Epstein Barr Virus - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

EPSTEIN BARR VIRUS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J...

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EPSTEIN BARR VIRUS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Epstein Barr Virus: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84209-4 1. Epstein Barr Virus-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on Epstein Barr virus. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON EPSTEIN BARR VIRUS ................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Epstein Barr Virus........................................................................ 6 E-Journals: PubMed Central ....................................................................................................... 59 The National Library of Medicine: PubMed ................................................................................ 59 CHAPTER 2. NUTRITION AND EPSTEIN BARR VIRUS ...................................................................... 67 Overview...................................................................................................................................... 67 Finding Nutrition Studies on Epstein Barr Virus....................................................................... 67 Federal Resources on Nutrition ................................................................................................... 68 Additional Web Resources ........................................................................................................... 69 CHAPTER 3. ALTERNATIVE MEDICINE AND EPSTEIN BARR VIRUS ................................................ 71 Overview...................................................................................................................................... 71 National Center for Complementary and Alternative Medicine.................................................. 71 Additional Web Resources ........................................................................................................... 75 General References ....................................................................................................................... 76 CHAPTER 4. CLINICAL TRIALS AND EPSTEIN BARR VIRUS............................................................. 77 Overview...................................................................................................................................... 77 Recent Trials on Epstein Barr Virus............................................................................................ 77 Keeping Current on Clinical Trials ............................................................................................. 78 CHAPTER 5. PATENTS ON EPSTEIN BARR VIRUS ............................................................................. 81 Overview...................................................................................................................................... 81 Patents on Epstein Barr Virus..................................................................................................... 81 Patent Applications on Epstein Barr Virus ................................................................................. 88 Keeping Current ........................................................................................................................ 102 CHAPTER 6. BOOKS ON EPSTEIN BARR VIRUS .............................................................................. 103 Overview.................................................................................................................................... 103 Chapters on Epstein Barr Virus................................................................................................. 103 CHAPTER 7. PERIODICALS AND NEWS ON EPSTEIN BARR VIRUS................................................. 105 Overview.................................................................................................................................... 105 News Services and Press Releases.............................................................................................. 105 Academic Periodicals covering Epstein Barr Virus ................................................................... 107 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 111 Overview.................................................................................................................................... 111 NIH Guidelines.......................................................................................................................... 111 NIH Databases........................................................................................................................... 113 Other Commercial Databases..................................................................................................... 115 APPENDIX B. PATIENT RESOURCES ............................................................................................... 117 Overview.................................................................................................................................... 117 Patient Guideline Sources.......................................................................................................... 117 Finding Associations.................................................................................................................. 120 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 123 Overview.................................................................................................................................... 123 Preparation................................................................................................................................. 123 Finding a Local Medical Library................................................................................................ 123 Medical Libraries in the U.S. and Canada ................................................................................. 123 ONLINE GLOSSARIES................................................................................................................ 129 Online Dictionary Directories ................................................................................................... 133

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EPSTEIN BARR VIRUS DICTIONARY.................................................................................... 135 INDEX .............................................................................................................................................. 193

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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 Epstein Barr virus 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 Epstein Barr virus, 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 Epstein Barr virus, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on Epstein Barr virus. 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 Epstein Barr virus, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on Epstein Barr virus. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON EPSTEIN BARR VIRUS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Epstein Barr virus.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and Epstein Barr virus, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “Epstein Barr virus” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Herpesvirus-Induced Diseases: Oral Manifestations and Current Treatment Options Source: CDA Journal. Journal of the California Dental Association. 28(12): 911-921. December 2000. Contact: Available from California Dental Association (CDA). 1201 K Street, Sacramento, CA 95814. (916) 443-0505. Summary: The dentist is often the first health professional to be contacted by patients who develop acute orofacial symptoms of viral conditions such as shingles (varicella zoster) or herpetic gingivostomatitis. This article reviews the natural history, typical and atypical oral manifestations, diagnosis, current treatment options, and advances in the prevention of common herpesvirus induced diseases, with particular attention to primary and recurrent varicella zoster virus and herpes simplex type 1 infections.

4

Epstein Barr Virus

Herpes simplex virus (HSV) infections tend to be chronic and recurring, with the list of known triggers of HSV reactivation including stress, surgical trauma, dental extraction, menses and other hormonal changes, infectious febrile (with fever) conditions and hyperthermia, ultraviolent radiation, and drugs such as corticosteroids and prostaglandin E2. Primary and recurrent oral HSV infections in patients with competent immune systems are self limited, generally requiring only symptomatic treatment. The author also discusses erythema multiforme, cytomegalovirus, and Epstein Barr virus. The author notes that the diagnosis, treatment, and management of virally induced oral diseases is a challenge because their presentation is atypical and may be complicated by immunosuppression. However, an increasing body of knowledge regarding the manifestations of viral infections in immunocompromised patients and the advances achieved in antiviral drug therapy during the past several years make the task less daunting for the dentist. 10 figures. 1 table. 64 references. •

Cold Sore Comfort Source: POZ. 38-41. April 2001. Contact: Available from POZ Publishing, LLC. 349 West 12th Street, New York, NY 10014. (815) 734-4151. E-mail: [email protected]. Summary: This article offers information about herpes simplex virus (HSV) and its implications for patients who are living with human immunodeficiency virus (HIV). Transmitted through contact with mucous membranes or small breaks in the skin, herpes (type 1 or 2) is usually marked by red, painful sores on the lips, genitals or anal area, swollen lymph nodes, or flu-like symptoms. After the initial outbreak, HSV takes refuge in the ganglia, the mass of nerve tissue at the base of the vertebrae, waiting to reemerge at a moment of immune stress. For people with HIV, even a dormant virus can be damaging. However, drugs to prevent herpes activity are nontoxic and may also help prevent HIV related lymphoma, a potentially fatal cancer showing up in more and more healthy people with HIV. Herpes' most serious medical consequence for people with HIV may be sustained increases in HIV viral load, though this matter is still subject to some debate. The article discusses the three available antivirals (acyclovir, valacyclovir, and famciclovir) that can help make sores go away faster, prevent outbreaks by suppressing HSV, and suppress Epstein Barr virus (EBV). One sidebar reviews the family of herpes viruses, to help readers differentiate them; another covers treatment strategies to try in addition to the antiviral drugs when coping with HSV outbreaks. The article concludes with a hotline number from the American Social Health Association (919-361-8488, or www.ashastd.org).

•

Oral Hairy Leukoplakia in a Patient with Acute Lymphocytic Leukemia Source: Oral Diseases. 5(1): 76-79. January 1999. Contact: Available from Stockton Press. Marketing Department, Houndmills, Basingstoke, Hampshire RG21 6XS, United Kingdom. (800) 747-3187. Summary: This article reports the first case of oral hairy leukoplakia (OHL) in an HIV negative 56 year old patient with acute lymphocytic leukemia (ALL). A white plaque was observed while the patient was in complete remission following chemotherapy scheme. The clinical and histopathologic findings were typical for OHL and the polymerase chain reaction method was positive for Epstein Barr virus DNA. The authors concludes that underdiagnosis and underreporting of OHL in patients with a malignant hematological disease and the apparent different environmental factors to which these non-AIDS patients have been exposed, probably constitute some of the

Studies

5

reasons for the very few OHL cases reported in these patients. The patient, after the excisional biopsy, received prophylactic antibiotics and acyclovir and had an uneventful recovery. Careful examination of patients with a malignant hematological disease or other immunodeficiency state is suggested, in order to add knowledge to the biologic mechanisms and behavior of OHL. 3 figures. 30 references. •

Update on Panniculitis Source: Mount Sinai Journal of Medicine, The. 68(4 and 5): 262-267. September-October 2001. Summary: This journal article provides health professionals with information on recent advances in the diagnosis, pathogenesis, and treatment of uncommon types of panniculitis, including histiocytic cytophagic panniculitis (HCP), erythema induratum, lipodermatosclerosis, pancreatic panniculitis, and alpha-1-antitrypsin (alpha-1 AT) deficiency panniculitis. HCP was originally classified as systemic histiocytosis. However, three recent developments have changed the understanding of this entity. The first was the realization that certain cases of so called systemic Weber-Christian panniculitis with visceral involvement actually represent HCP. The second development that changed the understanding of HCP was the realization that there is a clinical and histologic overlap of some cases of HCP with subcutaneous panniculitic T cell lymphoma. The third important recent development that has affected the concept of HCP is evidence of the presence of concomitant Epstein Barr virus (EBV) infection. One implication of these three developments is that if a patient presents with a panniculitis with prominent skin involvement and systemic signs and symptoms, a comprehensive diagnostic workup is mandatory. In addition, if there is evidence of extracutaneous involvement, tissue biopsies should be obtained from these sites. Last, if there is a suggestion of recent viral or infectious illness, the patient should be evaluated for EBV infection. Two new events have had an impact on the concept of erythema induratum. The first is the reemergence of tuberculosis with the human immunodeficiency virus pandemic and the development of polymerase chain reaction technology. Lipodermatosclerosis, a third type of panniculitis, causes damage to superficial capillaries. Vascular fragility causes repeated hemorrhage into the dermis, which manifests clinically as reddish brown discoloration of the legs from hemosiderin deposition. The pathology of lipodermatosclerosis is variable. Therapy focuses on the usual treatments for venous stasis, including bed rest, leg elevation, and stocking compression. Pancreatic panniculitis, a fourth type of panniculitis, is a rare condition in which necrosis of fat occurs in subcutaneous tissue and elsewhere in the setting of pancreatic disease. Patients who have pancreatic panniculitis present with tender, erythematous, fluctuant nodules that may drain an oily substance. As associated arthritis or polyserositis may also be present. Although therapy is directed at the primary disease, symptomatic treatment with support hose and leg elevation may be helpful. The final type of panniculitis, alpha-1 AT deficiency panniculitis, is characterized clinically by recurrent, tender, erythematous, subcutaneous ulcerating nodules usually seen on the trunk and extremities. Biopsy of well formed lesions shows a lobular panniculitis with mixed infiltrate of neutrophils and histiocytes. Therapies that appear most beneficial include dapsone and alpha-1-proteinase inhibitor replacement. 2 figures and 54 references. (AA-M).

•

Oral Hairy Leukoplakia Source: Consultant. 39(6): 1865. June 1999.

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Epstein Barr Virus

Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. (203) 661-0600. Summary: This single page case report offers readers a clinical photograph of a patient with oral hairy leukoplakia. The case report describes a 34 year old man with HIV infection who experienced worsening mouth pain while chewing. The patient was mildly cachectic (a state of general poor health) and had whitish, plaquelike lesions on the lateral aspect of the tongue. These lesions could not be scraped off with a tongue blade. A biopsy specimen of material from the tongue revealed profound acanthosis and epithelial hyperplasia. Intense replication of the Epstein Barr virus was found. The diagnosis of oral hairy leukoplakia was made. The author briefly reviews the condition of oral hairy leukoplakia. 1 figure. •

Viral Infections After Renal Transplantation Source: American Journal of Kidney Diseases. 37(4): 659-676. April 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: Viral infections are a leading cause of morbidity (illness) and mortality (death) in patients who receive renal (kidney) transplants. This article reviews a number of recent developments that have altered the understanding and management of these disorders. The pathogenetic (causative) roles of several viruses, including human herpes viruses 6 and 8, have been newly established. Molecular based diagnostic tests now make more rapid diagnosis possible. The licensing of new potent antiviral agents offers a wider choice of drugs for viral prevention and treatment. The authors caution that the use of more potent immunosuppressive agents (drugs used to prevent the recipient's body from rejecting the transplanted organ) is responsible in part for the increasing incidence of some viral infections, but this varies among drugs, and individual viruses differ in their sensitivity to immunosuppressive agents. The authors summarize the natural history, diagnosis, prevention, and treatment of many common viral infections after renal transplantation. Viral infections discussed include herpes viruses (including varicella zoster virus and Epstein Barr virus), cytomegalovirus, respiratory viruses (including influenza and adenoviruses), polyomaviruses (small DNA viruses), and parvovirus. The authors also consider the effect of immunosuppressive regimens on the reactivation of viral infections and the role of vaccinations and screening. 3 tables. 103 references.

Federally Funded Research on Epstein Barr Virus The U.S. Government supports a variety of research studies relating to Epstein Barr virus. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions.

2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

Studies

7

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 Epstein Barr virus. 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 Epstein Barr virus. The following is typical of the type of information found when searching the CRISP database for Epstein Barr virus: •

Project Title: AIDS CONSORTIUM

ASSOCIATED

MALIGNANCIES

CLINICAL

TRIALS

Principal Investigator & Institution: Krown, Susan E.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 31-JUL-2004 Summary: Memorial Sloan-Kettering Cancer Center is applying to continue as a Clinical Trials Member of the AIDS-associated Malignancies Clinical Trials Consortium (AMC). Our qualifications include: (1) A strong record of scientific and administrative contributions to the AMC since its inception in 1995; (2) Broad experience in the development and performance of innovative clinical trials, laboratory investigations and AIDS patient care relevant to the objectives of the AMC; (3) Expertise in infectious diseases required for the care of patients with AIDS- associated malignancies; (4) An extensive referral network that will facilitate accrual; (5) A well-developed clinical, laboratory and data management infrastructure and resources to support collection of tumor tissue and biological fluids for the AIDS Malignancy Banks; and, (6) A commitment to making AMC trials our highest priority. Particular strengths of our group include extensive experience in the early phase testing and evaluation of cytokines and cytokine modulators in cancer and AIDS; an active program for development and diagnostic and therapeutic applications of monoclonal antibodies in cancer; expertise in the development of novel therapeutic approaches for primary CNS lymphoma; expertise in the design, performance and analysis of phase I drug trials; and, experience in the diagnosis, treatment and monitoring of patients with HPV-associated anogenital squamous malignancies. Members of our group have been leaders in the analysis of prognostic factors in AIDS-associated KS and NHL and in the development of criteria for evaluating and staging AIDS-associated cancers, and have developed several innovative clinical trials for AIDS-associated malignancies that are in progress or being developed for future implementation through the AMC. In sum, our scientific and clinical resources make us uniquely positioned to continue to contribute to the collaborative clinical trials effort that has been developed in the AMC over the past 3 years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AIDS LYMPHOMA USING ANTISENSE TO EBV GENES Principal Investigator & Institution: Lacy, Jill; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-MAY-1995; Project End 30-NOV-2003 Summary: (Applicant's Abstract) The long-term goal of development of antisense-based, tumor-specific therapies lymphomas. EBV has been implicated in the etiology of malignancies, including AIDS- related, post-transplantation,

this application is the for the EBV-associated a variety of lymphoid Burkitt's and Hodgkin's

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lymphomas, and transformation by the virus may be mediated in part by latent viral gene products that impact on cell growth and death. Two latent viral proteins, EBNA-1 and LMP-1 appear to play a key role in transformation. EBNA-1 is required for episomal viral DNA replication and regulates transcription of other latent viral genes. LMP-1 alters growth properties and confers resistance to apoptosis through induction of antiapoptotic cellular genes. Given the key functions of EBNA-1 and LMP-1, they represent ideal targets for modulation by antisense strategies as a potential novel anti-tumor strategy. The applicant has demonstrated the feasibility and promise of this approach in in vitro studies using EBNA-1 and LMP-1 targeted antisense oligomers in lymphoblastoid cell lines (LCLs). These studies show that selected antisense oligomers specifically suppress the targeted viral proteins, and, importantly, elicit biological effects. Suppression of EBNA-1 is associated with inhibition of proliferation, decreased viral DNA content, down-regulation of EBNA-2 and LMP-1, and enhanced sensitivity to cytotoxic drugs. Antisense-mediated suppression of LMP-1 not only inhibits proliferation but also down-regulates anti-apoptotic genes, stimulates apoptosis, enhances chemosensitivity, and reverses resistance to cell cycle arrest by TGF-beta. These findings provide the basis for further studies of the biological and anti-tumor effects of antisense- mediated suppression of EBNA-1 and LMP-1. She will extend her in vitro studies using EBNA-1 and LMP-1 targeted antisense to tumor derived cell lines and will explore the susceptibility of EBNA-2 to antisense modulation. To address the therapeutic potential of antisense strategies, she will undertake a detailed investigation of the antitumor and chemosensitizing effects of EBNA-1 and LMP-1 targeted antisense using a SCID mouse model of EBV-associated lymphoma. These studies may shed further light on our understanding of the functions of latent viral proteins in the establishment and maintenance of EBV- related lymphomas, and furthermore, may provide the basis for a tumor- specific, non-toxic therapy for EBV-associated lymphomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS LYMPHOMAGENESIS

OF

POLYAMINE

METABOLISM

IN

EBV

Principal Investigator & Institution: Scott, Rona S.; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: Epstein-Barr virus (EBV) is a human tumor virus discovered in Burkitt's lymphoma (BL) and subsequently linked to multiple cancers. In vitro, EBV infection confers on B lymphocytes an unlimited growth potential termed immortalization. The long-term goal of this research is to understand the mechanisms by which EBV causes cancer. Toward this end, our laboratory has developed a novel cell system in which EBV episomes can be eradicated from Burkitt's lymphoma cells by treatment with low-dose hydroxyurea. Burkitt cells "cured" of EBV lose their malignant growth phenotype despite retaining the hallmark t(8;14) in which c-myc is translocated into an immunoglobulin locus. Using gene arrays to compare global gene expression patterns in paired EBV-positive and EBV-negative BL clones, a 3-fold reduction in spermidine/spermine N1-acetyltransferase (SSAT) in EBV-positive (malignant) cells was among the very limited changes that distinguished these closely related clones. Because the translocation and subsequent deregulation of c-myc in BL result in overexpression of ornithine decarboxylase (an enzyme involved in biosynthesis of polyamines essential to cell growth), the finding that EBV infection downregulates SSAT (an enzyme involved in polyamine catabolism) formed the basis for our hypothesis: EBV

Studies

9

infection manipulates the polyamine metabolic pathway to provide a growth advantage that not only favors viral persistence but also contributes to tumorigenesis in B cells. Specific aims to test this hypothesis are: 1) Quantify differences in polyamine catabolism between EBV-positive BL cells and their EBV-negative subclones by examining transcriptional and translational controls involved in SSAT regulation and by measuring polyamine levels; 2) Identify the type 1 latency viral gene product(s) that affect(s) SSAT expression, by stable transfection techniques; 3) Determine whether forced expression of SSAT reverses the malignant phenotype in EBV-positive cells, using a conditional expression SSAT construct or treatment with a polyamine analogue that is a potent inducer of SSAT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: B-ATF MALIGNANCIES

IN

B

CELL

GROWTH,

DEVELOPMENT

AND

Principal Investigator & Institution: Taparowsky, Elizabeth J.; Professor; Biological Sciences; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2001; Project Start 20-FEB-1998; Project End 31-JAN-2003 Summary: The functional characterization of tissue-specific transcription factors that regulate hematopoietic cell growth and lineage development will provide molecular targets for the design of strategies to manipulate the leukemic phenotype. B-ATF is a new basic leucine zipper (bZIP) protein that is expressed in a tissue-specific manner and is induced rapidly in human B cells following infection with Epstein-Barr virus (EBV) and the expression of the EBV-encoded transactivator protein, EBNA-2. B-ATF is a nuclear protein that heterodimerizes with members of the Jun family of oncoproteins to bind to AP-1 target DNA sites. In cultured cells engineered to overexpress B-ATF, Jun, and Fos, transcription of an AP-1 responsive reporter gene is repressed. This suggests that B-ATF functions as a negative regulator of AP-1, a transcription complex that normally is associated with the induction of cellular growth. Based on these observations, it remains unclear why EBNA-2, a viral latency gene product required for B cell immortalization and transformation, triggers the expression of B-ATF. To explore further the relationship between EBV and B-ATF, the cis-trans regulatory mechanisms responsible for enhanced expression of the human B-ATF gene by EBNA-2 will be investigated. To establish a functional role for B-ATF in B cells, experiments will be performed to assess the impact of B-ATF on the biochemical and biological function of the AP-1 transcription factor complex and on the activities of an additional B-ATFinteracting protein (BIP-13) that is expressed preferentially in human B cells. The requirement for spatial and temporal control of B-ATF expression in vivo will be investigated using in situ hybridization to fully characterize the B-ATF gene expression pattern in embryonic and adult mice. Transgenic technology will be used to establish if perturbation of B-ATF expression adversely impacts the development of the whole animal. The PI anticipates that these studies will elucidate the role of B-ATF in B cell growth and development and provide the information needed to assess the feasibility of using this new bZIP protein as a target in the management of B cell malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: C3D/EBV RECEPTOR LIGAND BINDING SITES Principal Investigator & Institution: Holers, V Michael.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508

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Timing: Fiscal Year 2002; Project Start 01-JUL-1991; Project End 30-JUN-2007 Summary: (provided by applicant): Human complement receptor type 2 (CR2/CD21) is an ~145 Kd Type I transmembrane protein that serves as a receptor for three classes of ligands. These include C3 cleavage fragments (C3d, C3dg and iC3b), Epstein-Barr virus gp350/220 and CD23. Each of these ligands interacts with the amino-terminal region of the receptor within 2 of 16 repetitive elements that have been designated short consensus repeats (SCRs). SCR-containing proteins that interact with complement C3 and/or C4 are part of a family called the Regulators of Complement Activation (RCA). While the biologic relevance of these proteins is well established, important structurefunction characteristics of SCR-containing proteins are poorly understood at the molecular level. We are studying CR2 as a model for receptor-ligand interactions in this family, initially focusing on the amino terminal domain that is designated herein the SCR1-2 domain and which interacts with each of the ligands described above. Preliminary studies using solution as well as x-ray crystallographic techniques have identified several protein-protein interfaces that are likely key to receptor interactions of CR2 with the C3d ligand as well as strongly suggested a model in which the non-ligandbound free and ligand-bound structures of the SCR1-2 domain differ in their conformation. In addition, recent data have shown that SCRs of CR2 outside of the SCR1-2 domain influence binding with C3d. We now propose to extend these studies by pursuing the following specific aims:Specific Aim #1: Determine the solution phase structure of the CR2 SCR1-2 domain in order to establish the physical relationship between the non-ligand-bound and C3d-ligand-bound receptor states.Specific Aim #2: Establish the relative roles of the three unique protein-protein interfaces apparent in the CR2 SCR1-2:C3d co-crystal structure in C3d ligand binding, signal transduction and the enhancement of in vivo immune responses.Specific Aim #3: Determine the relationship between the C3d, gp350/200 and CD23 ligand binding sites within the CR2 SCR1-2 domain.Specific Aim #4: Establish the solution structure of the CR2 SCR1-15/16 extracellular domain and determine the physical basis for the altered CR2-C3d ligandreceptor binding kinetics when comparing this full length receptor with the CR2 SCR1-2 domain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND MORTALITY IN NEUROFIBROMATOSIS BY GENOTYPE Principal Investigator & Institution: Mulvihill, John J.; Kimberly V. Yalley/ Professor of Genetic; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Manifestations of neurofibromatosis 1 (NF1) vary widely even within families, and progression may be rapid or static, early or late, or erratic. Benign and malignant neoplasms occur to excess in persons with NF1, but estimated rates vary greatly. Prognostic information on survival is sparse. To address these issues and to begin relating them to specific mutations within the NF1 gene, we will follow up a nationwide cohort of patients with neurofibromatosis who were identified as far back as 1924. The three specific aims are: 1) to follow-up the national cohort of NF1 patients, last updated to June 1983, to extend each affected lineage to all subsequent descendants and to establish an ongoing mechanism of follow-up; 2) for all NF1 persons in the cohort, to determine mortality by specific causes of death and cancer incidence and to compare it with expected numbers, based on age-, year-, and sex-specific cancer rates from the Danish Cancer Registry; and 3) to determine the specific mutation within the NF1 gene

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in individuals in all 78 lineages to explore possible mutation-specific associations with mortality and cancer rates. Following the successful protocol from our study in the early 1980s, follow-up will take place by personal contact, clinical examinations, retrieval of church records, the Danish Central Population Register, death certificates, and hospital, pathology, and postmortem reports, as well as at the Danish Cancer Registry. Survival curves will be prepared by standard life-table methods; a person-years-at-risk analysis and relative risk calculation will assess a possible excess of cancers. Feasibility analysis of familial aggregation of cancer will be conducted. Blood for DNA and RNA will be collected on all subjects, and relevant spouses with or without NF1, and lymphocytes will be transformed by Epstein-Barr virus on older subjects and those with lifethreatening disease. Duplicate specimen repositories will be established in Copenhagen and Pittsburgh. NF1 gene mutations will be sought by protein truncation assay, singlestranded conformation polymorphism gels, and automatic fluorescent sequencing. Patterns of mortality and cancer incidence will be compared by NF1 genotype. A longitudinal cohort will be established for subsequent studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER SUBTRACTION

