenovirus E1A (Ad-ElA), also inhibits the activity of pRb as well as other transcriptional cofactors such as the P/CAF and CBP/p300 histone acetyltransferases. In order to obtain mechanistic insights into the mode of cell transformation by HPV we propose to determine the X-ray crystal structures of HPV-E6 and E7 bound to relevant cellular protein targets and to biochemically characterize their respective protein-protein interactions. Specifically, we will (1) Determine the X-ray crystal structure of HPV-E7 alone and in complex with pRb, (2) Determine the X-ray crystal structure of Ad-E1A in complex with pRb, (3) Determine the structure of a pRb/E2F complex, characterize the binding properties of pRb to E2F in the presence or absence of HPV-E7 or Ad5-E1a, and use mutational analysis to probe the interactions of pRb with E2F, HPV-E7 and Ad-E1A, and (4) Determine the X-ray crystal structure of HPV-E6 alone and in complex with p53 and characterize the binding properties of the complex using mutational analysis. These studies will provide detailed mechanistic insights into the mode by which HPV-E6 and -E7 disrupt normal cellular processes for cell transformation and will lead to the structure-based design of small molecule E6- and E7- inhibitors to combat HPV-mediated cancers such as cervical cancer. •
Project Title: STUDY OF GENOMIC INSTABILITY CAUSED BY HPV16 E6 AND E7 Principal Investigator & Institution: Mccance, Dennis J.; Professor; Microbiology and Immunology; University of Rochester 517 Hylan Bldg., Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2005; Project Start 01-MAY-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Genomic instability, resulting in polyploid/ aneuploid cells, is a hallmark of invasive cancers, including those of the head and neck. The presence abnormal numbers of chromosomes in invasive cancer cells is due to loss of cell cycle regulation, resulting in lost of checkpoints and problems at mitosis. Human papillomaviruses (HPV) play a significant role in the etiological of head and neck cancers and we have shown that E6 and E7 from HPV type 16, a virus commonly associated with these cancers, cause polyploidy/ aneuploidy in human epithelial cells. Using microarrays comparing epithelial cells expressing E6 and E7 to control cells, we have found a number of genes involved in the G2 to M phase transition that are deregulated by these viral proteins. The fact that these viral genes cause chromosomal abnormalities suggests that studying their mechanisms of action, may have wider implications for other non-HPV induced cancers. We propose, firstly, to determine what part of mitosis/ cytokinesis is affected in E6/E7-expressing cells. Secondly, investigate the role played by the tumor suppressors, p53 and the retinoblastoma family in the control of G2/M transition. Thirdly, determine how specific G2 and M-phase genes are activated by E6 and E7 and fourthly elucidate, using microarrays, if there are different expression patterns between HPV positive and negative head and neck cancers.
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Project Title: THE FUNCTION OF PNUTS TARGETING SUBUNIT) IN THE CELL CYCLE
(PHOSPHATASE
63
NUCLEAR
Principal Investigator & Institution: Krucher, Nancy A.; Biology and Health Sciences; Pace University New York New York, Ny 10038 Timing: Fiscal Year 2007; Project Start 01-FEB-2007; Project End 31-JAN-2010 Summary: (provided by applicant): In cancer cells, division and replication occurs in the absence of signals to do so. Many proteins that control cell division are involved in cancer development. The activity of the tumor suppressor protein, Retinoblastoma (Rb), is often deregulated in cancer cells. Rb inhibits proliferation in cells in which it is active, but allows cell proliferation when it is inactive. Rb activity is controlled by its phosphorylation state which is regulated by cyclin dependent kinases (cdks) and Protein phosphatase 1 (PP1). PP1 activity is controlled by targeting subunits that bind to and direct it to specific substrates. There is a newly identified PP1-targeting subunit called PNUTS (Phosphatase Nuclear Targeting Subunit) which inhibits PP1 activity toward Rb in vitro. The PNUTS protein is highly expressed in two types of breast cancer cells, therefore the specific aims of this project are designed to elucidate the function of and regulation of PNUTS in cell cycle control. To investigate the role of PNUTS in the cell division cycle, we intend to use RNA interference (RNAi) to block PNUTS expression in breast cancer cells and examine the effects on the enzyme activity of PP1, Rb phosphorylation status and cell proliferation. In addition, the regulation of PNUTS activity by phosphorylation and its association with PP1 will be investigated. The elucidation of PNUTS function in the cell division cycle will provide insight into the control and regulation of cell proliferation. In cancer, cells divide and proliferate in an uncontrolled manner. Thus, the investigation of the molecules that control cell division may lead to information needed to understand cancer cell development and growth. This project is designed to study the function of a protein called PNUTS which is proposed to be an activator of cell proliferation in breast cancer. •
Project Title: THE MOLECULAR BIOLOGY OF RETINOBLASTOMA Principal Investigator & Institution: Albert, Daniel M.; Associate Surgeon in Ophthalmology; Ophthalmology and Visual Sci; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2005; Project Start 01-FEB-1999; Project End 31-JUL-2005 Summary: (from abstract). The PI proposes to continue with studies regarding the molecular biology of retinoblastoma, focusing on the evaluation of chemotherapeutic and chemopreventative actions of vitamin D analogs (Specific Aim 1) and the identification of the mechanism of action of these compounds on retinoblastoma (Specific Aim 2). The subaims are: (I a) Determine the effectiveness and toxicity of Iahydroxyvitamin D2 (Ia-hydroxy-D2), and compare its potency and toxicity to 1,25dihydroxy-16-ene-23-yne-vitarnin D3 (16,23-D3) in the treatment of transgenic and athvmic models of retinoblastoma. (Ib) Study the ability of these compounds to induce reduction tumor mass. (Ic) Compare the effectiveness of these analogs to standard chemotherapy used in the treatment of retinoblastoma and evaluate the effectiveness of vitamin D analogs as adjuvant therapy. (Id) Determine the effectiveness of these compounds on the midbrain tumors in "trilateral" retinoblastoma. (Ie) Evaluate the emergence of drug-resistant subpopulations of retinoblastoma cells. Subaims to Specific Aim 2 are: (2a) Study the relationship of vitamin D receptors to drug therapy effectiveness. (2b) Determine the mechanism by which cell proliferation arrest is mediated by vitamin D analogs with regard to cell cycle proliferation and cell death. (2c) Establish whether the mechanism of tumor growth arrest is regulated by p53 -
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dependent gene expression. (2d) Determine whether I a-hydroxy-D2 and 16,23 -D3 inhibit angiogenesis in a transgenic mouse model. These studies will complete the preclinical investigation of the efficacy of vitamin D analogs for human treatment. •
Project Title: THE RB GENE FAMILY IN CANCER INITIATION Principal Investigator & Institution: Sage, Julien; Pediatrics; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 31-MAY-2011 Summary: (provided by applicant): The retinoblastoma (RB) gene is a potent suppressor of human cancers. While RB is thought to have multiple functions during the cell cycle, the specific functions of RB that are critical for its tumor suppression activity are still unclear. We propose to test the idea that RB and its two related family members p107 and p130 play a pivotal role in preventing cancer initiation in vivo by controlling the transition between the GO and G1 phase of the cell cycle. Specifically, we hypothesize that the acute somatic loss of RB family function leads to defects in both cell cycle exit (G1->GO) and cell cycle re-entry (GO->G1) in critical cell populations, and that these defects may result in the initiation of tumorigenesis. We will test our hypothesis using mouse models with combinations of germline and conditional mutations of RB family genes. This mouse genetic approach will enable us to determine the role of RB family genes in spatially and temporally-defined cell populations. These mouse models will also allow us to recapitulate in vivo the early stages of cancer in humans. Studies in the first Specific Aim will characterize the function of RB family genes in cell cycle exit during embryonic development. RB patients develop retinoblastomas, which are retinal neural tumors, as early as the fetal stage. We will focus our studies on neural progenitors to explore the consequences of loss of RB family function on cell cycle exit and differentiation defects leading to cancer initiation. Studies in the second Specific Aim will determine if the RB family proteins are required for maintenance of differentiation in vivo. Specifically, we will investigate the consequences of acute loss of function of RB family genes on cell cycle re-entry of differentiated hepatocytes in vivo. These studies will be important to determine if some terminally differentiated cells may be at the origin of cancer. Studies in the third Specific Aim will combine molecular approaches and RNA interference in vivo to understand the molecular mechanisms underlying cell cycle re-entry upon loss of RB family function in vivo. We will focus our studies on candidate mediators of cell cycle re-entry in RB family mutant hepatocytes, including the E2F transcriptional activator and the Id2 transcriptional repressor. Understanding the molecular bases and the cellular consequences of the loss of RB family tumor suppressors in vivo will give important and novel insights into the mechanisms of cancer initiation. These studies will further provide the foundation for the detection and treatment of early stages of human cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE ROLE OF RB IN THE RETINA & OTHER TISSUES Principal Investigator & Institution: Harbour, James W.; Associate Professor; Ophthalmology and Visual Sci; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2006; Project Start 01-JUL-2000; Project End 31-JAN-2010 Summary: (provided by applicant): The retinoblastoma protein (Rb) is critical for suppressing cancer, regulating cell proliferation, and inhibiting cell death in the retina, retinal pigment epithelium, lens and other ocular tissues. The long-term goal of our
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research is to understand the importance of Rb in ocular health and disease, which may allow us to develop new therapies for eye disorders. Rb localizes to gene promoters through its interaction with E2F transcription factors, and it regulates gene expression by assembling multimeric chromatin remodeling complexes. Rb itself is regulated by two key phosphorylation events: phosphorylation of the C-terminus blocks the ability of Rb to inhibit cell proliferation, whereas additional phosphorylation of Rb at serine-567 blocks the ability of Rb to inhibit cell death. Concurrently, we have shown that Rb is critical for the differentiation and survival of ocular melanocytes - a type of pigment cell that plays an important role in the pathogenesis of ocular melanoma, albinism, microphthalmia and other eye diseases. When Rb is minimally phosphorylated, it is in its most active form and is able to cooperate with the microphthalmia transcription factor (MITF) to induce melanocytes to differentiate and cease proliferating. When Rb becomes partially phosphorylated, it looses the ability to inhibit cell proliferation but it still blocks cell death. When Rb is completely inactivated by phosphorylation of serine567, it can no longer prevent cell death. Appropriately, serine-567 phosphorylation occurs only in abnormal cells. We hypothesize that the separate regulation of cell proliferation and cell death by Rb according to its phosphorylation state serves as a buffer against inadvertent cell death during normal cell proliferation while providing a mechanism for eliminating abnormal cells that could lead to cancer and other diseases. Using our ocular melanocyte model, we propose a series of experiments organized around three specific aims to determine how Rb regulates cell proliferation, differentiation and cell death in ocular melanocytes. Understanding how Rb accomplishes these functions could result in new treatments to eliminate cancer cells and alternatively, to prevent the loss of normal cells and encourage tissue regeneration in eye diseases such as macular degeneration and retinitis pigmentosa. Consequently, these aims are highly relevant to the vision statement of the NEI, and they address several major program goals and objectives of the Retinal Diseases Program. •
Project Title: THERAPEUTIC TARGETING OF BETA-CATENIN IN COLON CANCER Principal Investigator & Institution: Drebin, Jeffrey A.; Professor and Chief, Division of Gastroi; Surgery; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2006; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Genetic deletions of the adenomatous polyposis coil (APC) tumor suppressor gene occur in the majority of colon cancers Loss of the APC gene products' ability to down-regulate the beta-catenin protein is hypothesized to represent a critical mechanism by which APC loss contributes to the etiology of colon cancer However, the APC protein interacts with multiple other proteins, including gamma-catenin and hDLG, that may play a role in neoplastic cell growth To date there has been little direct examination of the role of beta-catenin in the neoplastic behavior of human colon cancer cells The precise mechanisms by which beta-catenin signaling enhances the growth and survival of neoplastic cells are unknown, and the characterization of changes in gene expression resulting from beta-catenin-mediated transcriptional effects has been limited The overall goal of this project is to directly evaluate the role of beta-catenin on the neoplastic properties of APC-mutant intestinal neoplasms Antisense oligodeoxynucleotides capable of specifically suppressing betacatenin expression in human cancer cells have been identified The ability of the antibiotic doxycycline, at clinically achievable concentrations, to inhibit beta-catenin expression has also been elucidated These beta-catenin-suppressive agents will be used to define beta-catenin-dependent effects on cell cycle and apoptotic regulatory
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mechanisms in APC-mutant colon cancer cells Effects of beta- catenin on c-myc expression and function will be characterized Changes in gene expression profiles of APC-mutant colon cancer cells resulting from suppression of beta-catenin expression will be evaluated, and compared with changes induced by upstream alterations in APC or downstream alterations in Tcf4 activity Effects of suppressing beta-catenin on spontaneous adenoma formation will be evaluated using APC-mutant min mice and antitumor effects resulting from the in vivo suppression of beta-catenin expression will be evaluated in APC-mutant human colon cancer xenografts Collectively, these studies will define the role of beta-catenin in the neoplastic growth of APC-mutant colon cancer cells and will characterize the efficacy of chemopreventive and therapeutic strategies that target beta-catenin in vivo. •
Project Title: CHROMATIN
TRANSCRIPTIONAL
ACTIVATION
BY
REORGANIZING
Principal Investigator & Institution: Bartholomew, Blaine; Associate Professor; Medical Biochemistry; Southern Illinois University Carbondale 900 S. Normal, Woody Hall C206 Carbondale, Il 629014709 Timing: Fiscal Year 2005; Project Start 01-JAN-1993; Project End 31-DEC-2005 Summary: (provided by applicant): Chromatin remodeling serves as a functional key in multiple cellular processes, one of them being the regulation of gene expression through promoting formation of the transcription complex and elongation of the transcription complex. There are several well-documented examples of chromatin remodeling complexes working in conjunction with gene-specific transcription factors to make the DNA accessible to the transcription machinery. In addition, the nucleosome structure is a severe deterrent to the rearrangement of genes required for the production of immunoglobulins. Chromatin remodeling is apparently a mechanism used to tightly regulate vertebrate immune systems and is probably the key to the molecular mechanism underlying the "accessibility hypothesis" proposed 15 years ago. Chromatin remodeling is also involved in cell cycle control and interacts with the tumor suppressor protein Rb or retinoblastoma protein. In understanding how SWI/SNF and ISW2 remodel the nucleosome, it is important to know that it does not work randomly on chromatin, but they are recruited or targeted to specific locations by gene-specific transcription factors or repressors. Evidence indicates that chromatin remodeling can be tightly coordinated with DNA modifications such as methylation of DNA and DNA replication. The list of diseases linked to chromatin remodeling continues to grow and includes such diseases as rhabdoid tumours, a very aggressive form of pediatric cancers, breast cancer, leukemia, mental retardation, Williams syndrome, and Rett syndrome. It is not known which subunits of SWI/SNF interact with the transcription activator or how its interaction with the nucleosome may be different when recruited versus indiscriminate binding to nucleosomes. Our research plan is to examine the structure and its relation to function of the SWI/SNF chromatin remodeling complex by a series of approaches that uses either modified DNA or modified histone octamers. We will obtain the 3-dimensional structure of SWI/SNF by electron tomography and determine which regions interact with DNA and histone octamer by linking data from site-directed photoaffinity labeling and proteolysis to the structure. Next, we will determine how SWI/SNF and ISW2 remodel chromatin when recruited to specific sites within nucleosomal arrays by their respective "targeting" proteins. Data on these two different chromatin remodeling complexes suggest that they modulate chromatin structure in significantly different ways both in vivo and in vitro.
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Project Title: PROLIFERATION
TRANSCRIPTIONAL
CONTROL
IN
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HEPATOCYTE
Principal Investigator & Institution: Greenbaum, Linda E.; Medicine; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 21-SEP-2001; Project End 31-MAY-2006 Summary: (provided by applicant): The adult liver has a remarkable capacity to restore its mass in response to partial hepatectomy, liver transplantation, or toxic or inflammatory injury. Regeneration after partial hepatectomy is impaired in CCAAT enhancer binding protein beta(C/EBP-beta) -/- mice and is associated with decreased hepatocyte DNA synthesis, prolonged hypoglycemia and reduced expression of growth-associated and cell cycle-associated genes, including cyclin E. Resistance to Fasmediated apoptotic injury in C/EBP-beta -/- livers also links C/EBP-beta to the regulation of the initial liver injury response. Physiologic associations between C/EBPalpha and beta and the retinoblastoma protein in other cell types and the finding that pRb phosphorylation is decreased in C/EBP-beta -/- livers after partial hepatectomy link C/EBP-beta with pRb phosphorylation, cyclin E activation and hepatocyte cell cycle progression. Phosphorylation of specific domains in the C/EBP-beta protein overrides the block to cell cycle progression associated with induction of unmodified C/EBP-beta in cell models, suggesting that posttranslational modifications of C/EBP-beta are also necessary for hepatocyte cell cycle progression in the regenerating liver. The Specific Aims of this proposal are (1) To identify the component(s) of the apoptotic pathway that are abnormally regulated in Fas-antibody treated C/EBP-beta -/- livers and to determine if C/EBP-beta is also involved in the regulation of TNF-alpha mediated apoptotic liver injury. (2) To determine whether C/EBP-beta and/or C/EBP-alpha interactions with pRb are important for pRb phosphorylation, cyclin E activation and hepatocyte cell cycle progression. (3) To define the C/EBP-beta functional domains that are required for hepatocyte proliferation. C/EBP-beta proteins modified at residues that correspond to phosphoacceptor sites linked to signaling pathways in the regenerating liver will be introduced into CIEBP-beta -/- primary hepatocytes and assessed for their ability to facilitate hepatocyte cell cycle progression. Together these studies will provide important mechanistic insights regarding the basis for the response of the liver to injury and for hepatocyte proliferation following growth stimulation. This knowledge will be useful for the development of therapeutics to augment the regenerative capacity of the liver in a variety of liver diseases. •
Project Title: TRANSCRIPTIONAL RESPONSES IN NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Bowser, Robert P.; Associate Professor; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2005; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): The molecular mechanisms that regulate neuronal cell death during human neurodegenerative diseases remain unclear. One intracellular pathway that may function in regulating neuronal cell death includes the activation of cell cycle transcription factors that alter gene expression and chromatin structure. Key protein components of the cell cycle regulated death of neurons include p53, E2F1 and the retinoblastoma protein (pRb). These proteins participate in cell death induced by DNA damage, oxidative injury and the Abeta peptide. We have identified novel functional interactions between the FAC1 and ZF87/MAZ transcription factors with pRb_2F1 and propose that interactions between p53, pRb, E2F1, FAC1, and ZF87/MAZ pathways play a pivotal role to regulate cell survival or death during human
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neurodegenerative diseases. We hypothesize that altered expression of downstream genes and chromatin structure leads to neuronal cell death in neurodegenerative diseases. Our first Specific Aim will directly test the function of these transcription factors in two in vitro models of neurodegeneration. The second Aim will test the hypothesis that these transcriptional regulators regulate neurodegeneration in an animal model of neurologic disease. Specific drugs that affect cell cycle proteins will be examined for their ability to slow disease onset and increase survival in this animal model. The last Aim will examine the distribution and function of transcription factors during Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and to determine their presence in degenerating neurons. The combination of in vitro and in vivo studies will demonstrate the physiologic relevancy for our proposed model. Our proposed studies will greatly increase our understanding of the role that cell cycle transcription factors play in regulating neuronal death during human neurodegenerative diseases and lead to novel therapeutic strategies to enhance neuronal survival during brain injury and disease. •
Project Title: TUMOR SUPPRESSOR AND ONCOGENIC PATHWAYS IN THE PLACENTA Principal Investigator & Institution: Wu, Lizhao; Molecular Virology, Immunology & Medical Genetics; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2005; Project Start 12-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The overall goal of the K01 award is to allow Lizhao Wu, Ph.D. to devote full-time effort for research training under the co-mentorships of Drs. Leone, Rosol, and Robinson, to develop into an independent investigator in an academic institution. The retinoblastoma tumor suppressor (RB) gene was the first tumor suppressor identified. While loss-of-function mutations in RB were initially observed in inherited retinoblastoma, inactivation of RB has since been implicated in a wide variety of human tumors. Mounting evidence has implicated Rb in the control of several fundamental biological processes that have direct relevance to tumorigenesis and tumor progression. These processes include proliferation, apoptosis, and terminal differentiation. It was shown a decade ago that Rb is essential for embryonic viability. However, we recently identified a key role of Rb in the placenta that is required for embryonic development and viability because Rb-deficient embryos can be carried to term when their placentas are corrected through genetic or embryonic manipulations. To further understand the biological relevance of this novel function, we propose to achieve the following three specific aims: 1. To determine whether loss of Rb in the placenta is sufficient to induce embryonic lethality and/or pathological defects in wildtype fetuses. Wild-type embryos will be produced with Rb mutant placentas to determine whether Rb is acting in a cell autonomous fashion within the fetus, or if the Rb-associated defects seen in embryonic development are actually due to the observed placental defects. 2. To genetically dissect the role of Rb in different cellular compartments of the placenta. We will conditionally knock out Rb in either the labyrinth trophoblasts or the spongiotrophoblasts to determine in which cellular compartment the Rb function is important for placentation and fetal development. 3. To examine the genetic regulatory networks employed by Rb in the placenta. E2F1, E2F2, E2F3, and Id2 can mediate Rb function in vivo, and concomitant genetic deletion of Rb and either of E2F1, E2F3, or Id2 can suppress many of the defects seen in Rb-deficient embryos. Therefore, placentas deficient for Rb and either of E2F1, E2F2, E2F3, or Id2 will be analyzed to determine whether deletion of any of the four proteins can ameliorate or remedy the Rb placental phenotype. The funding of the K01 award will provide invaluable additional training to the applicant in areas of embryonic manipulation and
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pathology, and will foster the applicant's career development into an independent investigator in cancer-related research. •
Project Title: UBIQUITINATION DIFFERENTIATION
REGULATION
OF
TUMOR
CELL
Principal Investigator & Institution: Wu, Lingtao; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2005; Project Start 01-JAN-2005; Project End 31-DEC-2006 Summary: (provided by applicant): Induction of cell proliferation/differentiation (P/D) transition requires cell cycle arrest. P/D transition may result from a dual-function of cell cycle regulators that coordinate cell cycle arrest and differentiation activation. Cyclin-dependent kinase (CDK)-activating kinase (CAK) cross-regulates cell cycle and differentiation, while CAK activity is determined by its assembly factor and targeting subunit MAT1 (menage a trois 1). To date, how differentiation is induced from cancer cell proliferation remains unclear. The discovery that retinoic acid (RA) induces myeloid cell differentiation via retinoic acid receptor alpha (RARalpha) introduces a new era of study in cancer cell P/D transition. Our recent studies demonstrate that RA-induced P/D transition in human leukemic HL60 and neuroblastoma CHP126 cells is accompanied by both ubiquitination-proteolysis of MAT1 and decreased CAK phosphorylation of differentiation regulators including retinoblastoma tumor suppressor protein (pRb), RARalpha, and retinoid X receptor alpha (RXRalpha). Manipulating MAT1 abundance shows that MAT1 reduction mimics RA-induced P/D transition, while MAT1 overexpression resists this RA-action. Therefore, we hypothesize that RA-induced ubiquitination-proteolysis of MAT1 may decrease CAK phosphorylation of those differentiation regulators to induce cancer cell P/D transition. Our long-term goal is to understand the role of MAT1 ubiquitination in the switch from cancer cell proliferation to differentiation, which should aid the development of novel approaches to cancer therapy. To test our hypothesis, the experiments are proposed to: a) determine that MAT1 is a substrate for ubiquitination; b) investigate which form of MAT1 is ubiquitinated in vivo; and c) test whether ubiquitination of MAT1 decreases CAK activity to induce P/D transition. NTIS (National Technical Information Service) The NTIS (www.ntis.gov), a service of the U.S. Department of Commerce, has published the following information on sponsored studies related to retinoblastoma: •
"Alteration of the Retinoblastoma gene locus in radium-exposed individuals," published in 1991. Sponsored by: Argonne National Lab., IL.; Department of Energy, Washington, DC. Written by: J. P. Hardwick, R. Schlenker and E. Huberman. Abstract: This study was performed to determine if the Retinoblastoma suppressor gene was altered in individuals exposed to radium. We analyzed the Rb gene in 30 individuals, 17 of whom were exposed to radium either occupationally or iatrogenically. In the kidney DNA from four of nine radium-exposed individuals, the Rb gene was deleted. Three of these alterations in the Rb gene were internal deletions, which resulted in the absence of Rb mRNA accumulation. These results imply that the Rb gene is susceptible to radium-induced damage and confirm previous showing that radiation preferentially causes genomic deletions. The pronounced alterations in the non-
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tumorigenic femurs from radium-exposed individuals suggests that in the many years of exposure there was a selection of cells with alterations, presumably because of their growth advantage. Also it implies that deletions of one of the Rb alleles can be one of the events (perhaps an initial one) in the progression of radium-induced sarcomas. 11 refs., 2 figs. •
"Biology of Somatostatin and Somatostatin Receptors in Breast Cancer. - Annual rept. 12 Aug 96-11 Aug 97," published in September 1997. Sponsored by: McGill Univ., Montreal (Quebec). Written by: Y. C. Patel. Abstract: The longterm goal of our work is to elucidate the pattern of expression of the five somatostatin receptor (SSTR1-5) isoforms in breast cancer, to determine which SSTR subtypes and signalling mechanisms mediate the antiproliferative effects of somatostatin (SST), whether the available SST analogs are effective in binding to these antiproliferative SSTR subtypes, and whether the pattern of SSTR expression in tumors can provide an independent prognostic marker. Towards these goals, we have characterized the pattern of expression and relative abundance of mRNA and proteins for SSTR1-5 in 101 primary breast cancers. All tumors expressed at least one SSTR and the majority expressed multiple SSTRs including subtypes 2, 3, and 5 which bind to octapeptide SST analogs. A good correlation was found between SSTR protein expression by immunocytochemistry and mRNA analysis by RT-PCR. SSTRs exert significant antitumor activity both by cytostatic and cytotoxic (apoptotic) actions in breast cancer cells. Apoptosis is dependent on estrogen receptor expression and is potentiated by tamoxifen. Apoptosis is induced uniquely via the SSTR subtype and is associated with induction of wild type p53 and of Bax and endonuclease 2. By contrast, the other four SSTR subtypes signal cell cycle arrest with the following rank order SSTR5 > SSTR2 > SSTR4> SSTR1. These changes are associated with the induction of the Retinoblastoma protein pRB and the cyclin-dependent kinase inhibitor p21.
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"Dominant-Active Alleles of Rbi as Universal Tumor Suppressors of Mammary Carcinoma. - Final rept. 1 Sep 1997-31 Dec 2000," published in January 2001. Sponsored by: Toronto General Hospital (Ontario). Written by: E. Zacksenhaus. Abstract: The Retinoblastoma tumor suppressor, Rb, regulates cellular proliferation, differentiation and survival, and is functionally inactivated by mutations or phosphorylation in most human cancers. While the activation of endogenous Rb by dephosphorylation is thought to provide an effective approach to suppress normal as well as neoplastic cell proliferation, the inhibition of apoptosis by Rb may have detrimental consequences in vivo. To test these paradigms, we targeted phosphorylation- resistant, constitutively active Rb alleles, Rb-DELTA-Ks, to the mouse mammary gland under control of the MMTV-LTR and WAP promoters. Here we show that pubescent MMTV-LTR-Rb-DELTA-Ks initially displayed reduced epithelial cell proliferation and delayed growth and branching of the ductal tree. Post-puberty transgenic mice exhibited alveolar outgrowth, precocious expression of the milk gene beta-Casein and extended survival of differentiated epithelial cells. Strikingly, multiple MMTV-LTR-Rb-DELTA-K and WAP-Rb-DELTA-K transgenic females developed focal preneoplastic lesions within 10-15 months and some presented with full-blown mammary adenocarcinoma. Expression of the Rb-DELTA-K transgene in these breast tumors was greatly reduced. The observations that both activation and inactivation of Rb can induce cancer in experimental mouse models, as is the case with its major partner, E2F1, have direct implications for cancer therapy.
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"In vitro Rb-1 gene transfer to Retinoblastoma cell lines," published in April 1994. Sponsored by: Korea Atomic Energy Research Inst., Daeduk (Republic of Korea). Written by: S. W. Choi, Y. H. Ham and M. H. Kim. Abstract: After transfection of Rb-vector to packaging cell line (CRIP) by Ca-P precipitation method, we could select nineteen colonies of G-418 resistant clone by ring cloning. Each colony was transduced to NIH3T3 cells to select the one which produces high titer virus. After NIH3T3 cells transduction, we could get 28 colony counts for the high, 127 for the middle, and 6 for the low viral titer. With the supernatant of the high viral titer colony (CRIPRb 2-5). We transduct Retinoblastoma cell lines. 5 figs, 11 refs. (Author).
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"Mechanism of Retinoblastoma Protein-Mediated Terminal Cell Cycle Arrest. Annual summary rept. 1 Sep 2001-31 Aug 2004," published in September 2004. Sponsored by: Dana-Farber Cancer Inst., Boston, MA. Written by: H. N. Rajabi. Abstract: Inactivation of Retinoblastoma gene (Rb) is observed in several human cancers including those of the breast. A characteristic feature of many human cancers is the inability to maintain a terminal cell cycle arrest, whereas the Rb product (pRb) has been implicated in the maintenance of a terminal cell cycle arrest. However, in contrast to our knowledge of how pRb regulates proliferation in a cycling population, little is known how it maintains a permanent cell cycle arrest. The proposed studies are aimed at elucidating the molecular mechanism by which pRb accomplishes this task and plays the role of tumor suppressor of tumor formation. Our working hypothesis is that pRb, in cooperation with MyoD, participates in the transcriptional repression of one or more immediate early genes required for the induction of cyclin Dl. And this event ultimately prevents the re-entry into the cell cycle, thus maintaining a terminal cell cycle arrest. To test this hypothesis myogenic differentiation has been used as model, because it represents a differentiation system in which pRb has been implicated in a terminal cell cycle arrest both in vitro and in vivo. In the past year I have discovered that: (1) The induction of Fra-1 and not any other immediate early genes is blocked following restimulation of differentiated myoblasts. (2) Ectopic expression of the cell cycle inhibitory protein pl6, which bring about a cell cycle arrest distinct from a terminal cell cycle arrest, has no effect on expressions of both Fra-1 and cyclin Dl. In an effort to further study the regulation of the Fra-1 gene I have created Fra-1 promoter reporter and its deletion mutants. Also constructed a retrovirus vector for ectopic expression of Fra-1 to establish a causal relationship between Fra-1 and cyclin Dl. These results and reagents provide the basis upon which to discover the detailed mechanism by which pRb participates in a terminal cell cycle arrest.
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"Molecular analysis of Retinoblastoma in pediatrics," published in January 1993. Sponsored by: Korea Atomic Energy Research Inst., Daeduk (Republic of Korea). Written by: S. W. Choi and C. M. Kim. Abstract: Inactivation of RB protein produced by mutation of RB-1 gene is critical to the pathogenesis of Retinoblastoma. Since other factors besides this gene are thought to be involved in this mechanism, we performed the molecular analysis of Retinoblastoma for loss of RB-1 gene and N-myc gene amplification. Loss of RB-1 gene was found in five(56%) among nine patients with Retinoblastoma and total loss of the gene in one patient. We also found total loss of RB-1 gene in WERI cell line and a more than 100 fold amplification of N-myc in Y-79 cell line. The analysis of the relationship between molecular events and clinical characteristics such as age, sex, tumor laterality did not
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reveal any specific correlation. We suggest this method can be a useful tool for initially screening a large number of tumors and for genetic counseling and early detection of the tumor. (Author). •
"PCR detection of Retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas," published in 1993. Sponsored by: Argonne National Lab., IL.; Department of Energy, Washington, DC. Written by: M. E. Churchill, M. A. Gemmell and G. E. Woloschak. Abstract: From 1971 to 1986, Argonne National Laboratory conducted a series of largescale studies of tumor incidence in 40,000 BCF(sub 1) mice irradiated with (sup 60)Co (gamma) rays or JANUS fission-spectrum neutrons; normal and tumor tissues from mice in these studies were preserved in paraffin blocks. A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse Retinoblastoma (mRb) gene in the paraffin-embedded tissues. Microtomed sections were used as the DNA source in PCR reaction mixtures. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments (relative to control PCR products) on a Southern blot indicated a deletion of that portion of the mRb gene. The tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice (569 cGy of (sup 60)Co (gamma) rays or 60 cGy of JANUS neutrons, doses that have been found to have approximately equal biological effectiveness in the BCF, mouse) were analyzed for mRb deletions. In all normal mouse tissues studies, all six mRb exon fragments were present on Southem blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, I of 6 tumors from (gamma)-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice had a deletion in one or both mRb alleles. All deletions detected were in the 5(prime) region of the mRb gene.
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"Polymerase chain reaction detection of Retinoblastoma gene deletions in paraffinembedded mouse lung adenocarcinomas," published in 1991. Sponsored by: Argonne National Lab., IL.; Department of Energy, Washington, DC. Written by: M. E. Churchill, M. A. Gemmell and G. E. Woloschak. Abstract: A Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse Retinoblastoma (mRb) gene using microtomed sections from paraffinembedded radiation-induced and spontaneous tumors as the DNA source. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (569 cGy of (sup 60)Co (gamma) rays or 60 cGy of JANUS neutrons) were analyzed. Tumors in six neutron-irradiated mice also had no mRb deletions. However, one of six tumors from (gamma)-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene.
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"RIZ Gene in Human Breast Cancer. - Annual rept. 1 Sep 96-31 Aug 97," published in September 1997. Sponsored by: Burnham Inst., La Jolla, CA. Written by: S. Huang.
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Abstract: The RIZ gene was isolated based on binding to the Retinoblastoma tumor suppressor protein. RIZ gene normally produces two protein products, RIZ1 and RIZ2, that differ in length by the presence or absence of a conserved protein motif, the PR domain, found in a subfamily of Kruppel-like zinc finger genes. RIZ2 lacks the PR domain. RIZ gene maps to human chromosome band 1p36, a region that is commonly deleted or altered in a variety of human cancers including those of breast, neurocrest, colon, and liver tissues. RIZ1 and RIZ2 are widely expressed in normal tissues. However, RIZ1 was undetectable in 4 of 5 breast carcinoma specimens and in 4 of 10 breast cancer cell lines. •
"Role of Changes in the Expression of Cyclins and Retinoblastoma Protein in the Development of Breast Cancer. - Annual rept. 23 Sep 95-22 Sep 96," published in October 1996. Sponsored by: Colorado Univ. at Denver. School of Medicine. Written by: T. A. Langan. Abstract: The expression levels of a total of 15 cell cycle regulatory proteins have been determined in a panel of breast cancer and normal breast epithelial cell lines, as well as in a number of breast tissue and normal breast epithelial tissue samples. The results of these analyses indicate the presence of a defect in the expression of cyclin D1, Rb and/or the cyclin dependent kinase inhibitor protein, p16, in essentially all the breast cancer cell lines and tissues studied. The degree of overexpression of cyclin D1 is most closely reflected by changes in mRNA levels, although gene amplification and in one case an increase in half-life of the protein also contribute. Homozygous deletion of the p16 gene has been found to be a frequent mechanism for the absence of this tumor suppressor protein in breast cancer. Construction of replication incompetent adenovirus vectors for high efficiency transfection of breast cancer cells with genes encoding antisense cyclin D1 and sense p16 has been essentially completed. Human breast cancer cell lines tumorigenic in nude mice have been identified and will be transfected with these adenoviral vectors to directly test and confirm the role of cyclin D1 and p16 expression in breast cell tumorigenicity.
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"Sphingolipid-Mediated Apoptosis and Tumor Suppression in Breast Carcinoma. Annual rept. 30 Sep 95-29 Sep 96," published in October 1996. Sponsored by: Duke Univ. Medical Center, Durham, NC. Written by: Y. A. Hannun. Abstract: Ceramide has emerged as an important intracellular regulator of cell growth and viability. In breast carcinoma cells, we find that tumor necrosis factor a (TNFa) causes prolonged and significant accumulation of ceramide, which precedes cell death. We have investigated the mechanism of ceramide formation and the mechanism of ceramide action, with specific emphasis on their interactions with proteases. Our studies lead us to define two phases of the apoptotic pathway: in the first, signaling phase, TNFa: causes activation of proteases which lead to the accumulation of ceramide. In the second, execution phase, ceramide causes the activation of downstream death proteases as well as activation of the Retinoblastoma gene product. Addition of exogenous ceramides causes simultaneously cell cycle arrest and cell death. These studies are beginning to identify a growth suppressor pathway in breast carcinoma cells and the results are beginning to interrelate important components involved in the apoptotic response.
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"Tumor Suppressors and Breast Cancer: Molecular Interaction of Retinoblastoma Protein (Rb) with a New Rb-binding Protein (RIZ). - Annual rept. 1 May 1999-30 Apr 2000," published in May 2000. Sponsored by: Burnham Inst., La Jolla, CA. Written by: K. R. Ely. Abstract: Cancer arises from an accumulation of multiple mutations that may occur in oncogenes, tumor suppressor genes or DNA repair genes. Tumor suppressors control cell cycle and growth and mutations or alterations in these suppressors can be associated with the uncontrolled growth of malignant tumors. In this project, two tumor suppressors are targeted: the well-characterized Rb protein and a new protein that binds to it called RlZ, which is itself, a tumor suppressor. The goal is to use x-ray crystallography to study the interactions between Rb and RlZ and to identify the molecular contacts in these interactions. The results will be important to understanding the role of the new regulator protein RlZ in tumorigenesis in breast cancer. This IDEA project is focused on the first step in the process, i.e., crystallization of the proteins. The results to date report the growth of crystals of one functional domain of RlZ and of the pocket domain of Rb.
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.7 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 retinoblastoma, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type retinoblastoma (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for retinoblastoma (hyperlinks lead to article summaries): •
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A functional genetic screen identifies TFE3 as a gene that confers resistance to the anti-proliferative effects of the retinoblastoma protein and transforming growth factor-beta. Author(s): Nijman SM, Hijmans EM, El Messaoudi S, van Dongen MM, Sardet C, Bernards R. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16737956&query_hl=9&itool=pubmed_docsum
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A molecular study of first and second RB1 mutational hits in retinoblastoma patients. Author(s): de Andrade AF, da Hora Barbosa R, Vargas FR, Ferman S, Eisenberg AL, Fernandes L, Bonvicino CR. Source: Cancer Genetics and Cytogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16682285&query_hl=9&itool=pubmed_docsum
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A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Author(s): Matsubara H, Makimoto A, Higa T, Kawamoto H, Sakiyama S, Hosono A, Takayama J, Takaue Y, Murayama S, Sumi M, Kaneko A, Ohira M. Source: Bone Marrow Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15750608&query_hl=9&itool=pubmed_docsum
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A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity. Author(s): Sanchez-Sanchez F, Kruetzfeldt M, Najera C, Mittnacht S. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15643604&query_hl=9&itool=pubmed_docsum
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A retrospective review of visual outcome and complications in the treatment of retinoblastoma. Author(s): O'Doherty M, Lanigan B, Breathnach F, O'Meara A, Gallie B, Chan H, O'Keefe M. Source: Ir Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15782728&query_hl=9&itool=pubmed_docsum
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A second leiomyosarcoma in the urinary bladder of a child with a history of retinoblastoma 12 years following partial cystectomy. Author(s): Brucker B, Ernst L, Meadows A, Zderic S. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16470582&query_hl=9&itool=pubmed_docsum
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Abnormal gene expression profiles in unaffected parents of patients with hereditarytype retinoblastoma. Author(s): Chuang EY, Chen X, Tsai MH, Yan H, Li CY, Mitchell JB, Nagasawa H, Wilson PF, Peng Y, Fitzek MM, Bedford JS, Little JB. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16585164&query_hl=9&itool=pubmed_docsum
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Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma. Author(s): Siffroi-Fernandez S, Cinaroglu A, Fuhrmann-Panfalone V, Normand G, Bugra K, Sahel J, Hicks D. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15767480&query_hl=9&itool=pubmed_docsum
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Age at diagnosis of isolated unilateral retinoblastoma does not distinguish patients with and without a constitutional RB1 gene mutation but is influenced by a parentof-origin effect. Author(s): Schuler A, Weber S, Neuhauser M, Jurklies C, Lehnert T, Heimann H, Rudolph G, Jockel KH, Bornfeld N, Lohmann DR. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763650&query_hl=9&itool=pubmed_docsum
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Allelic loss in a minimal region on chromosome 16q24 is associated with vitreous seeding of retinoblastoma. Author(s): Gratias S, Rieder H, Ullmann R, Klein-Hitpass L, Schneider S, Boloni R, Kappler M, Lohmann DR. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17210724&query_hl=9&itool=pubmed_docsum
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Alterations of the retinoblastoma and p16 pathway correlate with promoter methylation in malignant fibrous histiocytomas. Author(s): Brinck U, Schlott T, Storber S, Stachura J, Bortkiewicz P, Nagel WD, Hasse FM, Cordon-Cardo C, Fischer G, Korabiowska M. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17094467&query_hl=9&itool=pubmed_docsum
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Alternative reading frame supports an alternative model for retinoblastoma. Author(s): Zacksenhaus E. Source: Cell Cycle (Georgetown, Tex.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12695682&query_hl=9&itool=pubmed_docsum
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An aggressive bone marrow evaluation including immunocytology with GD2 for advanced retinoblastoma. Author(s): Chantada GL, Rossi J, Casco F, Fandino A, Scopinaro M, de Davila MT, Abramson DH. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16794505&query_hl=9&itool=pubmed_docsum
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An observational study on retinoblastoma cases attending a medical college in Calcutta. Author(s): Mukhopadhyay S, Ghosh S, Chattopadhyay D, Dutta SK. Source: J Indian Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16856584&query_hl=9&itool=pubmed_docsum
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An oncolytic adenovirus selective for retinoblastoma tumor suppressor protein pathway-defective tumors: dependence on E1A, the E2F-1 promoter, and viral replication for selectivity and efficacy. Author(s): Jakubczak JL, Ryan P, Gorziglia M, Clarke L, Hawkins LK, Hay C, Huang Y, Kaloss M, Marinov A, Phipps S, Pinkstaff A, Shirley P, Skripchenko Y, Stewart D, ForrySchaudies S, Hallenbeck PL. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12670895&query_hl=9&itool=pubmed_docsum
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Analysis of the RB1 gene in children with retinoblastoma having residential connections to West Cumbria, England. Author(s): Cowell JK, Morris JA, Tawn EJ. Source: Journal of Radiological Protection : Official Journal of the Society for Radiological Protection. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15798281&query_hl=9&itool=pubmed_docsum
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Another liveborn after preimplantation genetic diagnosis for retinoblastoma. Author(s): Dommering CJ, Moll AC, Imhof SM, de Die-Smulders CE, Coonen E. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15629325&query_hl=9&itool=pubmed_docsum
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Arrest of mammalian fibroblasts in G1 in response to actin inhibition is dependent on retinoblastoma pocket proteins but not on p53. Author(s): Lohez OD, Reynaud C, Borel F, Andreassen PR, Margolis RL. Source: The Journal of Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12682090&query_hl=9&itool=pubmed_docsum
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Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma. Author(s): Ma HB, Hu HT, Di ZL, Wang ZR, Shi JS, Wang XJ, Li Y. Source: World Journal of Gastroenterology : Wjg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15655836&query_hl=9&itool=pubmed_docsum
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Atrophic chorioretinal scar and focal scleral bowing following thermochemotherapy with a diode laser for retinoblastoma. Author(s): de Graaf P, Castelijns JA, Moll AC, Imhof SM, Schouten-van Meeteren AY. Source: Ophthalmic Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16543200&query_hl=9&itool=pubmed_docsum
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Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma? Author(s): Beck Popovic M, Balmer A, Maeder P, Braganca T, Munier FL. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16003734&query_hl=9&itool=pubmed_docsum
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Beta-ray brachytherapy of retinoblastoma: feasibility of a new small-sized ruthenium-106 plaque. Author(s): Schueler AO, Fluhs D, Anastassiou G, Jurklies C, Sauerwein W, Bornfeld N. Source: Ophthalmic Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16166817&query_hl=9&itool=pubmed_docsum
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Beta-ray brachytherapy with 106Ru plaques for retinoblastoma. Author(s): Schueler AO, Fluhs D, Anastassiou G, Jurklies C, Neuhauser M, Schilling H, Bornfeld N, Sauerwein W. Source: International Journal of Radiation Oncology, Biology, Physics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16682139&query_hl=9&itool=pubmed_docsum
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Bilateral retinoblastoma presenting with simultaneous phthisis bulbi and buphthalmos. Author(s): Harrison D, Richards J, Andronikou S, Welman C. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12795436&query_hl=9&itool=pubmed_docsum
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Bilateral retinoblastoma, microphthalmia, and colobomas in the 13q deletion syndrome. Author(s): Schocket LS, Beaverson KL, Rollins IS, Abramson DH. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12796275&query_hl=9&itool=pubmed_docsum
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Bilateral spontaneously regressed retinoblastoma with preservation of vision. Author(s): Roberts BN, Pilz DT, Walters RF. Source: Eye (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9246292&query_hl=9&itool=pubmed_docsum
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Bilateral sporadic retinoblastoma in a child born after in vitro fertilization. Author(s): Cruysberg JR, Moll AC, Imhof SM. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12470166&query_hl=9&itool=pubmed_docsum
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Binding of phosphatase-1 delta to the retinoblastoma protein pRb involves domains that include substrate recognition residues and a pRB binding motif. Author(s): Bianchi M, Villa-Moruzzi E. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11162467&query_hl=9&itool=pubmed_docsum
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Binding of SV40 large T antigen to the retinoblastoma susceptibility gene product and related proteins. Author(s): Zalvide J, DeCaprio JA, Stubdal H. Source: Methods in Molecular Biology (Clifton, N.J.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11217388&query_hl=9&itool=pubmed_docsum
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Biochemical properties of the stimulatory activity of DNA polymerase alpha by the hyper-phosphorylated retinoblastoma protein. Author(s): Takemura M. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12049795&query_hl=9&itool=pubmed_docsum
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Biotin uptake and cellular translocation in human derived retinoblastoma cell line (Y79): a role of hSMVT system. Author(s): Kansara V, Luo S, Balasubrahmanyam B, Pal D, Mitra AK. Source: International Journal of Pharmaceutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16459033&query_hl=9&itool=pubmed_docsum
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Bone-specific heparan sulfates induce osteoblast growth arrest and downregulation of retinoblastoma protein. Author(s): Manton KJ, Sadasivam M, Cool SM, Nurcombe V. Source: Journal of Cellular Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16826571&query_hl=9&itool=pubmed_docsum
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Boundary detection of retinoblastoma tumors with neural networks. Author(s): Chai MI, Chai A, Sullivan P. Source: Computerized Medical Imaging and Graphics : the Official Journal of the Computerized Medical Imaging Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11179702&query_hl=9&itool=pubmed_docsum
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Boy with bilateral retinoblastoma due to an unusual ring chromosome 13 with activation of a latent centromere. Author(s): Morrissette JD, Celle L, Owens NL, Shields CL, Zackai EH, Spinner NB. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11170089&query_hl=9&itool=pubmed_docsum
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Brain necrosis after enucleation, external beam cobalt radiotherapy, and systemic chemotherapy for retinoblastoma. Author(s): Padula GD, McCormick B, Abramson DH. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11786070&query_hl=9&itool=pubmed_docsum
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Breast cancer metastasis suppressor 1 (BRMS1) forms complexes with retinoblastomabinding protein 1 (RBP1) and the mSin3 histone deacetylase complex and represses transcription. Author(s): Meehan WJ, Samant RS, Hopper JE, Carrozza MJ, Shevde LA, Workman JL, Eckert KA, Verderame MF, Welch DR. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14581478&query_hl=9&itool=pubmed_docsum
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BRG1 controls the activity of the retinoblastoma protein via regulation of p21CIP1/WAF1/SDI. Author(s): Kang H, Cui K, Zhao K. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14729964&query_hl=9&itool=pubmed_docsum
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Brief report: conservative treatment in unilateral retinoblastoma: a preliminary report. Author(s): Hadjistilianou T, Mastrangelo D, De Francesco S, Mazzotta C. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11984807&query_hl=9&itool=pubmed_docsum
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Ca(v)3.1 splice variant expression during neuronal differentiation of Y-79 retinoblastoma cells. Author(s): Bertolesi GE, Walia Da Silva R, Jollimore CA, Shi C, Barnes S, Kelly ME. Source: Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16678971&query_hl=9&itool=pubmed_docsum
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Cancer stem cell characteristics in retinoblastoma. Author(s): Seigel GM, Campbell LM, Narayan M, Gonzalez-Fernandez F. Source: Molecular Vision [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16179903&query_hl=9&itool=pubmed_docsum
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Cavitary changes in retinoblastoma: relationship to chemoresistance. Author(s): Mashayekhi A, Shields CL, Eagle RC Jr, Shields JA. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15885779&query_hl=9&itool=pubmed_docsum
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CDK2 catalytic activity and loss of nuclear tethering of retinoblastoma protein in childhood acute lymphoblastic leukemia. Author(s): Schmitz NM, Leibundgut K, Hirt A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16107892&query_hl=9&itool=pubmed_docsum
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Cell cycle control and beyond: emerging roles for the retinoblastoma gene family. Author(s): Genovese C, Trani D, Caputi M, Claudio PP. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936738&query_hl=9&itool=pubmed_docsum
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Cell cycle-controlled interaction of nucleolin with the retinoblastoma protein and cancerous cell transformation. Author(s): Grinstein E, Shan Y, Karawajew L, Snijders PJ, Meijer CJ, Royer HD, Wernet P. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16698799&query_hl=9&itool=pubmed_docsum
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Cervical cancer and human papillomaviruses: inactivation of retinoblastoma and other tumor suppressor pathways. Author(s): Jones EE, Wells SI. Source: Current Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100604&query_hl=9&itool=pubmed_docsum
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Changes in retinoblastoma gene expression during cervical cancer progression. Author(s): Salcedo M, Taja L, Utrera D, Chavez P, Hidalgo A, Perez C, Benitez L, Castaneda C, Delgado R, Gariglio P. Source: International Journal of Experimental Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12657136&query_hl=9&itool=pubmed_docsum
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Chemotherapy for retinoblastoma. Author(s): Chan HS, Gallie BL, Munier FL, Beck Popovic M. Source: Ophthalmology Clinics of North America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763191&query_hl=9&itool=pubmed_docsum
82
Retinoblastoma
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Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation. Author(s): Ying L, Marino J, Hussain SP, Khan MA, You S, Hofseth AB, Trivers GE, Dixon DA, Harris CC, Hofseth LJ. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16230367&query_hl=9&itool=pubmed_docsum
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Clinical implications of promoter hypermethylation in RASSF1A and MGMT in retinoblastoma. Author(s): Choy KW, Lee TC, Cheung KF, Fan DS, Lo KW, Beaverson KL, Abramson DH, Lam DS, Yu CB, Pang CP. Source: Neoplasia (New York, N.Y.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15799820&query_hl=9&itool=pubmed_docsum
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Clinical presentation of retinoblastoma in Eastern Nepal. Author(s): Badhu B, Sah SP, Thakur SK, Dulal S, Kumar S, Sood A, Das H, Sah RP. Source: Clinical & Experimental Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16033351&query_hl=9&itool=pubmed_docsum
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Constitutional and somatic RB1 mutation spectrum in nonfamilial unilateral and bilateral retinoblastoma in India. Author(s): Bamne MN, Ghule PN, Jose J, Banavali SD, Kurkure PA, Amare Kadam PS. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16225399&query_hl=9&itool=pubmed_docsum
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Continuing challenges in the management of retinoblastoma with chemotherapy. Author(s): Shields CL, Meadows AT, Leahey AM, Shields JA. Source: Retina (Philadelphia, Pa.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15579981&query_hl=9&itool=pubmed_docsum
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Correlation of clinicopathological features with immunohistochemical expression of cell cycle regulatory proteins p16 and retinoblastoma: distinct association with keratinisation and differentiation in oral cavity squamous cell carcinoma. Author(s): Muirhead DM, Hoffman HT, Robinson RA. Source: Journal of Clinical Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16467168&query_hl=9&itool=pubmed_docsum
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Current management of retinoblastoma. Author(s): Gombos DS. Source: Retina (Philadelphia, Pa.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15579979&query_hl=9&itool=pubmed_docsum
Studies
83
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Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells. Author(s): Eckstein LA, Van Quill KR, Bui SK, Uusitalo MS, O'Brien JM. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15728531&query_hl=9&itool=pubmed_docsum
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De novo intraocular retinoblastoma development after chemotherapy in patients with hereditary retinoblastoma. Author(s): Schueler AO, Anastassiou G, Jurklies C, Havers W, Wieland R, Bornfeld N. Source: Retina (Philadelphia, Pa.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16603962&query_hl=9&itool=pubmed_docsum
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Degradation of E2F by the ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. Author(s): Hateboer G, Kerkhoven RM, Shvarts A, Bernards R, Beijersbergen RL. Source: Genes & Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8956997&query_hl=9&itool=pubmed_docsum
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Dehydroepiandrosterone inhibits the proliferation of human umbilical vein endothelial cells by enhancing the expression of p53 and p21, restricting the phosphorylation of retinoblastoma protein, and is androgen- and estrogen-receptor independent. Author(s): Zapata E, Ventura JL, De la Cruz K, Rodriguez E, Damian P, Masso F, Montano LF, Lopez-Marure R. Source: Febs J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15752352&query_hl=9&itool=pubmed_docsum
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Dephosphorylated C/EBPalpha accelerates cell proliferation through sequestering retinoblastoma protein. Author(s): Wang GL, Timchenko NA. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15684384&query_hl=9&itool=pubmed_docsum
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Destruction of human retinoblastoma after treatment by the E variant of encephalomyocarditis virus. Author(s): Adachi M, Brooks SE, Stein MR, Franklin BE, Caccavo FA. Source: Journal of Neuro-Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16528457&query_hl=9&itool=pubmed_docsum
84
Retinoblastoma
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Detection of allelic imbalance in the gene expression of hMSH2 or RB1 in lymphocytes from pedigrees of hereditary, nonpolyposis, colorectal cancer and retinoblastoma by an RNA difference plot. Author(s): Murakami Y, Isogai K, Tomita H, Sakurai-Yageta M, Maruyama T, Hidaka A, Nose K, Sugano K, Kaneko A. Source: Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15480874&query_hl=9&itool=pubmed_docsum
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Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization. Author(s): Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE, Radlwimmer B, Lohmann DR, Lichter P. Source: Genes, Chromosomes & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15834944&query_hl=9&itool=pubmed_docsum
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Detection of germline mutations in argentine retinoblastoma patients: low and full penetrance retinoblastoma caused by the same germline truncating mutation. Author(s): Dalamon V, Surace E, Giliberto F, Ferreiro V, Fernandez C, Szijan I. Source: J Biochem Mol Biol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15469703&query_hl=9&itool=pubmed_docsum
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Diagnosis and current management of retinoblastoma. Author(s): Balmer A, Zografos L, Munier F. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936756&query_hl=9&itool=pubmed_docsum
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Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via the retinoblastoma pathway. Author(s): Gulmann C, Hegarty H, Grace A, Leader M, Patchett S, Kay E. Source: World Journal of Gastroenterology : Wjg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14695761&query_hl=9&itool=pubmed_docsum
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Differential response at the hGABP/E4TF1 site of retinoblastoma gene promoter in human testicular seminoma cells. Author(s): Shiraishi T, Yoshida T, Nakata S, Horinaka M, Wakada M, Mizutani Y, Miki T, Sakai T. Source: Oncol Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15809752&query_hl=9&itool=pubmed_docsum
Studies
85
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Difficulties in screening for retinoblastoma. Author(s): Wagner RS. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16121548&query_hl=9&itool=pubmed_docsum
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Direct binding of apoptosis signal-regulating kinase 1 to retinoblastoma protein: novel links between apoptotic signaling and cell cycle machinery. Author(s): Dasgupta P, Betts V, Rastogi S, Joshi B, Morris M, Brennan B, Ordonez-Ercan D, Chellappan S. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15210709&query_hl=9&itool=pubmed_docsum
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Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein-dependent and -independent pathways by cyclin-dependent kinase 4/6. Author(s): Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, TamamoriAdachi M, Miyasaka N, Kohsaka H. Source: Arthritis and Rheumatism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16802342&query_hl=9&itool=pubmed_docsum
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Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression. Author(s): Braden WA, Lenihan JM, Lan Z, Luce KS, Zagorski W, Bosco E, Reed MF, Cook JG, Knudsen ES. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908528&query_hl=9&itool=pubmed_docsum
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Distinct mechanisms for repression of RNA polymerase III transcription by the retinoblastoma tumor suppressor protein. Author(s): Hirsch HA, Jawdekar GW, Lee KA, Gu L, Henry RW. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15199152&query_hl=9&itool=pubmed_docsum
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Down-regulation of p21WAF1 promotes apoptosis in senescent human fibroblasts: involvement of retinoblastoma protein phosphorylation and delay of cellular aging. Author(s): Huang Y, Corbley MJ, Tang Z, Yang L, Peng Y, Zhang ZY, Tong TJ. Source: Journal of Cellular Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15389598&query_hl=9&itool=pubmed_docsum
86
Retinoblastoma
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Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Author(s): Munakata T, Nakamura M, Liang Y, Li K, Lemon SM. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16332962&query_hl=9&itool=pubmed_docsum
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Effect of promoter methylation of the p16 gene on phosphorylation of retinoblastoma gene product and growth of hepatocellular carcinoma cells. Author(s): Maeta Y, Shiota G, Okano J, Murawaki Y. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16254459&query_hl=9&itool=pubmed_docsum
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Effects of celecoxib in human retinoblastoma cell lines and in a transgenic murine model of retinoblastoma. Author(s): Tong CT, Howard SA, Shah HR, Van Quill KR, Lin ET, Grossniklaus HE, O'Brien JM. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16113385&query_hl=9&itool=pubmed_docsum
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Embryo screening approved for retinoblastoma. Author(s): Thornhill C. Source: The Lancet Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16229100&query_hl=9&itool=pubmed_docsum
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Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase. Author(s): Knight JS, Sharma N, Robertson ES. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16352731&query_hl=9&itool=pubmed_docsum
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Estimating the incidence of retinoblastoma in Texas. Author(s): Gombos DS, Diba R. Source: Tex Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16152911&query_hl=9&itool=pubmed_docsum
Studies
87
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Estrogen receptor isoform-specific regulation of the retinoblastoma-binding protein 1 (RBBP1) gene: roles of AF1 and enhancer elements. Author(s): Monroe DG, Secreto FJ, Hawse JR, Subramaniam M, Khosla S, Spelsberg TC. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16873370&query_hl=9&itool=pubmed_docsum
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Evidence of human papillomavirus infection, enhanced phosphorylation of retinoblastoma protein, and decreased apoptosis in sarcomatoid squamous cell carcinoma of uterine cervix. Author(s): Lin CP, Ho CL, Shen MR, Huang LH, Chou CY. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16445655&query_hl=9&itool=pubmed_docsum
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Evolutionary history of the retinoblastoma gene from archaea to eukarya. Author(s): Takemura M. Source: Bio Systems. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16181730&query_hl=9&itool=pubmed_docsum
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Exposure of orbital implants wrapped with polyester-urethane after enucleation for advanced retinoblastoma. Author(s): Heimann H, Bechrakis NE, Zepeda LC, Coupland SE, Hellmich M, Foerster MH. Source: Ophthalmic Plastic and Reconstructive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15778666&query_hl=9&itool=pubmed_docsum
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Expression analysis of 6p22 genomic gain in retinoblastoma. Author(s): Orlic M, Spencer CE, Wang L, Gallie BL. Source: Genes, Chromosomes & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16180235&query_hl=9&itool=pubmed_docsum
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Expression of cdc2 and p27(KIP1) phosphorylation in mitotic cells of the human retinoblastoma. Author(s): Kase S, Yoshida K, Ohgami K, Shiratori K, Suzuki Y, Nakayama KI, Ohno S. Source: International Journal of Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16465393&query_hl=9&itool=pubmed_docsum