VIRUS

DISCOVERY

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COMPUTATIONAL

Principal Investigator & Institution: Meyerson, Matthew L.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 24-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): We have developed a new method to discover microbial causes of human disease, sequence-based computational subtraction. In this method, sequences from diseased tissue are compared to the human genome computationally, and the filtered sequences are highly enriched for non-human nucleic acids. I propose to apply computational subtraction to search for viruses that cause lymphomas associated with immunodeficiency, most notably post-transplant lymphoproliferative disorder and HIV-associated lymphoma. First, I propose to use specimens of post-transplant lymphoproliferative disorder, known to be positive for Epstein-Barr virus, to refine our methods for library generation and sequencing. In particular, we would like to test the use of normalization, subtraction, and concatenation techniques. Once we have improved these techniques, I plan to focus on searching for novel viruses in immunodeficiency-associated lymphomas of unknown etiology. We plan to generate cDNA libraries from immunodeficiency-associated lymphoma biopsy specimens, to sequence a sampling of these libraries, and then to subtract the sequences computationally and experimentally against the human genome. Filtered sequences will be tested further for specific association with lymphoma using the polymerase chain reaction. Should we successfully identify novel lymphoma-associated sequences, we will then attempt to generate molecular clones of the entire putative viruses and begin to characterize the protein products of their genomes. Computational subtraction is a broadly applicable method. While we will begin our pathogen discovery projects in cancer, our methods will be broadly applicable to many human diseases. These include auto-immune diseases and inflammatory diseases, as well as uncharacterized epidemics, whether natural or bio-terrorist in origin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMISTRY AND BIOLOGY OF HUMAN LYMPHOCYTES Principal Investigator & Institution: Strominger, Jack L.; Professor of Biochemistry; Biochem and Molecular Biology; Harvard University Holyoke Center 727 Cambridge, Ma 02138 Timing: Fiscal Year 2001; Project Start 30-SEP-1988; Project End 30-NOV-2002 Summary: This application proposes studies in a variety of areas relating to the chemistry and biology of human lymphocytes. The problems being studied involve the molecular basis of immune recognition, including the recognition of tumor cells, as well as factors which govern and regulate proliferation of human lymphocytes. The techniques being employed include protein chemistry and crystallography, molecular genetics, cellular immunology and virology. Specific areas of investigation are: 1) protein chemistry and crystallography of and the relationship of structure to function in class I MHC molecules and their bound peptides, 2) similar studies of class II MHC molecules, 3) the interaction of CD4 with the class Il MHC molecule through its D3 and D4 domains and with the protein tyrosine kinase p56(lck) through its intracytoplasmic region, 5) protein chemistry of T cell receptors and the mechanisms of development of T cells, 6) the role of HLA-C in NK allorecognition and other studies of NK cells, 7) the mechanism of transformation of B and T cells by Epstein Barr Virus, and 8) the regulation of expression and function of tumor necrosis factor alpha. They relate to tumor immunology and tumor cell proliferation in a variety of ways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHIMERIC EBV SPECIFIC T CELLS WITH ANTI TUMOR ACTIVITY Principal Investigator & Institution: Brenner, Malcolm K.; Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Grafting of T lymphocytes with an antibodydirected specificity allows the cells to be targeted to any tumor-associated antigen for which a monoclonal antibody exists. Moreover, such chimeric T-cell receptors provide T-cell activation in a non-MHC-restricted manner, efficiently bypassing major mechanisms by which tumors commonly escape immune detection. We propose that expression of chimeric antitumor receptors on Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) will allow these cells to retain their known advantages while adding specificity and effector function directed to residual tumor cells, thereby extending the applicability of antitumor CTL immunotherapy. This hypothesis will be tested by expressing GD2-specific, single-chain antibody (scFv) chimeric T-cell receptors on either primary T lymphocytes or EBV-specific cytotoxic T-cell lines from neuroblastoma patients, and then evaluating the safety, in vivo expansion and persistence, and antitumor activity of the modified cells in patients with advanced neuroblastoma. These studies will be extended by preparing chimeric receptor-bearing T cells that express human scFV antibodies we have developed that are specific for neuroblastoma and testing their safety and efficacy in neuroblastoma patients. Upon conclusion of the project, we will have established whether EBV-specific CTLs can be used successfully as carriers for tumor-targeted chimeric receptors, and whether their functionality is superior to that of primary T cells expressing the same receptors. The value of Project 3 will be enhanced by interactions with Project 1 (new approaches to overcoming host resistance mechanism) as well as Project 2 (boosting of chimeric receptor T-cell responses with immunogenic peptides). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL RESEARCH OF INFECTIONS IN TRANSPLANTATION Principal Investigator & Institution: Paya, Carlos V.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-MAY-2002 Summary: (Adapted from Applicant s Abstract) One major barrier limiting the success of human allotransplantation is the transplantation related infectious complications. While significant progress has been made in the last decade in elucidating the pathogenesis and the optimal management of transplant infectious complications, a number of infections continue to cause significant morbidity and mortality in the transplant recipient. The applicant is an active clinical investigator in this field and has identified two major areas in which additional research is required to overcome the impact of these infections. These include addressing the role of the family of beta-herpes viruses (CMV, HHV-6, and HHV-7) and Epstein Barr Virus (EBV) induced posttransplant lymphoproliferative disease (PTLD). This clinical research is a fertile ground for training of future clinician investigators as it conveys multidisciplinary interaction: immunology, diagnostic virology, and transplantation medicine. Through this award, the applicant is seeking the support to obtain additional training in specific aspects of clinical research including formal courses in patient-oriented research, interactions with the clinical research unit (GCRC), GMP facilities, and additional training in immunotherapy of chronic viral infections in transplant patients. The applicant is seeking the support to, within a clinical research group, address the two mentioned focused areas in infectious diseases in transplantation and in which future clinician investigators will be formally trained. The specific aims that this application will pursue include: I) Study the clinical relevance of HHV-6 and HHV-7 in organ transplant recipients and their interaction with other opportunistic viral infections (CMV, EBV, HBV, and HCV). II) Define the clinical value of EBV viral load for the prevention and management of EBV-PTLD, and test the feasibility of cell-based immune therapy for the prevention and treatment of EBVPTLD in EBV naive solid organ transplant recipients. Altogether, this award will allow us to address, through rigorous patient-oriented research, two areas of transplant infectious complications, which are limiting success in human transplantation. Moreover, it will facilitate to train a cadre of future clinician investigators who will further advance this important field of clinical medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLONING OF NON-SYNDROMIC DEAFNESS GENES DFNA29 & DFNA32 Principal Investigator & Institution: Li, Xiaoyan C.; House Ear Institute 2100 W 3Rd St Los Angeles, Ca 90057 Timing: Fiscal Year 2001; Project Start 09-FEB-2001; Project End 31-JAN-2004 Summary: (from applicant's abstract): The long-term goal of this study is to understand the function and dysfunction of hearing at the molecular level. Hearing impairment is the most common human sensory disorder. Approximately 70 million people worldwide suffer from hearing loss over 55 dB. Genetic factors are one of the most important causes for hearing impairment. Approximately one in every 2,000 children is born with severe to profound hearing loss due to a genetic cause. Non-syndromic hearing loss occurs in isolation, and it accounts for approximately 80% of hereditary deafness. Studies on the molecular basis of non-syndromic hearing loss, especially the late onset forms, are not only important for improving our understanding of the molecular mechanisms of auditory development and function, but also for developing

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Epstein Barr Virus

more precise genetic counseling and therapeutics for both genetic and environmentrelated hearing impairment. We have mapped two new deafness loci, DFNA29 and DFNA32, using linkage analysis on two large US families with non-syndromic autosomal dominant progressive hearing loss. The PI proposes to identify the responsible genes, and to explore their function in the hearing process. The following specific aims are proposed: (1) Refine the critical region of DFNA29 and DFNA32 using recombinational mapping and linkage disequilibrium strategies. (2) Establish permanent cell lines from both affected and unaffected individuals by Epstein-Barr virus transformation. (3) Identify the molecular basis of these loci using a positional candidate gene approach. (4) Establish expression patterns of the genes responsible for DFNA29 and DFNA32 in the developing auditory and vestibular systems using PCR, RT-PCR, and RNA in situ hybridization. This specific aim represents a long-term direction of the study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COBRE:CENTER FOR MOLECULAR AND TUMOR VIROLOGY Principal Investigator & Institution: O'callaghan, Dennis J.; Professor; Microbiology and Immunology; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The purpose of this proposal submitted under the NIH IDEA Program is to promote sustainable improvements in research competitiveness and infrastructure at the LSU Health Sciences Center (LSUHSC) by establishing the Center of Biomedical Research Excellence (COBRE): Center for Molecular and Tumor Virology. Four senior virologists working in molecular, tumor, and immunological virology will serve as mentors to five junior level faculty members (one to be recruited in Year 2) to enhance their competitiveness for national funding and to increase the productivity of their developing research programs. A detailed plan to mentor these junior investigators with well-defined criteria to assess the development and competitiveness of their research programs is presented. The plan stresses close interaction of the mentors and junior faculty investigators and will create a Cell Culture and Molecular Analysis Core Facility that will complement the state-of-the-art services of the LSUHSC Research Core Facilities. In addition, an External Advisory Committee comprised of internationally recognized virologists, four being members of the National Academy of Sciences, will serve as reviewers of the Center for Molecular and Tumor Virology to provide oversight and peer review of the ongoing research projects and to offer suggestions that would contribute to the excellence of the Center. The Center is multidisciplinary as the projects of the junior faculty P.l.s interface with ongoing research in the Depts. of Medicine (viral diseases) and Physiology (altered endothelium) and our Cancer (tumor virology) and Arthritis (inflammation) Centers and address the mechanisms of different disease states resulting from viral infection. These diseases include herpesvirus induced severe inflammatory disease, cytomegalovirus induced alterations in endothelial cells leading to cardiovascular disease, molecular pathogenesis of yellow fever, and the role of polyamine metabolism in Epstein Barr virus lymphomagenesis. The Center has a thematic scientific focus in that molecular approaches applied to models of these disease states seek to elucidate the varied means by which viral gene products alter the cell and orchestrate events that result in disease. All four P.I.s are well trained in molecular virology at the doctoral and postdoctoral levels and will be provided the space, resources, and released time to develop state-ofthe-art research programs competitive for national funding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DAILY LOW-DOSE IL-2 AUGMENTS ANTI-CD20 ANTIBODY THERAPY Principal Investigator & Institution: Eisenbeis, Charles F.; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 19-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The anti-CD20 antibody, rituximab, is effective as a single agent for the treatment of human B-cell lymphomas. Despite a 50% response rate in intermediate grade lymphomas, the complete response rate is low, and no patients are cured of their disease. The mechanism of rituximab's activity against lymphoma remains unclear; almost all of the existing data is from in vitro studies using lymphoma cell lines, and suggests that rituximab functions through antibody- dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), direct induction of apoptosis, or a combination of these mechanisms. We have utilized a murine model of a spontaneously arising human malignant lymphoproliferation to study the mechanism of rituximab's cytotoxic activity in vivo. In this model, severe combined immune deficient (SCID) mice are engrafted with human peripheral blood leukocytes (hu-PBLs) via intraperitoneal injection (the hu-PBL-SCID model). If PBL from selected normal EpsteinBarr virus (EBV)-seropositive donors are injected, all mice develop lethal EBV-derived lymphoproliferative disease (EBV-LPD) within 8-12 weeks. This EBV-LPD is CD20+, is of human origin, and arises in the midst of engrafted normal human immune effector cells including CD8+ T cells and NK cells. In this model, rituximab is capable of eradicating established EBV-LPD, but only in mice pretreated with daily low-dose interleukin-2 (IL-2). The mechanism by which IL-2 promotes the cytotoxic function of rituximab is unknown, and is the focus of this proposal. A leading hypothesis is that IL2 exerts its effect through the modulation of activating and inhibitory Fc-gamma receptors (Fc-gamma- R), either on the tumor itself, or on required immune effector cells, thus leading to more effective ADCC. In the first aim we will determine the immune effector subset(s) necessary for the therapeutic effect of rituximab and daily low-dose IL-2. In the second aim, we will characterize the effect of IL-2 on the differential expression of Fc-gamma-RI, Fc-gamma-RII, and Fc-gamma-RIII on human and murine immune effector subsets, and determine the functional relevance of murine Fc-gamma-R molecules for the protective effect of rituximab and IL-2 therapy. For the third aim we will characterize the effect of daily low-dose IL-2 therapy on EBV-LPD tumors and their susceptibility to ADCC, apoptosis, and cell-mediated cytotoxicity. Insight gained from these studies should be applicable to the treatment of a variety of human malignancies for which antibody therapy currently exists, and may lead to further optimization of such therapies in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DENDRITIC CELLS AS ADJUVANTS FOR RESISTANCE TO HIV-1 Principal Investigator & Institution: Steinman, Ralph M.; Professor & Senior Physician; Lab/Bacterial Pathogenesis; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2001; Project Start 01-FEB-1997; Project End 31-MAR-2004 Summary: A successful HIV-1 vaccine will likely have to induce strong CD4 and CD8 T cell immunity. For example, there is evidence that CD4+ T cells are required for the function of virus-specific CD8+ T cells in many experimental models of immunity, and that CD8+ T cells provide resistance against SIV and HIV-1. Likewise, EBV-associated lymphoproliferative disorders develop in AIDS, suggesting a need for CD4+ T cells in resistance in EBV as well. Dendritic cells [DCs) are specialized antigen presenting cells

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Epstein Barr Virus

for initial combined CD4+ and CD8+ T cell immunity. Therefore our hypothesis is that the targeting of HIV-1 and EBV antigens to mature, immunostimulatory DCs will lead to strong virus-specific immunity. In the two years of this grant, we have learned to deliver HIV-1 and EBV antigens to DCs with different viral vectors, and we find that these DCs then stimulate strong T cell responses. In other grants, we have injected antigen-bearing DCs to healthy volunteers and elicited rapid and broad T cell immunity in situ. We will now pursue the data along 3 lines: 1] To optimize the use of DCs infected with a non- perturbing, envelope-pseudotyped HIV-1--to elicit strong immunity in culture. This approach will then be used to detect and quantify CD4 and CD8 immune status in important cohorts, 3e.g., exposed uninfected individuals, long term non-progressors, and patients receiving highly active anti-retroviral therapy; 2] To vaccinate, in collaboration with the Walter Reed Army Research Institute vaccine group, volunteers with autologous DCs charged with recombinant avipox. The immunity will then be compared to separate cohorts vaccinated with recombinant avipox directly; an approach that to date has not induced strong or reliable immunity. 3] To use DCs to elicit immunity to Epstein Barr Virus, especially CD4+ T cells specific to EBNA-1. We have identified strong CD4+ T cell responses to the critical EBNA-1 protein and now will use DCs to understand the processing of EBNA-1 and the biological functions of the reactive T cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF ASSAYS TO DETECT EBV IN BREAST CANCERS Principal Investigator & Institution: Gulley, Margaret L.; Pathology and Lab Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Previous studies have suggested that Epstein-Barr virus (EBV) is present in some breast cancers. Although an association of this common virus with breast cancer has implications for disease etiology and treatment, it remains controversial, largely because of methodological problems such as: 1) detected EBV was not always localized to neoplastic cells, as opposed to bystander lymphocytes; and 2) the assays were often suspect with regard to their sensitivity and specificity for EBV. Newer technologies for detecting viral pathogens (quantitative real-time polymerase chain reaction (PCR) combined with laser capture microdissection technology for localizing the virus to certain cells), now make it feasible to both quantify viral DNA in archival tissues and determine which cell tractions harbor virus. In this study, we will combine and adapt these advanced technologies to look for EBV within malignant cells of breast tumor tissues. The Specific Aims are to: 1) develop a quantitative real-time PCR assay targeting the EBV LMP1 gene by designing TaqMan probe and primers, with attention to optimizing assay sensitivity, specificity, and linearity; 2) test the utility of this LMP1 assay, as well as predeveloped quantitative PCR assays for the BamHlW and EBNA1 portions of the EBV genome, by applying them to DNA extracted from 20 model tumors (EBV-related nasopharyngeal carcinomas (NPC); 3) test the ability to localize EBV in NPC tissues by separating tumor cells from reactive cells using laser capture microdissection, and measuring viral load in each fraction using the 3 PCR assays; 4) obtain archival specimens from 100 women with invasive breast cancer, randomly sampled from a population-based cancer registry to include epidemiologically relevant characteristics already recorded in the registry, such as younger and older age, white and nonwhite race, and less and more aggressive disease (according to clinical stage,

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tumor size and grade, lymph node involvement, hormone-receptor status, vital status); 5) apply the 3 PCR assays to quantitate EBV in the 100 breast cancer tissues and calculate the ratio of EBV DNA to cellular (actin) DNA for each specimen; 6) use microdissection and PCR in samples with the highest EBV levels to determine if the EBV DNA is in the tumor cells or in the normal cell fraction; and, 7) conduct exploratory descriptive analyses of EBV presence in breast tumors by patient demographic and clinical variables to characterize EBV-associated cancers epidemiologically. Study strengths include consideration of an understudied, potentially treatable factor (i.e., EBV) in breast cancer, development of a novel laboratory strategy to overcome prior methodological problems in studying this association, and the first use of a carefully sampled, representative case series in such research. The new assays should facilitate, and epidemiologic findings provide direction for, larger studies of breast cancer etiology and prognosis. The work should also be relevant to possible therapeutic and preventive strategies aimed at eliminating infected cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EBNA-3C IN B LYMPHOCYTE TRANSFORMATION BY EBV Principal Investigator & Institution: Johannsen, Eric C.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant): This project will attempt to define the mechanism(s) by which the Epstein-Barr virus nuclear antigen 3C (EBNA-3C) promotes B lymphocyte transformation into lymphoblastoid cell lines (LCLs). Previous studies have established that EBV genomes lacking an intact EBNA-3C cannot growth transform B cells. The central hypothesis of this application is that EBNA-3C is essential for the establishment and maintenance of LCLs and that it exerts its effect by regulating the expression of critical cellular and viral genes. The requirement for continued EBNA-3C expression in the maintenance of LCLs will be tested using a recombinant EBV expressing a hydroxytamoxifen/EBNA-3C fusion protein. It is anticipated that, in the absence of hydroxytamoxifen, the tethering of this fusion protein in the cytoplasm will lead to growth arrest and/or apoptosis. In this case, the ability of transfected EBNA-3C as well as multiple EBNA-3C mutants to complement this defect will be assessed. If instead, EBNA-3C proves to be dispensable for the maintenance of transformation, a genetic analysis of EBNA- 3C mutants will be conducted for their ability to mediate the establishment of LCLs. The ability of these mutants to synergistically co-activate with the major viral transactivator (EBNA-2) will also be assessed. Using the above information, the transcriptional profile of EBNA-3C transformation competent mutants will be contrasted to mutants unable to mediate transformation in an effort to establish the major pathways through which EBNA-3C promotes B lymphocyte transformation. Biochemical methods including a yeast two hybrid screen and co-immunoprecipitation will also be employed to discover what cellular proteins interact with the identified EBNA-3C effector domains. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EBV PATHOGENESIS IN HIV-ASSOCIATED HAIRY LEUKOPLAKIA Principal Investigator & Institution: Walling, Dennis M.; Internal Medicine; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004

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Summary: Hairy leukoplakia (HLP) is a common opportunistic infection in human immunodeficiency virus (HIV)-infected individuals. HLP occurs on the lateral tongue and is caused by the Epstein-Barr virus (EBV). HLP is remarkable as the only pathologic manifestation of productive EBV infection and as the only non-malignant lesion of epithelial cell EBV infection. HLP offers insight into the mechanisms of EBV persistence and the role of specific EBV gene products in HIV-associated EBV pathogenesis. Three hypotheses will be tested: 1) That tongue epithelial cells are a second reservoir of persistent EBV infection in HIV-infected individuals. 2) That HLP results from a unique co-expression of both latent and productive EBV genes. 3) That novel molecular mechanisms regulate the unique pattern of EBV gene expression seen in HLP. In a clinical study protocol, HIV-infected volunteers with HLP will be treated with antiviral therapy to inhibit EBV replication and induce BV latency. Subsequent withdrawal of antiviral therapy will permit EBV reactivation. Tongue and blood lymphocyte tissues will be collected before, during, and after antiviral therapy. Molecular studies will investigate the molecular biology and epidemiology of EBV latency and reactivation. The role of gene expression in EBV pathogenesis will be investigated, including the functional consequences of EBV gene sequence variation and genetic recombination in HLP. Finally, the role of HIV-EBV interaction in HLP pathogenesis will be investigated. The results of this study will elucidate molecular mechanisms of EBV pathogenesis in HLP applicable to other EBV-associated diseases, including nasopharyngeal carcinoma and HIV-associated lymphomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EBV SPECIFIC THERAPY OF LYMPHOMA USING DENDRITIC CELLS Principal Investigator & Institution: Dhodapkar, Madhav V.; Assistant Professor; Lab/Cell Physiol & Immunology; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Epstein Barr virus (EBV) is a ubiquitous gamma herpes virus associated with the development of several B lymphoproliferative diseases including lymphoma in human immune deficiency virus (HIV) infected individuals. Cellular immunity plays a critical role in the control of EBV and other viral infections. However it has been difficult to boost this arm of the immune response using current approaches in humans. Dendritic cells (DCs) are specialized antigen presenting cells (APCs) capable of generating strong anti-viral immune responses. Our hypothesis is that Dcs will be effective adjuvants for the generation of EBV specific immune response for therapy and prevention of lymphoma in HIV infected individuals. Maturation of DCs ex vivo leads to an increase in their potency in vitro. We have recently demonstrated that a single injection of antigen bearing mature DCs, but not unpulsed DCs or antigens alone, generated broad CD4 and CD8+ve T cell immunity in healthy volunteers. These data provide the first controlled evidence of immunogenicity of DCs in humans. We will now examine the strength and durability of the T immunity using newer quantitative assays. In studies proposed herein, we will next determine the magnitude of EBV specific memory using DCs as APCs and EBV specific effector CTL response using newer sensitive assays (ELISPOT and MHC-tetramer binding) in patients with HIV infection, as compared to normal hosts. Using the ELISPOT assay, we will also examine the nature of CD4+ve T cell immunity to EBV in these populations. These studies will serve as a baseline for future immune therapeutic trials to boost EBV and HIV specific immune responses. Recent studies in our laboratory have demonstrated that DCs can acquire exogenous antigen from apoptotic cells and generate CD8+ CTLs. There fore we will

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examine if DCs are able to acquire antigen from apoptotic EBV infected cells, as a potentially novel strategy for generating EBV specific CTL responses in patients. The long term goals are to use DCs as adjuvants to boost EBV and HIV specific immune response in patients with HIV associated lymphoma. The proposed studies and career development plan will provide the necessary laboratory experience to complement the PI s prior expertise in clinical oncology research and lay the foundation for career as a physician-scientist in tumor immunology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EBV VECTORS FOR TARGETED GENE THERAPY OF BLYMPHOMAS Principal Investigator & Institution: Pagano, Joseph S.; Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 10-SEP-2000; Project End 31-AUG-2004 Summary: (Applicant's Abstract): The goal of this application is to effectively and selectively eliminate B-cell derived lymphoma and leukemia cells in cancer patients using a naturally targeted viral vector system. To achieve this goal, the applicant proposes to develop a novel combinatorial gene therapy approach as applied to Burkett B lymphoma based on i) a minimal "gene-less" B lymphotropic Epstein-Barr virus (miniEBV) vector, and ii) a genetically enhanced "hyper-suicide" HSV1 thymidine kinase (super-TK). Specifically, the following studies will be undertaken: Aim 1) To test the efficacy of B lymphotropic miniEBV vectors to deliver and express a suicide gene into human B-cell lymphomas following oncotropic and oncolytic strategies. This approach is based on the transfer of the viral thymidine kinase (TK) gene into B-cell derived lymphomas rendering them sensitive to the prodrug ganciclovir (GCV). For this endeavor miniEBV/sTK will be used to infect B-lymphoma cells in vitro and the transiently infected cells implanted in an animal model to analyze prodrug mediated eradication of the lymphoma using ex vivo protocol. Aim 2) Development of an in vitro cultured packaging cell system to produce helper-free infectious miniEBV. This will involve cloning the genome of EBV in a BAC based vector to delete the packaging sequence by homologous recombination. In addition, EBV negative cell lines will be evaluated for their permissivity to miniEBV replication and packaging into infectious virions. Aim 3) Use the results obtained in Aims 1-2 to test the miniEBV system for its efficiency and safety in a SCID-Human lymphoma/leukemia animal model using an in vivo protocol. Pre-established human B-lymphoma in vivo by intravenous (i.v.) injection with this system will be also evaluated in order to eliminate the disseminated Blymphoma from various organs of the animal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENHANCING T CELL THERAPY OF CANCER Principal Investigator & Institution: Heslop, Helen E.; Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: Not Available Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Epstein Barr Virus