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Expression of cone photoreceptor cGMP-phosphodiesterase alpha' subunit in Chinese hamster ovary, 293 human embryonic kidney, and Y79 retinoblastoma cells. Author(s): Piriev NI, Yamashita CK, Shih J, Farber DB. Source: Molecular Vision [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12655284&query_hl=9&itool=pubmed_docsum
88
Retinoblastoma
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Expression of costimulatory molecules on human retinoblastoma cells Y-79: functional expression of CD40 and B7H1. Author(s): Usui Y, Okunuki Y, Hattori T, Takeuchi M, Kezuka T, Goto H, Usui M. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17003458&query_hl=9&itool=pubmed_docsum
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Expression of p27(KIP1) and cell proliferation in human retina and retinoblastoma. Author(s): Kase S, Yoshida K, Ohgami K, Shiratori K, Harada T, Ohno S. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16309169&query_hl=9&itool=pubmed_docsum
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Expression of retinoblastoma and p53 pathway-related proteins in resectable invasive ductal carcinoma of the pancreas: potential cooperative effects on clinical outcome. Author(s): Hashimoto K, Nio Y, Koike M, Itakura M, Yano S, Higami T, Maruyama R. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15865092&query_hl=9&itool=pubmed_docsum
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Expression of retinoblastoma protein and P16 proteins in classic Hodgkin lymphoma: relationship with expression of p53 and presence of Epstein-Barr virus in the regulation of cell growth and death. Author(s): Kim LH, Peh SC, Poppema S. Source: Human Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16360421&query_hl=9&itool=pubmed_docsum
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Expression of retinoblastoma protein in breast cancer metastases to sentinel nodes: evaluation of its role as a marker for the presence of metastases in non-sentinel axillary nodes, and comparison to p16INK4a. Author(s): Grupka NL, Bloom C, Singh M. Source: Applied Immunohistochemistry & Molecular Morphology : Aimm / Official Publication of the Society for Applied Immunohistochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16540733&query_hl=9&itool=pubmed_docsum
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Expression of retinoblastoma protein in human growth hormone-secreting pituitary adenomas. Author(s): Donangelo I, Marcos HP, Araujo PB, Marcondes J, Filho PN, Gadelha M, Chimelli L. Source: Endocrine Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16000847&query_hl=9&itool=pubmed_docsum
Studies
89
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Extensively necrotic retinoblastoma is associated with high-risk prognostic factors. Author(s): Chong EM, Coffee RE, Chintagumpala M, Hurwitz RL, Hurwitz MY, Chevez-Barrios P. Source: Archives of Pathology & Laboratory Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17076529&query_hl=9&itool=pubmed_docsum
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Failure to detect mutations in the retinoblastoma protein-binding domain of the transcription factor E2F-1 in human cancers. Author(s): Nakamura T, Monden Y, Kawashima K, Naruke T, Nishimura S. Source: Japanese Journal of Cancer Research : Gann. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9045954&query_hl=9&itool=pubmed_docsum
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Familial risks for eye melanoma and retinoblastoma: results from the Swedish Family-Cancer Database. Author(s): Hemminki K, Chen B. Source: Melanoma Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16567975&query_hl=9&itool=pubmed_docsum
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Fine needle aspiration biopsy (FNAB) for retinoblastoma. Author(s): Karcioglu ZA. Source: Retina (Philadelphia, Pa.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12476095&query_hl=9&itool=pubmed_docsum
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First preimplantation genetic diagnosis of hereditary retinoblastoma using informative microsatellite markers. Author(s): Girardet A, Hamamah S, Anahory T, Dechaud H, Sarda P, Hedon B, Demaille J, Claustres M. Source: Molecular Human Reproduction. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12569181&query_hl=9&itool=pubmed_docsum
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Five novel single nucleotide polymorphisms of the RB1 gene (g.5625T>C, g.70169T>G, g.76875A>T, g.78026delA, and g.150072T>C) in retinoblastoma patients. Author(s): Alonso J, Moreno C, Lopez A, Mendiola M, Garcia-Miguel P, Abelairas J, Sarret E, Vendrell MT, Navajas A, Pestana A. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11317369&query_hl=9&itool=pubmed_docsum
90
Retinoblastoma
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Fluorine-18 fluorodeoxyglucose positron emission tomography (PET) to detect vital retinoblastoma in the eye: preliminary experience. Author(s): Moll AC, Hoekstra OS, Imhof SM, Comans EF, Schouten-van Meeteren AY, van der Valk P, Boers M. Source: Ophthalmic Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15255112&query_hl=9&itool=pubmed_docsum
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FMS (CSF-1 receptor) prolongs cell cycle and promotes retinoic acid-induced hypophosphorylation of retinoblastoma protein, G1 arrest, and cell differentiation. Author(s): Yen A, Sturgill R, Varvayanis S, Chern R. Source: Experimental Cell Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8940255&query_hl=9&itool=pubmed_docsum
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Focal stereotactic external beam radiotherapy as a vision-sparing method for the treatment of peripapillary and perimacular retinoblastoma: preliminary results. Author(s): Sahgal A, Millar BA, Michaels H, Jaywant S, Chan HS, Heon E, Gallie B, Laperriere N. Source: Clin Oncol (R Coll Radiol). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17051954&query_hl=9&itool=pubmed_docsum
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Footprinting the 'essential regulatory region' of the retinoblastoma gene promoter in intact human cells. Author(s): Temple MD, Murray V. Source: The International Journal of Biochemistry & Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15618023&query_hl=9&itool=pubmed_docsum
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For whom the bell tolls: susceptibility to common adult cancers in retinoblastoma survivors. Author(s): Kaye FJ, Harbour JW. Source: Journal of the National Cancer Institute. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14996847&query_hl=9&itool=pubmed_docsum
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Formation of the G-quadruplex and i-motif structures in retinoblastoma susceptibility genes (Rb). Author(s): Xu Y, Sugiyama H. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16464825&query_hl=9&itool=pubmed_docsum
Studies
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Free orbital fat graft to prevent porous polyethylene orbital implant exposure in patients with retinoblastoma. Author(s): Kim NJ, Choung HK, Khwarg SI, Yu YS. Source: Ophthalmic Plastic and Reconstructive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16052135&query_hl=9&itool=pubmed_docsum
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Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma. Author(s): Orjuela MA, Titievsky L, Liu X, Ramirez-Ortiz M, Ponce-Castaneda V, Lecona E, Molina E, Beaverson K, Abramson DH, Mueller NE. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15941952&query_hl=9&itool=pubmed_docsum
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Functional characterization of JMJD2A, a histone deacetylase- and retinoblastomabinding protein. Author(s): Gray SG, Iglesias AH, Lizcano F, Villanueva R, Camelo S, Jingu H, Teh BT, Koibuchi N, Chin WW, Kokkotou E, Dangond F. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15927959&query_hl=9&itool=pubmed_docsum
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Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein. Author(s): Balasenthil S, Vadlamudi RK. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12682072&query_hl=9&itool=pubmed_docsum
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Functional results after treatment of retinoblastoma. Author(s): Desjardins L, Chefchaouni MC, Lumbroso L, Levy C, Asselain B, Bours D, Vedrenne J, Zucker JM, Doz F. Source: Journal of Aapos : the Official Publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11997807&query_hl=9&itool=pubmed_docsum
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Further characterization of human mucin-like glycoprotein associated with photoreceptor cells by its introduction into Y79 retinoblastoma cells. Author(s): Yamashita T, Uehara F, Ozawa M, Ohba N. Source: Ophthalmic Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11914608&query_hl=9&itool=pubmed_docsum
92
Retinoblastoma
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G1 cell cycle arrest due to the inhibition of erbB family receptor tyrosine kinases does not require the retinoblastoma protein. Author(s): Gonzales AJ, Fry DW. Source: Experimental Cell Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15572027&query_hl=9&itool=pubmed_docsum
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Gadolinium enhancement: improved MRI detection of retinoblastoma extension into the optic nerve. Author(s): Ainbinder DJ, Haik BG, Frei DF, Gupta KL, Mafee MF. Source: Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8957804&query_hl=9&itool=pubmed_docsum
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Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Author(s): Grasemann C, Gratias S, Stephan H, Schuler A, Schramm A, Klein-Hitpass L, Rieder H, Schneider S, Kappes F, Eggert A, Lohmann DR. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16007192&query_hl=9&itool=pubmed_docsum
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Gene environment interactions in a cohort of irradiated retinoblastoma patients. Author(s): Kleinerman RA, Stovall M, Tarone RE, Tucker MA. Source: Radiation Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16044502&query_hl=9&itool=pubmed_docsum
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Gene expression networks underlying retinoic acid-induced differentiation of human retinoblastoma cells. Author(s): Li A, Zhu X, Brown B, Craft CM. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12601020&query_hl=9&itool=pubmed_docsum
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Genetic alterations on chromosome 19, 20, 21, 22, and X detected by loss of heterozygosity analysis in retinoblastoma. Author(s): Huang Q, Choy KW, Cheung KF, Lam DS, Fu WL, Pang CP. Source: Molecular Vision [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14551532&query_hl=9&itool=pubmed_docsum
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Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach. Author(s): Tosi GM, Trimarchi C, Macaluso M, La Sala D, Ciccodicola A, Lazzi S, Massaro-Giordano M, Caporossi A, Giordano A, Cinti C. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16007224&query_hl=9&itool=pubmed_docsum
Studies
93
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Genetic profile of 81 retinoblastoma patients from a referral hospital in southern India. Author(s): Harini R, Ata-ur-Rasheed M, Shanmugam MP, Amali J, Das D, Kumaramanickavel G. Source: Indian J Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15887714&query_hl=9&itool=pubmed_docsum
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Genetic teaching for the retinoblastoma patient. Author(s): Servodidio CA, Abramson DH. Source: Insight (American Society of Ophthalmic Registered Nurses). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9392772&query_hl=9&itool=pubmed_docsum
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Genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma. Author(s): Lefevre SH, Vogt N, Dutrillaux AM, Chauveinc L, Stoppa-Lyonnet D, Doz F, Desjardins L, Dutrillaux B, Chevillard S, Malfoy B. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11781822&query_hl=9&itool=pubmed_docsum
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Genomic amplification in retinoblastoma narrowed to 0.6 megabase on chromosome 6p containing a kinesin-like gene, RBKIN. Author(s): Chen D, Pajovic S, Duckett A, Brown VD, Squire JA, Gallie BL. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11861365&query_hl=9&itool=pubmed_docsum
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Genomic gains on chromosome 1q in retinoblastoma: consequences on gene expression and association with clinical manifestation. Author(s): Gratias S, Schuler A, Hitpass LK, Stephan H, Rieder H, Schneider S, Horsthemke B, Lohmann DR. Source: International Journal of Cancer. Journal International Du Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15825178&query_hl=9&itool=pubmed_docsum
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Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma. Author(s): Kato MV, Shimizu T, Nagayoshi M, Kaneko A, Sasaki MS, Ikawa Y. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8900237&query_hl=9&itool=pubmed_docsum
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Glaucoma in retinoblastoma. Author(s): de Leon JM, Walton DS, Latina MA, Mercado GV. Source: Seminars in Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16352492&query_hl=9&itool=pubmed_docsum
94
Retinoblastoma
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Globe conserving treatment of the only eye in bilateral retinoblastoma. Author(s): Lee V, Hungerford JL, Bunce C, Ahmed F, Kingston JE, Plowman PN. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14609838&query_hl=9&itool=pubmed_docsum
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Glucocorticoids induce G1 arrest of lymphoblastic cells through retinoblastoma protein Rb1 dephosphorylation in childhood acute lymphoblastic leukemia in vivo. Author(s): Addeo R, Casale F, Caraglia M, D'Angelo V, Crisci S, Abbruzzese A, Di Tullio MT, Indolfi P. Source: Cancer Biology & Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15034294&query_hl=9&itool=pubmed_docsum
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Glucose-regulated stresses cause decreased expression of cyclin D1 and hypophosphorylation of retinoblastoma protein in human cancer cells. Author(s): Tomida A, Suzuki H, Kim HD, Tsuruo T. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9000144&query_hl=9&itool=pubmed_docsum
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Glycosaminoglycans in human retinoblastoma cells: heparan sulfate, a modulator of the pigment epithelium-derived factor-receptor interactions. Author(s): Alberdi EM, Weldon JE, Becerra SP. Source: Bmc Biochemistry [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12625842&query_hl=9&itool=pubmed_docsum
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Grasses like mammals? Redundancy and compensatory regulation within the retinoblastoma protein family. Author(s): Sabelli PA, Larkins BA. Source: Cell Cycle (Georgetown, Tex.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16479170&query_hl=9&itool=pubmed_docsum
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Growth control by the retinoblastoma gene family. Author(s): Paggi MG, Felsani A, Giordano A. Source: Methods in Molecular Biology (Clifton, N.J.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12710677&query_hl=9&itool=pubmed_docsum
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Hereditary retinoblastoma, lipoma, and second primary cancers. Author(s): Li FP, Abramson DH, Tarone RE, Kleinerman RA, Fraumeni JF Jr, Boice JD Jr. Source: Journal of the National Cancer Institute. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8978411&query_hl=9&itool=pubmed_docsum
Studies
95
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Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plk1. Author(s): Gunawardena RW, Siddiqui H, Solomon DA, Mayhew CN, Held J, Angus SP, Knudsen ES. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15105433&query_hl=9&itool=pubmed_docsum
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High level amplification of N-MYC is not associated with adverse histology or outcome in primary retinoblastoma tumours. Author(s): Lillington DM, Goff LK, Kingston JE, Onadim Z, Price E, Domizio P, Young BD. Source: British Journal of Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12232763&query_hl=9&itool=pubmed_docsum
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Higher vessel densities in retinoblastoma with local invasive growth and metastasis. Author(s): Rossler J, Dietrich T, Pavlakovic H, Schweigerer L, Havers W, Schuler A, Bornfeld N, Schilling H. Source: American Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14742245&query_hl=9&itool=pubmed_docsum
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High-frequency ultrasound of anterior segment retinoblastoma. Author(s): Finger PT, Meskin SW, Wisnicki HJ, Albekioni Z, Schneider S. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15126167&query_hl=9&itool=pubmed_docsum
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High-throughput screening for the identification of small-molecule inhibitors of retinoblastoma protein phosphorylation in cells. Author(s): Barrie SE, Eno-Amooquaye E, Hardcastle A, Platt G, Richards J, Bedford D, Workman P, Aherne W, Mittnacht S, Garrett MD. Source: Analytical Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12895470&query_hl=9&itool=pubmed_docsum
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Histological indicators of prognosis in glioblastomas: retinoblastoma protein expression and oligodendroglial differentiation indicate improved survival. Author(s): Hilton DA, Penney M, Pobereskin L, Sanders H, Love S. Source: Histopathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15186270&query_hl=9&itool=pubmed_docsum
96
Retinoblastoma
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Histopathologic analysis of 232 eyes with retinoblastoma conducted in an Indian tertiary-care ophthalmic center. Author(s): Biswas J, Das D, Krishnakumar S, Shanmugam MP. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14560832&query_hl=9&itool=pubmed_docsum
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Histopathologic features of retinoblastoma and its relation with in vitro drug resistance measured by means of the MTT assay. Author(s): Schouten-van Meeteren AY, van der Valk P, van der Linden HC, Moll AC, Imhof SM, Huismans DR, Loonen AH, Veerman AJ. Source: Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11753969&query_hl=9&itool=pubmed_docsum
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Histopathological features and P-glycoprotein expression in retinoblastoma. Author(s): Filho JP, Correa ZM, Odashiro AN, Coutinho AB, Martins MC, Erwenne CM, Burnier MN Jr. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16186322&query_hl=9&itool=pubmed_docsum
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How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein. Author(s): Goodrich DW. Source: Journal of Cellular Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14502556&query_hl=9&itool=pubmed_docsum
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Human cytomegalovirus pp71: a new viral tool to probe the mechanisms of cell cycle progression and oncogenesis controlled by the retinoblastoma family of tumor suppressors. Author(s): Kalejta RF. Source: Journal of Cellular Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15352160&query_hl=9&itool=pubmed_docsum
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Human lactoferrin controls the level of retinoblastoma protein and its activity. Author(s): Son HJ, Lee SH, Choi SY. Source: Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936805&query_hl=9&itool=pubmed_docsum
Studies
97
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Human papillomavirus type 16 E6 promotes retinoblastoma protein phosphorylation and cell cycle progression. Author(s): Malanchi I, Accardi R, Diehl F, Smet A, Androphy E, Hoheisel J, Tommasino M. Source: Journal of Virology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15564485&query_hl=9&itool=pubmed_docsum
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Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members. Author(s): Duensing S, Munger K. Source: Journal of Virology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14581569&query_hl=9&itool=pubmed_docsum
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Human papillomavirus type 16 E7 up-regulates AKT activity through the retinoblastoma protein. Author(s): Menges CW, Baglia LA, Lapoint R, McCance DJ. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16740689&query_hl=9&itool=pubmed_docsum
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Human pituitary adenomas infrequently contain inactivation of retinoblastoma 1 gene and activation of cyclin dependent kinase 4 gene. Author(s): Honda S, Tanaka-Kosugi C, Yamada S, Sano T, Matsumoto T, Itakura M, Yoshimoto K. Source: Endocrine Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12940460&query_hl=9&itool=pubmed_docsum
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Human retinoblastoma cells are resistant to apoptosis induced by death receptors: role of caspase-8 gene silencing. Author(s): Poulaki V, Mitsiades CS, McMullan C, Fanourakis G, Negri J, Goudopoulou A, Halikias IX, Voutsinas G, Tseleni-Balafouta S, Miller JW, Mitsiades N. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15623796&query_hl=9&itool=pubmed_docsum
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Hyaluronic acid induces survival and proliferation of human myeloma cells through an interleukin-6-mediated pathway involving the phosphorylation of retinoblastoma protein. Author(s): Vincent T, Jourdan M, Sy MS, Klein B, Mechti N. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11278272&query_hl=9&itool=pubmed_docsum
98
Retinoblastoma
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Identification of 26 new constitutional RB1 gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients. Author(s): Alonso J, Frayle H, Menendez I, Lopez A, Garcia-Miguel P, Abelairas J, Sarret E, Vendrell MT, Navajas A, Artigas M, Indiano JM, Carbone A, Torrenteras C, Palacios I, Pestana A. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15605413&query_hl=9&itool=pubmed_docsum
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Immunohistochemical detection of multidrug-resistant protein expression in retinoblastoma treated by primary enucleation. Author(s): Wilson MW, Fraga CH, Fuller CE, Rodriguez-Galindo C, Mancini J, Hagedorn N, Leggas ML, Stewart CF. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16565357&query_hl=9&itool=pubmed_docsum
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Immunohistochemical detection of retinoblastoma protein and E2 promoter-binding factor-1 in ameloblastomas. Author(s): Kumamoto H, Ooya K. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16454815&query_hl=9&itool=pubmed_docsum
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Impact on survivors of retinoblastoma when informed of study results on risk of second cancers. Author(s): Schulz CJ, Riddle MP, Valdimirsdottir HB, Abramson DH, Sklar CA. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12764741&query_hl=9&itool=pubmed_docsum
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Inactivation of the p53 pathway in retinoblastoma. Author(s): Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C, Teunisse A, Lam S, Ramos Y, Mohan A, Johnson D, Wilson M, Rodriguez-Galindo C, Quarto M, Francoz S, Mendrysa SM, Guy RK, Marine JC, Jochemsen AG, Dyer MA. Source: Nature. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17080083&query_hl=9&itool=pubmed_docsum
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Inhibition of histone deacetylation by butyrate induces morphological changes in Y79 retinoblastoma cells. Author(s): Karasawa Y, Okisaka S. Source: Japanese Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15592778&query_hl=9&itool=pubmed_docsum
Studies
99
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Inhibition of retinoblastoma tumor suppressor activity by RNA interference in lung cancer lines. Author(s): Reed MF, Zagorski WA, Howington JA, Zilfou JT, Knudsen ES. Source: The Annals of Thoracic Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16798224&query_hl=9&itool=pubmed_docsum
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Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCdelta-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Author(s): Vucenik I, Ramakrishna G, Tantivejkul K, Anderson LM, Ramljak D. Source: Breast Cancer Research and Treatment. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15868430&query_hl=9&itool=pubmed_docsum
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Insights from animal models on the origins and progression of retinoblastoma. Author(s): Pacal M, Bremner R. Source: Current Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100602&query_hl=9&itool=pubmed_docsum
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Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses. Author(s): White MK, Khalili K. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936749&query_hl=9&itool=pubmed_docsum
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Intraocular cysticercosis simulating retinoblastoma in a 5-year-old child. Author(s): Agarwal B, Vemuganti GK, Honavar SG. Source: Eye (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12724724&query_hl=9&itool=pubmed_docsum
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Intraocular retinoblastoma: the case for a new group classification. Author(s): Linn Murphree A. Source: Ophthalmology Clinics of North America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763190&query_hl=9&itool=pubmed_docsum
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Intraocular surgery after treatment of germline retinoblastoma. Author(s): Moshfeghi DM, Wilson MW, Grizzard S, Haik BG. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16009848&query_hl=9&itool=pubmed_docsum
100
Retinoblastoma
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Intraosseous embryonal rhabdomyosarcoma as a second neoplasm following retinoblastoma. Author(s): Hwang JC, Ko JY, Hsiao CC, Chen WJ, Huang CC. Source: Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16373234&query_hl=9&itool=pubmed_docsum
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In-vitro fertilisation and retinoblastoma. Author(s): Moll AC, Imhof SM, Schouten-van Meeteren AY, van Leeuwen FE. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12711501&query_hl=9&itool=pubmed_docsum
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Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma. Author(s): Schmack I, Hubbard GB, Kang SJ, Aaberg TM Jr, Grossniklaus HE. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16876514&query_hl=9&itool=pubmed_docsum
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Isolation of the retinoblastoma cDNA from the marine flatfish dab (Limanda limanda) and evidence of mutational alterations in liver tumors. Author(s): Du Corbier FA, Stentiford GD, Lyons BP, Rotchell JM. Source: Environmental Science & Technology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16475367&query_hl=9&itool=pubmed_docsum
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IVF and retinoblastoma. Author(s): BenEzra D. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15722334&query_hl=9&itool=pubmed_docsum
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Jumonji regulates cardiomyocyte proliferation via interaction with retinoblastoma protein. Author(s): Jung J, Kim TG, Lyons GE, Kim HR, Lee Y. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15870077&query_hl=9&itool=pubmed_docsum
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Karyotyping in retinoblastoma--a statistical approach. Author(s): Joseph B, Paul PG, Elamparithi A, Roy J, Vidhya A, Shanmugam MP, Kumaramanickavel G. Source: Asian Pac J Cancer Prev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16435993&query_hl=9&itool=pubmed_docsum
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101
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Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitorinduced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells. Author(s): Wallick CJ, Gamper I, Thorne M, Feith DJ, Takasaki KY, Wilson SM, Seki JA, Pegg AE, Byus CV, Bachmann AS. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16007177&query_hl=9&itool=pubmed_docsum
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Kinetic characterization of the human retinoblastoma protein bipartite nuclear localization sequence (NLS) in vivo and in vitro. A comparison with the SV40 large Tantigen NLS. Author(s): Efthymiadis A, Shao H, Hubner S, Jans DA. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9268357&query_hl=9&itool=pubmed_docsum
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Kinetic properties of nuclear transport conferred by the retinoblastoma (Rb) NLS. Author(s): Hu W, Kemp BE, Jans DA. Source: Journal of Cellular Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15838894&query_hl=9&itool=pubmed_docsum
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Lack of efficacy of dilated screening for retinoblastoma. Author(s): Khan AO, Al-Mesfer S. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16121549&query_hl=9&itool=pubmed_docsum
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Lamina-associated polypeptide 2alpha regulates cell cycle progression and differentiation via the retinoblastoma-E2F pathway. Author(s): Dorner D, Vlcek S, Foeger N, Gajewski A, Makolm C, Gotzmann J, Hutchison CJ, Foisner R. Source: The Journal of Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16606692&query_hl=9&itool=pubmed_docsum
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Late-onset retinoblastoma in a well-functioning fellow eye. Author(s): de Jong PT, Mooy CM, Stoter G, Eijkenboom WM, Luyten GP. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16631255&query_hl=9&itool=pubmed_docsum
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Leiomyosarcoma of the bladder in a 16-year-old girl with a history of cyclophosphamide therapy for bilateral retinoblastoma during infancy. Author(s): Al-Zahrani AA, Kamal BA, Eldarawani HM, Hashim TM. Source: Saudi Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16598333&query_hl=9&itool=pubmed_docsum
102
Retinoblastoma
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Leiomyosarcoma of the distal femur in a patient with a history of bilateral retinoblastoma: a case report and review of the literature. Author(s): Ryan RS, Gee R, O'Connell JX, Harris AC, Munk PL. Source: Skeletal Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12759785&query_hl=9&itool=pubmed_docsum
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Limited redundancy in phosphorylation of retinoblastoma tumor suppressor protein by cyclin-dependent kinases in acute lymphoblastic leukemia. Author(s): Schmitz NM, Hirt A, Aebi M, Leibundgut K. Source: American Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936279&query_hl=9&itool=pubmed_docsum
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Long-term survival after recurrent retinoblastoma and second malignancy with massive lung metastasis. Author(s): Hajnzic TF, Marotti M, Vrsalovic R. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15309622&query_hl=9&itool=pubmed_docsum
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Loss of 10p material in a child with human papillomavirus-positive disseminated bilateral retinoblastoma. Author(s): Espinoza JP, Cardenas VJ, Luna CA, Fuentes HM, Camacho GV, Carrera FM, Garcia JR. Source: Cancer Genetics and Cytogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16102585&query_hl=9&itool=pubmed_docsum
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Loss of p75 neurotrophin receptor expression accompanies malignant progression to human and murine retinoblastoma. Author(s): Dimaras H, Coburn B, Pajovic S, Gallie BL. Source: Molecular Carcinogenesis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16555252&query_hl=9&itool=pubmed_docsum
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Management of advanced retinoblastoma. Author(s): Honavar SG, Singh AD. Source: Ophthalmology Clinics of North America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763192&query_hl=9&itool=pubmed_docsum
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Management of porous polyethylene implant exposure in patients with retinoblastoma following enucleation. Author(s): Kim JH, Khwarg SI, Choung HK, Yu YS. Source: Ophthalmic Surgery, Lasers & Imaging : the Official Journal of the International Society for Imaging in the Eye. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15580966&query_hl=9&itool=pubmed_docsum
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103
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Membrane depolarization stimulates the proliferation of SH-SY5Y human neuroblastoma cells by increasing retinoblastoma protein (RB) phosphorylation through the activation of cyclin-dependent kinase 2 (Cdk2). Author(s): Seo M, Kim Y, Lee YI, Kim SY, Ahn YM, Kang UG, Roh MS, Kim YS, Juhnn YS. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16824683&query_hl=9&itool=pubmed_docsum
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Metastatic retinoblastoma clinical features, treatment, and prognosis. Author(s): Gunduz K, Muftuoglu O, Gunalp I, Unal E, Tacyildiz N. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16828510&query_hl=9&itool=pubmed_docsum
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Metastatic retinoblastoma of the maxilla and mandible. Author(s): Taguchi A, Suei Y, Ogawa I, Naito K, Nagasaki T, Lee K, Fujita M, Tanimoto K. Source: Dento Maxillo Facial Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15829698&query_hl=9&itool=pubmed_docsum
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Minimally invasive method for repair of rhegmatogenous retinal detachment following treatment for retinoblastoma. Author(s): Buerk BM, Lai WW, Sharma MC, Shapiro MJ. Source: Ophthalmic Surgery, Lasers & Imaging : the Official Journal of the International Society for Imaging in the Eye. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16468560&query_hl=9&itool=pubmed_docsum
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Mothers' perceptions of children's quality of life following early diagnosis and treatment for retinoblastoma (Rb). Author(s): Sheppard L, Eiser C, Kingston J. Source: Child: Care, Health and Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15715692&query_hl=9&itool=pubmed_docsum
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Mutually exclusive expression of the L and M pigment genes in the human retinoblastoma cell line WERI: Resetting by cell division. Author(s): Deeb SS, Liu Y, Hayashi T. Source: Visual Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16961969&query_hl=9&itool=pubmed_docsum
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Naturally death-resistant precursor cells revealed as the origin of retinoblastoma. Author(s): Trinh E, Lazzerini Denchi E, Helin K. Source: Cancer Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15193252&query_hl=9&itool=pubmed_docsum
104
Retinoblastoma
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Need for high-quality studies in health technology assessments: the case of a systematic review of treatment for retinoblastoma. Author(s): McDaid CM, Hartley S, Bagnall AM, Ritchie G, Light K, Riemsma RP. Source: International Journal of Technology Assessment in Health Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16984673&query_hl=9&itool=pubmed_docsum
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New RB1 oncogenic mutations and intronic polymorphisms in Serbian retinoblastoma patients: genetic counseling implications. Author(s): Kontic M, Palacios I, Gamez A, Camino I, Latkovic Z, Rasic D, Krstic V, Bunjevacki V, Alonso J, Pestana A. Source: Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16972022&query_hl=9&itool=pubmed_docsum
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New retinoblastoma tumor formation in children initially treated with systemic carboplatin. Author(s): Lee TC, Hayashi NI, Dunkel IJ, Beaverson K, Novetsky D, Abramson DH. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14522776&query_hl=9&itool=pubmed_docsum
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Nm23 expression in retinoblastoma. Author(s): Krishnakumar S, Lakshmi A, Shanmugam MP, Vanitha K, Biswas J. Source: Ocular Immunology and Inflammation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15512982&query_hl=9&itool=pubmed_docsum
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Nonocular second primary tumors after retinoblastoma: retrospective study of 111 patients treated by electron beam radiotherapy with or without TEM. Author(s): Schlienger P, Campana F, Vilcoq JR, Asselain B, Dendale R, Desjardins L, Dorval T, Quintana E, Rodriguez J. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15289737&query_hl=9&itool=pubmed_docsum
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Novel germline mutation in the RB1 gene with multifocal bone tumors following retinoblastoma. Author(s): Matsumoto H, Kobayashi O, Tamura K, Sekine I, Yamamoto M. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14651550&query_hl=9&itool=pubmed_docsum
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105
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Novel retinoblastoma binding protein RBBP9 modulates sex-specific radiation responses in vivo. Author(s): Cassie S, Koturbash I, Hudson D, Baker M, Ilnytskyy Y, Rodriguez-Juarez R, Weber E, Kovalchuk O. Source: Carcinogenesis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16272168&query_hl=9&itool=pubmed_docsum
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Nucleocytoplasmic shuttling of the retinoblastoma tumor suppressor protein via Cdk phosphorylation-dependent nuclear export. Author(s): Jiao W, Datta J, Lin HM, Dundr M, Rane SG. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17043357&query_hl=9&itool=pubmed_docsum
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Nurse-initiated retinoblastoma service in New Zealand. Author(s): Strickland A. Source: Insight (American Society of Ophthalmic Registered Nurses). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16817566&query_hl=9&itool=pubmed_docsum
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Oct-1 DNA binding activity unresponsive to retinoblastoma protein expression prevents MHC class II induction in a non-small cell lung carcinoma cell line. Author(s): Osborne AR, Zhang H, Blanck G. Source: Molecular Immunology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16360016&query_hl=9&itool=pubmed_docsum
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Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma. Author(s): Mulvihill A, Budning A, Jay V, Vandenhoven C, Heon E, Gallie BL, Chan HS. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12912689&query_hl=9&itool=pubmed_docsum
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Optical coherence tomography in children with retinoblastoma. Author(s): Sony P, Garg SP. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15977862&query_hl=9&itool=pubmed_docsum
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Orbital implants in postenucleation retinoblastoma. Author(s): Tawfik HA, Zico OM. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11297471&query_hl=9&itool=pubmed_docsum
106
Retinoblastoma
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Outcome following initial external beam radiotherapy in patients with ReeseEllsworth group Vb retinoblastoma. Author(s): Abramson DH, Beaverson KL, Chang ST, Dunkel IJ, McCormick B. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15364710&query_hl=9&itool=pubmed_docsum
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Outcome of eyes with unilateral sporadic retinoblastoma based on the initial external findings by the family and the pediatrician. Author(s): Shields CL, Gorry T, Shields JA. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15206599&query_hl=9&itool=pubmed_docsum
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Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Author(s): Aerts I, Pacquement H, Doz F, Mosseri V, Desjardins L, Sastre X, Michon J, Rodriguez J, Schlienger P, Zucker JM, Quintana E. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15196536&query_hl=9&itool=pubmed_docsum
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Outpatient clinic for genetic counseling and gene testing of retinoblastoma. Author(s): Sugano K, Yoshida T, Izumi H, Umezawa S, Ushiama M, Ichikawa A, Hidaka A, Murakami Y, Kodama T, Suzuki S, Kaneko A. Source: International Journal of Clinical Oncology / Japan Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15162822&query_hl=9&itool=pubmed_docsum
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Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma. Author(s): Roesch A, Becker B, Meyer S, Hafner C, Wild PJ, Landthaler M, Vogt T. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15502804&query_hl=9&itool=pubmed_docsum
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Overexpression of tumour suppressor retinoblastoma 2 protein (pRb2/p130) in hepatocellular carcinoma. Author(s): Huynh H. Source: Carcinogenesis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15059924&query_hl=9&itool=pubmed_docsum
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p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death. Author(s): Hamdane M, Bretteville A, Sambo AV, Schindowski K, Begard S, Delacourte A, Bertrand P, Buee L. Source: Journal of Cell Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15741232&query_hl=9&itool=pubmed_docsum
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p53 gene gets altered by various mechanisms: studies in childhood sarcomas and retinoblastoma. Author(s): Ghule P, Kadam PA, Jambhekar N, Bamne M, Pai S, Nair C, Banavali S, Puri A, Agarwal M. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17136003&query_hl=9&itool=pubmed_docsum
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Patterns of cyclin E, retinoblastoma protein, and p21Cip1/WAF1 immunostaining in the oncogenesis of papillary thyroid carcinoma. Author(s): Brzezinski J, Migodzinski A, Toczek A, Tazbir J, Dedecjus M. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15709169&query_hl=9&itool=pubmed_docsum
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Periocular chemotherapy for retinoblastoma: success with problems? Author(s): Abramson DH. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15642840&query_hl=9&itool=pubmed_docsum
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Phosphorylated retinoblastoma protein complexes with pp32 and inhibits pp32mediated apoptosis. Author(s): Adegbola O, Pasternack GR. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15716273&query_hl=9&itool=pubmed_docsum
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Phosphorylation of mdm2 at serine 269 impairs its interaction with the retinoblastoma protein. Author(s): Gotz C, Kartarius S, Schwar G, Montenarh M. Source: International Journal of Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15703839&query_hl=9&itool=pubmed_docsum
108
Retinoblastoma
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pRb2/p130: a new candidate for retinoblastoma tumor formation. Author(s): De Falco G, Giordano A. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936755&query_hl=9&itool=pubmed_docsum
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Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. Author(s): Fueyo J, Alemany R, Gomez-Manzano C, Fuller GN, Khan A, Conrad CA, Liu TJ, Jiang H, Lemoine MG, Suzuki K, Sawaya R, Curiel DT, Yung WK, Lang FF. Source: Journal of the National Cancer Institute. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12734316&query_hl=9&itool=pubmed_docsum
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Progressive resorption of a presumed spontaneously regressed retinoblastoma over 20 years. Author(s): Lam A, Shields CL, Manquez ME, Shields JA. Source: Retina (Philadelphia, Pa.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15689823&query_hl=9&itool=pubmed_docsum
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Proton radiation therapy for retinoblastoma: comparison of various intraocular tumor locations and beam arrangements. Author(s): Krengli M, Hug EB, Adams JA, Smith AR, Tarbell NJ, Munzenrider JE. Source: International Journal of Radiation Oncology, Biology, Physics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15667981&query_hl=9&itool=pubmed_docsum
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Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene. Author(s): Dryja TP, Morrow JF, Rapaport JM. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9272170&query_hl=9&itool=pubmed_docsum
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Quantitative analysis of apoptosis in retinoblastoma. Author(s): Tatlipinar S, Soylemezoglu F, Kiratli H, Bilgic S. Source: Clinical & Experimental Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11886418&query_hl=9&itool=pubmed_docsum
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Quantitative analysis of CDKN2, p53 and retinoblastoma mRNA in human gastric carcinoma. Author(s): Chen YJ, Shih LS, Chen YM. Source: International Journal of Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9664118&query_hl=9&itool=pubmed_docsum
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Quantitative analysis of proliferation, apoptosis, and angiogenesis in retinoblastoma and their association with the clinicopathologic parameters. Author(s): Kerimogglu H, Kiratli H, Dincturk AA, Soylemezoglu F, Bilgic S. Source: Japanese Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14636846&query_hl=9&itool=pubmed_docsum
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Questioning the need for routine bone marrow aspiration and lumbar puncture in patients with retinoblastoma. Author(s): Azar D, Donaldson C, Dalla-Pozza L. Source: Clinical & Experimental Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12580896&query_hl=9&itool=pubmed_docsum
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Reduced retinoblastoma gene protein to Ki-67 ratio is an adverse prognostic indicator for ovarian adenocarcinoma patients. Author(s): Konstantinidou AE, Korkolopoulou P, Vassilopoulos I, Tsenga A, Thymara I, Agapitos E, Patsouris E, Davaris P. Source: Gynecologic Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12648589&query_hl=9&itool=pubmed_docsum
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Retinoblastoma in Taiwan: the effect of a government-sponsored national health insurance program on the treatment and survival of patients with retinoblastoma. Author(s): Su WW, Kao LY. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17162973&query_hl=9&itool=pubmed_docsum
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Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis. Author(s): Tort F, Bartkova J, Sehested M, Orntoft T, Lukas J, Bartek J. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17079443&query_hl=9&itool=pubmed_docsum
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Retinoblastoma regulatory pathway in lung cancer. Author(s): Wikenheiser-Brokamp KA. Source: Current Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100603&query_hl=9&itool=pubmed_docsum
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Retinoblastoma suppressor associated protein 46 (RbAp46) attenuates the betacatenin/TCF signaling through up-regulation of GSK-3beta expression. Author(s): Li GC, Wang ZY. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17201172&query_hl=9&itool=pubmed_docsum
110
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Retinoblastoma survivors: sarcomas and surveillance. Author(s): Meadows AT. Source: Journal of the National Cancer Institute. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17202103&query_hl=9&itool=pubmed_docsum
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Retinoblastoma-binding protein 2-homolog 1: a retinoblastoma-binding protein downregulated in malignant melanomas. Author(s): Roesch A, Becker B, Meyer S, Wild P, Hafner C, Landthaler M, Vogt T. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15803180&query_hl=9&itool=pubmed_docsum
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Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. Author(s): Kleinerman RA, Tucker MA, Abramson DH, Seddon JM, Tarone RE, Fraumeni JF Jr. Source: Journal of the National Cancer Institute. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17202110&query_hl=9&itool=pubmed_docsum
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Role of the retinoblastoma protein in differentiation and senescence. Author(s): Thomas DM, Yang HS, Alexander K, Hinds PW. Source: Cancer Biology & Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12750549&query_hl=9&itool=pubmed_docsum
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Role of the retinoblastoma tumor suppressor in the maintenance of genome integrity. Author(s): Knudsen ES, Sexton CR, Mayhew CN. Source: Current Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100601&query_hl=9&itool=pubmed_docsum
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S(+)-ketamine for long-term sedation in a child with retinoblastoma undergoing interstitial brachytherapy. Author(s): Kozek-Langenecker SA, Marhofer P, Sator-Katzenschlager SM, Dieckmann K. Source: Paediatric Anaesthesia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15725325&query_hl=9&itool=pubmed_docsum
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Selective ablation of retinoblastoma protein function by the RET finger protein. Author(s): Krutzfeldt M, Ellis M, Weekes DB, Bull JJ, Eilers M, Vivanco MD, Sellers WR, Mittnacht S. Source: Molecular Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15837424&query_hl=9&itool=pubmed_docsum
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Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene. Author(s): Nichols KE, Houseknecht MD, Godmilow L, Bunin G, Shields C, Meadows A, Ganguly A. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15884040&query_hl=9&itool=pubmed_docsum
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Shorter time to diagnosis and improved stage at presentation in Swiss patients with retinoblastoma treated from 1963 to 2004. Author(s): Wallach M, Balmer A, Munier F, Houghton S, Pampallona S, von der Weid N, Beck-Popovic M; Swiss Pediatric Oncology Group; Swiss Childhood Cancer Registry. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17000781&query_hl=9&itool=pubmed_docsum
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Simultaneous presentation of retinopathy of prematurity and bilateral familial retinoblastoma in a premature infant. Author(s): Benz MS, Escalona-Caamano EM, Murray TG. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12691233&query_hl=9&itool=pubmed_docsum
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Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein. Author(s): Boyer Arnold N, Korc M. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15811853&query_hl=9&itool=pubmed_docsum
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Small molecule inhibition of HDM2 leads to p53-mediated cell death in retinoblastoma cells. Author(s): Elison JR, Cobrinik D, Claros N, Abramson DH, Lee TC. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16966622&query_hl=9&itool=pubmed_docsum
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SPR-based immunocapture approach to creating an interfacial sensing architecture: Mapping of the MRS18-2 binding site on retinoblastoma protein. Author(s): Snopok B, Yurchenko M, Szekely L, Klein G, Kashuba E. Source: Analytical and Bioanalytical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17086389&query_hl=9&itool=pubmed_docsum
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Stabilization of the retinoblastoma protein by A-type nuclear lamins is required for INK4A-mediated cell cycle arrest. Author(s): Nitta RT, Jameson SA, Kudlow BA, Conlan LA, Kennedy BK. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16809772&query_hl=9&itool=pubmed_docsum
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The clinical spectrum and treatment outcome of retinoblastoma in Indian children. Author(s): Shanmugam MP, Biswas J, Gopal L, Sharma T, Nizamuddin SH. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15825743&query_hl=9&itool=pubmed_docsum
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The importance of excluding 13q deletion mosaicism in the diagnosis of retinoblastoma associated with dysmorphic features. Author(s): Van Esch H, Aerssens P, Fryns JP. Source: Genet Couns. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15844785&query_hl=9&itool=pubmed_docsum
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The RB protein family in retinal development and retinoblastoma: new insights from new mouse models. Author(s): Bremner R, Chen D, Pacal M, Livne-Bar I, Agochiya M. Source: Developmental Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15855771&query_hl=9&itool=pubmed_docsum
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The retinoblastoma protein in osteoblast differentiation and osteosarcoma. Author(s): Deshpande A, Hinds PW. Source: Current Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100605&query_hl=9&itool=pubmed_docsum
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The retinoblastoma protein--from bench to bedside. Author(s): Mittnacht S. Source: European Journal of Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15819393&query_hl=9&itool=pubmed_docsum
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The retinoblastoma tumour suppressor in model organisms--new insights from flies and worms. Author(s): Korenjak M, Brehm A. Source: Current Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100596&query_hl=9&itool=pubmed_docsum
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The role of nitric oxide synthases and nitrotyrosine in retinoblastoma. Author(s): Adithi M, Nalini V, Krishnakumar S. Source: Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15754329&query_hl=9&itool=pubmed_docsum
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The role of retinoblastoma protein family in the control of germ cell proliferation, differentiation and survival. Author(s): Toppari J, Suominenf JS, Yan W. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12752270&query_hl=9&itool=pubmed_docsum
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The tyrphostin AG1024 accelerates the degradation of phosphorylated forms of retinoblastoma protein (pRb) and restores pRb tumor suppressive function in melanoma cells. Author(s): von Willebrand M, Zacksenhaus E, Cheng E, Glazer P, Halaban R. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12649208&query_hl=9&itool=pubmed_docsum
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Uncommon presentation of pediatric ruptured intracranial aneurysm after radiotherapy for retinoblastoma. Case report. Author(s): Gonzales-Portillo GA, Valdivia JM. Source: Surgical Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16531206&query_hl=9&itool=pubmed_docsum
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Unexpected sensitivity to radiation of fibroblasts from unaffected parents of children with hereditary retinoblastoma. Author(s): Fitzek MM, Dahlberg WK, Nagasawa H, Mukai S, Munzenrider JE, Little JB. Source: International Journal of Cancer. Journal International Du Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12115515&query_hl=9&itool=pubmed_docsum
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Unilateral retinoblastoma in an adult: report of a case and review of the literature. Author(s): Mietz H, Hutton WL, Font RL. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9022103&query_hl=9&itool=pubmed_docsum
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Unilateral retinoblastoma, lack of familial history and older age does not exclude germline RB1 gene mutation. Author(s): Brichard B, Heusterspreute M, De Potter P, Chantrain C, Vermylen C, Sibille C, Gala JL. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16343894&query_hl=9&itool=pubmed_docsum
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Unique insertional translocation in a childhood Wilms' tumor survivor detected when his daughter developed bilateral retinoblastoma. Author(s): Punnett A, Teshima I, Heon E, Budning A, Sutherland J, Gallie BL, Chan HS. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12794701&query_hl=9&itool=pubmed_docsum
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Update on retinoblastoma. Author(s): Abramson DH, Schefler AC. Source: Retina (Philadelphia, Pa.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15579980&query_hl=9&itool=pubmed_docsum
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Update on retinoblastoma. Author(s): Sabado Alvarez C, Sastre Urgelles A, Abelairas Gomez JM. Source: Clin Transl Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15960926&query_hl=9&itool=pubmed_docsum
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Uric acid in the aqueous humor and tears of retinoblastoma patients. Author(s): Mendelsohn ME, Abramson DH, Senft S, Servodidio CA, Gamache PH. Source: Journal of Aapos : the Official Publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10532727&query_hl=9&itool=pubmed_docsum
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Use of preclinical models to improve treatment of retinoblastoma. Author(s): Dyer MA, Rodriguez-Galindo C, Wilson MW. Source: Plos Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16231976&query_hl=9&itool=pubmed_docsum
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Utility of pupillary dilation for detecting leukocoria in patients with retinoblastoma. Author(s): Canzano JC, Handa JT. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10506269&query_hl=9&itool=pubmed_docsum
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Value of topoisomerase II alpha, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu immunohistochemical expression for the prediction of biologic behavior in adrenocortical neoplasms. Author(s): Gupta D, Shidham V, Holden J, Layfield L. Source: Applied Immunohistochemistry & Molecular Morphology : Aimm / Official Publication of the Society for Applied Immunohistochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11556748&query_hl=9&itool=pubmed_docsum
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Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor. Author(s): Ledl A, Schmidt D, Muller S. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15806172&query_hl=9&itool=pubmed_docsum
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Visible light exposure induces VEGF gene expression through activation of retinoic acid receptor-alpha in retinoblastoma Y79 cells. Author(s): Akiyama H, Tanaka T, Doi H, Kanai H, Maeno T, Itakura H, Iida T, Kimura Y, Kishi S, Kurabayashi M. Source: American Journal of Physiology. Cell Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15613498&query_hl=9&itool=pubmed_docsum
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Visual fields in retinoblastoma survivors. Author(s): Abramson DH, Melson MR, Servodidio C. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15364711&query_hl=9&itool=pubmed_docsum
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Visual results in children treated for retinoblastoma. Author(s): Singh AD. Source: Eye (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11988807&query_hl=9&itool=pubmed_docsum
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Vitamin D analogs, a new treatment for retinoblastoma: The first Ellsworth Lecture. Author(s): Albert DM, Nickells RW, Gamm DM, Zimbric ML, Schlamp CL, Lindstrom MJ, Audo I. Source: Ophthalmic Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12324873&query_hl=9&itool=pubmed_docsum
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Vitamin D analogues increase p53, p21, and apoptosis in a xenograft model of human retinoblastoma. Author(s): Audo I, Darjatmoko SR, Schlamp CL, Lokken JM, Lindstrom MJ, Albert DM, Nickells RW. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14507860&query_hl=9&itool=pubmed_docsum
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What is the evidence supporting chemotherapy for intraocular retinoblastoma? Author(s): Hernandez JC. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9400805&query_hl=9&itool=pubmed_docsum
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Which retinoblastoma patients should be screened for RB1 mutations? Author(s): Cowell JK, Gallie BL. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10023301&query_hl=9&itool=pubmed_docsum
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Who is the boss in the retinoblastoma family? The point of view of Rb2/p130, the little brother. Author(s): Paggi MG, Giordano A. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11406530&query_hl=9&itool=pubmed_docsum
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Whole-eye versus lens-sparing megavoltage therapy for retinoblastoma. Author(s): Hungerford JL, Toma NM, Plowman PN, Doughty D, Kingston JE. Source: Front Radiat Ther Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9205887&query_hl=9&itool=pubmed_docsum
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Workup for metastatic retinoblastoma. A review of 261 patients. Author(s): Karcioglu ZA, al-Mesfer SA, Abboud E, Jabak MH, Mullaney PB. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9052637&query_hl=9&itool=pubmed_docsum
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Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status. Author(s): Ory B, Blanchard F, Battaglia S, Gouin F, Redini F, Heymann D. Source: Molecular Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17050806&query_hl=9&itool=pubmed_docsum
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CHAPTER 2. ALTERNATIVE MEDICINE AND RETINOBLASTOMA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to retinoblastoma. 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 retinoblastoma 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 retinoblastoma (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 retinoblastoma: •
A comparison of lipid metabolism in two human retinoblastoma cell lines. Author(s): Yorek MA, Figard PH, Kaduce TL, Spector AA. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4019105&query_hl=1&itool=pubmed_docsum
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A unique case of retinoblastoma masked by retinal detachment diagnosis and management. Author(s): Cangir A, Lee YY, Salmonsen P. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1574037&query_hl=1&itool=pubmed_docsum
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Accumulation of N-3 polyunsaturated fatty acids cultured human Y79 retinoblastoma cells. Author(s): Hyman BT, Spector AA. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7252513&query_hl=1&itool=pubmed_docsum
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Acute myeloblastic leukemia as a second malignancy in a patient with hereditary retinoblastoma. Author(s): Nishimura S, Sato T, Ueda H, Ueda K. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11689590&query_hl=1&itool=pubmed_docsum
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Adjuvant chemotherapy with vincristine, doxorubicin, and cyclophosphamide in the treatment of postenucleation high risk retinoblastoma. Author(s): Mustafa MM, Jamshed A, Khafaga Y, Mourad WA, Al-Mesfer S, Kofide A, ElHusseiny G, Gray A. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10524448&query_hl=1&itool=pubmed_docsum
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Apoptotic effects of different drugs on cultured retinoblastoma Y79 cells. Author(s): Lauricella M, Giuliano M, Emanuele S, Vento R, Tesoriere G. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9701726&query_hl=1&itool=pubmed_docsum
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Bcl-2- and CrmA-inhibitable dephosphorylation and cleavage of retinoblastoma protein during etoposide-induced apoptosis. Author(s): An B, Johnson DE, Jin JR, Antoku K, Dou QP. Source: International Journal of Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9852210&query_hl=1&itool=pubmed_docsum
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Bean yellow dwarf virus RepA, but not rep, binds to maize retinoblastoma protein, and the virus tolerates mutations in the consensus binding motif. Author(s): Liu L, Saunders K, Thomas CL, Davies JW, Stanley J. Source: Virology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10191192&query_hl=1&itool=pubmed_docsum
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Bilateral macular retinoblastoma managed by chemothermotherapy. Author(s): Shields JA, Shields CL, De Potter P, Needle M.
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Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8906043&query_hl=1&itool=pubmed_docsum •
Bone marrow transplantation for therapy-related acute myeloid leukemia in congenital retinoblastoma associated with 13q deletion syndrome. Author(s): Hon C, Chan GC, Ha SY, Ma SK, Wong KF, Au WY. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15170522&query_hl=1&itool=pubmed_docsum
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Causes of chemoreduction failure in retinoblastoma and analysis of associated factors leading to eventual treatment with external beam radiotherapy and enucleation. Author(s): Gunduz K, Gunalp I, Yalcindag N, Unal E, Tacyildiz N, Erden E, Geyik PO. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15465557&query_hl=1&itool=pubmed_docsum
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Cellular thiol status-dependent inhibition of tumor cell growth via modulation of retinoblastoma protein phosphorylation by (-)-epigallocatechin. Author(s): Kennedy DO, Kojima A, Moffatt J, Yamagiwa H, Yano Y, Hasuma T, Otani S, Matsui-Yuasa I. Source: Cancer Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11880178&query_hl=1&itool=pubmed_docsum
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Characterization of interior cleavage of retinoblastoma protein in apoptosis. Author(s): Fattman CL, An B, Dou QP. Source: Journal of Cellular Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9361194&query_hl=1&itool=pubmed_docsum
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Chemokine- and neurotrophic factor-induced changes in E2F1 localization and phosphorylation of the retinoblastoma susceptibility gene product (pRb) occur by distinct mechanisms in murine cortical cultures. Author(s): Strachan GD, Kopp AS, Koike MA, Morgan KL, Jordan-Sciutto KL. Source: Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15869948&query_hl=1&itool=pubmed_docsum
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Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. Author(s): Friedman DL, Himelstein B, Shields CL, Shields JA, Needle M, Miller D, Bunin GR, Meadows AT. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10623688&query_hl=1&itool=pubmed_docsum
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Chemoreduction followed by local therapy and adjuvant chemotherapy for advanced intraocular retinoblastoma: a pilot study in a single center. Author(s): Yoo KH, Sohn WY, Sung KW, Jung HL, Koo HH, Oh SY, Kang SW. Source: Journal of Korean Medical Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12483008&query_hl=1&itool=pubmed_docsum
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Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Author(s): Shields CL, Meadows AT, Shields JA, Carvalho C, Smith AF. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11545631&query_hl=1&itool=pubmed_docsum
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Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Author(s): Shields CL, Mashayekhi A, Cater J, Shelil A, Meadows AT, Shields JA. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15364213&query_hl=1&itool=pubmed_docsum
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Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors. Author(s): Shields CL, Mashayekhi A, Cater J, Shelil A, Meadows AT, Shields JA. Source: Trans Am Ophthalmol Soc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15747743&query_hl=1&itool=pubmed_docsum
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Chemoreduction for unilateral retinoblastoma. Author(s): Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Naduvilath TJ. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12470138&query_hl=1&itool=pubmed_docsum
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Chemoreduction in the initial management of intraocular retinoblastoma. Author(s): Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8906023&query_hl=1&itool=pubmed_docsum
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Chemoreduction in the management of retinoblastoma. Author(s): Shields JA, Shields CL, Meadows AT. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16139001&query_hl=1&itool=pubmed_docsum
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Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Author(s): Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Singh A, Friedman DL, Naduvilath TJ. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11992863&query_hl=1&itool=pubmed_docsum
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Chemotherapeutic trials in patients with metastatic retinoblastoma. Author(s): Lonsdale D, Berry DH, Holcomb TM, Nora AH, Sullivan MP, Thurman WG, Vietti TJ. Source: Cancer Chemother Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=5733085&query_hl=1&itool=pubmed_docsum
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Chemotherapy for extraocular retinoblastoma. Author(s): Pratt CB, Fontanesi J, Chenaille P, Kun LE, Jenkins JJ 3rd, Langston JW, Mounce KG, Meyer D. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8060814&query_hl=1&itool=pubmed_docsum
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Chemotherapy for retinoblastoma. Author(s): Akiyama K, Iwasaki M, Amemiya T, Yanai M. Source: Ophthalmic Paediatr Genet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2779981&query_hl=1&itool=pubmed_docsum
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Chemotherapy in metastatic retinoblastoma. Author(s): Kingston JE, Hungerford JL, Plowman PN. Source: Ophthalmic Paediatr Genet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3587892&query_hl=1&itool=pubmed_docsum
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Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Author(s): Murphree AL, Villablanca JG, Deegan WF 3rd, Sato JK, Malogolowkin M, Fisher A, Parker R, Reed E, Gomer CJ. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8906025&query_hl=1&itool=pubmed_docsum
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Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Author(s): Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, Ling V, Chan HS. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8906022&query_hl=1&itool=pubmed_docsum
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Choline uptake in cultured human Y79 retinoblastoma cells: effect of polyunsaturated fatty acid compositional modifications. Author(s): Hyman BT, Spector AA. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7057184&query_hl=1&itool=pubmed_docsum
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Clinical result of prolonged primary chemotherapy in retinoblastoma patients. Author(s): Kim JH, Yu YS, Khwarg SI, Choi HS, Shin HY, Ahn HS. Source: Korean J Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12882506&query_hl=1&itool=pubmed_docsum
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Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Author(s): Greenwald MJ, Goldman S, Strauss LC. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9776658&query_hl=1&itool=pubmed_docsum
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Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Author(s): Shields CL, Shields JA, Needle M, de Potter P, Kheterpal S, Hamada A, Meadows AT. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9400771&query_hl=1&itool=pubmed_docsum
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Combined chemotherapy and local treatment in the management of intraocular retinoblastoma. Author(s): Brichard B, De Bruycker JJ, De Potter P, Neven B, Vermylen C, Cornu G. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11984802&query_hl=1&itool=pubmed_docsum
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Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Author(s): Chan HS, DeBoer G, Thiessen JJ, Budning A, Kingston JE, O'Brien JM, Koren G, Giesbrecht E, Haddad G, Verjee Z, Hungerford JL, Ling V, Gallie BL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9816326&query_hl=1&itool=pubmed_docsum
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Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma. Author(s): Escalona-Benz E, Jockovich ME, Murray TG, Hayden B, Hernandez E, Feuer W, Windle JJ. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15623747&query_hl=1&itool=pubmed_docsum
Alternative Medicine 123
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Comparative utilization of n-3 polyunsaturated fatty acids by cultured human Y-79 retinoblastoma cells. Author(s): Yorek MA, Bohnker RR, Dudley DT, Spector AA. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6089899&query_hl=1&itool=pubmed_docsum
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Comparison of retinoblastoma reduction for chemotherapy vs external beam radiotherapy. Author(s): Sussman DA, Escalona-Benz E, Benz MS, Hayden BC, Feuer W, Cicciarelli N, Toledano S, Markoe A, Murray TG. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12860801&query_hl=1&itool=pubmed_docsum
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Complications of systemic chemotherapy as treatment of retinoblastoma. Author(s): Benz MS, Scott IU, Murray TG, Kramer D, Toledano S. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10766148&query_hl=1&itool=pubmed_docsum
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Conservative therapy in intraocular retinoblastoma: response/recurrence rate. Author(s): Schiavetti A, Hadjistilianou T, Clerico A, Bonci E, Ragni G, Castello MA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15654270&query_hl=1&itool=pubmed_docsum
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Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Author(s): Savatier P, Huang S, Szekely L, Wiman KG, Samarut J. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8108123&query_hl=1&itool=pubmed_docsum
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Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Author(s): Mukhopadhyay A, Banerjee S, Stafford LJ, Xia C, Liu M, Aggarwal BB. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12483537&query_hl=1&itool=pubmed_docsum
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Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients. Author(s): Shields CL, Shelil A, Cater J, Meadows AT, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14609913&query_hl=1&itool=pubmed_docsum
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Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells. Author(s): Morita M, Suyama H, Igishi T, Shigeoka Y, Kodani M, Hashimoto K, Takeda K, Sumikawa T, Shimizu E. Source: International Journal of Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17143528&query_hl=1&itool=pubmed_docsum
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Docosahexaenoic acid membrane content and mRNA expression of acyl-CoA oxidase and of peroxisome proliferator-activated receptor-delta are modulated in Y79 retinoblastoma cells differently by low and high doses of alpha-linolenic acid. Author(s): Langelier B, Furet JP, Perruchot MH, Alessandri JM. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13130515&query_hl=1&itool=pubmed_docsum
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Effect of docosahexaenoic acid on membrane fluidity and function in intact cultured Y-79 retinoblastoma cells. Author(s): Treen M, Uauy RD, Jameson DM, Thomas VL, Hoffman DR. Source: Archives of Biochemistry and Biophysics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1533110&query_hl=1&itool=pubmed_docsum
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Effect on ocular survival of adding early intensive focal treatments to a two-drug chemotherapy regimen in patients with retinoblastoma. Author(s): Wilson MW, Haik BG, Liu T, Merchant TE, Rodriguez-Galindo C. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16138999&query_hl=1&itool=pubmed_docsum
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Efficacy of induction chemotherapy in retinoblastoma, alone or combined with other adjuvant modalities. Author(s): Ghose S, Nizamuddin SH, Sethi A, Mohanti BK, Kumar H, Arya LS, Thavaraj V. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12051279&query_hl=1&itool=pubmed_docsum
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Encouraging result of tamoxifen in a retinoblastoma patient with central nervous system metastasis. Author(s): Tacyildiz N, Yavuz G, Unal E, Gunduz K, Gunalp I, Ekinci C. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14631622&query_hl=1&itool=pubmed_docsum
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Equiguard suppresses androgen-dependent LNCaP prostate cancer cell proliferation by targeting cell cycle control via down regulation of the retinoblastoma protein Rb and induction of apoptosis via the release of cytochrome c. Author(s): Lu X, Hsieh TC, Wu JM.