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Project Title: EPSTEIN BARR VIRUS INDUCED GENOMIC INSTABILITY Principal Investigator & Institution: Sixbey, John W.; Professor; Microbiology and Immunology; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2001; Project Start 05-APR-1995; Project End 31-MAR-2006 Summary: (provided by the applicant): The Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that, despite the life-time rapport typically achieved with its human host, can be associated with benign (infectious mononucleosis) and malignant (Burkitt's lymphoma, Hodgkin's lymphoma, primary central nervous system lymphoma) lymphoproliferative diseases. The overall objective of this grant is to understand molecular mechanisms by which EBV causes disease and their inter-relatedness to modes of viral persistence in the memory B lymphocyte reservoir. Physiologic signaling via the B cell antigen receptor (surface immunoglobulin) has major implications for the fate of any infected B cell, leading to cell proliferation and differentiation or, conversely, apoptosis. Because we showed up-regulation of recombinase activating genes RAG1 and RAG2 upon EBV infection of mature B cells, we now hypothesize that virus diversifies the B cell antigen receptor through induction of secondary immunoglobulin gene rearrangements as a means of assuring adequate survival signaling in infected cell progeny. Renewed V(D)J recombination outside the selective environment of bone marrow or germinal centers has potential pathogenic consequences that include autoimmunity, lymphoproliferation and chromosomal damage. The specific aims to test our hypothesis are: 1) to determine if secondary rearrangements of immunoglobulin variable region genes occur as a consequence of RAG induction by Epstein-Barr virus; 2) to determine if RAG1 and RAG2 are expressed in human peripheral blood lymphocytes in vivo as a consequence of acute EBV infection; 3) to analyze EBV DNA integration as a marker of illegitimate recombination prompted by viral induced RAG expression; 4) to determine the mechanism by which RAG1 and RAG2 are up regulated by latency protein EBNA1. The use of recombinant EBV expressing green fluorescent protein allows rapid selection of infected cells now capable of expressing RAG; concurrent analysis by flow cytometry for altered surface immunoglobulin; detection by PCR of broken DNA ends or excision circles that are byproducts of V(D)J recombination; and subsequent analysis for chromosomal abnormalities from aberrant RAG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EPSTEIN BARR VIRUS LATENCY Principal Investigator & Institution: Thorley-Lawson, David A.; Professor of Pathology; Pathology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 25-JAN-1995; Project End 31-JAN-2004 Summary: Epstein-Barr virus (EBV) is a B lymphotropic herpesvirus that usually persists benignly for the life time of the infected host, but can be predisposing for the development of certain lymphomas and carcinomas. Persistent infection in the peripheral blood of healthy carriers is quiescent, being restricted to latently infected, resting, memory B cells in which, at most, one or two latent genes are expressed. By comparison persistent infection in the mucosal lymphoid tissue appears to be more complex. There are infected naive and memory B cells, viral replication to produce infectious virus and at least one completely novel subset with a very high frequency of latently infected B cells. The virus is not randomly distributed through all of the B cells subsets. It is our hypothesis that the distribution of virus infected cells can be explained through analogy to normal B cell activation and differentiation within secondary lymphoid tissue. To test this idea we will focus on three main issues: 1. What is the

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nature of the novel B cell subset (CD38+CD10-IgD-) that we have found in the tonsils to be highly enriched for latently infected cells (approximately 1 in 500 are infected) and what is its relationship to classically defined memory B cells (CD38- CD10-IgD-) 2. Is EBV a mucosal specific virus i.e. is viral persistence actively maintained throughout the lymphoid tissue or quiescent everywhere except mucosal lymphoid tissue? Does the virus replicate in all lymphoid tissue or only mucosal lymphoid tissue? 3. Are virus infected cells in the lymphoid tissue able to undergo a germinal center reaction to enter the memory compartment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER

EPSTEIN-BARR

VIRUS

AND

POSTMENOPAUSAL

BREAST

Principal Investigator & Institution: Cerhan, James R.; Associate Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 05-SEP-2000; Project End 31-AUG-2003 Summary: Breast cancer is the most commonly diagnosed cancer among women in the United States. There is currently a controversy on whether the Epstein-Barr virus (EBV; Human Herpes Virus 4) plays a role in breast carcinogenesis. We propose to test the hypothesis that EBV is commonly found in invasive ductal carcinomas of the breast but not in normal adjacent tissue, and that the presence of EBV is associated with a more aggressive phenotype, a poor prognosis, and epidemiolgic risk factors that are associated with suppression of the cellular immune system including a diet high in animal fat or animal protein, a history of blood transfusion, and cigarette smoking. This study will be conducted in the Iowa Women's Health Study (IWHS), a prospective cohort study of postmenopausal breast cancer risk in over 40,000 older Iowa women who were first enrolled in 1986. We propose to retrieve tumor blocks from incident invasive ductal carcinomas first diagnosed in the IWHS between 1988 and 1990 (N=258) in collaboration with the State Health Registry of Iowa. Based on extensive prior experience, we expected to have 184 useable tumor blocks available for analysis. Diagnostic slides and pathology reports will be reviewed in order to grade the tumors and to select appropriate normal and tumor sections from paraffin blocks. Tumor blocks will be processed in th Mayo Tissue Acquisition and Processing Core. We will attempt to identify the presence of EBV in the tumor and adjacent histologically normal tissue using PCR-based methods to identify EBV, and immunohistochemical methods to identify EBNA-1 expression, allowing us to estimated the prevalence of EBV (any EBV; EBV-1; EBV-2) infection in a relatively large sample of invasive ductal carcinomas. We will also correlate EBV status in tumors with prognostic factors including tumor size, axillary lymph node status, estrogen and progesterone receptor status, and histologic grade. As secondary aims, we will evaluate whether EBV status predicts long-term (great than or equal to 10-year) survival after breast cancer diagnosis (overall survival; death due to breast cacncer), and whether certain epidemiologic risk factors that alter immune function allowing reactivation of EBV infection are more strongly associated with EBV+breast cancers. We have carefully designed this study within the resource constraints of the small grant program in order to clearly address our main hypotheses, and to begin to address our secondary aims, albeit with limited power, in order to generate preliminary data on which to base future studies within this cohort as well as other study populations. This proposal also fits well into the goals of the small grants program in cancer epidemiology since it address an emerging, high risk/high gain hypothesis that requires the types of data we will generate in order to justify a more definitive study.

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Epstein Barr Virus

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

Project Title: EXPOSURE TO ORGANOCHLORINES, EBV, AND THE RISK OF NHL Principal Investigator & Institution: Laden, Francine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 09-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): The worldwide increase in the incidence of nonHodgkin's lymphoma (NHL) over the past century is largely unexplained. Current epidemiologic evidence suggests a role in the etiology of the disease for organochlorine compounds, such as the pesticide DDT and the industrial chemicals polychlorinated biphenyls (PCBs) and for the Epstein-Barr Virus (EBV). The risks associated with high blood/adipose levels of organochlorines have ranged from two to four-fold. It is well established that EBV plays a causal role in many cases of NHL among patients who are immune suppressed, and the few studies assessing EBV in apparently normal populations have also shown that altered EBV antibody patterns are associated with NHL. Finally, strong statistically significant multiplicative interactions between EBV and organochlorines on the risk of NHL have been reported, with odds ratios as high as 22 for the high PCB/elevated EBV antibodies group compared to the low PCBs/Iow EBV antibodies group. All of the previous studies have been small and need to be replicated in other populations. We propose to utilize two large well-characterized collections of archived blood samples - the Nurses' Health Study, a study of women, and the Physician's Health Study, a study of men - to prospectively address the role of organochlorines and EBV and their potential interaction in the occurrence of NHL. We anticipate 400 incident cases in the combined study population, and we will match each case with two controls who had the same opportunity for development of disease. We will collect pathologic specimens and subtype each case using standard procedures, allowing us to evaluate whether these associations are specific to particular types of NHL. The vast resources of the two cohorts will allow us to assess possible confounders and effect modifiers, including but not limited to, gender and diet. This proposal is led by an experienced team of researchers who have expertise over a range of disciplines that inform this study, Together, we should gain substantial insight into the role of organochlorines and EBV in NHL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUCTIONS OF EPSTEIN BARR VIRUS NUCLEAR ANTIGEN 1 Principal Investigator & Institution: Yates, John L.; Research Associate Professor; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2001; Project Start 01-JUL-1986; Project End 31-MAY-2005 Summary: Epstein-Barr virus (EBV) is a herpesvirus which is associated with several malignancies. A central aspect of the life cycle and pathogenesis of EBV is a latent state of infection in which the viral chromosome is maintained as an episome. A single EBVencoded protein, EBNA-1, allows the EBV chromosome to be maintained by binding to oriP, where it directs DNA replication to initiate and where it also acts to prevent the EBV chromosome from being lost from mitotically active cells. The replication function of oriP appears to be essential for the infection of primary B cells, although it is not needed when EBV infects established cell lines in culture. Molecular and genetic studies are proposed to investigate how EBNA-1 and cellular factors direct replication to initiate at oriP. Four specific aims are described: (1) We have evidence that in order to support

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replication initiation, two dimers of EBNA-1 must form a precise structure at oriP that involves a large DNA bend. We will investigate the angle of bending and whether a specific geometry is required. (2) We will take advantage of a wealth of information about DNA replication that has emerged from studies of yeast and Xenopus to begin to investigate the human proteins that may control initiation of DNA replication at oriP, using chromatin immunopreciptation and in vivo footprinting assays. (3) We will isolate replication-defective mutants of EBNA-1 that retain all other EBNA-1 activities and, therefore, may fail to perform an initiation step, such as interact with a host factor. (4) We will determine precisely where replication initiates at oriP by mapping the 5' ends of leading nascent strands. Each of these independent and complementary approaches should provide key insight into how replication initiates at oriP. The studies will also to be relevant to our understanding the replication of human chromosomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF EBV EBNA-3C IN B CELL IMMORTALIZATION Principal Investigator & Institution: Sample, Clare E.; Associate Member; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2001; Project Start 01-APR-1992; Project End 30-NOV-2002 Summary: Epstein-Barr virus is one of a limited number of viruses associated with human cancers. The ability of EBV to transform primary B lymphocytes and establish a latent infection is a prerequisite to any EBV-associated malignancy. Our long-term objective is to identify the cellular pathways targeted by EBNA-3C that mediate its essential role in EBV-induced transformation. Specifically, we propose to: 1. Identify the mechanisms of transcriptional activation by EBNA-3C. 2. Determine the significance of EBNA-3C function within the context of EBV contributes to EBNA-3C's essential role in EBV-mediated transformation. We will evaluate the significance of those EBNA-3C functions that we have already identified, those identified in this proposal, as well as domains that have been conserved during evolution of human and primate viruses, by examining the ability of mutant EBNA-3C proteins to function transformations. 3.Identify cellular genes regulated by EBNA-3C. EBNA-3c is likely to regulate expression cellular genes that contribute to EBV-mediated transformation. EBNA-3Cregulated genes will be identified by examining pathways EBNA-3C is known to target as well as by representational difference analysis. Characterization of these genes is likely to identify cellular effectors of EBNA-3C function. The proposed experiments will enable us to determine the cellular pathways targeted by EBNA-3C and thus its unique contribution to EBV-mediated transformation. Analysis of these pathways using EBNA3C as a probe, is highly likely to not only further our understanding of EBV-associated malignancies, but also increase our knowledge of the control of cellular proliferation that may be disrupted in other types of cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE ENGINEERING OF NERVE STEM USING HSV AMPLICON VECTOR Principal Investigator & Institution: Saeki, Yoshinaga; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): The development of a novel strategy to genetically modify neural stem/progenitor cells (NSCs) both in vitro and in vivo will have a significant impact on the development of NSCs-mediated cell therapy for neurological

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Epstein Barr Virus

disorders as well as on the advance of basic developmental neurobiology. We recently have developed a packaging system for herpes simplex virus (HSV)-based amplicon vectors free from helper virus contamination or viral gene expression. Using this technology, we have demonstrated that genomic DNA inserts over 100 kilobases can be packaged into HSV virions, delivered intact, and expressed in cultured cells in vitro. By adding Epstein-Barr virus (EBV)-based replicon elements, HSV amplicons with genomic DNA inserts (HSV/EBV/genomic vectors) were shown to replicate and be maintained as extra chromosomal elements in infected cells, and express functional gene products for a long period of time. The unique properties of this vector system lead us to hypothesize that HSV/EBV/genomic vectors can be a platform technology to achieve some of the long-term goals toward the development of NSCs-mediated cell therapy, namely: 1) Complementing genetic defects of diseased NSCs in vitro and in vivo to treat genetic neurological disorders, 2) stable and cell type-specific transgene expression in neurons and glial cells differentiated from the transduced NSCs, and 3) genetic engineering of NSCs for controlled proliferation, migration, and differentiation in vivo after transplantation. To evaluate the feasibility of this approach, this project proposes to: 1) Verify episomal replication and maintenance of HSV/EBV/genomic vectors and evaluate furictional transgene expression from the vectors in dividing NSCs in culture, and 2) verify stable and cell-type-specific expression of genomic transgenes in terminally differentiated neurons and glial cells both in vitro and in vivo. We will examine five human genes, hypoxanthine-phosphoribosyltransferase, nestin, myelin basic protein, glial fibrillary acidic protein, and microtubule-associated protein tau as a housekeeping, NSC-specific, oligodendrocyte-specific, astrocyte-specific, and neuronspecific gene, respectively. These studies will provide further understanding of HSV/EBV/genomic vectors and confirm the advantages of genomic transgenes and EBV elements, which then should provide a strong basis for genetic engineering of NSCs using HSV/EBV/genomic vectors Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR HEREDITARY TUMORS IN MODELS OF NF2 % TSC Principal Investigator & Institution: Breakefield, Xandra O.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 23-JAN-1987; Project End 31-AUG-2006 Summary: (provided by applicant): Studies will be undertaken to develop modes of gene delivery to experimental neural tumors for therapeutic intervention. Neoplastic lesions associated with tuberous sclerosis (TSC) including subependymal glial nodules, giant cell astrocytomas and cortical hamartomas, are believed to represent the consequences of loss of tumor suppressor genes on growth of astrocytes, neuroprogenitor cells and mesenchymal elements. Tumor models in the TSC2 heterozygous and conditional knock-out mice have been chosen as they are genotypically similar to mutations seen in patient cells and derive spontaneously from endogenous cells. They include liver hemangiomas, renal cell carcinomas, cortical hamartomas, and potentially subependymal glial nodules. Gene delivery to these tumor cells will be explored using three types of hybrid amplicon vectors derived from herpes simplex virus type 1 (HSV): one bearing a tetracycline (tet)-regulatable transgene cassette; one bearing elements of adeno-associated virus (AAV) to promote chromosomal integration; and one with both Epstein Barr virus (EBV), elements to promote episomal retention, and retrovirus vector elements (RV), to convert ampliconinfected cells into retrovirus producer cells. Vectors will be delivered through the intra-

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vascular route, either directly or via endothelial carrier cells to vascularized tumor foci; by intrathecal injection for brain lesions; and by direct intratumoral injection to large tumor masses. The efficiency and longevity of gene delivery to tumors in vivo will be established using reporter genes. Effective delivery modalities will incorporate therapeutic transgenes for anti-angiogenic and apoptosis factors, and consequences to tumor growth and pathology will be evaluated. In parallel, we will incorporate additional elements into these vector systems to increase the fidelity of regulatable transgene expression and to facilitate gene delivery to slowly growing tumors, typically seen in patients. This will include, in the first case, use of a tetracycline-silencer element and elimination of the VP16 transactivating protein from virions to achieve a "full off? state in the absence of drug, and, in the second case, replacement of RV elements in the HSV/EBV vector with components of lentivirus (LV) vectors, which are able to integrate transgenes into both dividing and non-dividing cells. TSC2 +/-transgenic and TSC1 conditional knock-out animals will be provided by Dr. Kwiatkowski (Project 12); pathologic expertise by Dr. Louis (Core C); assistance with vector engineering by Dr. Sena-Esteves; and MRI analysis by Dr. Weissleder. This project is designed to develop a strategy for reducing bulk in slow growing, benign tumors using vectors safe enough for eventual human use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC LINKAGE IN LUPUS Principal Investigator & Institution: Harley, John B.; Professor; Oklahoma Medical Research Foundation Oklahoma City, Ok 73104 Timing: Fiscal Year 2001; Project Start 01-JUL-1987; Project End 31-JAN-2005 Summary: The genetic basis of systemic lupus erythematosis has been pursued using the last five years of funding from this grant (AR24717-07 to -11) to help perform and evaluate a genome scan in lupus. These results considered with those of our closest competitor show 26 possible genetic linkages with 11 of these having some support for linkage from both studies. In addition, we confirm evidence supporting the presence of linkage at D1s229. Other work has advanced Epstein-Barr virus as a possible etiologic agent in lupus. Data show association, are consistent with Epstein-Barr virus infection preceding lupus onset, and advance a plausible mechanism for lupus autoimmunity in some patients. Virus exposure data and differences between the anti-viral immune responses of lupus patients and normal are amenable to genetic analysis in our pedigrees. In aggregate, we have 2109 pedigrees multiplex for lupus containing 1227 subjects (275 affecteds & 752 unaffecteds). We hope to continue our work by pursuing the following specific aims: 1. Enlarge the pedigree collection; 2. Establish linkage using: A. Lupus (by revised ACR criteria), B. An environmental factor and intermediate phenotypes: i. Lupus and Epstein-Barr virus infection, ii. Anti-peptide antibodies against Epstein-Barr virus (& against lupus autoantigens), iii. Anti-Ro and anti-nRNP autoantibody responses, and C. Multi-locus effects, and 3. Reduce linkage intervals and evaluate candidate genes. Hopefully, results from this resubmitted project will help elucidate the complex genetics of lupus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC LINKAGE OF SPLICEOSOMAL AUTOIMMUNITY IN SLE Principal Investigator & Institution: James, Judith M.; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 24-SEP-2002; Project End 31-AUG-2007

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Epstein Barr Virus

Summary: (provided by applicant): Systemic lupus erythematosus is a complex, autoimmune disease with a suspected multifactorial etiology. Work during the previous funding cycle has defined several genomic areas that are important and has identified a candidate molecular mechanism for the development and pathogenesis of SLE through the anti-Sm and anti-nRNP autoimmune responses. At least 12 different regions with LOD>3.3 have been identified, several of which are supported by separate pedigree collections and by scientifically independent investigators. Now the time has come to build on this early success. We hope to apply strategies to identify the genes underlying one of these areas of interest. In particular, we have used an immunochemical approach to implicate Epstein-Barr virus in the pathogenesis of lupus, most obviously through the autoantibody response against the nRNP and Sm autoantigens. Now, we wish to extend our interest in the host response against Sm and nRNP to understand its genetics in the hope that we will be working toward a more comprehensive explanation of anti-Sm and anti-nRNP autoimmunity in SLE. Due to the extremely varied presentation of SLE and the likelihood that many different genes contribute to this disease process, we have stratified pedigrees and selected a lupus sub-phenotype for further evaluation. Our laboratory has a long-standing interest in patients with anti-Sm and anti-nRNP (or antispliceosomal) autoantibodies (1 -20). These patients are of special interest because of their association with a more severe disease course (21, 22), of the higher prevalence of these specificities in patients of African-American descent (23), clinical homogeneity of the affected patients (22, 24, 25), and the development of these autoantibodies in close proximity to disease onset (26). Indeed, patients with anti-Sm now have perhaps the most sophisticated conceptual construct to explain the development and pathogenesis of any group with SLE. In Project #3 of the Program project, we will focus upon enlarging a case-control cohort (enriched for anti-spliceosomal autoantibody positive SLE patients) that can be used for Project #3, as well as making a contribution to the infrastructure of the Program and toward the genetic solution of SLE. We will utilize this resource, as well as others in the program, to confirm linkage in the 20q 12 region that is of sufficient magnitude to be considered established (lodmax=4.3). We will then narrow the area of interest, assess association with this interval and identify the gene(s) responsible for this effect in African-American pedigrees with anti-spliceosomal autoantibodies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERACTNS

GENETIC

MODIFIERS

OF

EPSTEIN-BARR

VIRUS/HOST

Principal Investigator & Institution: Adamson, Amy L.; Biology; University of North Carolina Greensboro 103 Foust Building Greensboro, Nc 274026170 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Viruses often manipulate their host cellular environment in order to create favorable conditions for viral replication and survival. Virally-induced changes include alteration of the host cell cycle progression, signal transduction cascades, and transcriptional functions, among others. Epstein-Barr virus (EBV) is a human herpesvirus that infects approximately 90 percent of the world's population. EBV is the causative agent of infectious mononucleosis, and is associated with several forms of cancer, including Burkitt's lymphoma and nasopharyngeal carcinoma. EBV also produces oral hairy leukoplakia in AIDS patients. Interestingly, while infection with EBV is widespread, only certain populations of people seem to be susceptible to EBV-related cancers. To understand how EBV proteins interact with host cellular proteins, and how such interactions may promote disease, we have introduced the EBV immediate-early BZLF1 protein into the model organism Drosophila, and will

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perform genetic screens to identify cellular proteins that modulate Z activity. We will carry out an Fl screen of 20,000 flies, map the resulting modifiers, and determine if these modifying genes have human homologs. This work will produce a plethora of putative EBV enhancers or suppressors, which will be the basis for much future work. The results from this genetic screen will shed light onto the mechanisms by which EBV alters normal cellular functions, as well as how genetic predisposition may play a role in EBVrelated diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIV REPLICATION AND THYMOPOIESIS IN ADOLESCENTS Principal Investigator & Institution: Krogstad, Paul A.; Associate Professor; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): A large number of children with perinatallyacquired HIV infection are now surviving into adolescence and adulthood. For many of these, HIV infection was not diagnosed and treated until significant immunological abnormalities were already present. In addition, nearly all had poor suppression of HIV replication with the less potent treatment regimens available during their pre-adolescent years. We hypothesize that prolonged and poorly controlled HIV infection throughout childhood in these individuals will lead to premature immunological senescence in early to mid-adulthood, perhaps by accelerating the physiological thymic involution that occurs in childhood and adolescence. The general goal of the studies proposed is to better understand the immunological status and prognosis of long-term survivors of perinatal HIV infection, and to identify possible therapeutic strategies to promote a normal, healthy lifespan for this growing population of infected youths. Taking scientific advantage of the availability of a large local cohort of perinatally infected adolescents, we are proposing studies to examine the balance between the pathogenic properties of HIV, the suppressive and selective power of antiretroviral therapy, and the regenerative capacity of the immune system that exists in these individuals. The specific aims are: 1) To use in vivo labeling methods and other approaches to compare quantitative parameters of thymopoiesis from adolescents/young adults with perinatal HIV infection with those from two age-matched control groups: seronegative subjects, and youths with HIV infection acquired via recent adult behaviors; 2) To evaluate the relationship between these parameters of thymopoiesis, and the pol and nef genotypes and the replication properties of patient HIV isolates, and 3) To examine the magnitude and breadth of cellular immune responses of perinatally infected adolescents to HIV and common infectious agents (including cytomegalovirus, influenza, and Epstein-Barr Virus) compared to the age matched controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIV/HCV CO-INFECTION: HAART AND CVD PATHOPHYSIOLOGY Principal Investigator & Institution: Hurwitz, Barry E.; Professor; Psychology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): HAART medication has been implicated as a potential etiopathological source of the increased prevalence of cardiovascular disease (CVD) risk in HIV infected persons. Although recent reports indicate an increasing rate of Hepatitis C virus (HCV) coinfection in the HIV-infected, and HCV infection

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Epstein Barr Virus

independently communicates increased cardiovascular risk, the literature has not adequately assessed the possible role of HCV coinfection in cardiovascular pathogenesis in HIV spectrum disease. Comorbid conditions known as dysmetabolic syndrome X are independently associated with both HIV and HCV infection; the syndrome includes alterations in fat deposition, cardiac structure and function, and vascular endothelial function, as well as dyslipidemia and insulin resistance. Two pathophysiological sources in HIV and HCV infected persons is increased pathogen burden and diminished infection surveillance, which result in an elevation of proinflammatory processes. These processes have been shown to induce greater reactive oxygen species formation, which has been linked to atherogenesis and alterations in cardiac and vascular structure and function. Oxidative stress has also been associated with insulin resistance. Because of the possible role of HCV infection and HAART medication in cardiovascular disease risk and because proinflammatory and oxidative factors are likely mediators of this risk, the primary objective of the proposed study is to systematically examine these factors in 420 (of 465 screened) men and women, as a function of HIV and HCV infection, and coinfection. The influence of HAART treatment regimen (anti-retrovirals plus protease inhibitors [PI+] vs. anti-retrovirals without protease inhibitors [PI-]) on these outcomes will be assessed by nesting HAART regimen within the HIV+ groups, thereby yielding a six group comparison (HIV+PI+/HCV+ vs. HIV+PI-/HCV+ vs. HIV+PI+/HCV- vs. HIV+PI-/HCV- vs. HIV-/HCV+ vs. HIV-/HCV-). The secondary objective is to determine whether the data collected is described by the proposed pathophysiological model, which postulates that the burden of exposure to multiple infectious sources is associated with greater levels of proinflammatory factors and oxidative stress, and consequently greater CVD risk and diminished cardiovascular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HSV GENE VECTORS FOR TREATMENT OF ARTHRITIS Principal Investigator & Institution: Glorioso, Joseph C.; Professor and Chairman; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 20-APR-1997; Project End 31-MAR-2002 Summary: (Adapted from the applicant's abstract) - Rheumatoid arthritis is a chronic inflammatory disease affecting an estimated 10 million individuals in the United States alone. Currently, no effective long-term treatment other than joint replacement surgery is available. The overall aim of this proposal is to develop an in vivo gene therapy protocol for the treatment of arthritis. The first-generation gene therapy protocol using retroviral-mediated gene transduction demonstrated that antagonists of two cytokines, interleukin-l (IL-l) and tumor necrosis factor alpha (TNFa), can provide a significant therapeutic outcome in animal models of arthritis. These results are encouraging and provide the foundation of these proposed studies; however, it will never be practical to treat the millions of Americans who suffer from arthritis using an ex vivo strategy. Ex vivo treatments require sophisticated laboratories and protocols for transduction and selection of explanted cells. The goal of these studies is to develop an in vivo protocol in which gene transduction requires nothing more than an injection into the afflicted joint and thus, could become widely available in settings as simple as a physician's office. In vivo gene delivery will be accomplished with the injection of engineered Herpes simplex virus 1 (HSV1) vectors. HSV-l vectors have the advantages of high infectivity and the potential to express multiple transgenes. The major disadvantage of HSV vectors, their cytotoxicity, has largely been overcome by the deletion of the cytotoxic genes, ICP4, ICP22, ICP27, and UL41. These multiple deletion mutants are capable of

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replication only in complementing cell lines. They show greatly reduced cytotoxicity both in cell culture and in rabbit synovium with the acquired capacity for durable transgene expression in vivo. By using these replication-defective vectors, the principal investigator will be able to transduce synoviocytes in vivo to express antagonists of IL-l and TNFa, setting the stage for a simple and effective gene therapy treatment for arthritis. Four specific aims are proposed: 1) To construct HSV-l gene therapy vectors with further reduced cytotoxicity by deletion of the ICP0 gene; 2) to engineer HSV-1 vectors for coordinated expression of therapeutic genes; 3) to assess the effect of prior immunization with HSV on vector persistence and expression and to determine the effect of "antigenic stealthing" genes; 4) to assess the efficacy of HSV-l vectors for the direct in vivo gene therapy of the antigen-induced rabbit model of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN B CELL DIFFERENTIATION IN A MODEL SYSTEM Principal Investigator & Institution: Covey, Lori R.; Associate Professor; Cell Biology & Neuroscience; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2001; Project Start 05-AUG-2001; Project End 31-JUL-2002 Summary: (provided by applicant): We have identified a B-cell immunodeficiency that is distinguished by defective responses to CD4O and IL-4 signaling. B-cells from a young female patient (pt#l) have normal expression of CD4O but are clearly deficient in a subset of CD4O-mediated functions including early signals required for switch recombination. However, under specific in vitro conditions pt#1 B-cells can regain functional responsiveness and undergo switching to express downstream antibody classes or isotypes. Our preliminary data support a model whereby a signaling molecule or transcription factor in the CD4O signal transduction pathway leading to NF-kB activation is affected. This hypothesis is supported by our finding that pt#1 B-cells that are transformed by Epstein-Barr virus (EBV) do not express CD23 a cell surface molecule that is critically dependent on the viral latent infection membrane protein LMP)1 and the subsequent activation of NF-kB by this protein. Furthermore, LMP1 usurps the CD4O signaling pathway in order to maintain cell transformation. Surprisingly, the pt#1 EBV-transformed B-cells loose their transforming potential when grown in dilute culture conditions which also suggests that LMP1 activity is compromised. Thus, three related lines of data strongly suggest that the pt#1 defect is located in the CD4O signaling pathway that leads to NF-kB activation and the transcription of specific cellular genes involved in B-cell activation. We propose to use primary and transformed B-cells from pt#1 to characterize the underlying defect Leading to B-cell dysfunction. Efforts will be initially focused on the characterization of TRAF and NF-kB expression and function which are the most proximal and distal signaling events in the CD4O signaling cascade, respectively. The EBV-transformed pt#l B-cells will be used to analyze signaling of LMP1 via the CD4O pathway. Also, these cells will be used in transfection studies that are aimed at complimenting the pt#l defect and in the analysis of of NF-kappaB responsive promoters. Characterization of signaling pathways under the different growth conditions will provide information into the relationship between these signaling pathways and cell transformation. Finally, pt#l Tcells have subtle defects in helper function provided to control B-cells that manifest in inappropriate transcription of the heavy chain locus in response to CD4O signaling alone. Experiments are proposed to understand the basis of this functional defect. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HUMAN B CELL TRANSFORMATION BY EPSTEIN BARR VIRUS Principal Investigator & Institution: Martin, Jennifer M.; Molecular, Cellular & Dev Biol; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: In this project, the investigator proposes to analyze the contribution of latent membrane protein 1 (LMP-1) of EBV to immortalization of cells. She will use molecular genetic and biochemical analyses to determine the transmembrane topology of LMP-1, to study the quaternary structure of LMP-1 and its relevance to function, and determine the relationship between the function of the amino -terminus of LMP-1 and its structure, cytoskeletal association, turnover, and membrane patching. The specific aims of the research are (1) to determine the transmembrane topology of the LMP-1 protein in the immortalized cell, (2) to determine if homo- oligomerization is required for function of the LMP-1 in immortalization, and (3) to determine how the structure of the cytoplasmic N-terminus of LMP-1 relates to function and the biochemical properties of cytoskeletal association, membrane patching, and rapid turnover, all of which suggest receptorligand function. The investigator points out that while it is clear that the N-terminal of LMP-1 is responsible for transformation by EBV, there is controversy as to whether this is due simply to the structure of the molecule in the membrane, or due to proteinprotein interactions. Eventually, the investigator hopes to determine how LMP-1 functions in signal transduction leading to immortalization of B cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOTHERAPY FOR EBV POSITIVE HODGKIN'S DISEASE Principal Investigator & Institution: Lucas, Kenneth G.; Assistant Professor; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: (Provided by applicant): Patients with chemotherapy-refractory Hodgkin's disease (HD) have few treatment options. Approximately 40 percent of all cases of HD have been shown to be associated with Epstein Barr virus (EBV), characterized by a type II Latency pattern of infection and expression of fewer EBV antigens than in Latency III tumors. Previous studies have established that adoptive immunotherapy for EBV-induced lymphoproliferations in stem cell transplant and organ transplant patients (Latency III infections) with EBV-specific cytotoxic T lymphocytes (CTL) can lead to remission of disease. It is possible that similar strategies would be successful for Latency type II disorders. The objective of this study is to examine the clinical and immunologic effects of infusing donor-derived, EBVspecific CTL from HLA identical or haploidentical donors for patients with relapsed/refractory, EBV-positive HD. The spectrum of the EBV antigens recognized by the CTL preparation and from patient T cells postinfusion will be determined, as well as levels of EBV specific CTL precursors (CTLp) by limiting dilution analysis (LDA). The therapeutic outcome will be assessed with clinical and radiographic endpoints and will be correlated with the level of donor/host HLA disparity, CTL reactivity against Latency II antigens, and levels of EBV CTLp postinfusion. We will track the infused CTL using PCR assays for short tandem repeats (STR). While the initial group of patients will receive EBV CTL without prior immunosuppression, subsequent cohorts of patients will receive a single CTL infusion following fludarabine, which will be used as an immunosuppressive agent to facilitate lymphoid engraftment. Since immunosuppression may increase the risk of graft vs. host disease, the CTL infusates and patient blood specimens will be examined for the presence of donor-derived, recipient specific T cells by LDA. To assess risk for CTL

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rejection, LDA will also be performed on post-infusion blood specimens to detect hostderived CD4 and CD8 cells with reactivity against donor antigens. This study will provide information on 1) whether therapy with allogeneic EBV specific CTL has clinical efficacy against EBV-positive HD; 2) if effective, whether this is correlated with effector cells specific to EBV latency type II antigens, and 3) if not effective, whether the failure is associated with a short half-life of the infused CTL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOTHERAPY FOR EPSTEIN-BARR VIRUS-ASSOCIATED MALIGNAN Principal Investigator & Institution: Yang, Yiping; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Dr. Yang?s long-term career goal is to pursue translational research in the development of novel therapies for the malignancies. His immediate term career objective is to explore antigendefined immunotherapeutic approaches for Epstein Barr virus (EBV)-associated malignancies. EBV(+) tumors offer a unique opportunity to develop antigendefined immunotherapeutic strategies because specific EBV antigens expressed in tumor cells can serve as validated targets for T cell mediated specific tumor killing. The overall objective of this proposal is to study methods of immune manipulation targeting EBV-associated tumors, specifically nasopharyngeal carcinoma (NPC) and Hodgkin?s disease (HD). Strategies to be pursued include: 1) an antigen-specific cell vaccine to induce or enhance specific T cell responses in patients with NPC; 2) ex vivo expansion of antigen-specific T cells from patients with HD or NPC using dendritic cells transduced with self-inactivating recombinant lentiviral vectors of interest; and 3) combination of in vivo vaccination and ex vivo expansion strategies in NPC patients. Success in ex vivo expansion will lead to an adoptive immunotherapeutic trial. These EBV-associated tumors are seen as models for other tumors in which tumor specific antigens have been identified and the development of novel therapeutic approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOTHERAPY WITH PEPTIDE MHC TETRAMER ISOLATED T CELLS Principal Investigator & Institution: Lyerly, Herbert K.; Director; Surgery; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 16-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Recent advances in T cell phenotyping and high speed sorting have coalesced to allow the direct testing of an important basic tenet in immunotherapy-specifically that adoptive immunotherapy with antigen specific T cells will eradicate antigen expressing cells in vivo. Although immunotherapy with T cells activated and expanded in vitro have shown promise, an alternative broadly applicable strategy may allow therapy with antigen specific T cells prior to significant activation. Specifically, peptide major histocompatibility complex (MHC)-tetramers allow the identification of T cells that specifically bind to unique nanopeptides in the context of a specific human leukocyte antigen (HLA) allele. This technology allows for the sorting and isolation of highly purified populations of antigens specific T cells from peripheral blood mononuclear cells (PBMC). We have hypothesized that the adoptive immunotherapy with purified populations of antigen specific T cells will have clinical

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benefits in patients immunosuppressed following bone marrow/peripheral blood stem cell transplant. A relevant model system to test this hypothesis exists in immunocompromised patients with cytomegalovirus (CMV) infection or Epstein Barr virus (EBV) associated LPD (LPD). Clinical benefit has been achieved with administration CMV specific clones expanded in vitro and as few as 10(7) cells/M2PBMC activated in vitro with autologous EBV transformed B cells. While these strategies are clinically effective, they cannot be widely applied because they are complex and time-consuming, taking as long as to 3 to 4 months to generate the appropriate cells for administration. An exciting alternative to this laborious process would be to directly isolate CMV or EBV specific T cells from peripheral blood samples by high speed sorting with CMV or EBV peptide MHC tetramers. This strategy would allow for the rapid isolation of up to 10-40 x 10(6) antigen specific T cells. These cells could then be directly administered, or administered after a brief period of ex vivo activation and expansion. This application proposes pre-clinical studies and pilot clinical trials of adoptive immunotherapy with peptide MHC tetramer sorted T cells. It is anticipated that these studies would provide an important proof of principle for this general concept which would have wide application for antigen specific adoptive immunotherapy of vial disorders and cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INITIATION OF CELL INFECTION BY EPSTEIN-BARR VIRUS Principal Investigator & Institution: Hutt-Fletcher, Lindsey M.; Professor; Molecular Biology and Biochem; University of Missouri Kansas City Kansas City, Mo 64110 Timing: Fiscal Year 2001; Project Start 01-JAN-1984; Project End 31-DEC-2004 Summary: Epstein-Barr virus (EBV) is best known for its ability to infect and cause disease by immortalizing B lymphocytes. However, the virus also accesses epithelial cells with devastating consequences. It is strongly implicated in the development of nasopharyngeal carcinoma and may play a role in the emergence of certain gastric cancers. The long term goal of this research is to understand the molecular basis for the tissue tropism of EBV. Most is known about how EBV enters B cells. A current model proposes that virus uses minimally an attachment protein gp350/220 which binds to the complement receptor type 2 (CR2) and a complex of three glycoproteins gH-gL-gp42 which is involved in penetration. Successful penetration requires that gp42 bind to HLA class II which functions as a coreceptor on the B cell surface. Entry into epithelial cells is very different. A current model for epithelial cells proposes that entry requires neither use of CR2 nor an interaction between gp42 and HLA class II. Instead, new findings suggest the existence of both a novel receptor and a novel coreceptor on epithelial cells. The immediate goal of this application is to test these models with four specific aims. The first aim is to identify the coreceptor that enables a virus that lacks gp42 to infect epithelial cells. The second aim is to explore and compare the interactions of the gH complex with B cells and epithelial cells. The third aim is to identify the viral glycoprotein used by EBV to attach to CR2- negative epithelial cells. The final aim is to identify the receptor used by EBV to infect CR2-negative epithelial cells. Identification of receptor and coreceptor will be addressed by transfecting appropriate cells with epithelial cell cDNA expression libraries. Transfected cells will be probed with recombinant viruses lacking gp42, or expressing green fluoroscent protein. Interactions of cells with the gH complex will be explored by mutational analysis and complementation of virus lacking gH. Recombinant proteins, antibodies and viruses lacking a variety of glycoproteins will be used to identify the epithelial cell attachment protein. Dissection of the molecular events that enable EBV to access the cells it infects is critical to understanding the biology of this important human pathogen.

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

Project Title: INTERLEUKIN 10 RECEPTOR COMPLEX Principal Investigator & Institution: Pestka, Sidney; Adjunct Professor; Molecular Genetics & Microbiol; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 08854 Timing: Fiscal Year 2001; Project Start 15-FEB-1999; Project End 31-JAN-2004 Summary: (Adapted from Investigator's Abstract): The cytokine interleukin-10 (IL-10) exhibits a wide spectrum of effects on the immune system from inhibition to stimulation of various functions and cells. One receptor chain that binds IL-10 was identified and cloned (IL-10R1), however, the existence of this single receptor chain could not explain all the effects of IL-10. Accordingly, we set out to identify the second chain of the IL-10 receptor complex and were able to define and initially characterize the second chain, designated IL-10R2. Whereas each chain alone cannot impart full responsiveness of cells to IL-10, the combination of both chains can. With the identification of the second chain, IL-10R2, a number of questions regarding the functional IL-10 receptor complex can now be approached. This proposal is designed to answer questions about the role of the IL-10R2 chain in mediating IL-10 effects in the immune system and in some cancers. The overall hypothesis underlying this proposal is that both receptor chains are required for function of IL-10. The results will enable us to understand how IL-10 functions in the immune system. In addition, since Epstein- Barr virus (EBV) produces a viral homolog of IL-10 designated vIL-10, we will examine the differences in activity between IL-10 and vIL-10 that should provide insight into the role of vIL-10 in EBV-related malignancies. Specific aims of this study are: 1) the role of the Hu- IL-10R2 chain in IL-10 function; 2) determine how IL-10 inhibits functions of other cytokines; 3) regulation of the IL-10R2 gene; 4) determine regulation of the mRNAs of IL-10 and the IL-10 receptor chains (IL-10R1 and IL-10R2); 5) define the differences in function of cellular and viral IL-10. Our results should establish the role of the second chain in IL-10 receptor function, enhance our understanding of how IL-10 functions, and provide insight into the role of the EBV protein vIL-10 in EBV-induced cancers. Furthermore, because IL-10 is an important immunosuppressive cytokine in immune function such as in development of T-cell subsets, the knowledge gained should help us understand the mechanisms by which IL-10 mediates immunosuppression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LMP2A MODULATION OF B CELL SURVIVAL AND ACTIVATION Principal Investigator & Institution: Swanson-Mungerson, Michelle A.; Microbiology and Immunology; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: provided by applicant): The long-term goal of is to understand the role of Epstein-Barr Virus (EBV) latent membrane protein 2A (LMP2A) in maintaining EBV latency in B cells. The goal of this study is to determine if LMP2A alters B cell survival and function in vivo. Based on previous data, the hypothesis for this study is that LMP2A signals in Ig-bearing B cells to inhibit B cell activation, while promoting B cell survival in vivo. To test this hypothesis, the following aims will be performed: (1) Determine if LMP2A extends the survival of Ig-beadng B cells in vivo in the absence or presence of antigen. (2) Determine if LMP2A inhibits BCR signaling in Ig-bearing B cells induced by autoantigen. (3) Determine if LMP2A inhibits the function of B cells in

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response to antigen in vivo and in vitro. By crossing transgenic mice that express LMP2A in B cells to mice that produce B cells with BCR specific for hen-egg lysozyme (HEL), we have generated a novel system to test if LMP2A alters B cell survival and activation in vivo. BrdU-labeling, FACS analysis, antibody responses and Western Blot analysis will be utilized to determine if LMP2A alters the half life and activation of Igbearing B cells. These studies may provide rationales for therapeutics to eradicate EBV latent infection in B cells that precedes malignant tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MAINTENANCE OF EPSTEIN-BARR VIRUS GENOMES IN TUMOR CELLS Principal Investigator & Institution: Hearing, Janet C.; Molecular Genetics & Microbiol; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 15-DEC-1997; Project End 31-MAR-2003 Summary: The EBV genome is present in EBV-positive tumor cells and latently infected B cells as a plasmid that replicates once per cell cycle during S phase in parallel with the cellular chromosomes. Replication and maintenance of EBV plasmids in these cells requires only one viral protein, the EBV nuclear antigen-1 (EBNA-1). A complete description of the mechanism by which EBNA-1 supports the replication and maintenance of EBV genomes in dividing cells is central to understanding how this virus causes latent infections and the relationship of EBV with tumor cells. Three of the long-term goals of this laboratory are to determine how the binding of EBNA-1 to its recognition elements in the latent cycle origin of DNA replication (oriP) leads to the initiation of DNA replication, to understand how this event is regulated in a cell-cycle dependent manner, and to determine how EBV plasmids are stably maintained in dividing cells. In addition to its role in latent cycle DNA replication and plasmid maintenance, EBNA-1 negatively regulates its own promoter during latency and this activity is of considerable interest with respect to the ability of EBV to cause latent infections in vivo. The specific aims of this proposal are: 1) to identify the minimal DNA fragment that contains oriP replicator activity and determine which nucleotides within the fragment are required for replicator function; 2) to determine if EBV DNA latent cycle DNA replication is subject to the same controls that regulate cellular DNA replication and if oriP region I is required for the regulated replication of oriP plasmids; 3) to characterize the physical interaction of EBNA-1 with cellular proteins importinalpha and p32, and determine if these interactions are required for EBNA-1 autoregulation; 4) to determine if an evolutionarily-conserved eukaryotic cell protein interacts with EBNA-1 in EBV-infected B cells and is involved in the replication or maintenance of EBV genomes in latently-infected B cells and tumor cells, or viral gene regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF THE HSV-1 UL42 PROTEIN Principal Investigator & Institution: Parris, Deborah S.; Professor; Medical Microbiol & Immunology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 01-JUL-1986; Project End 31-MAR-2003 Summary: There is amazing conservation in the requirements for and mechanism of DNA replication among highly diverse organisms. Herpes simplex virus type 1 (HSV-1) is an excellent model system for eukaryotic DNA replication since the virus encodes most of the proteins required for this essential process and can be manipulated

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genetically with greater ease than higher eukaryotes. DNA polymerases are central to the process of DNA replication. A general requirement of replicative DNA polymerases is that they copy the template genome with rapidity and reasonable fidelity. A major means by which they achieve the necessary rate required for genome duplication is the use of accessory proteins to increase their processivity. The HSV-1 DNA polymerase (pol) forms a stable and specific complex with an accessory factor, UL42. Like other pol accessory proteins, UL42 increases the processivity of its cognate pol, but differs in several important ways. Its lack of requirement for clamp loading proteins distinguishes it from the toroid sliding clamps, such as PCNA and E. coli pol III beta. Furthermore its intrinsic ability to bind to DNA is unique among all other known processivity factors, including those which don't require clamp loaders, such as thioredoxin, the processivity factor for T7 bacteriophage pol. The latter ability also presents an apparent paradox for known mechanisms of processivity, in that UL42 could also serve as a brake to elongation. The major long-term goal of the proposed studies is to elucidate the mechanism by which UL42 increases pol processivity, and the resulting impact this mechanism has on other properties of the pol, including parameters required for fidelity of DNA replication. A combination of biochemical, biophysical, and genetic approaches will be used to address four specific aims: 1) To determine the effect of reduced DNA binding by mutant UL42 proteins on rates of elongation and pol processivity using transient kinetic analysis and direct binding studies; 2) To determine the effect of processivity and proof-reading capability on the individual parameters which affect fidelity in vitro, including nucleotide selection, failure to extend mismatched termini, and excision of mismatched primer termini, using kinetic analysis to dissect these processes; 3) To determine the biological impact of changes in fidelity parameters (caused by changes in processivity) on the frequency and types of mutations which occur during origin (ori)- dependent DNA replication in vivo; 4) To determine the ability of the ori-binding protein, UL9, which interacts with UL42, to facilitate the assembly and/or processivity of pol/UL42 complexes on blocked synthetic primer/templates. Functional analogs of HSV-1 pol and UL42 are encoded by all human herpesviruses, including Kaposi sarcoma-associated virus (HHV-8), Epstein Barr virus, and human cytomegalovirus, all of which are significant human pathogens, particularly for cancer and immunosuppressed patients. It is important to understand an the mechanism of UL42 action since disruption of the pol/UL42 complex has been proposed for development of antivirals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLATION IN ESTABLISHMENT OF LATENCY IN GHV68 Principal Investigator & Institution: Moser, Janice Marie.; Microbiology and Immunology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Methylation of CpG motifs has been identified as a global mechanism in the silencing of genes and it has been hypothesized that methylation is a critical component in the silencing of lytic viral genes during the establishment of latency of gammaherpesviruses. Human gammaherpesviruses such as Epstein Barr virus and Campos's Sarcoma Herpes virus are associated with several lymphoproliferative disorders. In vitro research has shown that during latency the promoter regions of genes necessary for lytic viral replication are hypermethylated while the promoters of latency-associated genes are hypomethylated. Since in vivo studies of these viruses are difficult due to their limited host range, gammaherpesvirus 68 (gHV68) is used as a model to study the effects of gammaherpesviruses in vivo. To

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address the role of cellular methyltransferases and methylation in the establishment and maintenance of latency of the virus, we propose to investigate the amount of methylation of both lytic and latent promoters during different time points of infection in the mouse. The level of methylation will be compared to the amount of lytic- and latency-specific viral transcripts present at the different days postinfection. Finally, the effect of the deletion of the cellular methyltransferase, Dnmt1, in gHV68-infected cells on the establishment of latency will be analyzed using the cre-lox gene-targeting system. These studies will advance our understanding of the mechanisms that govern the establishment and maintenance of latency in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODEL AGAMMAGLOBULINEMIA