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Source: International Journal of Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15547720&query_hl=1&itool=pubmed_docsum •
Etoposide and carboplatin in extraocular retinoblastoma: a study by the Societe Francaise d'Oncologie Pediatrique. Author(s): Doz F, Neuenschwander S, Plantaz D, Courbon B, Gentet JC, Bouffet E, Mosseri V, Vannier JP, Mechinaud F, Desjardins L, et al. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7707117&query_hl=1&itool=pubmed_docsum
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Experience with chemoreduction and focal therapy for intraocular retinoblastoma in a developing country. Author(s): Chantada GL, Fandino AC, Raslawski EC, Manzitti J, de Davila MT, Casak SJ, Scopinaro MJ, Schvartzman E. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15558702&query_hl=1&itool=pubmed_docsum
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Expression and prognostic value of the retinoblastoma tumour suppressor gene (RB1) in childhood acute lymphoblastic leukaemia. Author(s): Sauerbrey A, Stammler G, Zintl F, Volm M. Source: British Journal of Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8757515&query_hl=1&itool=pubmed_docsum
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Extraocular retinoblastoma: a 13-year experience. Author(s): Antoneli CB, Steinhorst F, de Cassia Braga Ribeiro K, Novaes PE, Chojniak MM, Arias V, de Camargo B. Source: Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12973854&query_hl=1&itool=pubmed_docsum
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Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Author(s): Shields CL, Honavar SG, Shields JA, Demirci H, Meadows AT, Naduvilath TJ. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11934319&query_hl=1&itool=pubmed_docsum
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Failure to activate interleukin 1beta-converting enzyme-like proteases and to cleave retinoblastoma protein in drug-resistant cells. Author(s): An B, Jin JR, Lin P, Dou QP.
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Source: Febs Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8980142&query_hl=1&itool=pubmed_docsum •
Failure to dephosphorylate retinoblastoma protein in drug-resistant cells. Author(s): Dou QP, Lui VW. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7585579&query_hl=1&itool=pubmed_docsum
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First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. Author(s): Beck MN, Balmer A, Dessing C, Pica A, Munier F. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10920136&query_hl=1&itool=pubmed_docsum
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Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. Author(s): Alonso M, Tamasdan C, Miller DC, Newcomb EW. Source: Molecular Cancer Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12589031&query_hl=1&itool=pubmed_docsum
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Forskolin and camptothecin induce a 30 kDa protein associated with melatonin production in Y79 human retinoblastoma cells. Author(s): Janavs JL, Florez JC, Pierce ME, Takahashi JS. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7823135&query_hl=1&itool=pubmed_docsum
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Glycine uptake by cultured human Y79 retinoblastoma cells: effect of changes in phospholipid fatty acid unsaturation. Author(s): Yorek MA, Hyman BT, Spector AA. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6848669&query_hl=1&itool=pubmed_docsum
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High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Author(s): Kremens B, Wieland R, Reinhard H, Neubert D, Beck JD, Klingebiel T, Bornfeld N, Havers W. Source: Bone Marrow Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12621463&query_hl=1&itool=pubmed_docsum
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High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Author(s): Namouni F, Doz F, Tanguy ML, Quintana E, Michon J, Pacquement H, Bouffet E, Gentet JC, Plantaz D, Lutz P, Vannier JP, Validire P, Neuenschwander S, Desjardins L, Zucker JM. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9616283&query_hl=1&itool=pubmed_docsum
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Histopathologic findings in eyes with retinoblastoma treated only with chemoreduction. Author(s): Demirci H, Eagle RC Jr, Shields CL, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12912690&query_hl=1&itool=pubmed_docsum
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Identification and functional characterization of riboflavin transporter in humanderived retinoblastoma cell line (Y-79): mechanisms of cellular uptake and translocation. Author(s): Kansara V, Pal D, Jain R, Mitra AK. Source: Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16117691&query_hl=1&itool=pubmed_docsum
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Identification of alpha 2-adrenergic receptor sites in human retinoblastoma (Y-79) and neuroblastoma (SH-SY5Y) cells. Author(s): Kazmi SM, Mishra RK. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2537639&query_hl=1&itool=pubmed_docsum
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In vitro effects of prostaglandins on human retinoblastoma cell line, Y-79 cells. Author(s): Nakamura M, Koshihara Y, Fujino Y, Mochizuki M, Minoda K, Masuda K. Source: Japanese Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3129606&query_hl=1&itool=pubmed_docsum
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In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Author(s): Inomata M, Kaneko A, Kunimoto T, Saijo N. Source: International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11820468&query_hl=1&itool=pubmed_docsum
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Increased cyclin E level in retinoblastoma cells during programmed cell death. Author(s): Lauricella M, Giuliano M, Emanuele S, Carabillo M, Vento R, Tesoriere G.
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Source: Cell Mol Biol (Noisy-Le-Grand). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9874510&query_hl=1&itool=pubmed_docsum •
Induction of apoptosis in cultured retinoblastoma cells by the protein phosphatase inhibitor, okadaic acid. Author(s): Inomata M, Saijo N, Kawashima K, Kaneko A, Fujiwara Y, Kunikane H, Tanaka Y. Source: Journal of Cancer Research and Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7499444&query_hl=1&itool=pubmed_docsum
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Induction of apoptosis in human retinoblastoma cells by topoisomerase inhibitors. Author(s): Giuliano M, Lauricella M, Vassallo E, Carabillo M, Vento R, Tesoriere G. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9660477&query_hl=1&itool=pubmed_docsum
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Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. Author(s): Tyagi A, Agarwal C, Agarwal R. Source: Molecular Cancer Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12479270&query_hl=1&itool=pubmed_docsum
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Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. Author(s): Park DS, Morris EJ, Bremner R, Keramaris E, Padmanabhan J, Rosenbaum M, Shelanski ML, Geller HM, Greene LA. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10777774&query_hl=1&itool=pubmed_docsum
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Involvement of the retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) cells. Author(s): Adhami VM, Afaq F, Ahmad N. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11676482&query_hl=1&itool=pubmed_docsum
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Iodine 125 plaque radiotherapy as salvage treatment for retinoblastoma recurrence after chemoreduction in 84 tumors. Author(s): Shields CL, Mashayekhi A, Sun H, Uysal Y, Friere J, Komarnicky L, Shields JA.
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Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16949158&query_hl=1&itool=pubmed_docsum •
Lack of activity of oral etoposide for relapsed intraocular retinoblastoma. Author(s): Dunkel IJ, Chantada GL, Fandino AC, Abramson DH. Source: Ophthalmic Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15255111&query_hl=1&itool=pubmed_docsum
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Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. Author(s): Li W, Fan J, Hochhauser D, Banerjee D, Zielinski Z, Almasan A, Yin Y, Kelly R, Wahl GM, Bertino JR. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7479800&query_hl=1&itool=pubmed_docsum
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Lack of response to chemoreduction in presumed well differentiated retinoblastoma. Author(s): Singh AD, Shields CL, Shields JA. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11911540&query_hl=1&itool=pubmed_docsum
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Laminin-induced retinoblastoma cell differentiation: possible involvement of a 100kDa cell-surface laminin-binding protein. Author(s): Albini A, Noonan DM, Melchiori A, Fassina GF, Percario M, Gentleman S, Toffenetti J, Chader GJ. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1532253&query_hl=1&itool=pubmed_docsum
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Long-term visual outcome following chemoreduction for retinoblastoma. Author(s): Demirci H, Shields CL, Meadows AT, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16286614&query_hl=1&itool=pubmed_docsum
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Loss of delta6-desaturase activity leads to impaired docosahexaenoic acid synthesis in Y-79 retinoblastoma cells. Author(s): Marzo I, Pineiro A, Naval J. Source: Prostaglandins, Leukotrienes, and Essential Fatty Acids. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9888202&query_hl=1&itool=pubmed_docsum
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Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors. Author(s): Shields CL, Mashayekhi A, Cater J, Shelil A, Ness S, Meadows AT, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15955977&query_hl=1&itool=pubmed_docsum
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Macular retinoblastoma: evaluation of tumor control, local complications, and visual outcomes for eyes treated with chemotherapy and repetitive foveal laser ablation. Author(s): Schefler AC, Cicciarelli N, Feuer W, Toledano S, Murray TG. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17070578&query_hl=1&itool=pubmed_docsum
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Medical therapy of retinoblastoma in children. Author(s): Acquaviva A, Barberi L, Bernardini C, D'Ambrosio A, Lasorella G. Source: Journal of Neurosurgical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7143085&query_hl=1&itool=pubmed_docsum
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Metastatic retinoblastoma to the orofacial region. Author(s): Ebata K, Mizutani H, Kaneda T, Horibe K. Source: Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1890525&query_hl=1&itool=pubmed_docsum
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Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells. Author(s): Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936077&query_hl=1&itool=pubmed_docsum
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Mitogen-induced rapid phosphorylation of serine 795 of the retinoblastoma gene product in vascular smooth muscle cells involves ERK activation. Author(s): Garnovskaya MN, Mukhin YV, Vlasova TM, Grewal JS, Ullian ME, Tholanikunnel BG, Raymond JR. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15069084&query_hl=1&itool=pubmed_docsum
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Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma. Author(s): Wilson MW, Rodriguez-Galindo C, Haik BG, Moshfeghi DM, Merchant TE, Pratt CB.
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Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11713087&query_hl=1&itool=pubmed_docsum •
Neoadjuvant chemotherapy for extensive unilateral retinoblastoma. Author(s): Bellaton E, Bertozzi AI, Behar C, Chastagner P, Brisse H, Sainte-Rose C, Doz F, Desjardins L. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12598448&query_hl=1&itool=pubmed_docsum
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New retinoblastoma tumors in children undergoing systemic chemotherapy. Author(s): Scott IU, Murray TG, Toledano S, O'Brien JM. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9869808&query_hl=1&itool=pubmed_docsum
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Occurrence of testicular metastasis in a child with bilateral retinoblastoma. Author(s): Kimball JC, Cangir A. Source: Cancer Treat Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=455320&query_hl=1&itool=pubmed_docsum
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Phospholipid incorporation and metabolic conversion of n-3 polyunsaturated fatty acids in the Y79 retinoblastoma cell line. Author(s): Goustard-Langelier B, Alessandri JM, Raguenez G, Durand G, Courtois Y. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10820439&query_hl=1&itool=pubmed_docsum
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Pilot study of sequential combination chemotherapy in advanced and recurrent retinoblastoma. Author(s): Advani SH, Rao SR, Iyer RS, Pai SK, Kurkure PA, Nair CN. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8259098&query_hl=1&itool=pubmed_docsum
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Postenucleation adjuvant therapy in high-risk retinoblastoma. Author(s): Honavar SG, Singh AD, Shields CL, Meadows AT, Demirci H, Cater J, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12096963&query_hl=1&itool=pubmed_docsum
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Practical approach to management of retinoblastoma. Author(s): Shields CL, Mashayekhi A, Demirci H, Meadows AT, Shields JA.
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Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15136321&query_hl=1&itool=pubmed_docsum •
Preliminary results of primary chemotherapy in retinoblastoma. Author(s): Bornfeld N, Schuler A, Bechrakis N, Henze G, Havers W. Source: Klinische Padiatrie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9293453&query_hl=1&itool=pubmed_docsum
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Protein phosphatase-1 activation and association with the retinoblastoma protein in colcemid-induced apoptosis. Author(s): Puntoni F, Villa-Moruzzi E. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10581203&query_hl=1&itool=pubmed_docsum
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Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Author(s): Ong CS, Tran E, Nguyen TT, Ong CK, Lee SK, Lee JJ, Ng CP, Leong C, Huynh H. Source: Oncol Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14767529&query_hl=1&itool=pubmed_docsum
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Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. Author(s): Vijayababu MR, Kanagaraj P, Arunkumar A, Ilangovan R, Aruldhas MM, Arunakaran J. Source: Journal of Cancer Research and Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16049707&query_hl=1&itool=pubmed_docsum
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Recurrent disseminated retinoblastoma in a 7-year-old girl treated successfully by high-dose chemotherapy and CD34-selected autologous peripheral blood stem cell transplantation. Author(s): Hertzberg H, Kremens B, Velten I, Beck JD, Greil J. Source: Bone Marrow Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11319597&query_hl=1&itool=pubmed_docsum
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Recurrent disseminated retinoblastoma treated by high-dose chemotherapy, total body irradiation, and autologous bone marrow rescue. Author(s): Saarinen UM, Sariola H, Hovi L.
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Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1793158&query_hl=1&itool=pubmed_docsum •
Relationship between histopathological features of chemotherapy treated retinoblastoma and P-glycoprotein expression. Author(s): Souza Filho JP, Martins MC, Caissie AL, Torres VL, Fernandes LH, Erwenne CM, Burnier MN Jr. Source: Clinical & Experimental Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15932532&query_hl=1&itool=pubmed_docsum
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Resolution of iris neovascularization following chemoreduction of advanced retinoblastoma. Author(s): Shields CL, Sun H, Manquez ME, Leahey A, Meadows AT, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908826&query_hl=1&itool=pubmed_docsum
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Restoration of foveal anatomy and function following chemoreduction for bilateral advanced retinoblastoma with total retinal detachment. Author(s): Shields CL, Materin MA, Shields JA. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16286630&query_hl=1&itool=pubmed_docsum
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Results of a prospective study for the treatment of retinoblastoma. Author(s): Chantada G, Fandino A, Davila MT, Manzitti J, Raslawski E, Casak S, Schvartzman E. Source: Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14770442&query_hl=1&itool=pubmed_docsum
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Results of a stage-based protocol for the treatment of retinoblastoma. Author(s): Schvartzman E, Chantada G, Fandino A, de Davila MT, Raslawski E, Manzitti J. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8622068&query_hl=1&itool=pubmed_docsum
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Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Author(s): Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8906024&query_hl=1&itool=pubmed_docsum
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Retinoblastoma at Groote Schuur Hospital 1952-1972. Author(s): Sevel D, Sealy R, Lawton E. Source: Trans Ophthalmol Soc U K. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4135763&query_hl=1&itool=pubmed_docsum
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Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Author(s): Chantada GL, Dunkel IJ, de Davila MT, Abramson DH. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15258027&query_hl=1&itool=pubmed_docsum
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Retinoblastoma protein is required for efficient colorectal carcinoma cell apoptosis by histone deacetylase inhibitors in the absence of p21Waf. Author(s): Wagner S, Roemer K. Source: Biochemical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763542&query_hl=1&itool=pubmed_docsum
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Retinoblastoma protein-initiated cellular growth arrest overcomes the ability of cotransfected wild-type p53 to induce apoptosis. Author(s): Shinohara H, Zhou J, Yoshikawa K, Yazumi S, Ko K, Yamaoka Y, Mizukami T, Yoshida T, Akinaga S, Tamaoki T, Motoda H, Benedict WF, Takahashi R. Source: British Journal of Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10993652&query_hl=1&itool=pubmed_docsum
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Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Author(s): Gombos DS, Kelly A, Coen PG, Kingston JE, Hungerford JL. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11801509&query_hl=1&itool=pubmed_docsum
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Retinoblastoma. Author(s): Ellsworth RM. Source: Mod Probl Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=876116&query_hl=1&itool=pubmed_docsum
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Retinoblastoma: care and support of the pediatric patient and family. Author(s): Brady G. Source: Insight (American Society of Ophthalmic Registered Nurses). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14596138&query_hl=1&itool=pubmed_docsum
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RNA synthesis inhibitors increase melatonin production in Y79 human retinoblastoma cells. Author(s): Janavs JL, Pierce ME, Takahashi JS. Source: Brain Research. Molecular Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8028483&query_hl=1&itool=pubmed_docsum
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Role of chemotherapy alone or in combination with hyperthermia in the primary treatment of intraocular retinoblastoma: preliminary results. Author(s): Levy C, Doz F, Quintana E, Pacquement H, Michon J, Schlienger P, Validire P, Asselain B, Desjardins L, Zucker JM. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9924303&query_hl=1&itool=pubmed_docsum
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Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate. Author(s): Ahmad N, Adhami VM, Gupta S, Cheng P, Mukhtar H. Source: Archives of Biochemistry and Biophysics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11811957&query_hl=1&itool=pubmed_docsum
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Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity. Author(s): Li W, Fan J, Bertino JR. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11289134&query_hl=1&itool=pubmed_docsum
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Sequential two-step cleavage of the retinoblastoma protein by caspase-3/-7 during etoposide-induced apoptosis. Author(s): Fattman CL, Delach SM, Dou QP, Johnson DE. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11420704&query_hl=1&itool=pubmed_docsum
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Socioeconomic impact of modern multidisciplinary management of retinoblastoma. Author(s): Wilson MW, Haik BG, Rodriguez-Galindo C. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16882777&query_hl=1&itool=pubmed_docsum
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Synergistic cytotoxic interactions between sodium butyrate, MG132 and camptothecin in human retinoblastoma Y79 cells. Author(s): Lauricella M, Calvaruso G, Giuliano M, Carabillo M, Emanuele S, Vento R, Tesoriere G.
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Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11006574&query_hl=1&itool=pubmed_docsum •
The alpha 2-adrenoceptors of the human retinoblastoma cell line (Y79) may represent an additional example of the alpha 2C-adrenoceptor. Author(s): Gleason MM, Hieble JP. Source: British Journal of Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1358385&query_hl=1&itool=pubmed_docsum
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The effect of chemoreduction on retinoblastoma-induced retinal detachment. Author(s): Shields CL, Shields JA, DePotter P, Himelstein BP, Meadows AT. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9168421&query_hl=1&itool=pubmed_docsum
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The International Classification of Retinoblastoma predicts chemoreduction success. Author(s): Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16996605&query_hl=1&itool=pubmed_docsum
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The outcome of chemoreduction treatment in patients with Reese-Ellsworth group V retinoblastoma. Author(s): Gunduz K, Shields CL, Shields JA, Meadows AT, Gross N, Cater J, Needle M. Source: Archives of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9869790&query_hl=1&itool=pubmed_docsum
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The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes. Author(s): Xiao H, Goodrich DW. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16091739&query_hl=1&itool=pubmed_docsum
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The role of chemotherapy in orbital involvement of retinoblastoma. The experience of a single institution with 33 patients. Author(s): Doz F, Khelfaoui F, Mosseri V, Validire P, Quintana E, Michon J, Desjardins L, Schlienger P, Neuenschwander S, Vielh P, et al. Source: Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8033054&query_hl=1&itool=pubmed_docsum
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The use of chemotherapy for extraocular retinoblastoma. Author(s): Pratt CB, Crom DB, Howarth C. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4046972&query_hl=1&itool=pubmed_docsum
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Thermochemotherapy in hereditary retinoblastoma. Author(s): Schueler AO, Jurklies C, Heimann H, Wieland R, Havers W, Bornfeld N. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12488270&query_hl=1&itool=pubmed_docsum
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Topotecan combination chemotherapy in two new rodent models of retinoblastoma. Author(s): Laurie NA, Gray JK, Zhang J, Leggas M, Relling M, Egorin M, Stewart C, Dyer MA. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16243833&query_hl=1&itool=pubmed_docsum
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Treatment of intraocular retinoblastoma with carboplatin and etoposide chemotherapy. Author(s): Greenwald MJ, Strauss LC. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9003332&query_hl=1&itool=pubmed_docsum
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Treatment of intraocular retinoblastoma with vincristine and carboplatin. Author(s): Rodriguez-Galindo C, Wilson MW, Haik BG, Merchant TE, Billups CA, Shah N, Cain A, Langston J, Lipson M, Kun LE, Pratt CB. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12743157&query_hl=1&itool=pubmed_docsum
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Treatment of malignant meningitis in retinoblastoma. Author(s): Stannard CE, Sealy R, Sevel D, Brinton FA. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1242674&query_hl=1&itool=pubmed_docsum
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Treatment of retinoblastoma patients with chemoreduction plus local therapy: experience of the AC Camargo Hospital, Brazil. Author(s): Antoneli CB, Ribeiro KC, Steinhorst F, Novaes PE, Chojniak MM, Malogolowkin M.
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Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16794500&query_hl=1&itool=pubmed_docsum •
Treatment of retinoblastoma vitreous base seeding. Author(s): Madreperla SA, Hungerford JL, Doughty D, Plowman PN, Kingston JE, Singh AD. Source: Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9442787&query_hl=1&itool=pubmed_docsum
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Treatment of trilateral retinoblastoma with vincristine and cyclophosphamide. Author(s): Malik RK, Friedman HS, Djang WT, Falletta JM, Buckley E, Kurtzberg J, Kinney TR, Stine K, Chaffee S, Hayes J, et al. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3777087&query_hl=1&itool=pubmed_docsum
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Vincristine- and cisplatin-induced apoptosis in human retinoblastoma. Potentiation by sodium butyrate. Author(s): Conway RM, Madigan MC, Billson FA, Penfold PL. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9893663&query_hl=1&itool=pubmed_docsum
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Visual function after laser hyperthermia and chemotherapy for macular retinoblastoma. Author(s): Lueder GT, Goyal R. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8610810&query_hl=1&itool=pubmed_docsum
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Visual outcome in macular retinoblastoma treated with primary chemotherapy. Author(s): Balasubramanya R, Pushker N, Bajaj MS, Rani A, Ghose S, Arya LS. Source: Ophthalmologica. Journal International D'ophtalmologie. International Journal of Ophthalmology. Zeitschrift Fur Augenheilkunde. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14573975&query_hl=1&itool=pubmed_docsum
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Visual results in children treated for macular retinoblastoma. Author(s): Watts P, Westall C, Colpa L, MacKeen L, Abdolell M, Gallie B, Heon E. Source: Eye (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11913894&query_hl=1&itool=pubmed_docsum
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Vitreous relapse following primary chemotherapy for retinoblastoma: is adjuvant diode laser a risk factor? Author(s): Gombos DS, Cauchi PA, Hungerford JL, Addison P, Coen PG, Kingston JE. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16707528&query_hl=1&itool=pubmed_docsum
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What is the best method of prevention of therapeutic failures in CNS in high risk retinoblastoma? Author(s): Grzeskowiak-Melanowska J, Skoczen S, Armata J. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8950344&query_hl=1&itool=pubmed_docsum
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What is the best treatment for retinoblastoma? Author(s): Harbour JW. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15364232&query_hl=1&itool=pubmed_docsum
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://health.aol.com/healthyliving/althealth
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/naturalmedicine.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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Open Directory Project: http://dmoz.org/Health/Alternative/
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
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 3. BOOKS ON RETINOBLASTOMA Overview This chapter provides bibliographic book references relating to retinoblastoma. In addition to online booksellers such as www.amazon.com and www.bn.com, the National Library of Medicine is an excellent source for book titles on retinoblastoma. Your local medical library also may have these titles available for loan.
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 retinoblastoma at online booksellers’ Web sites, you may discover non-medical books that use the generic term “retinoblastoma” (or a synonym) in their titles. The following is indicative of the results you might find when searching for retinoblastoma (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
21st Century Complete Medical Guide to Childhood Cancer (including Neuroblastoma, Brain, Bone, Blood Cancers, Retinoblastoma, Rhabdomyosarcoma, and others). on Diagnosis and Treatment Options PM Medical Health News (2002); ISBN: 1592480136; http://www.amazon.com/exec/obidos/ASIN/1592480136/icongroupinterna
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Effects of ionizing radiation on retinoblastoma and on the normal ocular fundus in infants: A photographic and fluorescien angiographic study (Acta ophthalmologica : Supplementum) Niels Ehlers (1987); ISBN: B0007BDTFA; http://www.amazon.com/exec/obidos/ASIN/B0007BDTFA/icongroupinterna
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Gale Encyclopedia of Cancer: Retinoblastoma M.S., C.G.C. Lisa Andres (2004); ISBN: B0006VTQFI; http://www.amazon.com/exec/obidos/ASIN/B0006VTQFI/icongroupinterna
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Gale Encyclopedia of Medicine: Retinoblastoma CGC Lisa Andres MS (2004); ISBN: B00075V2TG; http://www.amazon.com/exec/obidos/ASIN/B00075V2TG/icongroupinterna
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Retinoblastoma & Pseudoglioma (Lancaster Course in Ophthalmic Histopathology) Daniel M. Albert and Delia N. Sang (1988); ISBN: 0803638396; http://www.amazon.com/exec/obidos/ASIN/0803638396/icongroupinterna
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Retinoblastoma (Contemporary Issues in Ophthalmology, Vol 2) Frederick C. Blodi (1985); ISBN: 0443084149; http://www.amazon.com/exec/obidos/ASIN/0443084149/icongroupinterna
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Roentgenographic diagnosis of retinoblastoma Raymond L Pfeiffer (1936); ISBN: B0008CMMH4; http://www.amazon.com/exec/obidos/ASIN/B0008CMMH4/icongroupinterna
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Second malignant neoplasms of the head and neck in survivors of retinoblastoma : An article from: Ear, Nose & Throat Journal Christopher T Wenzel, Edward C Halperin, and Samual R Fisher (2005); ISBN: B000BCPIOU; http://www.amazon.com/exec/obidos/ASIN/B000BCPIOU/icongroupinterna
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The Official Parent's Sourcebook on Retinoblastoma: Directory for the Internet Age Icon Health Publications (1980); ISBN: B000MUDC9E; http://www.amazon.com/exec/obidos/ASIN/B000MUDC9E/icongroupinterna
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Turning Points in Cataract Formation, Syndromes & Retinoblastoma (Developments in Ophthalmology) W. Straub (1982); ISBN: 3805535643; http://www.amazon.com/exec/obidos/ASIN/3805535643/icongroupinterna
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type retinoblastoma (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Books. From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine8: •
Polymerase chain reaction detection of retinoblastoma gene deletions in paraffinembedded mouse lung adenocarcinomas [microform] Author: Churchill, Mark E.; Year: 1991; Argonne, Ill.: Argonne National Laboratory, [1991?]
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Retinoblastoma Author: Blodi, Frederick C. (Frederick Christopher),; Year: 1985; New York: Churchill Livingstone, 1985; ISBN: 9780443084 http://www.amazon.com/exec/obidos/ASIN/9780443084/icongroupinterna
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In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a Books button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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Turning points in cataract formation, syndromes, and retinoblastoma Author: Straub, Wolfgang.; Year: 1983; Basel; New York: Karger, 1983; ISBN: 9783805535 http://www.amazon.com/exec/obidos/ASIN/9783805535/icongroupinterna
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CHAPTER 4. MULTIMEDIA ON RETINOBLASTOMA Overview In this chapter, we show you how to find bibliographic information related to multimedia sources of information on retinoblastoma.