FOR

GENE

THERAPY

IN

X

LINKED

Principal Investigator & Institution: Rawlings, David J.; Associate Professor; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-JUL-2001 Summary: (Adapted from applicant's abstract). Human X-linked agammaglobulinemia (XLA) results from deficient function of Bruton's tyrosine kinase (Btk). In affected males, the production of B lineage cells is profoundly reduced resulting in life threatening humoral immunodeficiency. Definitive genetic therapy utilizing expression of wild type Btk in stem cells or B lineage progenitors would represent a significant advantage over the current supportive management of XLA. The Investigator proposes to establish preclinical cellular models for the genetic treatment of XLA through three aims. Aim 1. Development of a multistage human B cell culture system that can be used to evaluate reconstitution of B cell function in vitro. The Investigator will improve the derivation of B cells representing multiple stages of the B lineage from long-term human B progenitor cell cultures. This will be done by exploiting a range of culture modifications and signals that lead to activation, maturation, and production of secreted immunoglobulin by immature B cells. Soluble factors and cell surface ligands on stromal cells will be evaluated. The Investigator will also utilize in vivo transfer studies in SCID/NOD mice. Aim 2: Development and testing of the capacity of retroviral vectors capable of high level, sustained expression in hematopoietic stem cells, and of novel hybrid adenoviral/EBV episome vectors for Btk gene transfer and rescue of Btk signaling in vitro. Alternative gene transfer systems will be evaluated using a new signaling competent human B cell model developed by the Investigator's laboratory. This will allow the Investigator to rapidly test the transduction efficiency, and the levels and duration of protein expression of alternative vectors. In addition, the Investigator will directly evaluate the capacity of these vectors to rescue Btk dependent signaling events and determine the dosage of Btk required for functional reconstitution in human B cells. Aim 3. Evaluation of the capacity of those gene transfer vectors that successfully restore Btk signaling in vitro to reconstitute Btk dependent immune function in vivo in Btk-/mice, and ultimately, in vitro in long term cultured XLA B cells. The Investigator will evaluate gene transfer using hematopoietic stem cells and growth factor expanded B progenitors from Btk-/-mice as target cell populations. Reconstitution of B lineage development and function will be evaluated using multiple measures of Btk dependent immune function. Those vectors demonstrating optimal restoration of Btk function in vivo will be utilized for gene transfer into stem cells or B progenitors in pre-clinical studies of patients with XLA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR CHARACTERIZATION OF ABF-1 IN B CELLS Principal Investigator & Institution: Vierra, Craig A.; Biological Sciences; University of the Pacific-Stockton 3601 Pacific Ave Stockton, Ca 95211 Timing: Fiscal Year 2003; Project Start 01-JUL-2000; Project End 30-JUN-2006 Summary: (provided by applicant): The basic helix-loop-helix (HLH) transcription factor called activated B cell factor 1 (ABF-1) is expressed in a subset of lymphoid tissues, including lymph nodes, activated B cells and Epstein-Barr virus-transformed B cell lines designated as lymphoblastoid cell lines (LCLs). The viral protein Epstein-Barr virus 2 (EBNA-2) has been identified as a potential regulator of the ABF-1 gene. The proposed studies are aimed at investigating the role of EBNA-2 and its influence on ABF-1 gene activity, and the identification of ABF-l-regulated target genes in B cells. A broad spectrum of genetic and biochemical techniques will be used, including gene cloning and sequencing, DNA microarray analysis, DNA transfections, electrophoretic-mobility shift assays, Western- and Northern blotting and quantitative real-time polymerase chain reaction (PCR). The results of these studies will enhance our understanding of the mechanisms by which EBNA-2 controls cellular gene expression and B-cell immortilization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NATURAL IGM ANTILYMPHOCYTE AUTOANTIBODIES INHIBIT HIV-1 Principal Investigator & Institution: Lobo, Peter I.; Director of Renal Transplant Med. and Hi; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): There is a marked variability in the period of latency between infection by HIV- l and the onset of AIDS. The latency period is determined by host factors that control viral infectivity. Chemokine receptors (CCR5 and CXCR4) serve as co-receptors for HIV-1 entry into cells. The pivotal role of the interactions between HIV-1 and chemokine receptor was realized with epidemiological data clearly demonstrating that individuals expressing mutant CCR5 receptors had a slower progression of their HIV-1 infection. We provide preliminary data indicating that IgM autoantibodies that bind to CCR5 and CXCR4 on lymphocytes are present in normal human serum. Futhermore, our preliminary studies show that IgM anti-lymphocyte antibodies obtained from normal individuals or asymptomatic HIV-1 infected individuals significantly inhibits HIV-1 from infecting cells. We have shown that this subset of IgM antilymphocyte autoantibodies with HIV-1 inhibitory activity is depleted in patients with AIDS. At this stage, it is unclear whether the subset of IgM antilymphocyte antibody with HIV-1 inhibitory activity is predominantly the antibody that binds to chemokine receptors on the lymphocyte or whether this HIV-1 inhibitory subset in addition consists of other antibodies binding to non-chemokine receptors, e.g. to CD4. These IgM anti-CCR5 and CXCR4 autoantibodies do not significantly inhibit chemotaxis even though they partially inhibit chemokines from binding to the receptors. In the proposed in-vitro studies, we plan to focus on human IgM anti-lymphocyte autoantibodies to better characterize the subset of anti-lymphocyte antibodies that prevent HIV-1 from infecting susceptible cells. (i) Human B lymphocytes will be transformed with EBV virus in an effort to find B cell clones secreting IgM that bind to lymphocytes and inhibit HIV-1 infectivity. Each clone will be evaluated for their range of inhibitory activity towards a defined panel of different HIV-1 strains. Several of the

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monoclonal IgM clones with HIV-1 inhibitory activity will be further evaluated for their binding specificity and affinity to chemokine receptors and CD4 receptors and their effect on chemotaxis. (ii) We will also determine if there are HIV-1 inhibitory clones secreting IgM that has no binding activity to chemokine receptors. A successful outcome with the proposed studies could better our understanding on pathogenesis of H1V-1 infection and may provide strategies to prolong the asymptomatic state after HIV-1 infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROIMMUNE MODULATION OF VIRUS IMMUNITY IN AGING Principal Investigator & Institution: Stowe, Raymond P.; Pathology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: This proposal is responsive to topic #I 1, Psychoneuroimmunology. Herpesviruses commonly establish infections in humans. These infections are usually characterized by an acute phase associated with minor morbidity and mortality followed by a chronic latent phase reflecting a balance between viral replication and the host immune response. Control over herpesvirus reactivation is primarily mediated by cellular immunity which declines with advancing age. As a result, herpesvirus infections are important pathogens in the elderly and result in considerable cost to the health care system. Another factor associated with herpesvirus reactivation is stress, and there has been considerable speculation linking stress and the appearance, duration, and intensity of herpesvirus infections. The immunological decrements associated with stress are of particular concern in the elderly because they already have age-related reductions in cellular immunity. Preliminary analysis of three elderly subjects has demonstrated lytic replication of Epstein-Barr virus (EBV), a member of the herpesvirus family. Therefore, the applicant will test the hypothesis that aging will decrease EBVspecific cellular immunity and increase reactivation of latent EBV. Furthermore, stress will result in higher viral load. Importantly, little is known about the immunobiology of EBV in aging. Studies outlined in this proposal will provide preliminary data regarding age-related declines in herpesvirus-specific T-cell immunity and subsequent latent virus reactivation. These data will subsequently be used to support an R01 application to develop a mechanistic investigation on how neuroendocrine hormones modulate herpesvirus-specific immunity in the elderly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NON-VIRAL CUTANEOUS GENE DELIVERY Principal Investigator & Institution: Kashani-Sabet, Mohammed; Dermatology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Our goal is to develop effective and safe cutaneous gene delivery for the therapy of skin disorders. Ongoing progress in molecular genetics has generated an array of potential molecular targets for the treatment of skin diseases. The inability to efficiently deliver corrective genes to involved tissue and cellular sites in vivo has precluded the development of effective gene therapies for these diseases. This proposal begins to address this need by focusing on increasing both the level and the duration of expression of genes delivered by cutaneous administration of plasmid DNA, using recent advances in gene transfer techniques. The goal of our proposed studies is: a) to develop maximally efficient cutaneous gene transfer; and b) to use this optimal

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gene delivery approach to demonstrate a measurable therapeutic endpoint in an appropriate animal model system. Our specific aims are: Aim 1. To maximize the level and duration of cutaneous gene transfer. We will examine the utility of a novel, longexpressing plasmid vector, a novel cationic polymer, and multiple dosing schedules in producing maximally efficient cutaneous gene transfer. We will examine skin gene transfer using both intradermal and topical routes of administration. We will also examine site-specific gene transfer into the skin by the use of keratinocyte-specific promoter elements. Specifically, we will assess: a) Expression plasmid design. We will examine the efficacy of a novel Epstein-Barr virus (EBV)-based plasmid that has resulted in significantly prolonged gene expression upon systemic gene transfer in mice to deliver the reporter genes luciferase and beta-galactosidase to the skin of mice. b) Cationic polymer formulation. Recent studies have shown that the use of novel PEI:DNA complexes has resulted in substantially increased levels of gene transfer upon systemic administration of reporter genes to mice. We will determine the impact of PEIbased gene transfer on the level of reporter gene expression in the skin of mice. c) Number and frequency of doses. We will determine the effects of dosing schedules of naked DNA or DNA:cationic polymer complexes on the level and duration of skin gene transfer. d) Gene transfer in the skin by the use of skin-specific promoter elements. We will investigate restriction of expression to the keratinocytic system by incorporating the keratin 14 promoter in the EBV-based expression plasmid. Aim 2. To use the optimal cutaneous gene transfer approach developed in Aim 1 to express a biologically relevant gene and examine its therapeutic effects. We will examine the over expression of the xeroderma pigmentosum C (XPC) gene to attempt to demonstrate that re-introduction of the transgene to a knockout mouse can benefit the host. We will determine whether efficient expression of the XPC gene in mice will alter the response to UV-mediated DNA damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OCULAR HERPES SIMPLEX VIRUS Principal Investigator & Institution: Kaufman, Herbert E.; Professor and Head; Ophthalmology; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 01-FEB-1978; Project End 30-NOV-2004 Summary: Recurrent herpes simplex is a leading cause of infectious corneal disease in the United States. Fewer than 10% of episodes of ocular HSV are "primary herpes"; the other 90% are caused by reactivation of the virus from the ganglion. If these reactivations could be prevented, the problem of ocular herpes would be dramatically reduced. Although chronic administration of acyclovir has been shown to reduce ocular recurrent disease by about 40%, shedding occurs in the absence of disease, suggesting that reactivation of the latent virus is not prevented. The general goal of these studies has been and continues to be understanding the factors that trigger recurrent ocular herpes in order to devise new strategies to prevent and treat the disease. During the next project period we will focus on the prevention of herpetic recurrences through three pharmacologic mechanisms - inhibition of signals causing recurrences, inhibition of cellular processes essential for synthesis of nucleotides and other factors required by the virus, and inhibition of viral-encoded enzymes that are not present in the replicationincompetent neuron. Three specific aims are proposed: 1) To evaluate the potential signaling function of prostaglandin agonists in the reactivation of herpes simplex virus and to identify pharmacological agents that can be used to inhibit these signals and thereby prevent virus reactivation and recurrent disease; 2) To evaluate inhibitors of cyclin-dependent kinases (cdks) as a means of preventing virus reactivation and treating

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infection by interfering with cellular synthetic processes necessary for viral multiplication; and 3) To evaluate inhibition of enzymes that are encoded by the virus but are not present in the replication-incompetent neuronal host cells, for example by agents such as HBPG and 6-anilino uracil, as a means of preventing viral reactivation from latency. Identifying a means of preventing recurrences of herpes simplex in the eye may also yield information useful in the management of HSV-2, which infects several million people, as well as varicellazoster virus (VZV), which causes chicken pox and shingles, Epstein Barr virus (EBV), which causes both mononucleosis and cancers, and other viral diseases such as cytomegalovirus (CMV) retinitis and herpes encephalitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL THERAPEUTICS FOR VIRAL MALIGNANCIES Principal Investigator & Institution: Faller, Douglas V.; Professor and Director; Gene Regulation Laboratories 45 Beaver Rd Weston, Ma 02493 Timing: Fiscal Year 2002; Project Start 07-JUN-1999; Project End 31-AUG-2004 Summary: (provided by applicant): Epstein-Barr virus (EBV) is associated with a number of human lymphoid malignancies and carcinomas for which there are presently few effective treatments. Each year in the U.S., there are approximately 27,000 people afflicted with diseases caused by the Epstein-Barr virus, and an additional 107,000 people afflicted with malignancies associated with the Epstein-Barr virus. Worldwide, EBV-associated diseases are even more common, and current treatments are typically unsuccessful. Under FDA IND #47,529, we are currently testing Arginine Butyrate in combination with ganciclovir for treatment of these malignancies. Arginine Butyrate induces the latent EBV-enzyme thymidine kinase (TK), which, in turn, renders the EBVpositive malignant cells susceptible to killing by the anti-viral agent ganciclovir. This therapeutic strategy has been successful in early trials. Arginine butyrate, however, has drawbacks as a therapeutic, requiring constant, IV infusion to achieve detectable plasma levels. The development of new, oral agents will allow this therapy to be extended to a larger population of patients and a wider group of diseases. We already have proof-of principal that such orally-active agents can be developed. Our aims from the Phase I STTR were to identify new, long-lived, orally-bioavailable derivatives of our first, prototype drug, Arginine Butyrate, as therapeutics for the therapy of Epstein Barr virus (EBV)-associated malignancies. In this Phase II application, we propose to conduct formal preclinical development studies of a lead new compound, as required by the FDA, to obtain Investigational New Drug Status to begin Phase I clinical trials in humans. The aims of this proposal are: To prepare a medicinal formulation of the sodium salt of ST101, a synthetic SCFAD which ates EBV TK expression, to refine oral dosing-regimens for ST101, to prepare an Investigational New Drug (IND) Application for sodium ST101, and to evaluate additional SCFADs for activity in induction of EBV TK. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OVERCOMING TUMOR IMMUNE EVASION STRATEGIES IN HODGKIN'S LYMPHOMA Principal Investigator & Institution: Rooney, Cliona M.; Associate Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The malignant B-lineage Reed-Sternberg (H-RS) cells in about half of all cases of Hodgkin lymphoma express Epstein-Barr virus (EBV)

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antigens, rendering this tumor highly attractive for cytotoxic T-lymphocyte (CTL) immunotherapy. However, these tumor-associated viral antigens are either subdominant (LMP1 and LMP2) or not presented to the immune system (EBNAI and BARFO). The H-RS cells also express molecules that are inhibitory to CTL, such as TGFbeta, the chemoattractant TARC and Fas-ligand that can comprise immunotherapy even when immune epitopes are effectively presented to CTLs. The studies proposed here seek to overcome these immune evasion tactics by redirecting immune responses to the LMP2 viral antigen, using LMP2a-transduced dendritic cells, and by genetically modifying CTLs in vitro so that they will resist the inhibitory effects of TGF-beta and Fas ligand. The latter aim will rely on a transgenic dominant-negative TGF-beta type 2 receptor expressed on CTLs and the adenoviral RID protein, which should render CTLs resistant to inhibition by TGF-beta and killing through Fas ligand-receptor interactions. Our preliminary studies suggest that there may be few T helper epitopes in LMP2. Since persistence in vivo is dependent on the availability of help, we will also explore the possibility that EBNA1, expressed as a retrogen in dendritic cells (using technology developed in project 4) will reactivate EBNA1-specific CD4+ T cells that can provide cognate help for LMP2-specific CTL as well as broaden the cytotoxic repertoire of the tumor specific CTL by reactivating CD4+ EBNA1-specific CTL. The hypotheses underlying these aims will be tested both in vitro and in vivo (Phase l/ll trials in patients with post-transplant or relapsed EBV-positive Hodgkin Lymphoma). Upon successful completion of the project, we will have learned whether our experimental modifications are safe in patients and whether they will render CTLs resistant to several of the immune evasion strategies commonly used by tumor cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY PROGRAM Principal Investigator & Institution: Garcea, Robert L.; Professor; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-MAR-1988; Project End 31-JAN-2006 Summary: (Applicant's Description) The Pediatric Oncology Program is comprised of clinical oncologists, surgeons, pathologists, and basic scientists whose interests are related to the diseases of pediatric cancer patients. The overall goal of the Pediatric Oncology Program is to reduce the cancer burden in the pediatric population by its research, education, and clinical programs. To accomplish this goal, the Program has established an integrated group of members, organized in four focus areas: 1) clinical investigations, 2) a clinical and research bone marrow transplant (BMT) program, 3) clinical translational research in leukemias, cytogenetics, and brain tumors, 4) basic science research in DNA tumor viruses, lymphocyte signal transduction, and fusion protein transcription factors created by chromosomal translocations in childhood ALL. The clinical program is an active participant in the Children's Cancer Group (CCG), and utilizes investigator-initiated protocols developed by Cancer Center members and by the cooperative group whenever possible. Each year approximately 150 new oncology patients are evaluated and/or treated by the oncology staff, and an additional 25-35 children are transplanted on various protocols in the pediatric BMT unit. Protocol development over the past year has included 13 investigator-initiated and 49 CCG protocols, with 153 patients enrolled. Program members are highly interactive with respect to clinical protocol development, translational research, and basic research, as evidenced by the fact that 36% of the 132 publications have intra-or inter-program collaborations despite the fact that most members are new. Future plans will build upon this foundation of interaction in specific areas including: 1)continue integration of

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Pediatric and Adult programs in Neuro-oncology and BMT; 2)development of a Cancer Genetics Clinic to serve as a focus for new translational and basic research; 3)establishment of a clinical and basic research interest group for studying EBV-related lymphoproliferative disease; 4)increased research in cancer survivorship; and 5)faculty career development for new translational and basic scientists interested in areas related to Pediatric Oncology. This is one of a few approved Pediatric Oncology programs within NCI designated Comprehensive Cancer Centers whose growth has been supported by the UCCC and whose growth is projected to continue in the next five years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PERSISTENT ADENO-EBV VECTORS FOR GENE THERAPY Principal Investigator & Institution: Dong, Jian-Yun; Associate Professor; Microbiology and Immunology; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: Recombinant adenovirus is one of the most promising vectors for gene therapy of genetic and metabolic diseases due to its highly efficient gene delivery. Recent studies have shown that the success of adenovirus-mediated gene therapy is limited by two major drawbacks, inflammatory reactions elicited by low levels of viral gene expression in transduced cells and the short duration of therapeutic gene expression. The major goal of this proposal is to develop a hybrid adeno-EBV vector system that would provide persistent gene expression without immunogenicity in transduced cells. The vector is a complex form of a deltavector (or gutless vector). It harbors an EBV replicon that can be launched within the target cells in a stable circular form, and it is devoid of all adenoviral genes to avoid cytotoxicity T-lymphocyte (CTL) responses. Our efforts have been focused on developing the four essential components of the vector: 1) a CRE-loxP-independent packaging system to produce high-titer deltavectors, 2) a cloning strategy to construct large linear delta-vectors, 3) a linear EBV vector that can be recircularized from the delta-vector, and 4) a molecular switch to regulate the release of the EBV vector from the adenovirus construct. We have successfully constructed and tested all four components, and we have developed a highly efficient packaging system to produce gutless-adenovirus vectors. We will continue our research to combine these components into a single vector system that can introduce therapeutic genes into target cells without induction of CTL response by the host. We will also characterize these hybrid vectors in cell culture and in animal models. We will develop additional helper viruses with different serotypes to test the feasibility of repeated gene transfer and expanding the vector tropism by rotating the serotypes of the helper viruses. When we achieve our goals, we will have a vector system that can efficiently transfer gene in vivo, that can provide persistent gene expression, that does not induce CTLs, that can be repeatedly administered, and that has an expanded tissue tropism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POLARIZATION OF DENDRITIC CELLS BY CD8 T CELLS Principal Investigator & Institution: Kalinski, Pawel; None; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007

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Summary: (provided by applicant): Cellular immunity is key to our resistance against cancer and chronic infections. Effective cell-mediated immunity requires the participation of dendritic cells (DC), CDS+ T cells (CTL), and CD4+ IFN-gammaproducing type-1 T helper (Thl) cells. CD40L-expressing CD4+ cells are a source of DCmediated helper signals for the optimal induction and persistence of cytotoxic CD8+ T cell responses. In contrast, it is unclear whether and to what extent the optimal magnitude and the Thl polarization of CD4+ cell responses depend on the feedback signals from CD8+ T cells. Based on our recent observations that human CD8+ T cells activate DC and prime them for high IL-12 production, we hypothesize that at least some populations of CD8+ T cells may provide DC-mediated helper signals for tumorspecific Thl cells and may be utilized to boost the effectiveness of DC -mediated cancer immunotherapy. Defining the role(s) of CD8+ T cells in the development and proper functioning of Thl cells is important for our understanding of the pathology and for the design of immunotherapy in cancer and chronic infections with intracellular pathogens. It may also provide tools to correct the aberrant Th1/Th2 response patterns in autoimmune diseases and allergy. This study will pursue three specific aims: 1. We will analyze the impact of different populations of CD8+ T cells on the ability of DC to provide activating, polarizing, and survival signals for naive and memory CD4+ Th cells. 2. Determine the DCl-polarizing potential of virus-specific and tumor-specific CD8 T cells, and evaluate in vitro the potential for using "heterologous CD8 help" from virusspecific CD8 T cells to boost the induction of human tumor-specific Thl responses. 3. Determine the roles of virus-specific and tumor-specific CD8+ T cells in the development of Thl-type immunity in vivo, and to use the "heterologous" CD8 help to boost the induction anti-tumor immunity by DC-mediated vaccination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRE-DIAGNOSTIC MARKERS OF INFECTION AND RISK OF MS Principal Investigator & Institution: Ascherio, Alberto; Associate Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2004 Summary: We propose to conduct a prospective investigation to assess whether infection with the Epstein-Barr Virus or Chlamydia pneumoniae increases the risk of multiple sclerosis (MS). For this purpose we have identified two large populations of individuals whose blood samples were collected and stored several years ago and are available fore analyses, and we are in the process of documenting cases of MS that occurred in these populations after the date of blood collection. One population comprises over 3 million US Army personnel whose blood samples are stored in the Department of Defense (DOD) Serum Repository; the other comprises 125,000 participants in the Kaiser Permanente Health Plan (KPHP), whose blood samples were collected over 20 years ago. The identification and diagnostic confirmation of the cases of MS occurring in these populations has already been funded in part by a pilot grant from the National Multiple Sclerosis Foundation. Based on our preliminary work, we estimate that we will be able to document 216 cases of MS with onset after the date of collection of the stored serum samples. Main hypotheses to be addressed are that risk of MS is increased among individuals infected with EBV or C pneumoniae, as determined by the presence of specific serum antibodies, and that elevated antibody titers against EBV or C pneumoniae antigens predate the onset of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF EBV INFECTION IN EPITHELIAL CELLS Principal Investigator & Institution: Kenney, Shannon C.; Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-AUG-1993; Project End 31-JAN-2004 Summary: Epstein-Barr virus (EBV) infection in humans is associated with the development of both lymphoid and epithelial cell malignancies. EBV can infect cells in either a "latent" or lytic form. Transformation of cells by EBV is associated with the latent form of infection. EBV infection of normal epithelial cells in vivo occurs only in differentiated cells and is completely lytic. In contrast, EBV infection in the epithelial tumor, undifferentiated nasopharyngeal carcinoma (NPC), is primarily latent. Lytic EBV infection is mediated by the expression of the EBV immediate- early (IE) protein, BZLF1 and BRLF1. The BZLF1 protein activates the switch from latent to lytic infection in B cells. However, in epithelial cells, we have recently shown that expression of the BRLF1 immediate- early protein can induce the switch from latent to lytic infection in vitro. Similarly, the BZLF1 protein can also induce lytic viral replication in epithelial cells. The transcriptional control of the BZLF1 and BRLF1 promotes by cellular proteins thus plays an essential role in modulating the stringency of viral latency. Our preliminary data indicate that epithelial cell differentiation activates both the BZLF1 and BRLF1 promoters, suggesting that the lack of BZLF1/BRLF1 transcription in NPC could reflect the undifferentiated state of these tumors. Conversely, we have recently shown that the EBV IE proteins regulate epithelial cell differentiation, as well as cell cycle progression. We hypothesize that regulation of epithelial cell differentiation and cell cycle progression by EBV IE proteins is required for maximal efficiency of lytic replication in vivo. In this grant, we propose to continue our long-term studies investigating the mechanisms by which EBV latency is maintained or disrupted, with particular emphasis upon understanding the biology of EBV infection in epithelial cells. Our specific aims are the following: 1) We will identify the cellular protein(s) which activate the BZLF1 and BRLF1 promoters during epithelial cell differentiation in vitro. 2) We will further explore the mechanism(s) by which the BRLF1 gene product disrupts viral latency in epithelial cells in vitro, and determine if either BZLF1 or BRLF1 gene product disrupts viral latency in epithelial cells in vitro, and determine if either BZLF1 or BRLF1 expression is sufficient to activate lytic viral infection in undifferentiated NPC in vivo. 3) We will define the effects of the BZLF1 and BRLF1 immediate- early proteins upon epithelial cell differentiation and cell cycle regulation, and determine if these effects are important for disruption of viral latency in transient transfection experiments. The proposed studies should help define why EBV infection is normally lytic in epithelial cells (but not B cells), and will explore the mechanisms by which EBV infection becomes latent during the development of NPC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF EPSTEIN-BARR VIRUS LATENCY Principal Investigator & Institution: Lieberman, Paul M.; Associate Professor; Wistar Institute Philadelphia, Pa 191044268 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Epstein-Barr virus (EBV) latent infection is associated with several human cancers, including Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma. The latent viral genome exists as a multicopy episome that replicates in synchrony with the cellular chromosomal DNA. Latent cycle