Bibliography: Multimedia on Retinoblastoma 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 LocatorPlus. Once you are in the search area, simply type retinoblastoma (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: 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 retinoblastoma: •
Retinoblastoma and pseudoglioma [slide] Source: [Daniel M. Albert, Delia N. Sang]; Year: 1981; Format: Slide; Philadelphia, PA.: F.A. Davis, c1981
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APPENDIX A. HELP ME UNDERSTAND GENETICS Overview This appendix presents basic information about genetics in clear language and provides links to online resources.9
The Basics: Genes and How They Work This section gives you information on the basics of cells, DNA, genes, chromosomes, and proteins. What Is a Cell? Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the body’s hereditary material and can make copies of themselves. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order: •
Cytoplasm: The cytoplasm is fluid inside the cell that surrounds the organelles.
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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.
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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.
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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.
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This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.
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Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.
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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.
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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.
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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.
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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of
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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.
Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.
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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.
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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •
The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.
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•
The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.
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The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.
Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene’s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)
The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.
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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene’s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene’s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes. What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.
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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody
Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.
Example Immunoglobulin G (IgG)
Enzyme
Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.
Phenylalanine hydroxylase
Messenger
Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.
Growth hormone
Structural component
These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.
Actin
Transport/storage
Ferritin
How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene’s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for
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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”
Through the processes of transcription and translation, information from genes is used to make proteins.
Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.
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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.
Mitosis and meiosis, the two types of cell division. How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.
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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.
Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.10 What Is a Gene Mutation and How Do Mutations Occur? A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism. Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are 10
This section has been adapted from the National Library of Medicine’s handbook, Help Me Understand Genetics, which presents basic information about genetics in clear language and provides links to online resources: http://ghr.nlm.nih.gov/handbook.
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responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders. How Can Gene Mutations Affect Health and Development? To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene. Do All Gene Mutations Affect Health and Development? No, only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria. For More Information about DNA Repair and the Health Effects of Gene Mutations •
The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. (Refer to the questions in the far right column.) See http://learn.genetics.utah.edu/units/disorders/whataregd/.
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Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called “What Is A Cell?”, scroll down to the heading “DNA Repair Mechanisms.” See http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html. What Kinds of Gene Mutations Are Possible?
The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include: •
Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.
•
Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.
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Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.
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Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
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Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.
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Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
•
Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?
Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy.
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The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.
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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders. What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient. Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence
Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.
Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.
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Prevalence
The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.
Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.
Mortality
Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.
An estimated 12,000 people worldwide died from syndrome C in 2002.
Lifetime risk
Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.
Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.
Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •
The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)
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One or more major signs or symptoms of the disorder (for example, sickle cell anemia)
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The parts of the body affected by the condition (for example, retinoblastoma)
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The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)
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A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)
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The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).
Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).
Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk. What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors
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such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders. It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.
Some disorders are seen in more than one generation of a family. Why Is It Important to Know My Family Medical History? A family medical history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives,
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including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Families have many factors in common, including their genes, environment, and lifestyle. Together, these factors can give clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition. A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia. While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder. Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses. The easiest way to get information about family medical history is to talk to relatives about their health. Have they had any medical problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family medical history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly. What Are the Different Ways in which a Genetic Condition Can Be Inherited? Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved: Inheritance Pattern Autosomal dominant
Description One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.
Examples Huntington disease, neurofibromatosis type 1
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Autosomal recessive
Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.
cystic fibrosis, sickle cell anemia
X-linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
fragile X syndrome
X-linked recessive
X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
hemophilia, Fabry disease
Codominant
In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
ABO blood group, alpha-1 antitrypsin deficiency
Mitochondrial
This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.
Leber hereditary optic neuropathy (LHON)
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Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer. Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Other genetic factors can also influence how a disorder is inherited. If a Genetic Disorder Runs in My Family, What Are the Chances That My Children Will Have the Condition? When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example: •
Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.
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Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.
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X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.
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X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.
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Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.
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Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial
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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and
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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited
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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.
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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.
Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.
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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •
A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.
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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.
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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)
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Abnormal test results that suggest a genetic or chromosomal condition.
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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.
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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)
A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •
Interpret and communicate complex medical information.
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Help each person make informed, independent decisions about their health care and reproductive options.
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Respect each person’s individual beliefs, traditions, and feelings.
A genetics professional will NOT: •
Tell a person which decision to make.
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Advise a couple not to have children.
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Recommend that a woman continue or end a pregnancy.
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Tell someone whether to undergo testing for a genetic disorder. How Can I Find a Genetics Professional in My Area?
To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •
GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.
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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.
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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.
Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing. What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing. What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include:
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•
Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.
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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.
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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.
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Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.
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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.
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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.
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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).
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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent. What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.
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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing. What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result. What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn
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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test. Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs. What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible. What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.
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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation. How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.
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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy. What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •
Replacing a mutated gene that causes disease with a healthy copy of the gene.
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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
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Introducing a new gene into the body to help fight a disease.
Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures. How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.
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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.
Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.
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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •
How can “good” and “bad” uses of gene therapy be distinguished?
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Who decides which traits are normal and which constitute a disability or disorder?
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Will the high costs of gene therapy make it available only to the wealthy?
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Could the widespread use of gene therapy make society less accepting of people who are different?
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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?
Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people. Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.
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The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome. What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences. What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program. What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and
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organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide. What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •
Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.
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The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.
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Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.
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The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research. What Are the Next Steps in Genomic Research?
Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •
Determine the function of genes and the elements that regulate genes throughout the genome.
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Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.
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Discover the 3-dimensional structures of proteins and identify their functions.
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Explore how DNA and proteins interact with one another and with the environment to create complex living systems.
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Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.
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Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.
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Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.
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Continue to explore the ethical, legal, and social issues raised by genomic research. What Is Pharmacogenomics?
Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.
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APPENDIX B. 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 Institute11: •
National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/HealthInformation/Publications/
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/
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These publications are typically written by one or more of the various NIH Institutes.
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidcr.nih.gov/HealthInformation/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/healthinformation/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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
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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).
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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine13: •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/index.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
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See http://www.nlm.nih.gov/databases/index.html.
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The NLM Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type retinoblastoma (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 13715 38 72 6 0 13831
HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by retinoblastoma (or synonyms) at the following Web site: http://text.nlm.nih.gov. Coffee Break: Tutorials for Biologists19 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 14
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
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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). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18
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. 19 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
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used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 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.21 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: •
MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.
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Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Retinoblastoma In the following section, we will discuss databases and references which relate to the Genome Project and retinoblastoma. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type retinoblastoma (or synonyms) into the search box, and click Go. If too many results appear, you can narrow the search by adding the word clinical. Each report will have additional links to related research and databases. The following is an example of the results you can obtain from the OMIM for retinoblastoma: 20
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. 21 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. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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IMPRINTING GENE RELATED to RETINOBLASTOMA Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=308290 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
•
Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
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Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
•
Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell
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anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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GEO DataSets: Curated gene expression and molecular abundance data sets assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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GEO Profiles: Individual gene expression and molecular abundance profiles assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi, and then select the database that you would like to search. Or, to search across databases, you can enter retinoblastoma (or synonyms) into the search box and click Go.
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Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the GDB Human Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search All Biological Data by Name/GDB ID. Type retinoblastoma (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word and or or (using or might be useful when using synonyms).
23
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://www.gdb.org/gdb/aboutGDB.html#mission.
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APPENDIX C. 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 retinoblastoma 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 This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to retinoblastoma. 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 retinoblastoma. 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 retinoblastoma:
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Cancer http://www.nlm.nih.gov/medlineplus/cancer.html Cancer in Children http://www.nlm.nih.gov/medlineplus/cancerinchildren.html Eye Cancer http://www.nlm.nih.gov/medlineplus/eyecancer.html Eye Diseases http://www.nlm.nih.gov/medlineplus/eyediseases.html Melanoma http://www.nlm.nih.gov/medlineplus/melanoma.html Retinal Disorders http://www.nlm.nih.gov/medlineplus/retinaldisorders.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click Search. This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to retinoblastoma. 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://health.nih.gov/index.asp. Under Search Health Topics, type retinoblastoma (or synonyms) into the search box, and click Search. NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing short yet comprehensive guidelines on over 1,000 diseases. NORD primarily focuses on rare diseases that might not be covered by the previously listed sources. NORD’s Web address is http://www.rarediseases.org/. A complete guide on retinoblastoma can be purchased from NORD for a nominal fee.
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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: •
Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMD®Health: http://www.webmd.com/diseases_and_conditions/default.htm
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to retinoblastoma. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with retinoblastoma. 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 retinoblastoma. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://sis.nlm.nih.gov/dirline.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. Simply type in retinoblastoma (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://healthhotlines.nlm.nih.gov/. 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.
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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type retinoblastoma (or a synonym) into the search box, and click Submit Query.
Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families25: •
Genetic Alliance: http://geneticalliance.org
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Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html
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Madisons Foundation: http://www.madisonsfoundation.org/
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March of Dimes: http://www.marchofdimes.com
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National Organization for Rare Disorders (NORD): http://www.rarediseases.org/ For More Information on Genetics
The following publications offer detailed information for patients about the science of genetics: •
What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html
•
A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html
•
Genetic Mapping: http://www.genome.gov/10000715
25
Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.
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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
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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
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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
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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html
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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on retinoblastoma: •
Basic Guidelines for Retinoblastoma Retinoblastoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001030.htm
•
Signs & Symptoms for Retinoblastoma Blindness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003040.htm Painful eye Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003032.htm Poor vision Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003029.htm Pupil, white spots Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003315.htm
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•
Diagnostics and Tests for Retinoblastoma CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm CT scan of the head Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003786.htm Echoencephalogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003797.htm Head and eye echoencephalogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003797.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Ultrasound Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003336.htm
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Surgery and Procedures for Retinoblastoma Laser surgery Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002958.htm
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Background Topics for Retinoblastoma Chemotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002324.htm Iris Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002386.htm
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
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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
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RETINOBLASTOMA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [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] Acetyltransferases: Enzymes catalyzing the transfer of an acetyl group, usually from acetyl coenzyme A, to another compound. EC 2.3.1. [NIH] Actin: Essential component of the cell skeleton. [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 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] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH]
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Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenoma: A benign 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 Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [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] 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]
Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [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] 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]
Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [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
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substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albinism: General term for a number of inherited defects of amino acid metabolism in which there is a deficiency or absence of pigment in the eyes, skin, or hair. [NIH] 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] Alkalinization: The process by which a substance becomes an alkali. An alkali is the opposite of an acid. [NIH] 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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allelic Imbalance: A situation where one member (allele) of a gene pair is lost (loss of heterozygosity) or amplified. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antichymotrypsin: Glycoprotein found in alpha(1)-globulin region in human serum. It inhibits chymotrypsin-like proteinases in vivo and has cytotoxic killer-cell activity in vitro. The protein also has a role as an acute-phase protein and is active in the control of immunologic and inflammatory processes, and as a tumor marker. It is a member of the serpin superfamily. [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-Linolenic Acid: A fatty acid that is found in plants and involved in the formation of prostaglandins. [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]
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Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Ameloblastoma: An epithelial tumor of the jaw originating from the epithelial rests of Malassez or from other epithelial remnants of the developing period of the enamel. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino 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] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] 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] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] 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] 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] Anaplasia: Loss of structural differentiation and useful function of neoplastic 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] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [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
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of surgery or other painful procedures. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [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] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [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] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anogenital: Pertaining to the anus and external genitals. [EU] Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH]
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Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress 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] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
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] Antiplasmin: A member of the serpin superfamily found in human plasma that inhibits the lysis of fibrin clots which are induced by plasminogen activator. It is a glycoprotein, molecular weight approximately 70,000 that migrates in the alpha 2 region in immunoelectrophoresis. It is the principal plasmin inactivator in blood, rapidly forming a very stable complex with plasmin. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [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] Aqueous: Having to do with water. [NIH] Aqueous humor: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH]
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Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Artificial Eye: Usually made of artificial plastic material or glass to which small quantities of metallic oxides have been added in order to imitate the features and coloring of the various parts of t he human eye; a prosthesis made of glass, plastic, or similar material. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] 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] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] 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] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [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] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH]
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Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [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] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH] Beta-Galactosidase: A group of enzymes that catalyzes the hydrolysis of terminal, nonreducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause gangliodisosis GM1. EC 3.2.1.23. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bewilderment: Impairment or loss of will power. [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] 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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [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]
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Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] 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] 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] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Bone Development: Gross development of bones from fetus to adult. It includes osteogenesis, which is restricted to formation and development of bone from the undifferentiated cells of the germ layers of the embryo. It does not include osseointegration. [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 aspiration: The removal of a small sample of bone marrow (usually from the hip) through a needle for examination under a microscope. [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] 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]
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Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cadherins: A group of functionally related glycoproteins responsible for the calciumdependent cell-to-cell adhesion mechanism. They are divided into subclasses E-, P-, and Ncadherins, which are distinct in immunological specificity and tissue distribution. They promote cell adhesion via a homophilic mechanism. These compounds play a role in the construction of tissues and of the whole animal body. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60 kD and 19 kD, respectively. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones, myosin light chain, and the regulatory subunit of cAMP-dependent protein kinase. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes in T-lymphocytes that act by inhibiting T-cell activation. EC 3.1.3.-. [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] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca
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acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [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] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardia: That part of the stomach surrounded by the esophagogastric junction, characterized by the lack of acid-forming cells. [NIH] Cardiac: Having to do with the heart. [NIH] 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] Cardiovirus: A genus of the family Picornaviridae causing encephalitis and myocarditis in rodents. Encephalomyocarditis virus is the type species. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [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] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ,
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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] 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] CDC2: It is crucial for entry into mitosis of eukaryotic cells. [NIH] Celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is being studied for cancer prevention. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Cycle Proteins: Proteins that control the cell division cycle. This family of proteins includes a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases (phosphoprotein phosphatase) as well as their putative substrates such as chromatin-associated proteins, cytoskeletal proteins, and transcription factors. [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 Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [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 Physiology: Characteristics and physiological processes of cells from cell division to cell death. [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
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same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrioles: Self-replicating, short, fibrous, rod-shaped organelles. Each centriole is a short cylinder containing nine pairs of peripheral microtubules, arranged so as to form the wall of the cylinder. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Centrosome: The cell center, consisting of a pair of centrioles surrounded by a cloud of amorphous material called the pericentriolar region. During interphase, the centrosome nucleates microtubule outgrowth. The centrosome duplicates and, during mitosis, separates to form the two poles of the mitotic spindle (mitotic spindle apparatus). [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [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] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemokines, C: Group of chemokines without adjacent cysteines that are chemoattractants for lymphocytes only. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [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]
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Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]
Chemotherapy: Treatment with anticancer drugs. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] 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] Chondrocytes: Polymorphic cells that form cartilage. [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] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chromosome Segregation: The orderly segregation of chromosomes during meiosis or mitosis. [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 Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [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] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [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]
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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] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] 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] 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] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] 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]
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] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [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] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH]
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Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [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 '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] Complement 1: The first complement component to act in the cytolysis reaction. It is a trimolecular complex held together with Ca ions and, when activated, has esterase activity which initiates the next step in the sequence. [NIH] Complement 1 Inactivators: Compounds which inhibit, antagonize, or inactivate complement 1. A well-known inhibitor is a serum glycoprotein believed to be alpha-2neuroaminoglycoprotein. It inhibits the activated (esterase) form of complement 1 as well as kinin-forming, coagulation, and fibrinolytic systems. Deficiency of this inactivator has been found in patients with hereditary angioneurotic edema. These compounds are members of the serpin superfamily. [NIH] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] 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,
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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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [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] Concentric: Having a common center of curvature or symmetry. [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] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] 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] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or
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treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] 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 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] Corpus: The body of the uterus. [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] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Crenarchaeota: A kingdom in the domain Archaea comprised of thermoacidophilic, sulfurdependent organisms. The two orders are Sulfolobales and Thermoproteales. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] 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 cell line: Cells of a single type that have been grown in the laboratory for several generations (cell divisions). [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] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]
Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cystectomy: Used for excision of the urinary bladder. [NIH]
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Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cystitis: Inflammation of the urinary bladder. [EU] 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] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytokinesis: Division of the rest of cell. [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] 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] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]
De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum
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reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [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] 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] 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]
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 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] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [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] Discrimination: The act of qualitative and/or quantitative differentiation between two or
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more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissection: Cutting up of an organism for study. [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] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dosimetry: All the methods either of measuring directly, or of measuring indirectly and computing, absorbed dose, absorbed dose rate, exposure, exposure rate, dose equivalent, and the science associated with these methods. [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 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] 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] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dwarfism: The condition of being undersized as a result of premature arrest of skeletal
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growth. It may be caused by insufficient secretion of growth hormone (pituitary dwarfism). [NIH]
Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysgenesis: Defective development. [EU] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [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] 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] 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] 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] 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] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encephalocele: Cerebral tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur.
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[NIH]
Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, 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] Encephalomyocarditis Virus: The type species of cardiovirus causing encephalomyelitis and myocarditis in rodents, pigs, and monkeys. Infection in man has been reported with CNS involvement but without myocarditis. [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] 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] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [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] 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 the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enucleation: Removal of the nucleus from an eucaryiotic cell. [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]
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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] 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] 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] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erythroblasts: Immature, nucleated erythrocytes occupying the stage of erythropoiesis that follows formation of erythroid progenitor cells and precedes formation of reticulocytes. Popularly called normoblasts. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Escalation: Progressive use of more harmful drugs. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [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]
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Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [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] Euryarchaeota: A kingdom of Archaea comprising the methanogens, extreme halophiles (Halobacteriales), sulfate-reducing species (Archaeoglobales), and the thermophiles (Thermococcales and Thermoplasmales). [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] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] 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] Eye Color: Color of the iris. [NIH] 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,
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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] Fast Neutrons: Neutrons, the energy of which exceeds some arbitrary level, usually around one million electron volts. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [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] Fibrinolysis: The natural enzymatic dissolution of fibrin. [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] Fibronectins: Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. [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] Flavopiridol: Belongs to the family of anticancer drugs called flavinols. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension.
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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] 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] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [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] Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Gallate: Antioxidant present in tea. [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] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [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]
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Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [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 Amplification: A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication. [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 Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH] Gene Fusion: Fusion of structural genes to analyze protein behavior or fusion of regulatory sequences with structural genes to determine mechanisms of regulation. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes
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may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genes, Regulator: Genes which regulate or circumscribe the activity of other genes; specifically, genes which code for proteins (repressors or activators) which regulate the genetic transcription of the structural genes and/or regulatory genes. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetic transcription: The process by which the genetic information encoded in the gene, represented as a linear sequence of deoxyribonucleotides, is copied into an exactly complementary sequence of ribonucleotides known as messenger RNA. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germ Layers: The three layers of cells comprising the early embryo. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [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] 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]
Glomerular Mesangium: The thin membrane which helps to support the capillary loops in a renal glomerulus. It is connective tissue composed of mesangial cells - myofibroblasts phenotypically related to vascular smooth muscle cells (muscle, smooth, vascular), phagocytes, and the mesangial extracellular matrix. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [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
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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] 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] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [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] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Growth Plate: The area between the epiphysis and the diaphysis within which bone growth occurs. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Hair Cells: Mechanoreceptors located in the organ of Corti that are sensitive to auditory stimuli and in the vestibular apparatus that are sensitive to movement of the head. In each case the accessory sensory structures are arranged so that appropriate stimuli cause movement of the hair-like projections (stereocilia and kinocilia) which relay the information centrally in the nervous system. [NIH] Hair Color: Color of hair or fur. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half
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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] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Helix-loop-helix: Regulatory protein of cell cycle. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [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] 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 C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [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] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH]
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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] Hepatocyte: A liver cell. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [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 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]
Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] 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 therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [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]
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Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see 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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] 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] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization
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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] Immunodeficiency: The decreased ability of the body to fight infection and disease. [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] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] 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] 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]
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Infiltrating cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called invasive cancer. [NIH] 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] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] 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] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] 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] 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] Interferons: Proteins secreted by vertebrate cells in response to a wide variety of inducers. They confer resistance against many different viruses, inhibit proliferation of normal and malignant cells, impede multiplication of intracellular parasites, enhance macrophage and granulocyte phagocytosis, augment natural killer cell activity, and show several other immunomodulatory functions. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [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]
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Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Neoplasms: Tumors or cancer of 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] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]
Intraocular: Within the eye. [EU] Intravesical: Within the bladder. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] 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]
Invasive cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins
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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] Ketamine: A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (receptors, NMethyl-D-Aspartate) and may interact with sigma receptors. [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] Kinesin: A microtubule-associated mechanical adenosine triphosphatase, that uses the energy of ATP hydrolysis to move organelles along microtubules toward the plus end of the microtubule. The protein is found in squid axoplasm, optic lobes, and in bovine brain. Bovine kinesin is a heterotetramer composed of two heavy (120 kDa) and two light (62 kDa) chains. EC 3.6.1.-. [NIH] Kinetic: Pertaining to or producing motion. [EU] Kinetochores: Large multiprotein complexes that bind the centromeres of the chromosomes to the microtubules of the mitotic spindle during metaphase in the cell cycle. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large
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intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laterality: Behavioral manifestations of cerebral dominance in which there is preferential use and superior functioning of either the left or the right side, as in the preferred use of the right hand or right foot. [NIH] Leiomyosarcoma: A tumor of the muscles in the uterus, abdomen, or pelvis. [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] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
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] Leukemia: Cancer of blood-forming tissue. [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] 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] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipoma: A benign tumor composed of fat cells. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Regeneration: Repair or renewal of hepatic tissue. [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] Local therapy: Treatment that affects cells in the tumor and the area close to it. [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
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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] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is already abnormal, it can result in neoplastic transformation. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumbar puncture: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a spinal tap. [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] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] 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
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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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] 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 fibrous histiocytoma: A sarcoma that usually begins in soft tissue. It usually appears as an enlarging, painful mass that can cause fracture due to destruction of the bone by a spreading tumor. [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] Mammography: Radiographic examination of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [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 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] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]
Membrane: A very thin layer of tissue that covers a surface. [NIH]
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Membrane Fluidity: The motion of phospholipid molecules within the lipid bilayer, dependent on the classes of phospholipids present, their fatty acid composition and degree of unsaturation of the acyl chains, the cholesterol concentration, and temperature. [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] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [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] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] 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] 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] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the
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second trimester. [NIH] 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] Mitotic Spindle Apparatus: An organelle consisting of three components: (1) the astral microtubules, which form around each centrosome and extend to the periphery; (2) the polar microtubules which extend from one spindle pole to the equator; and (3) the kinetochore microtubules, which connect the centromeres of the various chromosomes to either centrosome. [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] 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] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different
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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] Motility: The ability to move spontaneously. [EU] 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, Smooth, Vascular: The nonstriated, involuntary muscle tissue of blood vessels. [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] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] 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] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nasopharynx: The nasal part of the pharynx, lying above the level of the soft palate. [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] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephropathy: Disease of the kidneys. [EU]
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Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] 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] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] 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
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nuclei during their decay. [NIH] Nevi and Melanomas: A collective term for the various types of nevi and melanomas. [NIH] Nevus: A benign growth on the skin, such as a mole. A mole is a cluster of melanocytes and surrounding supportive tissue that usually appears as a tan, brown, or flesh-colored spot on the skin. The plural of nevus is nevi (NEE-vye). [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 Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nucleates: Bacteria-inducing ice nucleation at warm temperatures (between zero and minus ten degrees C.). [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
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form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleosomes: The repeating structural units of chromatin, each consisting of approximately 200 base pairs of DNA wound around a protein core. This core is composed of the histones H2A, H2B, H3, and H4. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Octamer: Eight molecules of histone. [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] Oligodendroglial: A cell that lays down myelin. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU] Opacity: Degree of density (area most dense taken for reading). [NIH] 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] Ophthalmic: Pertaining to the eye. [EU] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
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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] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Orbital Implants: Rounded objects made of coral, teflon, or alloplastic polymer and covered with sclera, and which are implanted in the orbit following enucleation. An artificial eye is usually attached to the anterior of the orbital implant for cosmetic purposes. [NIH] Orderly: A male hospital attendant. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Organogenesis: Clonal propagation which involves culturing explants from roots, leaves, or stems to form undifferentiated callus tissue; after the cells form shoots, they are separated and rooted. Alternatively, if the callus is put in liquid culture, somatic embryos form. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Osseointegration: The growth action of bone tissue, as it assimilates surgically implanted devices or prostheses to be used as either replacement parts (e.g., hip) or as anchors (e.g., endosseous dental implants). [NIH] 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] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] 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] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH]
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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 Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] 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] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [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] Palladium: A chemical element having an atomic weight of 106.4, atomic number of 46, and the symbol Pd. It is a white, ductile metal resembling platinum, and following it in abundance and importance of applications. It is used in dentistry in the form of gold, silver, and copper alloys. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] 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] Papillary tumor: A tumor shaped like a small mushroom, with its stem attached to the epithelial layer (inner lining) of an organ. [NIH] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH]
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Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternal Age: Age of the father. [NIH] Paternity: Establishing the father relationship of a man and a child. [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] Pathologies: The study of abnormality, especially the study of diseases. [NIH] PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [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 compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [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] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH]
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Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [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] Phosphoprotein Phosphatase: A group of enzymes removing the serine- or threoninebound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992) EC 3.1.3.16. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylating: 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] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [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]
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]
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Pineal Body: A small conical midline body attached to the posterior part of the third ventricle and lying between the superior colliculi, below the splenium of the corpus callosum. [NIH] Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [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] Placentation: Development of a site of fetomaternal union for physiologic exchange, a placenta or placenta-like organ. [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] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasminogen Inactivators: Important modulators of the activity of plasminogen activators. Four inhibitors, all belonging to the serpin family of proteins, have been implicated in plasminogen activation inhibition. They are PAI-1, PAI-2, protease-nexin, and protein C inhibitor (PAI-3). All inhibit both the tissue-type and urokinase-type plasminogen activators. [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [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] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous
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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] 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] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [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] Polyploid: An organism with more than two chromosome sets in its vegetative cells. [NIH] Polyploidy: The chromosomal constitution of a cell containing multiples of the normal number of chromosomes; includes triploidy (symbol: 3N), tetraploidy (symbol: 4N), etc. [NIH]
Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [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] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a
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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] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [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] Primary tumor: The original tumor. [NIH] Primitive neuroectodermal tumors: PNET. A type of bone cancer that forms in the middle (shaft) of large bones. Also called Ewing's sarcoma/primitive neuroectodermal 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] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] 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]
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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] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]
Prone: Having the front portion of the body downwards. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein 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] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] 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 Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pupil: The aperture in the iris through which light passes. [NIH] Pupillary dilation: The action of stretching or enlarging the pupil e.g. by atropine. [EU] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] 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] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons,
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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] 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] 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] Radium: A radioactive element symbol Ra, atomic number 88, disintegration of uranium and is is used clinically as a source brachytherapy. [NIH]
of the alkaline earth series of metals. It has the atomic and atomic weight 226. Radium is the product of the present in pitchblende and all ores containing uranium. It of beta and gamma-rays in radiotherapy, particularly
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] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [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] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [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] 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] 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] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH]
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Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [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] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [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 cell carcinoma: A type of kidney cancer. [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] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [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]
Reticulocytes: Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic "reticulum"
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(not the same as the endoplasmic reticulum), hence the name reticulocytes. [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 Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [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] Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field. [NIH] Retinoblastoma Protein: Product of the retinoblastoma tumor suppressor gene. It is a nuclear phosphoprotein hypothesized to normally act as an inhibitor of cell proliferation. Rb protein is absent in retinoblastoma cell lines. It also has been shown to form complexes with the adenovirus E1A protein, the SV40 T antigen, and the human papilloma virus E7 protein. [NIH]
Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH]
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Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [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] 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 developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Ruthenium: A hard, brittle, grayish-white rare earth metal with an atomic symbol Ru, atomic number 44, and atomic weight 101.07. It is used as a catalyst and hardener for platinum and palladium. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [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] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate
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affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second cancer: Refers to a new primary cancer that is caused by previous cancer treatment, or a new primary cancer in a person with a history of cancer. [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] Secretin: A hormone made in the duodenum. Causes the stomach to make pepsin, the liver to make bile, and the pancreas to make a digestive juice. [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] 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] 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] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Seminoma: A type of cancer of the testicles. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid
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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] Serine Endopeptidases: Any member of the group of endopeptidases containing at the active site a serine residue involved in catalysis. EC 3.4.21. [NIH] Serine Proteinase Inhibitors: Exogenous or endogenous compounds which inhibit serine endopeptidases. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serpins: A family of serine proteinase inhibitors which are similar in amino acid sequence and mechanism of inhibition, but differ in their specificity toward proteolytic enzymes. This family includes alpha 1-antitrypsin, angiotensinogen, ovalbumin, antiplasmin, alpha 1antichymotrypsin, thyroxine-binding protein, complement 1 inactivators, antithrombin III, heparin cofactor II, plasminogen inactivators, gene Y protein, placental plasminogen activator inhibitor, and barley Z protein. Some members of the serpin family may be substrates rather than inhibitors of serine endopeptidases, and some serpins occur in plants where their function is not known. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [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
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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] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Skull Base: The inferior region of the skull consisting of an internal (cerebral), and an external (basilar) surface. [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] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [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] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Soft tissue sarcoma: A sarcoma that begins in the 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] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH]
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Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spina bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [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 tap: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a lumbar puncture. [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] 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] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly
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to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [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] Steroids: Drugs used to relieve swelling and inflammation. [NIH] Stillbirth: The birth of a dead fetus or baby. [NIH] 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] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [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] 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] Subconjunctival: Situated or occurring beneath the conjunctiva. [EU] 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] Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH]
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Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] 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] Symphysis: A secondary cartilaginous joint. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] 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] Systemic: Affecting the entire body. [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] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [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] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] 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] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of
Dictionary 263
neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [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] 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] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] 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] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] 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] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [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]
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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] 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] 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] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [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] 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]
Dictionary 265
Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other 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] Tumor-derived: Taken from an individual's own tumor tissue; may be used in the development of a vaccine that enhances the body's ability to build an immune response to the tumor. [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] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Uranium: A radioactive element of the actinide series of metals. It has an atomic symbol U, atomic number 92, and atomic weight 238.03. U-235 is used as the fissionable fuel in nuclear weapons and as fuel in nuclear power reactors. [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] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethane: Antineoplastic agent that is also used as a veterinary anesthetic. It has also been used as an intermediate in organic synthesis. Urethane is suspected to be a carcinogen. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder.