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DNA replication initiates at OriP and EBNA1 is the only viral protein required for OriPdependent replication and plasmid maintenance. EBNA1 binds to multiple sites in OriP, but has no intrinsic helicase or other enzyme activity associated with DNA replication function. We have used DNA affinity chromatography to isolate and identify several cellular proteins that associate with OriP in an EBNA1-dependent manner. Our preliminary data indicates that these proteins contribute to plasmid maintenance and the regulation of DNA replication. Several of these proteins have known function at human telomeres, including Telomeric Repeat Binding Factor 2 (TRF2), hRap1, and Tankyrase. TRF2 and hRap1 bind telomeric repeats and regulate chromosome stability. We now show that EBNA1 stimulates TRF2 binding to the nonamer repeats (TTAGGG) in the Dyad symmetry region of OriP. Mutation of the nonamer repeats reduced plasmid maintenance function of OriP and sensitizes OriP to genotoxic stress. We propose that the nonamer-binding proteins function as a DNA damage checkpoint that regulates replication of OriP. Failure to regulate replication leads to a loss of stable plasmid maintenance. However, it is not clear how nonamer-binding proteins execute this function. In this application we propose to determine the structural organization of nonamer binding proteins at OriP. We will determine their protein interactions and their ability to effect single strand formation, subcellular localization, nuclear matrix attachment, and DNA looping between regions of OriP. We have also found that nonamer-binding proteins possess poly-ADP ribose activity, and we will determine how NAD levels and DNA damage may regulate the activity of PARP proteins associated with OriP. We will also determine if EBNA1 is a substrate of PARP in vivo, and if this modification regulates replication or plasmid maintenance function. We will investigate the role of nonamer-binding proteins in modifying OriP DNA and/or chromatin structure. Finally, we will determine if nonamers provide a DNA checkpoint function by arresting OriP replication in response to genotoxic stress. We hypothesize that the nonamer-binding proteins increase stability of the latent viral genome by protecting it from catastrophic recombination and degradation. The experiments proposed in this application will reveal important new insights into the mechanism of EBV latent cycle DNA replication and plasmid maintenance, and may have important implication for other latent herpesviruses, as well as the functions of cellular proteins involved in telomere maintenance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF EBNA3C IN B LYMPHOCYTE TRANSFORMATION Principal Investigator & Institution: Robertson, Erle S.; Associate Professor; Microbiology and Immunology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 20-SEP-1996; Project End 31-JUL-2002 Summary: (provided by applicant): Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus which is the etiological agent of infectious mononucleosis. EBV is also associated with a number of malignancies which includes Burkitt's lymphoma, Nasopharyngeal carcinoma, Oral Hairy leukoplakia, Hodgkin's lymphoma, Adult T-cell lymphomas and lymphoproliferative diseases in transplant and AIDS patients. In vitro, EBV infects and growth transforms B-lymphocytes so that they proliferate continually into lymphoblastoid cell lines (LCLs). In these infected B lymphocytes EBV expresses eleven genes one of which is the Epstein-Barr nuclear antigen (EBNA) 3C. This protein is essential for B lymphocyte transformation and there is a mounting body of evidence demonstrating that EBNA3C is linked to cellular and viral transcription. However, the mechanism by which EBNA3C regulates events involved in EBV mediated B

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lymphocyte transformation is not fully understood. The specific aims of this proposal are: (1) To investigate the roles of EBNA3C in regulating viral and cellular gene expression in EBV transformed primary human B-lymphocytes. (2) To identify cellular proteins interacting with EBNA3C and the critical functional domains interacting with these cellular proteins. (3) To genetically characterize the EBNA3C gene by introduction of specific mutations in the open reading frame and testing for transformation of primary B-lymphocytes and to analyze the properties of the recombinant LCLs transformed by latently infected EBNA3C mutant viruses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF HERV-K18 SUPERANTIGEN IN EBV LYMPHOMAGENESIS Principal Investigator & Institution: Sutkowski, Natalie A.; Pathology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): More than 90% of adults are latently infected throughout their lifetime with the ubiquitous herpesvirus Epstein-Barr virus (EBV). While EBV infection is usually asymptomatic during childhood, it is estimated that half of first-time infected adolescents or adults develop infectious mononucleosis, a disease characterized by polyclonal B cell activation and massive expansion of T cells. EBV is an oncogenic virus; it is associated with Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma. At least 1% of organ and bone marrow transplant recipients develop EBV+ lymphomas; and EBV lymphoproliferative disorders are common in AIDS patients. The tumors are often associated with vast T cell infiltrates. The SCID/hu mouse is well accepted as an animal model for EBV lymphomagenesis, because SCID mice adoptively transferred with EBV seropositive PBMC from healthy human donors develop EBV+ B cell lymphomas at a high rate. These tumors are strictly T cell dependent and can be prevented by blocking the B-T interaction. We have recently established that EBV transactivates a human endogenous retrovirus, HERV-K18, that encodes a superantigen, which strongly activates T cells. This is the first described report of a pathogen inducing a host cell superantigen. We propose that HERV-K18 Env superantigen activated T cells contribute to EBV lymphomagenesis. This proposal seeks to test whether blocking the superantigen driven T cell response prevents tumorigenesis in the SCID/hu lymphoma mouse model. We propose to block T cell activation by: I. developing monoclonal antibodies specific for the HERV-K18 superantigen; II. blocking CD28/ICOS costimulation; III. induction of T cell anergy; and IV. ligation of immunoinhibitory receptor PD-1. Since several other herpesviruses are associated with superantigen or superantigen-like activity, these experiments may have broad-reaching implications for herpesvirus biology. Overall, these studies represent a completely new approach towards understanding the potential role of T cells in herpesvirus oncogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF ORF K13 IN AIDS RELATED MALIGNANCIES Principal Investigator & Institution: Chaudhary, Preet M.; Professor; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: Infection with the human herpes virus 8 (HHV8) has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multi-centric Castleman's disease, angio-

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immunoblastic lymphadenopathy with dysproteinemia, and multiple myeloma. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. Although HHV8 has been found to encode homologs of several cellular oncogenes and growth factors, almost all of them lack expression in latently infected KS and PEL cells, thereby arguing against their casual role in the pathogenesis of these disorders. We have discovered that orf-K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein), is capable of blocking apoptosis induced by death receptors belonging to the Tumor Necrosis Factor Receptor (TNFR) family. More importantly, orfK13 is capable of activating the NF-kappaB pathway, which has been previously implicated in the pathogenesis of EBV (Epstein Barr virus)- and HTLV1 (Human T cell Leukemia virus 1)- associated lymphoproliferative disorders. As orf-K13 is one of the few HHV8 encoded proteins which are expressed in latently infected KS and PEL cells, the above results make it an ideal candidate for causing the cellular transformation associated with infection by HHV8. The overall objective of this proposal is to test the above hypothesis using in vitro and in vivo models. In aim 1, biochemical and molecular characterization of the mechanisms underlying the NF-kappaB activating ability of orfK13 will be carried out with the hope of identifying the interactions critical for this activity. In aim 2, biological consequences of orf-K13 mediated NF-kappaB will be studied and its effect on cellular activation, proliferation and transformation characterized. Aim 3 will focus on further characterization of the anti-apoptotic properties of orf-K13 and its biological consequences. In aim 4, transgenic approach will be used to study the in vivo role of orf-K13 in the pathogenesis of AIDS- related malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRATEGIES FOR PRIMATE TRANSGENESIS Principal Investigator & Institution: Golos, Thaddeus G.; Associate Professor; Primate Research Center; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: The nonhuman primate remains the most relevant model for many aspects of human physiology and disease, including reproduction and pregnancy, virology and immunology, higher brain functions including emotion, and the biology of aging. Yet, the primate lags behind rodents in experimental genetic manipulation, e.g., transgenesis. Very recent advances in the manipulation of primate reproduction (ovarian stimulation, embryo development in vitro) have changed the landscape of what is feasible with the nonhuman primate model. In this application, we propose four Specific Aims to develop approaches for the achievement of transgenic primates. Specific Aim 1 is to deliver transgenes to rhesus monkey preimplantation embryos with Epstein-Barr Virus (EBV)based and retrovirus-based vectors. Specific Aim 2 is to establish nonsurgical embryo transfer methods for the rhesus monkey. Specific Aim 3 is to define beta-galactosidase transgene expression in the rhesus placenta directed by trophoblast-specific promoters, and in the neonate by ubiquitously expressed housekeeping promoters. Specific Aim 4 is to develop conditional expression of transgenes in vitro and in vivo with a tetracycline-based regulatory system. The proposed studies will employ a mammalian "housekeeping" or strong viral promoter to direct a model transgene (betagalactosidase) coupled to a reporter which can be monitored noninvasively (green fluorescent protein, GFP). GFP will allow us to readily visualize successful transduction of embryos, and beta-gal is an easily visualized transgene in the fetus and neonate. We will use the chorionic gonadotropin alpha subunit promoter to direct transgene

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expression to the placenta as a model system for the tissue-specific expression of transgenes. The development of a general approach to manipulate placental function would not only demonstrate the feasibility of the method, but would have great significance for furthering our understanding of maternal-fetal interactions, including implantation, preeclampsia, intrauterine growth retardation, premature rupture of the membranes and preterm labor. Availability of a transgenic primate resource will promote the creative use of the nonhuman primate model, and will have vast overall significance in the study of human disease and primate experimental embryology, with relevance for other studies with rhesus embryonic stem cells and rhesus embryo clonin for the derivation of MHC-identical monkeys for virology and vaccine development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL ANALYSIS OF THE THIRD COMPONENT OF COMPLEMENT Principal Investigator & Institution: Lambris, John D.; Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-DEC-1992; Project End 31-AUG-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STUDIES OF EPSTEIN-BARR VIRUS Principal Investigator & Institution: Miller, I George.; John F. Enders Professor; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-JAN-1979; Project End 31-DEC-2002 Summary: Epstein Barr virus (EBV) is associated with diverse cancers, including nasopharyngeal cancer, non-Hodgkin's lymphoma occurring in immunodeficient individuals, Hodgkin's disease and Burkitt's lymphoma. In all EBV-associated tumors the virus remains in a latent state of limited gene expression. Latency is maintained by regulation of the EBV BZLF1 gene, whose product ZEBRA, a b-ZIP transcriptional activator, obligates the virus to enter lytic replication. Our global objective is to understand the mechanism of this switch between latency and the lytic cycle. Studies of the functions of ZEBRA required for activation of lytic cycle gene expression focus on two groups of mutants that are discordant in their capacity to activate transcription and to disrupt latency. These mutants, containing alterations in the DNA recognition domain or in the accessory activation domain, should point to additional functions that are needed to activate the latent virus. Analysis of the downstream targets of ZEBRA include investigations of DNA context effects that permit a promoter to respond to ZEBRA, identification of cellular genes that are activated by ZEBRA, and identification of cellular and viral proteins that directly interact with the ZEBRA protein. Experiments that explore control of expression of the BZLF1 gene include determination whether Zp and Rp, the two promoters that control BZLF1 transcription, are coordinately or sequentially regulated. Clues to the relative importance of cellular or viral factors in BZLF1 regulation should come from study of well characterized EBV transformed cell lines that differ markedly in their responses to chemical inducing stimuli. The proposed experiments take a biologic perspective and utilize molecular genetic and biochemical techniques to explore a central unsolved question in the pathogenesis of this human tumor virus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STUDY OF KSHV REACTIVATION AND PATHOGENESIS Principal Investigator & Institution: Jung, Jae U.; Associate Professor; Microbiol & Molecular Genetics; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Kaposi's syndrome (KS) is a multifocal vascular tumor of mixed cellular composition that is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). A new member of the herpesvirus group, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been consistently identified in KS body cavity- based lymphoma and some forms of Castleman's disease. Although still limited, the presently available data provide compelling evidence that KSHV is the long-sought infectious cause of KS. The proposed research is directed toward investigating modulation of cellular signaling by a newly identified KSHV K15 - At a position equivalent to the gene encoding the LMP2A of Epstein Barr virus (EBV), KSHV contains a distinct open reading frame called K15. Although K15 does not exhibit homology to LMP2A, both proteins contain similar structural organization including multiple transmembrane spanning domains and signal transducing modules. We hypothesize that K15 modulates cellular signal transducing activity to that K15 alters cellular signal transducing activity to regulate viral lytic reactivation and to contribute to deregulation of cell growth control. Initial research will focus on the characterization of expression of K15 gene in various KSHV infected cells and tumor tissues. Detailed biochemical studies on the role of K15 will include mutational analysis, effect on cellular signal transduction, and identification of cellular partners. To define the role of K15 in viral lytic reactivation and transformation, we propose to test whether K15 is capable of substituting for the LMP2A function in EBV LMP2A- lymphoblastoid cell lines (LCLs) and for the Tip function in context of herpesvirus saimiri. The proposed studies will increase our understanding of molecular mechanism of the KSHV latency and pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SUPERANTIGENS IN EPSTEIN-BARR VIRUS PATHOLOGY Principal Investigator & Institution: Rankin, Christopher T.; Macrogenics, Inc. 1500 E Gude Dr, Ste B Rockville, Md 20850 Timing: Fiscal Year 2003; Project Start 06-JUN-2003; Project End 31-MAY-2004 Summary: (provided by applicant): Superantigens (SAG) are believed to contribute to the pathogenesis of certain infectious agents by activating a broad subset of primary Tcells. Through association with MHC class II molecules outside of the peptide recognition cleft, the SAG is able to bind and activate T-cells expressing a particular Tcell receptor (TCR) beta chain variable gene. Recent experiments have identified a SAG, encoded by the human endogenous retrovirus K18 env (HK18 env) gene, which is transcriptionally activated following infection with the Epstein-Barr virus (EBV). EBV is a ubiquitous, B-cell tropic herpesvirus, which has been identified as a causative agent for infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder characterized by mononuclear leukocytosis. The association of EBV and a SAG activity provides an attractive hypothesis for the mechanism of EBV related T-cell proliferation. However, the exact role of the SAG in EBV infection and pathology is not currently known. The goal of this phase I application is to evaluate the role of the recently identified SAG molecule, HERV-K18 Env, in EBV infection and pathology. Our working hypothesis is that SAG activated T-cells supply an essential component necessary for the

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development of EBV associated B-cell lymphomas. Thus, blocking T-cell activation by the SAG could effectively prevent the development of EBV tumors. If this hypothesis is correct, these studies will provide a basis for phase II studies in primate models of EBV infection, in order to examine the potential for anti-SAG antibodies as preventative or therapeutic agents against EBV related disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: T CELL IMMUNITY TO MHV 68, A MURINE GAMMA HERPESVIRUS Principal Investigator & Institution: Blackman, Marcia A.; Associate Member; Trudeau Institute, Inc. Saranac Lake, Ny 12983 Timing: Fiscal Year 2001; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: Herpesviruses induce persistent infections in humans and have significant health implications. For example, Epstein-Barr virus (EBV), which establishes latency in B cells, is associated with infectious mononucleosis (glandular fever) and the development of malignancy. Cytolytic CD8+ T lymphocytes (CTL) are believed to play a major role in controlling the acute and latent stages of infection and are also a major component of the mononucleosis. However, the relationship between CTL responses to the acute and latent phases of infection and the involvement of CD8+ T cells in mononucleosis are poorly understood. MHV-68 is a murine gamma-herpesvirus with significant biological similarity to EBV and structural homology to Herpesvirus samiri and human herpesvirus-8 (associated with Kaposi's sarcoma). This virus provides an important experimental model for dissecting the CD8+ T cell response to persistent herpesvirus infection. Intranasal infection of mice with MHV-68 establishes an acute infection in the lungs, which is cleared within 8 days, and a persistent, latent infection in B cells that lasts for the life of the animal. In addition, about three weeks after infection (after clearance of infectious virus from the lung), the virus causes a pathogenesis similar to the infectious mononucleosis that sometimes is associated with EBV infection of adolescents. The experiments outlined in this proposal will determine the relationship between the CD8+ T cell response to acute and latent MHV-68 infection, and the CD8+ T cells involved in the mononucleosis syndrome. Aim 1 will determine the genetic influence on the development of the mononucleosis phase of the disease, and will characterize the longevity and function of the activated CD8+ T cells in the peripheral blood. Aim 2 will identify the antigens recognized by CD8+ T cells in the peripheral blood during the mononucleosis phase of the infection. In particular, these studies will determine whether the predominance of activated Vb4+CD8+ T cells in the peripheral blood is driven by a viral peptide antigen or a superantigen. Finally, in Aim 3, the T cell epitopes that drive the CTL response to acute MHV-68 infection will be identified to investigate the establishment of T cell memory to a persistent virus infection. These studies will also determine the relationship between the CD8+ T cells involved in the infectious mononucleosis, and the CD8+ T cell response to primary infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TACI AND B CELL FUNCTION AND TRANSFORMATION Principal Investigator & Institution: Bram, Richard J.; Associate Professor Pediatrics, Immunolo; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 16-DEC-1997; Project End 30-NOV-2002 Summary: (adapted from the investigator's abstract) Latent infection by the Epstein Barr virus (EBV) has been implicated as a causative factor in the development of Burkitts

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lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and immunodeficiency associated lymphoproliferative disease. The exact mechanisms involved in transformation remain a mystery, however. The applicant has identified a novel B-cell surface receptor whose expression in markedly increased following EBV immortalization of B lymphocytes and in EBV-infected Burkitts lymphomas. TACI (for Transmembrane Activator and CAML Interactor) was isolated by a yeast two- hybrid screen with the intracellular Ca2+ regulating protein CAML as bait. As predicted, crosslinking the TACI receptor activates the NF-AT (Ca2+dependent) transcription factor. Surprisingly, TACI also potently activates API and NF-kB transcription factors following stimulation. TACI appears to be a new member of the family of Tumor Necrosis Factor Receptors (TNFR), which include TNFR, FAS, CD40, and other receptors implicated in initiating growth and programmed cell death in lymphocytes. An attractive hypothesis is that TACI contributes to the transformation of B cells through its activation of multiple transcription factors following EBV infection. The goals of this project are to elucidate the mechanisms of action of TACI in normal and EBV-associated Burkitt lymphoma cells, and to determine its contribution to cellular transformation. Experiments will focus on determining the mechanism of action of TACI by identifying its functional domains, and identifying both extracellular and intracellular protein contacts that mediate its action. Additionally, targeted disruption of the TACI gene in mice will allow the identification of its normal role in regulation of the immune system. Lastly, the proposed project will explore the possibility that experimental manipulation of TACI signaling activating in tumor cells may provide new means to inhibit growth or accelerate death of cancer cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TCR TRANSDUCTION FOR EBV SPECIFIC IMMUNOTHERAPY Principal Investigator & Institution: Orentas, Rimas J.; Assistant Professor; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (provided by applicant): TCR TRANSDUCTION FOR EBV-SPECIFIC IMMUNOTHERAPY. Adoptive immunotherapy with polyclonal cytotoxic T cell lines (CTL) has met with clinical success in the treatment of post-transplant lymphoma, an Epstein-Barr virus (EBV)-associated malignancy that expresses the most immunodominant EBV latency antigens. This strategy is not applicable to two other EBV-associated malignancies, Hodgkin's disease (appx. 50 percent of cases are EBVassociated) and nasopharyngeal carcinoma (100 percent EBV-associated). These malignancies only express the EBV latency antigens LMP-1, LMP-2, and EBNA-1; none of which induce a strong immune response. These represent sub-dominant tumorassociated antigens. The goal of this project is to provide an immunotherapeutic option to patients suffering from these diseases by cloning individual T cell receptor molecules (TCR) that recognize LMP-1 and LMP-2 in an HLA-restricted manner, and introducing these recombinant TCR into HLA-A2 lymphocytes. Toward that goal, CTL clones specific for LMP-2 will be generated, the TCR alpha and beta chains molecularly cloned, and then transferred to retroviral expression vectors. These vectors will then be used to transduce CTL clones of known specificity as well as activated primary lymphocytes in bulk culture. The specific aims of this project seek to determine which TCRs are the best candidates for genetic transduction by comparing the CTL activity of the original cell to the lytic activity newly conferred upon the transduced cell. It remains to be determined whether it is the primary sequence of the TCR or the physiology of the transduced cell that determines the cytolytic activity conferred by the new receptor. We will also

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determine the structure of the TCR-CD3 complex in transduced cells, and in examining the bulk transduced lymphocyte population determine which cells are capable of expressing the transduced receptor. Should the retroviral vector used in these studies not give long-term expression of the transduced TCR, we also propose a newer generation of retroviral vectors that would be used instead. Once transduced, the newly expressed TCR-alpha and beta chains will have to compete with the endogenous TCR elements for association with the CD3 receptor complex and subsequent transit to the cell surface. Data obtained from this project will allow correlation between levels of retroviral gene transduction, mRNA expression, intracellular protein expression (the assembly of ICR subunits in the endoplasmic reticulum), cell surface expression of transduced TCR, and lytic function to be made. With a better understanding of these first principles of functional ICR assembly in primary lymphocytes, other malignancies with known tumor-associated antigens could be targeted by this approach as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE BCL-2 HOMOLOGUES OF GAMMA HERPESVIRUSES Principal Investigator & Institution: Hardwick, J Marie.; Professor; Molecular Microbiol and Immun; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 30-JUN-2007 Summary: (provided by applicant): Gamma herpesviruses are associated with animal and human tumors of both immunocompromised and otherwise normal individuals. Like many DNA viruses, these viruses encode homologues of cellular proteins that differ in significant ways from their cellular counterparts. The retention of some functions, gain of new functions and loss of other functions by these viral versions apparently results in specific advantages to the virus. Individual gamma herpesviruses encode one or more open reading frames with recognizable homology to such cellular factors as chemokines, interleukins, interleukin receptors, cyclin, FLIP and BCL-2. Common to all gamma herpesviruses sequenced to date is a viral homologue of cellular BCL-2. The human Bcl-2 gene was first identified at the characteristic translocation breakpoints in follicular lymphoma leading to overexpression of BCL-2 protein. Shortly thereafter, BCL-2 was shown to function as an unusual oncogene by inhibiting cell death without stimulating cell proliferation. The role of viral BCL-2 homologues in viral replication and pathogenesis are yet unclear. In addition, the function of cellular BCL-2 is not fully understood and these pared down viral versions of cellular BCL-2 are likely to reveal important clues about their functions. We seek to characterize the functions of the BCL-2 homologues encoded by Kaposi's sarcoma herpesvirus (KSBcI-2) and EpsteinBarr virus (BHRF1 and BALF1). In Aim 1, we will study the function of BHRF1/KSBcI-2 in membranes and compare its ability to form pores, translocate molecules of different sizes and regulate mitochondrial function compared to cellular BCL-2 family proteins. These results are expected to help separate the protective functions of BCL-2 family proteins from their killing function and other potential functions. In Aim 2, we will explore the molecular mechanisms by which BALF1 inhibits the anti-apoptotic function of BF-IRF1. In Aim 3, the expression patterns of BHRF1 and BALF1 during virus infections will be explored by inserting tags into the their reading frames within the Epstein-Barr virus genome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THERAPEUTIC INDUCTION OF THE EBV LYTIC CYCLE IN TUMORS Principal Investigator & Institution: Israel, Bruce F.; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Many tumors (especially B-cell lymphomas) associated with AIDS and immunosuppression are infected by EBV in a latent form. There are no established antiviral therapies that target latent EBV, so treatment relies upon conventional cytotoxic and immune-reconstituting therapies, which often fail. However, it is known that transcriptional activation of either EBV immediate-early gene (BZLFl or BRLFl) results in the switch to the cytolytic form of EBV infection. In the cytolytic type of EBV infection, virally encoded kinases are expressed that phosphorylate the prodrug ganciclovir (GCV) into its toxic form. We have recently shown that both irradiation (XRT) and certain chemotherapeutic agents can induce cytolytic EBV. We hypothesize that intentional activation of cytolytic viral genes in EBVpositive malignancies can allow tumor-specific targeting for clinical effect. We have three specific aims. First, to perform a phase I study examining whether XRT induces lytic EBV in AIDS-related CNS lymphomas (which are 100% EBV-positive), and whether GCV can enhance therapy when combined with XRT. Similarly, in aim 2, we will use clinical samples from different EBV-positive tumors before and following XRT or chemotherapy to characterize and model the induction of the EBV lytic cascade in human tumors in vivo. Third, we have developed novel methodologies for targeted gene delivery of BZLF1 to EBV-positive tumors and will investigate their use in vitro/in vivo for inducing lytic EBV expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THYROID PEROXIDASE AS AN AUTOANTIGEN Principal Investigator & Institution: Rapoport, Basil; Professor; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048 Timing: Fiscal Year 2002; Project Start 01-JUL-1985; Project End 31-MAR-2006 Summary: Thyroid peroxidase (TPO), a thyroid cell surface protein, is the major autoantigen in autoimmune thyroid disease in humans. Understanding the precise molecular interaction between autoantibodies and T cells with TPO is a necessary step towards understanding the basis of the autoimmune response to TPO. We plan the following specific studies:- 1. TPO AUTOANTIBODY EPITOPES Polyclonal TPO autoantibodies in patients' sera are primarily directed to a restricted immunodominant region (IDR). We propose to identify many, if not all, TPO amino acid residues that comprise these epitopes using complementary approaches which, together, can help to complete the many pieces in the puzzle:- (i) Epitopic footprinting and identification of protected residues. Amino acids adjacent to these sentinel residues will then be identified by mutagenesis guided by the known three-dimensional structure of myeloperoxidase; (ii) X-ray diffraction crystals of TPO-TPO autoantibody complexes. 2. MOLECULAR CLONING OF NEW TPO AUTOANTIBODIES Human monoclonal autoantibodies are key reagents for defining B and T cell epitopes, as well as studying TPO processing and presentation to T cells. Autoantibodies cloned thus far are almost exclusively to the IDR. Important members of the TPO autoantibody repertoire remaining to be cloned include:- (i) Autoantibodies to the unique C-terminal region of the TPO molecule ectodomain with EGF-like and Sushi domains (amino acids 742-848); (ii) autoantibodies with dual thyroglobulin and TPO specificity ("TG-PO"). Important

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questions to be answered by these studies include:- (i) Are autoantibodies to the Cterminus the main component of serum autoantibodies with epitopes outside the IDR? (ii) Are some non-IDR TPO autoantibodies functionally important by inhibiting TPO enzymatic activity? 3. NATURALLY PROCESSED AND PRESENTED HUMAN T CELL EPITOPES FOR TPO Identification of TPO T cell epitopes is an important goal for understanding the autoimmune response to TPO. Identification of naturally processed peptide epitopes (NPPE) is preferable to testing T cell responsiveness with panels of synthetic peptides. We, therefore propose to extract TPO peptides from MHC molecules in APC and identify directly their amino acid sequence. We will use two different models:- (i) Human Epstein-Barr virus transformed human B cells that can capture, internalize and process TPO; (ii) Mouse fibroblasts co-expressing both human TPO and MHC class II molecules, whose injection induces TPO antibodies with the same epitopes as human autoantibodies. These studies will help answer the following questions:- (i) Which TPO T cell epitopes are most likely to be of pathophysiological importance? (ii) Does similarity between NPPE generated in different systems contribute to epitopic restriction of TPO autoantibodies? (iii) Conversely, do human autoantibodies influence the spectrum of NPPE generated from TPO. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TOWARDS A MOUSE MODEL OF CLASSICAL HODGKIN'S DISEASE Principal Investigator & Institution: Rajewsky, Klaus; Cbr Institute for Biomedical Research 800 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Classical Hodgkin's disease (HD) is the most common lymphoma in the Western World. The malignant cells in HD are the so-called Hodgkin and Reed-Sternberg (HRS) cells, which comprise only a few percent or less of the lymphoma tissue. In roughly half of the patients, the HRS cells are infected with Epstein-Barr-Virus (EBV) and express the EBV-encoded membrane proteins LMP1 and LMP2A. These proteins are constitutively active and in B cells partially mimic signals of the CD40 co-receptor and the antigen receptor (BCR), respectively. Based on these circumstances and on our own molecular analysis of Ig gene rearrangements in micro manipulated HRS cells we have developed a scenario of HD pathogenesis. In this scenario, HRS cells derive in most instances from pre-apoptotic germinal center (GC) B cells rescued by some transforming event(s). In EBV+ HD, LMP1 and LMP2A may participate in this initial rescue. The aim of this proposal is to reconstruct this scenario in the mouse by conditional gene targeting techniques. We have developed a mouse mutant in which Cre recombinase is efficiently expressed in GC but not naive B cells. This will be used to target expression of LMP2A and/or LMP1 to GC B cells in vivo. The interference of the viral proteins with the GC reaction will be investigated. Rescue of pre-apoptotic GC B cells that have lost BCR expression because of somatic hypermutation might be observed, as well as lymphomagenesis, given the known oncogenic properties of LMP1. These experiments will be complemented by an attempt to target another potential tumor determinant of HRS cells into GC B cells, namely the activated form of Notch1. This molecule has recently been shown to be expressed in HRS cells at high levels and in an activated form. Notch1 is particularly attractive in this context, because it is involved in lineage decisions in lymphocyte progenitors, promoting T cell development. Curiously, HRS cells have down regulated many B cellspecific genes and express molecular markers of other hematopoietic lineages, including T cells. Notch1, which is also a potent oncogene if ectopically expressed, might thus

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contribute to this curious phenotype as well as to HRS cell transformation. Combining LMP2A, LMP1 and Notch1 expression in GC B cells by conditional gene targeting might lead to a mouse model of HD. Apart from lymphomagenesis, the proposed experiments should also lead to new insights into the biology of the GC reaction in the context of EBV infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT OF EBV ASSOCIATED LYMPHOPROLIFERATIVE DISEASE Principal Investigator & Institution: Moss, Denis J.; Queensland Institute of Medical Research Bramston Terr, Herston Brisbane, Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2003 Summary: The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in solid organ transplant patients poses a considerable challenge due to the underlying immunosuppression which inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. Preliminary studies developed in our laboratory suggest that it may be possible to overcome this inherent problem using a novel protocol to activate autologous EBV-specific CTL lines from these patients and to show for the first time their potential use for immunotherapy against PTLD in solid organ transplant patients. To establish the clinical use of this protocol, we propose to conduct a phase I/II clinical trial in a cohort of solid organ transplant patients with PTLD. To achieve this, we have drawn together scientific expertise within the EBV Unit at QIMR and major transplant units in Australia. In the first instances, we propose to further refine the in vitro conditions for activating EBV-specific CTL from solid organ transplant patients who are on high levels of immunosuppression. Two absolute requirements have been set: (1) EBV specificity at the CTL peptide epitope level; and (2) complete lack of anti-donor alloreactivity which would threaten the integrity of the transplanted graft. Having defined these conditions, we propose to conduct a phase I/II trial by adoptively transferring autologous EBV-specific CTL into solid organ heart, lung, and heart/lung transplant patients with PTLD. As far as we are aware, this represents the first such trial to be conducted and seeks to (1) determine the safety of adoptively transferring EBVspecific CTL into solid organ transplant patients; (2) determine the longevity of these CTL in vivo using a genetic marker; and (3) determine the extent of clinical regression of PTLD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISORDERS

TREATMENT

OF

VIRUS

ASSOCIATED

PROLIFERATIVE

Principal Investigator & Institution: Fingeroth, Joyce D.; Assistant Professor of Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: Dr. Fingeroth is a clinician-scientist dedicated to patient-oriented research. The laboratory studies lymphotrophic herpesviruses (EBV and more recently HHV-8) that cause proliferative disorders in the compromised host and that are associated with several human tumors. Laboratory studies are organized to proceed from basic observations to translational research to the development of clinical protocols. Dr Fingeroth has mentored several young clinical and basic science investigators that have gone on to develop independent careers in patient-oriented research. She has support for her laboratory and excellent resources in the Division of Inf. Dis. at BWH/DFCI. The

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long-term goal of the proposed patient-oriented project is to develop an investigative group dedicated to identifying new mechanisms for eradicating virus infected human tumors based on the biology of the virus. This will be achieved through integrated studies directed by Dr. Fingeroth who will commit a minimum of 50 percent of her time to this effort. Although DNA tumor viruses encode gene products that are capable of destroying virus infected cells, these genes are silent during immortalizing/tumorigenic infection. Herpesviruses synthesize many proteins that support nucleic acid synthesis and protein processing functions required for efficient replication of viral DNA. The unique properties of viral enzymes has permitted development of antiviral drugs that can be converted to cytotoxic compounds with great specificity in virus infected cells. Some of these viral proteins form the basis of cytotoxic gene therapy (i.e. HSV TK and ganciclovir). The aims of this patient-oriented project are to identify gamma herpesvirus proteins, beginning with EBVTK and related early replicative products, that provide rational targets for cytotoxic anti-tumor therapy. This will be achieved by (1) by investigating the properties of gamma herpesvirus proteins predicted by homology to alpha/beta herpesviruses to function as targets for antiviral therapy - and documenting that they do so (2) by determining how the genes encoding these proteins are regulated in order to augment their expression in virus-infected tumors (3) by testing in vitro results in an animal model of EBV-associated lymphoproliferative disease and (4) by generating clinical protocols based on these findings to minimize the time between proof of concept and patient availability. Specific destruction of EBV infected lymphocytes by antiviral therapy could provide a significant new mechanism for eradicating EBV infected cells as in the case of B lymphoproliferative disease. The study is also likely to contribute significant knowledge in the basic understanding of EBV early gene regulation, and to identify other potentially cytotoxic effector proteins for treatment of virus infections, virus associated tumors and for gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRISOMY 21 NONDYSJUNCTION Principal Investigator & Institution: Sherman, Stephanie L.; Professor of Human Genetics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: No research subjects are admitted to the GCRC under this protocol. It utilizes the Molecular Cell Biology Lab to transform and store immortal Epstein-Barr virus lymphocyte cell lines from patient samples sent directly to the lab. The cell lines then serve as a permanent DNA/RNA resource, as well as an in vitro model system for molecular genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRAL DECOY RECEPTORS Principal Investigator & Institution: Fremont, Daved H.; Assistant Professor of Pathology; Pathology and Immunology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): The goal of the proposed research is to reveal structural and mechanistic details of how viral decoy receptors function to enable immune evasion. The focus will be on two gammaherpesvirus proteins, M3 from murine gammaherpesvirus 68 (MHV68) and BARF1 from Epstein-Barr virus (EBV). Both of these secreted proteins are thought to block host immune surveillance mechanisms by

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sequestering key extracellular mediators of inflammatory response pathways. They are also encoded by novel sequences unrelated to any known host proteins with similar functions. While M3 is a broad-spectrum chemokine binding protein, able to sequester members of all four chemoattractant cytokine families (CC, CXC, CX3C, and C), BARF1 appears to be highly specific for the short-chain helical-bundle cytokine macrophage colony-stimulating factor (CSF-1). Thus, the unmasking of their subterfuge mechanisms will allow for the comparison of promiscuous molecular recognition on the one hand, and highly selective engagement on the other. These aims will be addressed experimentally through the use of bacterial and baculovirus mediated protein expression, x-ray crystallography, biophysical interaction analysis, and structure-based molecular design. Novel decoy receptor variants will be developed and investigated within a functional context. A detailed mechanistic understanding of the distinct decoy strategies employed by M3 and BARF1 should provide insights into chemokine and cytokine molecular recognition events generally. Further, our experimental results may find application in the control of gammaherpesvirus pathogenesis and, by exploiting similar strategies as these decoy receptors, the development of new agents for the control of inflammatory disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL ETIOLOGY OF HODGKINS DISEASE Principal Investigator & Institution: Mueller, Nancy E.; Professor; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2001; Project Start 20-JUN-1997; Project End 31-MAY-2004 Summary: Recent findings on Hodgkin's disease (HD) present a number of important questions. The established risk factors point to age of infection as an important modifier of risk. Cases have altered antibody profiles to the Epstein-Barr virus (EBV) preceding and following diagnosis. The new finding is that 30-50% of HD cases' tumors contain monoclonal EBV genome, with a restricted latent protein expression. How these risk factor, serologic, and molecular data fit together and whether EBV-genome negative HD represents a separate etiology are unknown. This Program Project is designed to test three alternate models of the role of the EBV in the pathogenesis of HD: the EBV is solely related to EBV-genome positive HD with EBV-genome negative disease due to non-viral causes; HD is a virally induced malignancy with the EBV responsible for EBVgenome positive disease and another unidentified virus(es) linked to EBV- genome negative disease; or the EBV plays a crucial early role in the pathogenesis of essentially all HD cases but the genome is selectively lost in some patients. Three companion projects will address the following: the role of EBV in the epidemiology of HD (600 cases and 600 population controls); the association of pre- diagnosis EBV serology with EBV genome status of tumor biopsy in HD (200 cases and 200 matched controls); and characterization of the EBV infection and the cellular immune response in HD cases (160 cases and 160 bone marrow donor controls). The Projects are supported by a serology/pathology Core and an Administrative Core. The combined mutually standardized data from the population studies, plus extensive biomarkers including EBV serology and viral probes, and detailed immunologic markers will result in a substantial and rich database. The program brings together an experienced multidisciplinary group of investigators; by working together we should gain insight into the etiology of HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRAL TRANSCRIPTION IN EBV TRANSFORMED B CELLS Principal Investigator & Institution: Speck, Samuel H.; Professor; Microbiology and Immunology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUL-1986; Project End 31-MAR-2007 Summary: (provided by applicant): This is a competing renewal of an ROl grant with the long term goal of understanding how Epstein-Barr virus (EBV) gene expression is regulated during immortalizing latency. EBV establishes a life-long infection within the infected host, and is closely associated with the development of endemic Burkitt's lymphoma, nasopharyngeal carcinoma, 30-50 percent of Hodgkin's disease, and nearly half of the lymphomas that arise in immunosuppressed patients. Notably, EBV infection of peripheral resting B cells results in growth transformation resulting, ex vivo, in the generation of immortalized lymphoblastoid cell lines. Based on recent analyses of EBV infection in seropositive individuals, it seems likely that the ability of EBV to drive B cell proliferation, and subsequent differentiation, plays an important role in the dissemination of virus infected B cells and the establishment of a long-lived latency reservoir in memory B cells (in which there is very limited viral gene expression). Understanding how EBV regulates viral gene expression during immortalizing latency may ultimate provide strategies for interfering with this phase of the virus life cycle, which could interfere with the establishment of latency in the memory B cell compartment. Within the scope of this proposal, we will continue to focus our analyses on identifying and characterizing cis-elements involved in regulated EBNA gene expression during the immortalizing latency program of EBV. Aim 1. Generation of a cottontop marmoset LCL immortalized with a packaging defective and replication null EBV to serve as an inducible reservoir for non-immortalizing EBV mutants. Aim 2. Generation and characterization of EBV harboring mutations in cis-elements thought to be involved in regulating EBNA gene transcription in EBV immortalized lymphoblastoid cell lines. Aim 3. Analysis of the requirements for Wp activity during initial stages of infection of primary B cells. Aim 4. Analysis of Wp methylation during the establishment and maintenance of immortalizing latency in B cells - role of methylation in regulating Wp activity in lymphoblastoid cell lines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: X LINKED DISORDERS Principal Investigator & Institution: Warren, Stephen T.; William Patterson Timmie Professor and c; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: No research subjects are admitted to the GCRC under this protocol. It utilizes the Molecular Cell Biology Lab to transform and store immortal Epstein-Barr virus lymphocyte cell lines from patient samples sent directly to the lab. The cell lines then serve as a permanent DNA/RNA resource, as well as an in vitro model system for molecular genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “Epstein Barr virus” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for Epstein Barr virus in the PubMed Central database: •

Characteristics of viral protein expression by Epstein-Barr virus-infected B cells in peripheral blood of patients with infectious mononucleosis. by Wagner HJ, Hornef M, Middeldorp J, Kirchner H.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170223

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Evaluation of Two Slide Agglutination Tests and a Novel Immunochromatographic Assay for Rapid Diagnosis of Infectious Mononucleosis. by Gomez MC, Nieto JA, Escribano MA.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95967

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Evaluations of enzyme-linked immunosorbent assay procedure for determining specific Epstein-Barr virus serology and of rapid test kits for diagnosis for infectious mononucleosis. by Gerber MA, Shapiro ED, Ryan RW, Bell GL.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229495

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Expansion of a CD28-Intermediate Subset among CD8 T Cells in Patients with Infectious Mononucleosis. by Uda H, Mima T, Yamaguchi N, Katada Y, Fukuda M, Fujii N, Nakamura K, Saiki O.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=136291

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Requirement for CD40 Ligand, CD4 + T Cells, and B Cells in an Infectious Mononucleosis-Like Syndrome. by Brooks JW, Hamilton-Easton AM, Christensen JP, Cardin RD, Hardy CL, Doherty PC.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=113004

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction

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The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with Epstein Barr virus, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “Epstein Barr virus” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for Epstein Barr virus (hyperlinks lead to article summaries): •

Acute complications of Epstein-Barr virus infectious mononucleosis. Author(s): Jenson HB. Source: Current Opinion in Pediatrics. 2000 June; 12(3): 263-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10836164&dopt=Abstract

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Acute renal failure: unusual complication of Epstein-Barr virus-induced infectious mononucleosis. Author(s): Lei PS, Lowichik A, Allen W, Mauch TJ. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 December; 31(6): 1519-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11096030&dopt=Abstract

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Association of Epstein Barr Virus (EBV) with nasopharyngeal carcinoma (NPC). Author(s): Shah SH, Soomro IN, Haroon S, Moatter T. Source: J Pak Med Assoc. 2000 June; 50(6): 182-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10979624&dopt=Abstract

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Characterization of the expanded T cell population in infectious mononucleosis: apoptosis, expression of apoptosis-related genes, and Epstein-Barr virus (EBV) status. Author(s): Verbeke CS, Wenthe U, Bergler WF, Zentgraf H. Source: Clinical and Experimental Immunology. 2000 May; 120(2): 294-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10792379&dopt=Abstract

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Coinfection by multiple strains of Epstein-Barr virus in infectious mononucleosis in immunocompetent patients. Author(s): Plaza G, Santon A, Bellas C. Source: Acta Oto-Laryngologica. 2003 May; 123(4): 543-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797591&dopt=Abstract

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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Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Author(s): Haque T, Taylor C, Wilkie GM, Murad P, Amlot PL, Beath S, McKiernan PJ, Crawford DH. Source: Transplantation. 2001 October 27; 72(8): 1399-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11685111&dopt=Abstract

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Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Transplantation 2001; 72: 1399. Author(s): Khanna A. Source: Transplantation. 2001 October 27; 72(8): 1352-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11685102&dopt=Abstract

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Epstein Barr virus associated pediatric nasopharyngeal carcinoma: its correlation with p53 and bcl-2 expression. Author(s): Preciado MV, Chabay PA, De Matteo EN, Gismondi MI, Rey G, Zubizarreta P. Source: Medical and Pediatric Oncology. 2002 May; 38(5): 345-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11979459&dopt=Abstract

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Epstein Barr virus genome in nasopharyngeal carcinomas from New Zealand. Author(s): Popat SR, Liavaag PG, Morton R, McIvor N, Irish JC, Freeman JL. Source: Head & Neck. 2000 August; 22(5): 505-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10897111&dopt=Abstract

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Epstein Barr virus-associated lymphoma in HIV-infected children. Author(s): Preciado MV, Fallo A, Chabay P, Calcagno L, De Matteo E. Source: Pathology, Research and Practice. 2002; 198(5): 327-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12092768&dopt=Abstract

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Epstein-Barr virus (EBV) in infectious mononucleosis: detection of the virus in tonsillar B lymphocytes but not in desquamated oropharyngeal epithelial cells. Author(s): Niedobitek G, Agathanggelou A, Steven N, Young LS. Source: Molecular Pathology : Mp. 2000 February; 53(1): 37-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10884920&dopt=Abstract

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Epstein-Barr virus DNA is detected in peripheral blood mononuclear cells of EBVseronegative infants with infectious mononucleosis-like symptoms. Author(s): Ikuta K, Saiga K, Deguchi M, Sairenji T. Source: Virus Genes. 2003; 26(2): 165-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803468&dopt=Abstract

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Epstein-Barr virus infectious mononucleosis. Author(s): Papesch M, Watkins R. Source: Clinical Otolaryngology and Allied Sciences. 2001 February; 26(1): 3-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11298158&dopt=Abstract

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Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction. Author(s): Kurth J, Hansmann ML, Rajewsky K, Kuppers R. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 April 15; 100(8): 4730-5. Epub 2003 March 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665622&dopt=Abstract

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Epstein-Barr virus-related gastric pseudolymphoma in infectious mononucleosis. Author(s): Kitayama Y, Honda S, Sugimura H. Source: Gastrointestinal Endoscopy. 2000 August; 52(2): 290-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10922116&dopt=Abstract

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Ex vivo generation of effective Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T lymphocytes from the peripheral blood of immunocompetent Epstein Barr virusseronegative individuals. Author(s): Metes D, Storkus W, Zeevi A, Patterson K, Logar A, Rowe D, Nalesnik MA, Fung JJ, Rao AS. Source: Transplantation. 2000 November 27; 70(10): 1507-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11118098&dopt=Abstract

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Fatal central nervous system lesions emerging during anti-CD20 monoclonal antibody therapy (Rituximab) for a post transplantation Epstein Barr virus-linked lymphoma. Author(s): Sirvent-Von Bueltzingsloewen A, Sirvent N, Morand P, Cassuto JP. Source: Medical and Pediatric Oncology. 2003 June; 40(6): 408-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692818&dopt=Abstract

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Gene array identification of Epstein Barr virus-regulated cellular genes in EBVconverted Burkitt lymphoma cell lines. Author(s): Baran-Marszak F, Fagard R, Girard B, Camilleri-Broet S, Zeng F, Lenoir GM, Raphael M, Feuillard J. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 November; 82(11): 1463-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12429807&dopt=Abstract

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Hepatic leiomyomatous neoplasm associated with Epstein Barr virus infection in an adult with acquired immunodeficiency syndrome. Author(s): Wang MH, Wu CT, Hung CC, Liang JD, Chen PJ. Source: J Formos Med Assoc. 2000 November; 99(11): 873-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11155782&dopt=Abstract

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High expression of MDM2 protein and low rate of p21(WAF1/CIP1) expression in SCID mice Epstein Barr virus-induced lymphoproliferation. Author(s): El Mansouri S, Martin A, Mercadier A, Capoulade C, Marechal V, Wiels J, Feuillard J, Raphael M. Source: The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society. 1999 October; 47(10): 1315-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10490460&dopt=Abstract

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Increased numbers of CD38 molecules on bright CD8+ T lymphocytes in infectious mononucleosis caused by Epstein-Barr virus infection. Author(s): Zidovec Lepej S, Vince A, Dakovic Rode O, Remenar A, Jeren T. Source: Clinical and Experimental Immunology. 2003 September; 133(3): 384-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930365&dopt=Abstract

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Infectious mononucleosis patients temporarily recognize a unique, cross-reactive epitope of Epstein-Barr virus nuclear antigen-1. Author(s): McClain MT, Rapp EC, Harley JB, James JA. Source: Journal of Medical Virology. 2003 June; 70(2): 253-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12696112&dopt=Abstract

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Initial spontaneous remission of posttransplantation Epstein Barr virus-related B-cell lymphoproliferative disorder of the skin in a renal transplant recipient: case report and review of the literature on cutaneous B-cell posttransplantation lymphoproliferative disease. Author(s): Blokx WA, Andriessen MP, van Hamersvelt HW, van Krieken JH. Source: The American Journal of Dermatopathology. 2002 October; 24(5): 414-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357204&dopt=Abstract

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Is the Epstein Barr virus implicated in Ewing sarcoma? Author(s): Kebudi R, Bilgic B, Gorgun O, Ayan I, Demiryont M. Source: Medical and Pediatric Oncology. 2003 April; 40(4): 256-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12555258&dopt=Abstract

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Maintenance and characterization of an Epstein Barr virus-infected CD56-negative T cell lymphoma. Author(s): Maekawa I, Satoh H, Aoki N, Morishita Y, Tsukamoto N, Karasawa M, Nonaka Y, Shiota M, Nojima Y, Mori S. Source: Japanese Journal of Cancer Research : Gann. 2002 January; 93(1): 61-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11802809&dopt=Abstract

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Peripheral T-cell lymphoma other than angioimmunoblastic T-cell lymphoma (AILD), with follicular dendritic cells proliferation and infection of B immunoblasts with Epstein Barr virus. Author(s): Nakamura N, Suzuki S, Tasaki K, Asano S, Sai T, Wakasa H, Abe M. Source: Fukushima J Med Sci. 1999 June; 45(1): 45-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10748555&dopt=Abstract

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Pleuropneumonia as the sole manifestation of Epstein-Barr virus--associated infectious mononucleosis. Author(s): Miron D, Merzel Y, Lev A, Meir JJ, Horowitz Y. Source: Isr Med Assoc J. 2002 September; 4(9): 733-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12440247&dopt=Abstract

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Prospective study of the natural history of infectious mononucleosis caused by Epstein-Barr virus. Author(s): Rea TD, Russo JE, Katon W, Ashley RL, Buchwald DS. Source: The Journal of the American Board of Family Practice / American Board of Family Practice. 2001 July-August; 14(4): 234-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11458965&dopt=Abstract

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Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Author(s): Nepomuceno RR, Balatoni CE, Natkunam Y, Snow AL, Krams SM, Martinez OM. Source: Cancer Research. 2003 August 1; 63(15): 4472-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907620&dopt=Abstract

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Recurrent infectious mononucleosis caused by Epstein-Barr virus with persistent splenomegaly. Author(s): Pichler R, Berg J, Hengstschlager A, Maschek W, Wiesinger J, Schon H. Source: Military Medicine. 2001 August; 166(8): 733-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11515329&dopt=Abstract

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Serologic profile of Epstein-Barr virus infection in acute infectious mononucleosis. Author(s): Brkic S, Jovanovic J, Preveden T, Vukobratov Z. Source: Med Pregl. 2003 January-February; 56(1-2): 7-16. English, Croatian. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793180&dopt=Abstract

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CHAPTER 2. NUTRITION AND EPSTEIN BARR VIRUS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and Epstein Barr virus.