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[NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]
Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Urothelium: The epithelial lining of the urinary tract. [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] 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] 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] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [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]
Dictionary 267
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 Proteins: Proteins found in any species of virus. [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] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] 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] Vulva: The external female genital organs, including the clitoris, vaginal lips, and the opening to the vagina. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink
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tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] 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]
269
INDEX 3 3-dimensional, 66, 152, 183, 198 A Abdomen, 198, 206, 221, 233, 235, 245, 246, 260, 261, 267 Abdominal, 198, 245 Aberrant, 38, 40, 43, 47, 198 Ablation, 34, 53, 60, 110, 130, 198 Acetylcholine, 198, 241, 242 Acetyltransferases, 62, 198 Actin, 38, 77, 153, 198, 240 Acute lymphoblastic leukemia, 81, 94, 102, 198 Acute lymphocytic leukemia, 198 Acute myelogenous leukemia, 198 Acute myeloid leukemia, 119, 198, 251 Acute nonlymphocytic leukemia, 198 Acute renal, 198, 228 Acyl, 58, 124, 198, 238 Adaptability, 198, 209 Adenine, 146, 198, 199, 252 Adenocarcinoma, 70, 109, 199, 229, 242 Adenoma, 66, 199 Adenosine, 147, 199, 234, 247 Adenosine Triphosphate, 147, 199, 247 Adenovirus, 13, 19, 31, 53, 62, 73, 77, 83, 108, 179, 199, 255 Adipose Tissue, 17, 199 Adjuvant, 63, 118, 120, 122, 124, 130, 131, 134, 139, 199 Adjuvant Therapy, 63, 131, 134, 199 Adolescence, 199, 246 Adrenergic, 127, 199, 221 Adverse Effect, 41, 199, 258 Aerobic, 199, 239 Affinity, 57, 199, 259 Agar, 199, 248 Ageing, 22, 199 Agonist, 49, 199, 262 Airway, 39, 59, 200 Alanine, 57, 200 Albinism, 65, 200 Algorithms, 200, 206 Alkaline, 200, 201, 207, 253 Alkalinization, 52, 200 Alkaloid, 200, 204, 207 Alleles, 25, 27, 70, 72, 148, 165, 200, 229, 236 Allelic Imbalance, 84, 200
Allergen, 40, 200, 257 Alopecia, 200, 215 Alpha 1-Antichymotrypsin, 200, 258 Alpha 1-Antitrypsin, 200, 258 Alpha Particles, 200, 252 Alpha-1, 161, 165, 200, 247 Alpha-Linolenic Acid, 124, 200 Alternative medicine, 200 Alveolar Process, 201, 254 Ameloblastoma, 98, 201 Amino Acid Sequence, 201, 202, 214, 222, 258 Amino Acids, 49, 58, 148, 152, 158, 201, 202, 204, 212, 214, 246, 249, 251, 256, 258, 261, 264 Amino-terminal, 96, 201 Ammonia, 201, 227 Amnion, 201 Amniotic Fluid, 174, 176, 201 Amplification, 71, 93, 95, 201 Amyloid, 58, 201 Anaesthesia, 110, 201, 231 Analogous, 14, 201, 264 Anaphylatoxins, 201, 213 Anaplasia, 38, 201 Anatomical, 201, 211, 219, 231, 257 Anemia, 31, 160, 161, 164, 165, 170, 190, 201, 212, 224 Anemic, 32, 201 Anesthesia, 200, 201, 220, 234 Aneuploidy, 62, 158, 159, 202 Angioplasty, 25, 202 Angiotensinogen, 202, 258 Animal model, 20, 26, 29, 32, 34, 68, 99, 202, 265 Annealing, 202, 249 Anogenital, 29, 202 Anterior chamber, 202, 233 Antibacterial, 202, 260 Antibiotic, 65, 202, 216, 218, 260, 262 Antibodies, 153, 202, 228, 230, 231, 239, 248, 253 Antibody, 30, 50, 67, 153, 199, 202, 213, 228, 229, 231, 233, 237, 239, 253, 257, 260, 268 Anticoagulant, 202, 251 Antigen, 54, 57, 61, 79, 86, 99, 101, 199, 202, 213, 217, 229, 230, 231, 232, 237, 255, 257
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Antigen-Antibody Complex, 202, 213 Antigen-presenting cell, 202, 217 Anti-infective, 203, 230 Anti-inflammatory, 203, 209, 245 Anti-Inflammatory Agents, 203, 209 Antimicrobial, 203, 218 Antineoplastic, 52, 203, 208, 215, 218, 245, 249, 265, 266 Antineoplastic Agents, 52, 203, 266 Antioxidant, 203, 224, 245 Antiplasmin, 203, 258 Antiproliferative, 32, 53, 70, 128, 203 Anuria, 203, 234 Anus, 61, 202, 203, 212, 253 Aphakia, 203, 255 Aplastic anemia, 31, 203 Aqueous, 114, 203, 205, 211, 216, 230, 235 Aqueous humor, 114, 203, 211 Arachidonic Acid, 203, 251 Archaea, 87, 203, 215, 222, 238 Arginine, 201, 204, 229, 242 Arterial, 25, 32, 41, 204, 230, 251 Arteries, 204, 206, 215 Arterioles, 204, 206, 208 Artery, 42, 49, 202, 204, 220, 233, 256 Articular, 204, 244 Artificial Eye, 204, 244 Aseptic, 204, 244, 261 Aspartic Acid, 57, 204 Aspiration, 89, 204 Assay, 35, 96, 204 Ataxia, 44, 189, 204, 262 Atrophy, 100, 189, 204, 241 Atropine, 204, 252 Attenuated, 32, 204 Atypical, 50, 169, 204 Auditory, 204, 227 Autoimmune disease, 57, 204 Autologous, 32, 126, 132, 204 Axillary, 88, 204 Axons, 204, 244, 255 B Bacteria, 145, 153, 157, 198, 202, 203, 204, 220, 222, 229, 238, 242, 248, 253, 260, 264, 266 Bacterium, 204, 228 Basal Ganglia, 204, 205 Basal Ganglia Diseases, 204, 205 Base Sequence, 157, 205, 224 Basement Membrane, 205, 222, 234 Benign, 78, 199, 205, 235, 240, 242, 245, 253, 267
Benign tumor, 205, 235 Beta-Galactosidase, 23, 205 Beta-pleated, 201, 205 Bewilderment, 205, 214 Bilateral, 78, 79, 80, 82, 93, 94, 101, 102, 111, 114, 118, 131, 133, 205, 255 Bile, 205, 224, 230, 235, 257 Binding Sites, 24, 205 Bioassay, 205 Biological Assay, 30, 205 Biological therapy, 205, 227 Biomarkers, 51, 91, 206 Biopsy, 89, 206 Biosynthesis, 203, 206, 251, 258 Biotechnology, 5, 74, 141, 152, 179, 181, 186, 188, 189, 190, 206 Bladder, 10, 11, 16, 53, 75, 101, 206, 214, 215, 216, 224, 233, 241, 251, 265, 266 Blastocyst, 206, 214, 248 Blood Glucose, 206, 228, 232 Blood Platelets, 206, 258 Blood pressure, 164, 206, 208, 230, 239, 259 Blot, 42, 72, 206 Body Fluids, 206, 207, 218, 259, 265 Bone Development, 25, 59, 206 Bone Marrow, 31, 75, 76, 109, 126, 132, 180, 198, 203, 206, 226, 231, 236, 239, 240, 251, 259 Bone marrow aspiration, 109, 206 Bowel, 206, 233, 241, 261 Brachytherapy, 78, 110, 206, 232, 233, 253, 268 Bradykinin, 207, 242 Bronchial, 207 Bronchitis, 207, 211 Bronchopulmonary, 59, 207 Bronchopulmonary Dysplasia, 59, 207 Buccal, 174, 176, 207 Bypass, 17, 32, 51, 207 C Cadherins, 40, 207 Calcineurin, 83, 207 Calcium, 207, 213, 258 Callus, 207, 219, 244 Calmodulin, 207 Calpain, 46, 207 Camptothecin, 126, 135, 207 Canonical, 23, 208 Capillary, 24, 207, 208, 226, 266 Carbon Dioxide, 208, 223, 225, 248 Carboplatin, 34, 100, 104, 105, 125, 127, 137, 208
Index 271
Carcinogen, 48, 208, 265 Carcinogenesis, 29, 36, 37, 84, 102, 105, 106, 208, 210 Carcinogenic, 13, 208, 232, 243, 251, 265 Carcinoma, 43, 51, 70, 73, 77, 88, 105, 107, 108, 128, 132, 134, 208, 242 Cardia, 84, 208 Cardiac, 207, 208, 221, 240 Cardiovascular, 183, 208, 258 Cardiovascular disease, 183, 208 Cardiovirus, 208, 220 Carotene, 208, 255 Case report, 102, 113, 208 Case series, 48, 208 Caspase, 53, 97, 126, 135, 208 Cataract, 141, 142, 203, 208, 255 Catheterization, 202, 208 Causal, 39, 71, 209 Cause of Death, 72, 209, 216 CDC2, 87, 209 Celecoxib, 86, 209 Cell Adhesion, 207, 209, 232 Cell Cycle, 11, 12, 13, 16, 18, 19, 20, 23, 24, 25, 26, 27, 28, 31, 33, 35, 36, 38, 39, 40, 44, 45, 46, 49, 51, 53, 55, 56, 57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 73, 74, 76, 82, 85, 90, 92, 94, 96, 97, 101, 112, 124, 155, 156, 209, 212, 215, 222, 228, 234, 252, 266 Cell Cycle Proteins, 26, 57, 68, 209 Cell Death, 9, 34, 36, 44, 52, 63, 64, 67, 73, 107, 111, 116, 127, 132, 156, 203, 209, 222, 240 Cell Differentiation, 41, 47, 60, 69, 90, 129, 209, 258, 260 Cell Lineage, 60, 209 Cell membrane, 209, 217, 247 Cell motility, 46, 209 Cell Physiology, 35, 115, 209 Cell proliferation, 12, 18, 23, 24, 25, 26, 31, 33, 38, 40, 41, 46, 47, 49, 53, 55, 57, 63, 64, 69, 70, 83, 88, 113, 123, 124, 209, 255, 258 Cell Respiration, 209, 239 Cell Size, 209, 224 Cell Survival, 9, 53, 57, 58, 67, 209, 227 Cell Transplantation, 132, 209 Central Nervous System, 124, 198, 200, 207, 210, 224, 227, 244, 258 Centrioles, 210 Centromere, 80, 148, 151, 210 Centrosome, 36, 97, 210, 239
Ceramide, 73, 210 Cerebellar, 204, 210, 254 Cerebral, 204, 205, 210, 219, 221, 235, 259 Cerebral Cortex, 204, 210 Cerebrospinal, 210, 236, 260 Cerebrospinal fluid, 210, 236, 260 Cerebrovascular, 205, 208, 210, 263 Cerebrum, 210, 248, 265 Cervical, 29, 50, 61, 81, 210 Cervix, 30, 87, 210 Character, 210, 217 Chemokines, 57, 210 Chemokines, C, 57, 210 Chemopreventive, 66, 135, 210 Chemotactic Factors, 210, 213 Chemotherapeutics, 35, 211 Chin, 91, 211, 238 Cholesterol, 147, 205, 211, 215, 238, 262 Chondrocytes, 20, 211, 223 Chorioretinitis, 211, 255 Choroid, 211, 255 Chromatin, 21, 31, 34, 38, 49, 65, 66, 67, 203, 209, 211, 236, 243 Chromosome Fragility, 211, 264 Chromosome Segregation, 36, 211 Chronic, 26, 59, 82, 189, 207, 211, 218, 220, 231, 234, 235, 249, 261 Chronic Disease, 211, 235 Chronic Obstructive Pulmonary Disease, 59, 211 Chronic renal, 211, 249 Ciliary, 203, 211 Ciliary processes, 203, 211 Cirrhosis, 211, 228 CIS, 211, 225, 226, 255 Cisplatin, 52, 138, 212 C-kit receptor, 212, 260 Cleave, 125, 212 Clinical Medicine, 182, 212, 250 Clinical trial, 12, 34, 50, 179, 180, 183, 186, 212, 246, 251, 253 Cloning, 21, 23, 71, 206, 212, 232, 235 Coagulation, 46, 206, 207, 212, 213, 223, 228, 263 Cobalt, 80, 212 Cochlea, 212, 232 Codon, 52, 153, 212 Coenzyme, 198, 212 Cofactor, 212, 251, 258, 263 Collagen, 205, 212, 222, 223, 248, 250 Colon, 41, 54, 65, 73, 162, 189, 212, 213, 235 Colonoscopy, 164, 213
272
Retinoblastoma
Colorectal, 84, 134, 213 Colorectal Cancer, 84, 213 Combination chemotherapy, 131, 137, 213 Comorbidity, 50, 213 Complement, 46, 201, 213, 214, 226, 232, 233, 257, 258 Complement 1, 213, 258 Complement 1 Inactivators, 213, 258 Complement Activation, 46, 201, 213 Complementary medicine, 117, 214 Compliance, 50, 214 Computational Biology, 186, 188, 214 Concentric, 214, 242 Conception, 47, 155, 214, 223, 259, 261 Concomitant, 68, 214 Cones, 214, 255 Confusion, 162, 214, 218, 265 Conjugated, 214, 216, 242, 243 Conjunctiva, 214, 261 Connective Tissue, 206, 212, 214, 223, 224, 226, 236, 238, 256 Consciousness, 214, 217, 218, 252 Consensus Sequence, 214 Conserved Sequence, 13, 214 Constitutional, 6, 8, 75, 76, 82, 98, 214, 255 Constriction, 148, 151, 214, 233, 256 Consultation, 170, 171, 174, 175, 214 Contraindications, ii, 214 Convulsion, 205, 215 Cornea, 202, 203, 215, 257, 261 Corneum, 215, 221 Coronary, 49, 208, 215 Coronary heart disease, 208, 215 Corpus, 215, 246, 248, 267 Cortex, 215, 221, 254 Cortical, 119, 215, 257, 262 Cranial, 215, 244, 246 Crenarchaeota, 203, 215 Crossing-over, 215, 253 Crystallization, 74, 215 Cues, 57, 60, 215 Cultured cell line, 38, 215 Cultured cells, 33, 215 Curative, 215, 263 Cutaneous, 42, 215 Cyclic, 20, 207, 215, 227, 242, 247 Cyclin-Dependent Kinases, 39, 102, 209, 215 Cyclophosphamide, 101, 118, 127, 138, 215 Cystectomy, 75, 215 Cysteine, 44, 207, 210, 216, 261 Cystine, 216
Cystitis, 16, 216 Cytochrome, 124, 216, 245 Cytogenetics, 75, 102, 216, 256 Cytokine, 40, 216 Cytokinesis, 62, 216 Cytomegalovirus, 96, 216 Cytoplasm, 145, 146, 147, 153, 203, 209, 216, 236, 239, 240, 242, 256 Cytosine, 146, 216, 252 Cytoskeletal Proteins, 207, 209, 216 Cytoskeleton, 216, 232, 238 Cytostatic, 70, 216 Cytotoxic, 52, 70, 124, 135, 200, 216, 253, 258 Cytotoxicity, 212, 216 D Daunorubicin, 216, 218 De novo, 83, 156, 216 Death Certificates, 164, 216 Decidua, 216, 248 Defense Mechanisms, 217, 232 Degenerative, 21, 26, 217, 229, 237, 244, 255 Deletion, 4, 6, 8, 9, 33, 36, 37, 48, 49, 56, 68, 71, 72, 73, 78, 112, 119, 158, 203, 217, 225, 236 Dementia, 159, 217 Denaturation, 217, 249 Dendrites, 217, 241 Dendritic, 53, 217, 237, 255 Dendritic cell, 53, 217 Deoxyribonucleic, 146, 217, 256 Deoxyribonucleic acid, 146, 217, 256 Deoxyribonucleotides, 217, 226 Depolarization, 103, 217, 258 Deuterium, 217, 230 Diabetes Mellitus, 18, 217, 227, 228 Digestion, 205, 206, 217, 233, 235, 261, 266 Digestive tract, 217, 259, 260 Dihydrotestosterone, 217, 254 Dihydroxy, 63, 217 Dilation, 207, 217 Diploid, 22, 202, 217, 239, 248, 264 Discrimination, 176, 177, 182, 217 Disease Progression, 34, 218 Disorientation, 214, 218 Dissection, 60, 218 Dissociation, 199, 218, 233 Distal, 84, 102, 218, 252 Dominance, 218, 221, 235 Dosimetry, 51, 218 Doxorubicin, 118, 135, 218
Index 273
Doxycycline, 16, 65, 218 Drive, 11, 20, 30, 38, 218 Drug Resistance, 96, 218 Drug Tolerance, 218 Duct, 208, 218, 222, 245, 256, 260 Duodenum, 205, 218, 257, 261 Dura mater, 218, 238, 245 Dwarfism, 20, 218 Dyes, 201, 219, 224, 261 Dysgenesis, 56, 219 Dysplasia, 189, 219 Dystrophic, 46, 219 Dystrophy, 189, 219 E Ectopic, 27, 35, 57, 71, 219 Effector, 51, 198, 213, 219, 247 Efficacy, 19, 32, 34, 64, 66, 77, 101, 124, 219, 264 Elastin, 212, 219, 222 Elective, 110, 135, 219 Electrocoagulation, 212, 219 Electrolyte, 219, 234, 259 Electrons, 203, 205, 219, 233, 245, 252, 253 Elementary Particles, 219, 241, 251 Embryo, 56, 61, 86, 155, 156, 157, 165, 201, 206, 209, 219, 226, 231, 244 Embryogenesis, 219, 260 Emphysema, 200, 211, 219 Enamel, 201, 219, 234 Encephalocele, 219, 241 Encephalomyelitis, 220 Encephalomyocarditis Virus, 83, 220 Endarterectomy, 202, 220 Endemic, 220, 260 Endocrine System, 220, 241 Endogenous, 19, 46, 70, 207, 220, 251, 258, 264 Endothelial cell, 46, 83, 220, 223, 263 Endothelium, 32, 220, 242 Endothelium, Lymphatic, 220 Endothelium, Vascular, 220 Endothelium-derived, 220, 242 Endotoxin, 220, 265 End-stage renal, 211, 220, 249 Enhancer, 17, 67, 87, 220, 254 Enucleation, 31, 80, 87, 98, 102, 119, 121, 126, 220, 244 Environmental Exposure, 220, 243 Environmental Health, 28, 185, 186, 220 Enzymatic, 49, 58, 207, 208, 213, 215, 220, 223, 249, 255 Epidemic, 221, 260
Epidermal, 39, 221, 234, 237, 267 Epidermis, 29, 215, 221, 229, 234 Epidermoid carcinoma, 128, 221, 260 Epigastric, 221, 245 Epinephrine, 199, 221, 241, 242, 265 Epistasis, 56, 221 Epithelial, 29, 36, 37, 40, 49, 50, 51, 59, 62, 70, 73, 199, 201, 216, 221, 234, 245, 266 Epithelial Cells, 36, 37, 40, 49, 51, 62, 70, 221, 234 Epithelium, 16, 36, 37, 94, 205, 220, 221, 233, 245, 255 Erectile, 221, 246 Erythroblasts, 31, 221 Erythrocytes, 201, 206, 207, 221, 228, 254, 257 Erythroid Progenitor Cells, 221 Erythropoiesis, 31, 53, 221 Escalation, 50, 221 Esophagus, 61, 217, 221, 247, 261 Essential Tremor, 189, 221 Estradiol, 37, 49, 221 Estrogen, 22, 49, 70, 83, 87, 91, 221, 257, 262 Estrogen receptor, 22, 49, 70, 87, 91, 221 Ether, 203, 222 Ethnic Groups, 170, 173, 222 Etoposide, 22, 118, 125, 127, 129, 135, 137, 222 Eukaryotic Cells, 14, 209, 216, 222, 231, 244, 265 Euryarchaeota, 203, 222 Excitation, 222, 224, 241 Excrete, 203, 222, 234 Exhaustion, 51, 222 Exocrine, 222, 245 Exogenous, 22, 73, 220, 222, 225, 251, 258 Exon, 72, 222 External-beam radiation, 222, 233, 253, 268 Extracellular, 41, 44, 46, 57, 58, 201, 214, 222, 223, 226, 232, 259 Extracellular Matrix, 41, 214, 222, 223, 226, 232 Extracellular Matrix Proteins, 41, 222 Extracellular Space, 222 Extraction, 203, 222, 255 Extraocular, 121, 125, 137, 222 Eye Color, 157, 222 Eye Infections, 199, 222 F Facial, 4, 7, 103, 223
274
Retinoblastoma
Family Planning, 186, 223 Fast Neutrons, 223, 241 Fat, 46, 91, 199, 203, 206, 208, 210, 215, 223, 235, 249, 259 Fathers, 165, 223 Fatty acids, 223, 251 Femur, 102, 223 Fetus, 68, 173, 174, 176, 180, 206, 223, 248, 250, 261, 266 Fibrin, 203, 223, 263 Fibrinolysis, 46, 223 Fibroblast Growth Factor, 16, 76, 223 Fibroblasts, 34, 47, 50, 51, 52, 60, 61, 77, 85, 113, 123, 223, 232 Fibronectins, 222, 223 Fibrosis, 59, 157, 160, 164, 165, 189, 223, 257 Fixation, 223, 257 Flavopiridol, 126, 135, 223 Flow Cytometry, 55, 223 Fluorescence, 224 Fluorescent Dyes, 224 Folate, 29, 34, 224 Fold, 71, 224 Folic Acid, 224 Forearm, 206, 224 Frameshift, 158, 224 Frameshift Mutation, 158, 224 Fundus, 140, 224 G Galactosides, 205, 224 Gallate, 135, 224 Gallbladder, 77, 198, 224 Gamma Rays, 224, 252, 253 Ganglia, 198, 205, 224, 241, 246 Gas, 52, 201, 208, 224, 225, 230, 242, 252, 254, 266 Gas exchange, 225, 254, 266 Gastric, 84, 108, 225 Gastrin, 225, 229 Gastrointestinal, 207, 221, 225, 258, 261, 265 Gastrointestinal tract, 225, 258, 265 Gels, 34, 225 Gene Amplification, 71, 73, 225 Gene Deletion, 72, 141, 225 Gene Expression Profiling, 35, 43, 225 Gene Fusion, 34, 225 Gene Products, rev, 225, 226 Gene Silencing, 97, 225 Gene Targeting, 38, 225
Gene Therapy, 19, 32, 53, 178, 179, 199, 225 Genes, env, 164, 226 Genes, Regulator, 46, 226 Genetic Engineering, 206, 212, 226 Genetic testing, 167, 171, 172, 173, 175, 176, 177, 182, 226, 249 Genetic transcription, 226, 251, 264 Genital, 226, 267 Genomics, 183, 226 Genotype, 33, 226, 247 Germ Cells, 156, 180, 226, 237, 244, 262 Germ Layers, 206, 226 Germline mutation, 47, 84, 104, 108, 226, 229 Gestation, 53, 226, 248 Gland, 49, 70, 226, 236, 245, 248, 251, 261, 263 Glioma, 19, 126, 226 Glomerular, 18, 226, 234 Glomerular Mesangium, 18, 226 Glomerulus, 226 Glucose, 18, 94, 189, 206, 217, 226, 228, 232, 247 Glucose Intolerance, 217, 227 Glutamic Acid, 224, 227, 228, 241, 250 Glutamine, 58, 227 Glycine, 126, 227, 241, 258 Glycoprotein, 91, 96, 133, 200, 203, 227, 234, 263, 265 Glycosaminoglycans, 94, 222, 227 Governing Board, 227, 250 Grade, 16, 227 Graft, 25, 32, 41, 91, 227 Grafting, 25, 32, 42, 227, 231 Granule, 227, 256 Granulocyte, 227, 232 Growth factors, 54, 227 Growth Plate, 20, 227 Guanine, 146, 227, 252 Guanylate Cyclase, 227, 242 H Hair Cells, 35, 227 Hair Color, 157, 227 Half-Life, 73, 227 Haploid, 228, 248 Haptens, 199, 228 Heart attack, 208, 228 Helix-loop-helix, 43, 56, 228 Hemochromatosis, 173, 228 Hemodialysis, 228, 234
180,
174,
259,
156,
257,
227,
213,
Index 275
Hemoglobin, 147, 201, 221, 228, 235 Hemoglobinopathies, 226, 228 Hemoglobinuria, 189, 228 Hemolytic, 31, 228 Hemophilia, 165, 189, 228 Hemorrhage, 219, 228, 261 Hemostasis, 228, 232, 258 Heparin, 228, 258 Hepatic, 12, 17, 228, 235 Hepatitis, 86, 229 Hepatocellular, 50, 86, 106, 229 Hepatocellular carcinoma, 86, 106, 229 Hepatocyte, 67, 229 Hereditary, 4, 41, 75, 83, 84, 89, 94, 110, 113, 118, 137, 145, 146, 156, 165, 171, 200, 213, 226, 228, 229, 241, 255 Hereditary mutation, 156, 226, 229 Heredity, 148, 225, 226, 229 Herpes, 32, 44, 229 Herpes Zoster, 229 Heterodimers, 229, 232 Heterogeneity, 199, 229 Heterozygotes, 61, 218, 229 Histology, 37, 95, 229, 245 Histone Deacetylase, 21, 62, 80, 91, 134, 229 Histones, 21, 38, 148, 207, 211, 229, 243 Homeobox, 21, 229 Homeostasis, 12, 49, 229 Homologous, 200, 215, 225, 229, 257, 262 Hormonal, 37, 204, 205, 229 Hormone, 20, 30, 37, 49, 153, 199, 205, 219, 221, 225, 229, 232, 257, 258, 262, 263 Hormone therapy, 199, 229 Horny layer, 221, 229 Human growth hormone, 88, 229 Human papillomavirus, 29, 61, 62, 81, 87, 97, 102, 230 Humoral, 57, 230 Humour, 230 Hybrid, 23, 230 Hybridization, 43, 84, 230 Hybridomas, 230, 232 Hydrogen, 57, 205, 217, 222, 230, 235, 239, 241, 243, 245, 246, 251 Hydrogen Peroxide, 57, 230, 235 Hydrolysis, 205, 212, 230, 234, 247, 249, 251 Hyperplasia, 25, 32, 40, 41, 230 Hypersensitivity, 200, 230, 257 Hypertension, 208, 230 Hyperthermia, 127, 135, 138, 230
Hypertrophy, 18, 44, 230 Hypoglycemia, 67, 230 I Immune response, 57, 199, 202, 204, 228, 230, 257, 261, 265, 267 Immune system, 28, 66, 202, 205, 230, 231, 236, 266, 267 Immunity, 28, 200, 230 Immunization, 230, 257 Immunodeficiency, 189, 231 Immunofluorescence, 50, 231 Immunoglobulins, 66, 231 Immunohistochemistry, 40, 42, 88, 114, 231 Immunologic, 200, 210, 231, 253 Immunology, 24, 30, 56, 62, 68, 104, 105, 199, 224, 231 Immunophilin, 207, 231 Immunosuppressive, 207, 215, 231 Impairment, 6, 8, 204, 205, 223, 231, 238 Implant radiation, 231, 232, 233, 253, 268 Implantation, 214, 231 In situ, 42, 231 In Situ Hybridization, 42, 231 Incision, 231, 233 Induction, 35, 44, 59, 67, 69, 70, 71, 105, 124, 128, 231, 234 Infancy, 8, 29, 101, 183, 231 Infection, 87, 204, 205, 210, 211, 216, 220, 222, 227, 231, 236, 241, 261, 267 Infiltrating cancer, 232, 233 Informed Consent, 174, 177, 182, 232 Initiation, 35, 37, 39, 44, 64, 232, 251, 264 Initiator, 205, 232 Inner ear, 35, 232 Inorganic, 212, 232, 261 Insertional, 114, 232 Insight, 25, 56, 63, 93, 105, 134, 232 Insulin, 30, 205, 232 Insulin-dependent diabetes mellitus, 232 Integrins, 19, 40, 232 Interferons, 39, 232 Interleukin-6, 97, 232 Internal radiation, 232, 233, 253, 268 Interphase, 210, 233 Interstitial, 16, 110, 206, 222, 232, 233, 268 Intestinal, 65, 208, 233, 237 Intestinal Neoplasms, 65, 233 Intestine, 206, 213, 233, 234 Intoxication, 233, 267 Intracellular, 46, 67, 73, 231, 232, 233, 242, 253, 258
276
Retinoblastoma
Intracranial Aneurysm, 113, 233 Intravesical, 53, 233 Intrinsic, 49, 54, 199, 205, 233 Invasive, 16, 61, 62, 88, 95, 103, 230, 232, 233 Invasive cancer, 62, 232, 233 Involuntary, 205, 215, 221, 233, 240, 254 Ionization, 233 Ionizing, 48, 140, 200, 220, 233, 253 Ions, 205, 207, 213, 218, 219, 230, 233 Iris, 133, 197, 202, 215, 222, 233, 252 Irradiation, 50, 126, 132, 233, 268 Ischemia, 204, 233 K Karyotype, 150, 233 Keratin, 233, 234 Keratinocytes, 46, 234 Ketamine, 110, 234 Kidney Disease, 185, 189, 234 Kidney Failure, 159, 220, 234 Kidney Failure, Acute, 234 Kidney Failure, Chronic, 234 Kinesin, 93, 234 Kinetic, 101, 233, 234 Kinetochores, 36, 234 L Labile, 213, 234 Labyrinth, 68, 212, 232, 234, 257, 266 Laminin, 129, 205, 222, 234 Large Intestine, 213, 217, 233, 234, 253, 259 Latent, 80, 86, 235, 250 Laterality, 71, 235 Leiomyosarcoma, 75, 101, 102, 235 Lens, 40, 64, 116, 203, 208, 235, 267 Lesion, 235 Lethal, 41, 42, 235 Leucine, 43, 49, 235 Leucocyte, 200, 235, 236 Leukaemia, 125, 235 Leukemia, 13, 44, 55, 66, 81, 118, 189, 218, 226, 235 Ligament, 235, 251 Ligands, 28, 40, 232, 235 Ligase, 86, 235 Linkages, 58, 227, 228, 229, 235 Lipid, 30, 117, 232, 235, 238, 245 Lipid Peroxidation, 235, 245 Lipoma, 94, 235 Liver Regeneration, 12, 235 Liver Transplantation, 67, 235 Lobe, 94, 229, 235 Local therapy, 120, 137, 235
Localization, 30, 34, 42, 44, 57, 101, 119, 231, 235 Localized, 223, 231, 234, 236, 248 Locomotion, 236, 248 Loop, 20, 52, 53, 236 Loss of Heterozygosity, 92, 200, 236 Lucida, 234, 236 Lumbar, 109, 236, 260 Lumbar puncture, 109, 236, 260 Lymph, 204, 210, 220, 230, 236 Lymph node, 204, 210, 236 Lymphatic, 220, 231, 236, 238, 259, 260 Lymphatic system, 236, 259, 260 Lymphoblastic, 94, 125, 236 Lymphoblasts, 198, 236 Lymphocytes, 57, 84, 202, 207, 210, 217, 230, 231, 235, 236, 260, 267 Lymphoid, 202, 235, 236 Lymphoma, 88, 189, 236 Lysine, 228, 229, 236 M Macrophage, 53, 57, 156, 232, 236 Macula, 236, 237 Macula Lutea, 236, 237 Macular Degeneration, 65, 237 Malabsorption, 189, 237 Malignancy, 14, 35, 102, 118, 120, 237, 245 Malignant, 11, 19, 39, 42, 49, 74, 76, 102, 106, 110, 137, 141, 189, 199, 203, 232, 237, 240, 244, 253, 256, 262 Malignant fibrous histiocytoma, 76, 237 Malignant tumor, 74, 237, 244, 256 Malnutrition, 204, 237, 240 Mammary, 22, 49, 54, 70, 237, 262 Mammography, 164, 237 Mandible, 103, 201, 211, 237, 254 Medial, 42, 237, 243 Mediate, 15, 30, 47, 49, 52, 61, 68, 70, 86, 237 Mediator, 85, 237, 258 Medical Records, 164, 177, 237, 255 MEDLINE, 186, 188, 190, 237 Medullary, 61, 237 Medulloblastoma, 51, 237 Meiosis, 155, 211, 237, 262 Melanin, 233, 237, 247, 265 Melanocytes, 43, 65, 237, 242 Melanoma, 4, 11, 42, 43, 50, 65, 89, 106, 110, 113, 189, 193, 237, 242, 265 Melanosomes, 237 Membrane Fluidity, 124, 238 Memory, 217, 238
Index 277
Meninges, 210, 218, 238 Meningitis, 137, 238 Mental Retardation, 4, 7, 66, 169, 171, 173, 191, 238 Mercury, 224, 238 Mesenchymal, 41, 50, 238 Metabolite, 238, 250 Metaphase, 234, 238 Metastasis, 50, 77, 80, 95, 102, 124, 131, 238 Metastatic, 43, 54, 61, 75, 103, 116, 121, 130, 238, 257 Metastatic cancer, 55, 238 Microbe, 238, 263 Microbiology, 30, 62, 204, 238 Microorganism, 212, 238, 267 Microscopy, 34, 205, 238 Microtubules, 210, 234, 238, 239, 245 Migration, 25, 41, 55, 238 Miscarriage, 176, 238 Mitochondria, 130, 146, 147, 159, 165, 166, 239, 244 Mitochondrial Swelling, 239, 240 Mitosis, 62, 155, 203, 209, 210, 211, 239 Mitotic, 31, 36, 37, 87, 210, 222, 234, 239 Mitotic Spindle Apparatus, 210, 239 Modification, 17, 21, 43, 49, 54, 57, 115, 226, 239, 252 Modulator, 94, 239 Monitor, 107, 239, 242 Monoclonal, 36, 230, 233, 239, 253, 268 Monoclonal antibodies, 36, 239 Monocytes, 232, 239 Mononuclear, 239, 265 Monosomy, 7, 159, 202, 239 Morphogenesis, 23, 59, 239 Morphological, 50, 98, 199, 219, 237, 239 Morphology, 23, 88, 114, 203, 208, 239 Mosaicism, 6, 9, 112, 156, 239 Motility, 105, 240, 258 Muscle Fibers, 240 Muscle, Smooth, Vascular, 226, 240 Muscular Atrophy, 189, 240 Mutagenesis, 18, 29, 33, 240 Mutagens, 224, 240 Myelin, 240, 243 Myelofibrosis, 32, 240 Myeloma, 97, 240 Myocarditis, 208, 220, 240 Myofibrils, 207, 240 Myopia, 240, 254, 255 Myosin, 207, 240 Myotonic Dystrophy, 168, 189, 240, 264
N Nasopharynx, 50, 240 NCI, 1, 24, 51, 184, 211, 240, 246 Necrosis, 35, 80, 100, 203, 240 Neoplasia, 38, 56, 82, 189, 240 Neoplasm, 100, 240, 245, 256, 265 Nephropathy, 18, 234, 240 Nerve Growth Factor, 58, 241 Nervous System, 38, 168, 189, 210, 227, 237, 241, 246, 266 Networks, 37, 50, 56, 60, 68, 79, 92, 241 Neural, 29, 38, 64, 79, 201, 219, 230, 241, 255 Neural tube defects, 29, 241 Neuroblastoma, 69, 101, 103, 127, 140, 241 Neurodegenerative Diseases, 13, 58, 67, 205, 241 Neuroendocrine, 59, 61, 241 Neurologic, 68, 219, 241 Neuronal, 13, 45, 57, 58, 67, 80, 107, 241 Neurons, 13, 57, 67, 128, 217, 224, 241, 262 Neuropathy, 165, 241 Neuropeptides, 207, 241 Neurophysiology, 217, 241 Neuroretinitis, 241, 255 Neurotoxic, 57, 241 Neurotransmitter, 198, 199, 204, 207, 227, 241, 242, 258, 261 Neutrons, 72, 200, 223, 233, 241, 252 Nevi and Melanomas, 43, 242 Nevus, 43, 242 Night Blindness, 242, 255 Nitric Oxide, 113, 242 Nitrogen, 200, 215, 222, 223, 227, 234, 242, 264 Non-small cell lung cancer, 124, 242 Norepinephrine, 199, 241, 242 Nuclear Envelope, 146, 242 Nuclear Pore, 242 Nuclear Proteins, 49, 225, 242 Nucleates, 210, 242 Nuclei, 200, 219, 225, 226, 229, 239, 241, 242, 244, 251 Nucleic acid, 205, 216, 230, 231, 240, 242, 243, 252, 256 Nucleic Acid Hybridization, 230, 242 Nucleoproteins, 242, 243 Nucleosomes, 66, 243 Nurse Practitioners, 174, 243 O Observational study, 77, 243 Octamer, 66, 243
278
Retinoblastoma
Ocular, 35, 50, 64, 104, 105, 124, 127, 134, 140, 243 Ointments, 243, 245 Oligodendroglial, 95, 243 Oliguria, 234, 243 Oncogenic, 16, 22, 25, 29, 38, 43, 45, 51, 54, 61, 104, 232, 243, 251, 252 Oncolysis, 243 Oncolytic, 19, 77, 243 Opacity, 208, 243 Operon, 243, 251, 254 Ophthalmic, 78, 87, 90, 91, 93, 96, 102, 103, 105, 115, 119, 121, 129, 134, 141, 243 Opsin, 243, 255, 256 Optic Chiasm, 243, 244 Optic Nerve, 92, 100, 241, 243, 244, 245, 255, 257 Orbit, 34, 244 Orbital, 87, 91, 105, 136, 244 Orbital Implants, 87, 244 Orderly, 211, 244 Organ Culture, 36, 244, 263 Organelles, 145, 146, 210, 216, 234, 237, 239, 244, 248, 254 Organogenesis, 23, 55, 244 Orofacial, 130, 244 Osseointegration, 206, 244 Ossification, 20, 25, 244 Osteoarthritis, 20, 244 Osteogenesis, 25, 59, 206, 244 Osteogenic sarcoma, 244 Osteosarcoma, 4, 9, 25, 59, 112, 116, 244 Ovalbumin, 244, 258 Ovaries, 173, 244, 258 Ovary, 87, 221, 244, 245 Overall survival, 50, 244 Overexpress, 40, 245 Ovum, 216, 226, 245, 267, 268 Oxidation, 203, 216, 235, 245 Oxidative Phosphorylation, 147, 245 Oxidative Stress, 31, 57, 245 P P53 gene, 107, 245 Pachymeningitis, 238, 245 Paclitaxel, 124, 245 Palate, 240, 245 Palladium, 245, 256 Palliative, 245, 263 Pancreas, 88, 198, 206, 228, 232, 245, 257, 265 Pancreatic, 41, 189, 245 Pancreatic cancer, 41, 189, 245
Papilla, 245 Papillary, 16, 43, 107, 245 Papillary tumor, 16, 245 Papilloma, 44, 245, 255 Papillomavirus, 245 Paraffin, 72, 141, 245 Paroxysmal, 189, 246 Particle, 13, 32, 246, 264 Patch, 36, 246 Paternal Age, 48, 246 Paternity, 173, 246 Pathologic, 203, 206, 215, 230, 246, 254 Pathologic Processes, 203, 246 Pathologies, 55, 246 PDQ, 184, 246 Pediatrics, 64, 71, 102, 104, 111, 114, 135, 246 Pelvic, 246, 251 Pelvis, 198, 235, 236, 244, 246, 266 Penis, 61, 246 Pepsin, 246, 257 Peptide, 19, 24, 67, 223, 234, 246, 249, 251 Peripheral blood, 132, 246 Peripheral Nervous System, 241, 246, 261 Petroleum, 245, 246 PH, 50, 114, 117, 246 Phagocytosis, 232, 246 Pharmacologic, 32, 201, 228, 247, 263 Pharynx, 240, 247 Phenotype, 6, 8, 14, 19, 20, 30, 33, 40, 54, 56, 68, 225, 247 Phenylalanine, 153, 247, 265 Phosphodiesterase, 87, 247 Phospholipases, 247, 258 Phospholipids, 223, 238, 247 Phosphoprotein Phosphatase, 209, 247 Phosphorus, 207, 247 Phosphorylase, 207, 247 Phosphorylated, 17, 30, 37, 57, 65, 79, 107, 113, 212, 247 Phosphorylates, 54, 247 Phosphorylating, 57, 247 Photocoagulation, 212, 247 Photoreceptor, 21, 87, 91, 247, 256 Physical Examination, 171, 247 Physiologic, 67, 68, 199, 206, 228, 247, 248, 253, 254 Pigment, 65, 94, 103, 200, 237, 247, 255 Pilot study, 120, 131, 247 Pineal Body, 248 Pineal gland, 4, 248 Pituitary Gland, 223, 248
Index 279
Placenta, 56, 68, 221, 248 Placentation, 56, 68, 248 Plants, 27, 200, 204, 208, 226, 239, 242, 248, 249, 258, 264, 266 Plaque, 78, 128, 202, 248 Plasma, 29, 146, 200, 202, 203, 209, 220, 223, 227, 228, 234, 240, 248, 257, 263 Plasma cells, 202, 240, 248 Plasmid, 225, 248, 266 Plasminogen Inactivators, 248, 258 Plastids, 244, 248 Platelet Activation, 248, 259 Platelet Aggregation, 201, 242, 248 Platelets, 207, 242, 248 Pneumonia, 215, 248 Podophyllotoxin, 222, 248 Point Mutation, 16, 249 Polycystic, 189, 249 Polyethylene, 91, 102, 249 Polymerase, 72, 79, 85, 86, 141, 249, 251, 254 Polymerase Chain Reaction, 72, 249 Polymorphic, 27, 211, 249 Polymorphism, 175, 249 Polypeptide, 101, 201, 212, 214, 230, 249, 268 Polyploid, 62, 249 Polyploidy, 62, 249 Polyposis, 65, 213, 249 Polysaccharide, 202, 249, 251 Polyunsaturated fat, 118, 122, 123, 131, 249 Posterior, 204, 211, 233, 245, 248, 249, 257 Postnatal, 249, 260 Postsynaptic, 249, 258 Post-translational, 39, 54, 57, 249 Potentiating, 205, 249 Potentiation, 138, 250, 258 Practicability, 250, 264 Practice Guidelines, 187, 250 Precancerous, 28, 210, 250 Precipitation, 71, 250 Preclinical, 39, 108, 114, 250 Precursor, 103, 202, 203, 215, 219, 220, 242, 247, 250, 264, 265 Predisposition, 42, 45, 250 Premalignant, 250 Prenatal, 29, 173, 176, 219, 250 Prevalence, 59, 161, 250 Primary tumor, 43, 104, 250 Primitive neuroectodermal tumors, 237, 250
Probe, 62, 96, 250 Prodrug, 122, 250 Prognostic factor, 89, 250 Progression, 11, 14, 16, 19, 20, 23, 25, 33, 34, 35, 36, 37, 38, 40, 45, 49, 50, 55, 57, 61, 67, 68, 70, 81, 85, 96, 97, 99, 101, 102, 106, 202, 215, 250, 265 Progressive, 108, 159, 209, 211, 217, 218, 221, 234, 240, 241, 244, 248, 250, 255, 265 Projection, 217, 242, 244, 250, 254 Proline, 44, 49, 212, 250 Promoter, 16, 18, 20, 24, 31, 32, 43, 45, 49, 59, 71, 76, 77, 82, 84, 86, 90, 98, 251 Promotor, 251, 254 Promyelocytic leukemia, 44, 251 Prone, 22, 159, 168, 251 Prospective study, 133, 251 Prostaglandins, 127, 129, 200, 203, 251 Prostate, 30, 37, 47, 50, 124, 128, 189, 206, 251, 265 Protease, 46, 200, 248, 251 Protease Inhibitors, 46, 251 Protein Binding, 60, 251, 263 Proteoglycans, 205, 222, 251 Proteolytic, 45, 200, 213, 251, 258 Protocol, 51, 72, 133, 179, 251 Protons, 200, 230, 233, 251, 252 Proto-Oncogene Proteins, 245, 251, 252 Proto-Oncogene Proteins c-mos, 245, 252 Proximal, 28, 84, 218, 252 Psychic, 238, 252, 257 Psychoactive, 252, 267 Puberty, 70, 252 Public Policy, 186, 252 Publishing, 193, 252 Pulmonary, 59, 200, 206, 207, 234, 252, 254, 266 Pulmonary Artery, 206, 252 Pulmonary Edema, 234, 252 Pulmonary Ventilation, 252, 254 Pupil, 3, 196, 215, 217, 252 Pupillary dilation, 114, 252 Purifying, 15, 252 Purines, 205, 252, 258 Pyrimidines, 205, 252, 258 Q Quality of Life, 103, 252, 261 Quiescent, 24, 26, 31, 36, 41, 44, 60, 252 R Race, 48, 233, 238, 252 Radiation therapy, 50, 108, 198, 199, 222, 232, 233, 252, 268
280
Retinoblastoma
Radioactive, 227, 230, 231, 232, 233, 239, 242, 243, 253, 265, 268 Radioimmunotherapy, 253 Radiolabeled, 233, 253, 268 Radium, 69, 104, 253 Randomized, 219, 253 Reactive Oxygen Species, 57, 253 Reagent, 53, 253 Receptors, Serotonin, 253, 258 Recombinant, 19, 179, 253, 266 Recombination, 33, 37, 225, 253 Rectal, 51, 253 Rectum, 203, 212, 213, 217, 224, 234, 251, 253 Recurrence, 120, 123, 125, 128, 253 Red blood cells, 221, 228, 254 Red Nucleus, 204, 254 Reductase, 29, 254 Refer, 1, 4, 151, 155, 157, 162, 180, 207, 213, 223, 229, 235, 236, 241, 253, 254, 266 Reflex, 3, 254 Refraction, 240, 254, 260 Refractory, 30, 47, 219, 254 Regeneration, 13, 35, 44, 59, 65, 67, 223, 254 Regimen, 124, 219, 254 Relapse, 139, 254 Reliability, 34, 254 Remission, 253, 254 Renal cell carcinoma, 43, 254 Repressor, 16, 24, 26, 30, 64, 243, 254 Reproductive cells, 158, 169, 170, 226, 229, 254 Resorption, 108, 254 Respiratory distress syndrome, 207, 254 Respiratory System, 29, 254 Response Elements, 16, 20, 254 Reticulocytes, 221, 254 Retinal, 5, 10, 29, 34, 64, 103, 112, 117, 125, 133, 136, 193, 243, 244, 255, 256 Retinal Detachment, 103, 117, 133, 136, 255 Retinal Ganglion Cells, 244, 255 Retinal pigment epithelium, 64, 255 Retinitis, 65, 255 Retinitis Pigmentosa, 65, 255 Retinoid, 69, 255 Retinol, 255, 256 Retinopathy, 111, 247, 255 Retrospective, 75, 104, 106, 255 Retrospective study, 104, 255 Retroviral vector, 225, 255
Retrovirus, 71, 256 Rhabdomyosarcoma, 100, 140, 256 Rheumatoid, 85, 256 Rhodopsin, 243, 255, 256 Riboflavin, 127, 256 Ribonucleic acid, 153, 256 Ribose, 199, 256 Ribosome, 153, 256, 264 Rigidity, 248, 256 Risk factor, 42, 48, 139, 251, 256 Rod, 21, 204, 210, 247, 256 Ruthenium, 78, 256 S Salivary, 216, 245, 256 Salivary glands, 216, 256 Saphenous, 32, 256 Saphenous Vein, 32, 256 Sarcoma, 43, 129, 135, 237, 250, 256, 259 Satellite, 44, 256 Scatter, 256, 265 Schizoid, 256, 267 Schizophrenia, 166, 256, 257, 267 Schizotypal Personality Disorder, 256, 267 Sclera, 211, 214, 244, 257 Sclerosis, 68, 162, 189, 257 Screening, 11, 19, 21, 72, 85, 86, 95, 101, 111, 164, 173, 174, 176, 212, 246, 257 Second cancer, 98, 257 Secondary tumor, 238, 257 Secretin, 88, 257 Secretion, 40, 55, 219, 230, 232, 257, 266 Secretory, 55, 257 Segregation, 36, 211, 253, 257 Seizures, 246, 257 Selective estrogen receptor modulator, 257, 262 Semen, 251, 257 Semicircular canal, 232, 257 Seminoma, 84, 257 Semisynthetic, 208, 222, 257 Senescence, 14, 22, 43, 46, 51, 59, 110, 257 Sensitization, 135, 257 Sensor, 28, 257 Sequence Homology, 26, 257 Sequencing, 53, 181, 249, 258 Serine, 46, 65, 107, 128, 130, 247, 252, 258 Serine Endopeptidases, 258 Serine Proteinase Inhibitors, 258 Serotonin, 93, 241, 253, 258, 264 Serous, 220, 258 Serpins, 46, 258 Serum, 200, 201, 213, 234, 258, 265
Index 281
Sex Characteristics, 199, 252, 258, 262 Sex Determination, 27, 189, 258 Side effect, 180, 183, 199, 205, 215, 258, 261, 263 Signal Transduction, 17, 45, 52, 207, 258 Signs and Symptoms, 4, 167, 168, 173, 254, 259 Skeletal, 8, 20, 44, 61, 102, 218, 240, 259 Skeleton, 198, 223, 259 Skull, 4, 50, 219, 241, 244, 259, 262 Skull Base, 50, 259 Small cell lung cancer, 259 Small intestine, 218, 229, 233, 259 Smooth muscle, 25, 32, 39, 42, 130, 201, 207, 226, 259, 261 Social Environment, 252, 259 Social Work, 170, 259 Sodium, 135, 138, 259 Soft tissue, 4, 43, 51, 110, 206, 237, 259 Soft tissue sarcoma, 51, 110, 259 Solid tumor, 43, 50, 93, 218, 259 Soma, 27, 259 Somatic, 6, 10, 25, 39, 48, 64, 82, 156, 159, 170, 199, 219, 230, 237, 239, 244, 246, 259, 262 Somatic cells, 156, 159, 170, 237, 239, 259 Somatic mutations, 10, 39, 159, 259 Soybean Oil, 249, 259 Specialist, 174, 194, 217, 259 Specificity, 19, 53, 199, 207, 258, 260, 263 Spectrum, 23, 37, 38, 72, 82, 112, 260 Sperm, 27, 34, 155, 156, 158, 159, 168, 169, 170, 173, 180, 211, 226, 229, 254, 259, 260, 262 Spina bifida, 241, 260 Spinal cord, 210, 211, 218, 220, 238, 241, 245, 246, 254, 260 Spinal tap, 236, 260 Spinous, 221, 234, 260 Spleen, 31, 216, 236, 260 Sporadic, 8, 29, 39, 43, 47, 79, 91, 92, 106, 241, 260 Squamous, 29, 48, 82, 87, 221, 242, 260 Squamous cell carcinoma, 82, 87, 221, 242, 260 Squamous cells, 260 Stabilization, 15, 46, 112, 260 Stem Cell Factor, 55, 212, 260 Stem Cells, 26, 31, 56, 123, 221, 260 Stenosis, 32, 260, 261 Stereotactic, 90, 260 Sterility, 215, 261
Steroids, 37, 261 Stillbirth, 171, 261 Stimulus, 218, 222, 254, 261 Stomach, 198, 205, 208, 217, 221, 224, 225, 229, 246, 247, 257, 259, 260, 261 Stool, 212, 234, 261 Strand, 146, 249, 261 Stress, 28, 31, 44, 51, 245, 250, 261 Stricture, 260, 261 Stroke, 164, 185, 208, 261 Stroma, 233, 261 Subacute, 231, 261 Subclinical, 231, 257, 261 Subconjunctival, 34, 261 Subspecies, 260, 261 Substrate, 13, 22, 69, 79, 261 Sulfates, 79, 261 Sulfur, 215, 222, 261 Sulfuric acid, 261 Supportive care, 246, 261 Suppression, 15, 17, 19, 26, 30, 31, 41, 44, 46, 51, 52, 60, 64, 66, 73, 123, 225, 261, 262 Suppressive, 15, 45, 59, 60, 65, 113, 262 Survival Rate, 20, 244, 262 Symphysis, 211, 251, 262 Synapse, 199, 262, 264 Synaptic, 241, 258, 262 Systemic, 34, 80, 104, 123, 131, 206, 221, 231, 233, 253, 262, 268 T Tamoxifen, 70, 124, 257, 262 Telangiectasia, 189, 262 Telomerase, 52, 262 Telomere, 51, 52, 262 Temporal, 42, 50, 60, 236, 262 Terminator, 212, 262 Testicles, 257, 262 Testicular, 84, 131, 262 Testis, 221, 262 Testosterone, 37, 254, 262 Tetracycline, 16, 18, 20, 218, 262 Thalamic, 204, 262 Thalamic Diseases, 204, 262 Therapeutics, 67, 126, 127, 128, 263 Thermal, 218, 241, 249, 263 Threonine, 247, 252, 258, 263 Thrombin, 223, 248, 251, 263 Thrombomodulin, 251, 263 Thrombosis, 232, 251, 261, 263 Thyroid, 20, 61, 107, 173, 263, 265 Thyroid Gland, 173, 263
282
Retinoblastoma
Thyroid Hormones, 263, 265 Thyroxine, 247, 258, 263 Tissue Culture, 23, 29, 46, 263 Tissue Distribution, 207, 263 Tomography, 66, 90, 105, 263 Topical, 230, 245, 263 Topoisomerase inhibitors, 128, 263 Toxic, iv, 12, 52, 53, 58, 67, 145, 204, 216, 219, 220, 230, 241, 248, 263 Toxicity, 12, 32, 63, 179, 238, 263 Toxicology, 12, 186, 263 Toxins, 57, 202, 231, 239, 253, 264 Trace element, 212, 264 Trachea, 247, 263, 264 Transcriptase, 256, 262, 264 Transduction, 71, 258, 264 Transfection, 71, 73, 206, 225, 264 Translation, 13, 32, 44, 153, 154, 225, 264 Translational, 14, 225, 264 Translocation, 43, 79, 114, 116, 127, 211, 264 Transmitter, 198, 237, 242, 264 Transplantation, 75, 119, 126, 132, 211, 231, 234, 264 Trauma, 205, 240, 263, 264 Treatment Outcome, 50, 112, 264 Trinucleotide Repeat Expansion, 168, 264 Trinucleotide Repeats, 264 Trisomy, 7, 159, 202, 264 Trophic, 57, 78, 264 Tropism, 20, 108, 264 Tryptophan, 212, 258, 264 Tuberous Sclerosis, 189, 265 Tumor marker, 200, 206, 265 Tumor model, 33, 265 Tumor Necrosis Factor, 73, 265 Tumor suppressor gene, 4, 29, 54, 61, 62, 65, 74, 75, 92, 236, 245, 255, 265 Tumor-derived, 15, 265 Tumorigenic, 29, 53, 70, 73, 265 Tumour, 11, 86, 106, 112, 118, 125, 134, 136, 243, 265 Tyrosine, 43, 92, 265 U Ubiquitin, 23, 38, 42, 62, 83, 86, 265 Ultraviolet radiation, 156, 265 Uranium, 253, 265 Uremia, 234, 265 Ureters, 265, 266 Urethane, 87, 265 Urethra, 246, 251, 265, 266 Urinary, 16, 75, 215, 216, 243, 266
Urinary tract, 16, 266 Urinary tract infection, 16, 266 Urine, 203, 206, 228, 234, 243, 256, 265, 266 Urokinase, 46, 248, 266 Urothelium, 16, 266 Uterus, 173, 210, 215, 217, 224, 235, 244, 266 V Vaccine, 199, 251, 265, 266 Vacuoles, 244, 266 Vagina, 61, 210, 266, 267 Vaginal, 266, 267 Vascular, 25, 32, 34, 130, 211, 220, 226, 231, 242, 248, 263, 266 Vasodilators, 242, 266 Vector, 19, 71, 178, 179, 232, 264, 266 Vegetative, 249, 266 Vein, 26, 32, 83, 242, 256, 266 Venous, 251, 266 Ventilation, 207, 266 Venules, 206, 208, 220, 266 Vestibular, 227, 266 Vestibule, 212, 232, 257, 266 Veterinary Medicine, 186, 266 Vinca Alkaloids, 266, 267 Vincristine, 118, 137, 138, 267 Viral, 13, 20, 31, 32, 57, 61, 62, 71, 77, 96, 115, 178, 223, 225, 226, 243, 256, 264, 265, 267 Viral Proteins, 57, 62, 267 Virulence, 204, 205, 263, 267 Virus, 12, 13, 19, 28, 32, 62, 71, 86, 88, 118, 178, 208, 220, 226, 230, 248, 255, 264, 267 Viscera, 259, 267 Visual field, 115, 243, 255, 267 Vitreous, 76, 125, 138, 139, 211, 235, 255, 267 Vitreous Body, 211, 255, 267 Vitreous Humor, 255, 267 Vitro, 14, 18, 19, 21, 22, 24, 25, 32, 38, 40, 44, 45, 46, 47, 49, 57, 59, 63, 66, 68, 71, 79, 96, 100, 101, 127, 173, 200, 205, 226, 228, 231, 249, 263, 267 Vivo, 12, 14, 16, 18, 19, 21, 22, 23, 25, 28, 32, 34, 37, 38, 40, 41, 42, 44, 45, 46, 49, 51, 54, 59, 60, 61, 64, 66, 68, 69, 70, 71, 94, 101, 105, 200, 205, 226, 228, 231, 267 Vulva, 61, 267 W Warts, 230, 249, 267 White blood cell, 156, 198, 202, 227, 236, 240, 248, 267
Index 283
Windpipe, 247, 263, 267 Withdrawal, 53, 60, 267 Womb, 266, 267 Wound Healing, 223, 232, 267 X Xenograft, 115, 202, 265, 267
X-ray, 47, 58, 62, 74, 224, 233, 242, 252, 253, 261, 267 X-ray therapy, 233, 267 Y Yeasts, 247, 268 Z Zygote, 214, 240, 268 Zymogen, 251, 268