Finding Nutrition Studies on Epstein Barr Virus The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “Epstein Barr virus” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “Epstein Barr virus” (or a synonym): •

Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Author(s): Department of Cell and Molecular Biology, Umea University, Sweden. Source: Wang, S Rowe, M Lundgren, E Cancer-Res. 1996 October 15; 56(20): 4610-3 00085472

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Immunocytochemical localization of lysozyme and lactoferrin attached to surface bacteria of the palatine tonsils during infectious mononucleosis. Author(s): Department of Otolaryngology, Institute of Clinical Medicine, University of Tromso, Tromso, Norway. [email protected] Source: Stenfors, Lars Eric Bye, Helga Marie Raisanen, Simo J-Laryngol-Otol. 2002 April; 116(4): 264-8 0022-2151

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Modulation of the free sphingosine levels in Epstein Barr virus transformed human B lymphocytes by phorbol dibutyrate. Author(s): Department of Chemistry, University La Sapienza, Rome, Italy. Source: Miccheli, A Ricciolini, R Lagana, A Piccolella, E Conti, F Biochim-Biophys-Acta. 1991 October 16; 1095(1): 90-2 0006-3002

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

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Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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CHAPTER 3. ALTERNATIVE MEDICINE AND EPSTEIN BARR VIRUS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to Epstein Barr virus. 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 Epstein Barr virus 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 “Epstein Barr virus” (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 Epstein Barr virus: •

38.13: a monoclonal antibody directed against a Burkitt's lymphoma-associated antigen and its use as carrier for toxins. Author(s): Wiels J, Balana A, Tursz T. Source: Iarc Sci Publ. 1985; (60): 457-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4065950&dopt=Abstract

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A bicistronic retrovirus vector containing a picornavirus internal ribosome entry site allows for correction of X-linked CGD by selection for MDR1 expression. Author(s): Sokolic RA, Sekhsaria S, Sugimoto Y, Whiting-Theobald N, Linton GF, Li F, Gottesman MM, Malech HL. Source: Blood. 1996 January 1; 87(1): 42-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8547675&dopt=Abstract

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A case of hemophagocytic lymphohistiocytosis with prolonged remission after syngeneic bone marrow transplantation. Author(s): Hasegawa D, Sano K, Kosaka Y, Hayakawa A, Nakamura H. Source: Bone Marrow Transplantation. 1999 August; 24(4): 425-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10467334&dopt=Abstract

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A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with the NK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion. Author(s): Knudsen H, Gronbaek K, thor Straten P, Gisselo C, Johansen P, Timshel S, Bergmann OJ, Hansen NE, Ralfkiaer E. Source: The British Journal of Dermatology. 2002 January; 146(1): 148-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11841384&dopt=Abstract

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A clinical, molecular and cytogenetic study of 12 cases of human herpesvirus 8 associated primary effusion lymphoma in HIV-infected patients. Author(s): Boulanger E, Agbalika F, Maarek O, Daniel MT, Grollet L, Molina JM, Sigaux F, Oksenhendler E. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2001; 2(3): 172-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11920242&dopt=Abstract

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A cutaneous agranular CD2- CD4+ CD56+ “lymphoma”: report of two cases and review of the literature. Author(s): Kameoka J, Ichinohasama R, Tanaka M, Miura I, Tomiya Y, Takahashi S, Yamada M, Ishikawa I, Kadowaki I, Sasaki O, Kimura J, Meguro K, Ooya K, Ito S. Source: American Journal of Clinical Pathology. 1998 October; 110(4): 478-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9763034&dopt=Abstract

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A diacetylenic spiroketal enol ether epoxide, AL-1, from Artemisia lactiflora inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion possibly by suppression of oxidative stress. Author(s): Nakamura Y, Kawamoto N, Ohto Y, Torikai K, Murakami A, Ohigashi H. Source: Cancer Letters. 1999 June 1; 140(1-2): 37-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10403539&dopt=Abstract

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A human monoclonal autoantibody specific for human platelet glycoprotein IIb (integrin alpha IIb) heavy chain. Author(s): Kunicki TJ, Furihata K, Kekomaki R, Scott JP, Nugent DJ. Source: Hum Antibodies Hybridomas. 1990; 1(2): 83-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1715776&dopt=Abstract

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A method for analysing case-control studies with ordinal exposure variables. Author(s): Cuzick J.

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Source: Biometrics. 1985 September; 41(3): 609-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3000467&dopt=Abstract •

A new view of the etiology of nasopharyngeal carcinoma. Author(s): Hirayama T, Ito Y. Source: Preventive Medicine. 1981 September; 10(5): 614-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6272265&dopt=Abstract

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A suppressive effect of an Epstein-Barr virus-immortalized cell line on leukemic cells. Author(s): Kin Y, Shibuya M, Maru Y. Source: Clinical Biochemistry. 2001 September; 34(6): 507-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11676982&dopt=Abstract

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Abietane diterpenoids from the cones of Larix kaempferi and their inhibitory effects on Epstein-Barr virus activation. Author(s): Ohtsu H, Tanak R, In Y, Matsunaga S, Tokuda H, Nishino H. Source: Planta Medica. 2001 February; 67(1): 55-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270723&dopt=Abstract

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Absence of tumor promoting activity of Euphorbia milii latex on the mouse back skin. Author(s): Delgado IF, De-Carvalho RR, De-Oliveira AC, Kuriyama SN, Oliveira-Filho EC, Souza CA, Paumgartten FJ. Source: Toxicology Letters. 2003 November 30; 145(2): 175-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14581170&dopt=Abstract

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Activation of an ataxia telangiectasia mutation-dependent intra-S-phase checkpoint by anti-tumour drugs in HL-60 and human lymphoblastoid cells. Author(s): Sugimoto K, Tamayose K, Takagi M, Yamada K, Sasaki M, Mizutani S, Oshimi K. Source: British Journal of Haematology. 2000 September; 110(4): 819-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11054063&dopt=Abstract

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Acute lymphoblastic leukemia in the context of a disorder resembling X-linked lymphoproliferative (XLP) syndrome. Author(s): Risitano AM, Camera A, Chiurazzi F, Rossi M, D'Arco AM, Rotoli B. Source: Haematologica. 2002 August; 87(8): Elt36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161381&dopt=Abstract

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Adoptive cell therapy with donor lymphocytes for EBV-associated lymphomas developing after allogeneic marrow transplants.

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Author(s): O'Reilly RJ, Lacerda JF, Lucas KG, Rosenfield NS, Small TN, Papadopoulos EB. Source: Important Adv Oncol. 1996; : 149-66. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8791134&dopt=Abstract •

Adoptive immunotherapy following allogeneic bone marrow transplantation. Author(s): Dazzi F, Goldman JM. Source: Annual Review of Medicine. 1998; 49: 329-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9509267&dopt=Abstract

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African Burkitt's lymphoma and an Epstein-Barr virus-enhancing plant Euphorbia tirucalli. Author(s): Osato T, Mizuno F, Imai S, Aya T, Koizumi S, Kinoshita T, Tokuda H, Ito Y, Hirai N, Hirota M, et al. Source: Lancet. 1987 May 30; 1(8544): 1257-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2884382&dopt=Abstract

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AIDS primary central nervous system lymphoma. Author(s): Flinn IW, Ambinder RF. Source: Current Opinion in Oncology. 1996 September; 8(5): 373-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9026061&dopt=Abstract

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AIDS-related primary CNS lymphoma: a brief review. Author(s): Taiwo BO. Source: Aids Read. 2000 August; 10(8): 486-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10967810&dopt=Abstract

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An Epstein-Barr virus-infected lymphoblastoid cell line (D430B) that grows in SCIDmice with the morphologic features of a CD30+ anaplastic large cell lymphoma, and is sensitive to anti-CD30 immunotoxins. Author(s): Tazzari PL, de Totero D, Bolognesi A, Testoni N, Pileri S, Roncella S, Reato G, Stein H, Gobbi M, Stirpe F. Source: Haematologica. 1999 November; 84(11): 988-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10553158&dopt=Abstract

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Angiocentric lymphomatoid granulomatosis and severe hypogammaglobulinaemia. Author(s): Varoczy L, Gergely L, Szakall S, Illes A. Source: Haematologia. 2002; 32(4): 535-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803130&dopt=Abstract

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Epstein Barr virus binding induces internalization of the C3d receptor: a novel immunotoxin delivery system. Author(s): Tedder TF, Goldmacher VS, Lambert JM, Schlossman SF.

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Source: Journal of Immunology (Baltimore, Md. : 1950). 1986 August 15; 137(4): 1387-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3016095&dopt=Abstract •

Infectious mononucleosis preceding acute myelomonocytic leukemia. Author(s): Pedersen PR, Gerber P, Sweeney G, Blom J. Source: The American Journal of the Medical Sciences. 1975 January-February; 269(1): 131-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=165722&dopt=Abstract

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Infectious mononucleosis prior to acute leukemia: a possible role for the Epstein-Barr virus. Author(s): Levine PH, Stevens DA, Coccia PF, Dabich L, Roland A. Source: Cancer. 1972 October; 30(4): 875-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4342855&dopt=Abstract

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Successful bone marrow transplantation in a boy with X-linked lymphoproliferative syndrome and acute severe infectious mononucleosis. Author(s): Pracher E, Panzer-Grumayer ER, Zoubek A, Peters C, Gadner H. Source: Bone Marrow Transplantation. 1994 May; 13(5): 655-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8054918&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•


•

Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

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The following is a specific Web list relating to Epstein Barr virus; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Anorexia Nervosa Source: Integrative Medicine Communications; www.drkoop.com Epstein-Barr Virus Source: Integrative Medicine Communications; www.drkoop.com Mononucleosis Source: Integrative Medicine Communications; www.drkoop.com Urinary Tract Infection Source: Healthnotes, Inc.; www.healthnotes.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. CLINICAL TRIALS AND EPSTEIN BARR VIRUS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning Epstein Barr virus.

Recent Trials on Epstein Barr Virus The following is a list of recent trials dedicated to Epstein Barr virus.8 Further information on a trial is available at the Web site indicated. •

Ganciclovir Plus Arginine Butyrate in Treating Patients With Cancer or Lymphoproliferative Disorders Associated with the Epstein Barr Virus Condition(s): angiocentric immunoproliferative lesions; childhood Hodgkin's lymphoma; childhood non-Hodgkin's lymphoma; Leukemia; Lymphoma; small intestine cancer Study Status: This study is currently recruiting patients. Sponsor(s): Boston Medical Center Purpose - Excerpt: RATIONALE: The Epstein Barr virus can cause cancer and lymphoproliferative disorders. Ganciclovir is an antiviral drug that acts against the Epstein Barr virus. Arginine butyrate may make virus cells more sensitive to ganciclovir. Combining ganciclovir and arginine butyrate may kill more Epstein Barr virus cells and tumor cells. PURPOSE: Phase I trial to study the effectiveness of arginine butyrate plus ganciclovir in treating patients who have cancer or lymphoproliferative disorders that are associated with the Epstein Barr virus. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006340

8

These are listed at www.ClinicalTrials.gov.

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•

Effects of Long-Term Treatment with Valaciclovir (Valtrex) on Epstein-Barr Virus Condition(s): Epstein Barr Virus Infection; Healthy Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will examine the effects of long-term antiviral therapy with valaciclovir (Valtrex) on Epstein-Barr virus infection. This virus infects more than 95 percent of people in the United States. Most are infected in childhood, have no symptoms, and are unaware of their infection. People infected as adolescents or adults may develop infectious mononucleosis, which usually resolves completely. Once infected, most people shed the virus from their throat occasionally, and all carry the virus in their white blood cells for life. This study will determine whether the amount of virus in the blood declines or disappears with long-term valaciclovir treatment. Normal volunteers who are not taking any antiviral medicines and patients enrolled in NIH's protocol no. 97-I-0168 (Evaluation of Valaciclovir for Prevention of Herpes Simplex Virus Transmission) or Glaxo-Wellcome protocol HS2AB 3009 at collaborating centers may be eligible for this study. Patients in the multi-center study must be about to start valaciclovir therapy for at least 1 year. All candidates must be 18 years of age or older. Study participants will be seen in clinic for about 1 hour every 3 months for a year. During these visits, they will provide information about the medicines they are taking, gargle twice with salt water and spit the fluid into a tube, and have blood drawn (no more than 8 teaspoons each visit). The blood and gargled fluid will be tested for the amount of Epstein-Barr virus and antibodies to the virus. (Blood samples will also be tested for HLA type in order to do immunologic studies in the laboratory. HLA is a marker of the immune system that is similar to blood-typing testing.) The results in people taking valaciclovir will be compared with those in people not taking the drug. People whose results show the virus has disappeared from the body will continue to be followed twice a year for 5 years with the blood and gargling tests to continue to look for evidence of virus. Also, people who develop symptoms resembling mononucleosis (e.g., enlarged lymph nodes with fever and sore throat) will be asked to have their blood tested for the virus. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005924

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

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trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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CHAPTER 5. PATENTS ON EPSTEIN BARR VIRUS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “Epstein Barr virus” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on Epstein Barr virus, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Epstein Barr Virus By performing a patent search focusing on Epstein Barr virus, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 9Adapted

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

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The following is an example of the type of information that you can expect to obtain from a patent search on Epstein Barr virus: •

5-(E)-Bromovinyl uracil analogues and related pyrimidine nucleosides as anti-viral agents and methods of use Inventor(s): Chai; Yongseok (Athens, GA), Cheng; Yung-Chi (Woodbridge, CT), Chu; Chung K. (Athens, GA), Li; Ling (Hamden, CT) Assignee(s): The University of Georgia Research Foundation, Inc. (Athens, GA), Yale University (New Haven, CT) Patent Number: 6,653,318 Date filed: July 21, 1999 Abstract: The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster virus and Epstein Barr Virus, as well as cancers which are complications of Epstein Barr virus. Excerpt(s): The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster Virus, Epstein Barr Virus and Kaposi's Sarcoma virus, also known as HV-8 and related complications of these viral infections. In another aspect of the present invention, the use of one or more nucleoside compound to increase the rentention or the metabolic/catabolic half-life of 5-fluorouracil (FU) in cancer patients is also described. As human bacterial infections have become more manageable and treatable through the use of increasingly available antibiotic agents, viral infections have remained a more difficult and less treatable target. Emphasis in finding agents to treat viral infections has remained a high priority. Problematic virus is Varicella zoster virus, Epstein Barr virus and Kaposi's Sarcoma virus. Varicella zoster virus (VZV), a member of the herpes virus family, is a main causative agent for a primary infection (varicella and chickenpox) as well as a recurrent disease (zoster and shingles). Snoeck, et al., "Chemotherapy of varicella-zoster virus-infections." Intl. J. Antimicrob. Agents 1994, 4, 211-226. The course of varicella is generally benign in immunocompetent patients, however, in immunocompromised patients, particularly patients suffering from the acquired immune deficiency syndrome (AIDS), transplant recipients, and cancer patients, VZV infections can be life-threatening. Snoeck, et al. "Current pharmacological approaches to the therapy of varicella zoster virus infections. A guide to treatment.", Drugs 1999, 57, 187-206; and Lee, P. J. and Annunziato, P. "Current management of herpes zoster." Infections in Medicine 1998, 15, 709-713. Web site: http://www.delphion.com/details?pn=US06653318__

•

Cytotoxic T-cell epitopes Inventor(s): Burrows; Jacqueline Margaret (Bald Hills, AU), Burrows; Scott Renton (Bald Hills, AU), Kerr; Beverley Mavis (Gumdale, AU), Khanna; Rajiv (Hentson, AU), Moss; Denis James (Arana Hills, AU), Suhrbier; Andreas (Newmarket, AU) Assignee(s): The Council of the Queensland Institute of Medical Research (Queensland, AU) Patent Number: 5,869,453 Date filed: January 27, 1997

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Abstract: The present invention provides cytotoxic Epstein-Barr virus T-cell epitopes. The epitopes are selected from the group consisting of QAKWRLQTL, RYSIFFDY, HLAAQGMAY, YPLHEQHGM, SVRDRLARL, AVLLHEESM, VSFIEFVGW, FRKAQIQGL, PYLFWLAAI, TVFYNIPPMPL, PGDQLPGFSDGRACPV, VEITPYKPTW, and variants thereof. In addition, the present invention provides compositions including these epitopes for use in inducing CTL's in a subject. Excerpt(s): The present invention relates to cytotoxic T-cell (CTL) epitopes within Epstein-Barr virus. The present invention also relates to the use of the epitopes in subunit vaccines. Epstein-Barr virus (EBV) is a herpes virus that infects approximately 80% of individuals in Western societies. Following primary infection, a life long latent EBV infection of B cells is established. When primary infection is delayed until adolescence, which occurs in 10-20% of individuals in Western societies, there is an approximately 50% chance of developing infectious mononucleosis. There are two EBV types, A and B. The A type appears to predominate in the majority of lymphoid infections of healthy seropositive individuals. In such individuals, latently infected B cells appear to be controlled by CD8+ cytotoxic T cells (CTL) specific for the latent antigens, which include the EBV nuclear antigens (EBNAs) 2-6 and the latent membrane antigens (LMP) 1-3 (Moss, D. J. et al. 1992). Recent developments suggests that CD4+ CTL may also play a part in controlling this infection. These CTL are known to recognise short peptide epitopes derived from antigenic determinants in association with MHC class I molecules on the surface of an appropriate antigen presenting cell. LCLs displaying HLA class I and II alleles and presenting epitopes within EBV latent antigens are frequently used as a target cell for defining the specificity of CTL clones. Web site: http://www.delphion.com/details?pn=US05869453__ •

Diagnostic reagents for the detection of antibodies to EBV Inventor(s): Middeldorp; Jaap Michiel (Oss, NL), van Grunsven; Wouterus Marinus Johannes (Oss, NL) Assignee(s): Akzo Nobel N.V. (Arnhem, NL) Patent Number: 5,827,646 Date filed: September 14, 1994 Abstract: The present invention is directed to diagnostic reagents for the detection of antibodies against the Epstein Barr Virus and a method for the detection of antibodies to the Epstein Barr Virus in a sample. The diagnostic reagents according to the invention comprise a combination of at least part of an Epstein Barr viral structural protein, preferably a Epstein Barr VCA-protein or an Epstein Barr MA protein, and at least part of an Epstein Barr EBNA protein. Preferably, the VCA-protein is VCA-p18 protein, the MA-protein is MA-gp350/220 protein and the EBNA-protein is EBNA-1 protein.It has been found that the combination of a VCA-protein or a MA-protein, and an EBNA protein, into a single diagnostic assay yields an EBV-antibody detection method with greater sensitivity and accuracy than current methods. Excerpt(s): The present invention is directed to diagnostic reagents for the detection of antibodies against the Epstein Barr Virus and a method for the detection of antibodies to the Epstein Barr Virus in a sample. In the vast majority of cases EBV infection results in a lymphoproliferative disease that may be temporarily debilitating, but is always benign and self-limiting. In certain immunosuppressed individuals, however, the result can be full-blown malignancy. This occurs in individuals who are immuno-suppressed

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intentionally, particularly children receiving organ transplants who are treated with cyclosporine A, or opportunistically, as in the case with individuals infected with HIV, or genetically, as in the case of affected males carrying the XLP (x-linked lymphoproliferative syndrome) gene. In these cases the resulting malignancies derive from the polyclonal proliferation of EBV-infected B cells. In addition, in such patients uncontrolled epithelial replication of the virus is detectable in lesions of oral hairy leukoplakia. Thus, the immune response plays a central role in the control of EBV infection. The presence of EBV in cells or tissues can be demonstrated by detection of the viral genome or demonstration of the EBNA-1 protein, the sole latency associated protein product that is universally expressed in EBV-infected cells. Web site: http://www.delphion.com/details?pn=US05827646__ •

Haematopoietic cytokine Epstein Barr virus-induced protein Inventor(s): Devergne; Odile (Brookline, MA), Kieff; Elliott D. (Brookline, MA) Assignee(s): Brigham & Women's Hospital, Inc. (Boston, MA) Patent Number: 5,830,451 Date filed: July 19, 1996 Abstract: A novel heterodimeric haematopoietic cytokine formed from the Epstein Barr Virus-Induced protein 3 (EBI3) and the p35 subunit of Interleukin-12 (IL12) is disclosed. Substantially pure preparations of this EBI3/p35 cytokine, and antibodies thereto, are provided. In addition, isolated nucleic acids encoding the EBI3/p35 cytokine, and recombinant host cells transformed with these nucleic acids, are also provided. Methods of treating patients, using the EBI3/p35 cytokine or nucleic acids encoding the cytokine, are disclosed. The invention also provides for diagnostic assays for detecting pregnancy or threatened spontaneous abortion using antibodies to the cytokine. Excerpt(s): This invention claims priority from a provisional application, U.S. Ser. No.60/005,092, filed Oct. 11, 1995. The present invention relates to the fields of immunology and cytokines. The present invention provides a novel purified complex, EBI3/p35, and further provides nucleic acids encoding this novel complex. The EBI3/p35 complex, and nucleic acids operably encoding it, may be formulated in pharmaceutical compositions and used in the treatment of various conditions. In addition, antibodies to EBI3/p35 may be used in diagnostic tests. Interleukin-12 (IL12) is a 70-kDa heterodimeric cytokine composed of two disulfide-linked glycosylated chains, p40 and p35. The p35 subunit is structurally related to other alpha-helix rich haematopoietin cytokines, while the p40 subunit is a member of the haematopoietin receptor family. IL 12 was originally identified and purified from the culture cell supernatant of Epstein-Barr virus (EBV) transformed B lymphoblastoid cell lines, based on its ability to stimulate the maturation of cytotoxic lymphocytes (Cytotoxic Lymphocyte Maturation Factor) and the cytotoxicity of NK cells (Natural Killer cell Stimulatory Factor). IL12 has pleiotropic effects on T and NK cells including: (i) induction of IFN-.gamma. production; (ii) proliferation; and (iii) enhancement of cytotoxic activity. More recently, IL12 was shown to play a major role in the regulation of immune responses, by promoting the development of T helper type 1 (Th 1) responses, while inhibiting the development of Th2 cells (reviewed in Trichieri, (1993) Immunol. Today 14:335). Effects of IL12 on B lymphocyte differentiation (Jelinek et al., (1995) J. Immunol. 154:1606) and on human haematopoiesis (Bellone et al., (1994) J. Immunol. 153:930) have also been reported.

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Web site: http://www.delphion.com/details?pn=US05830451__ •

Method for diagnosis of Epstein-Barr virus associated disease Inventor(s): Parks; D. Elliot (Del Mar, CA), Smith; Richard S. (Del Mar, CA) Assignee(s): Ortho Diagnostics Systems, Inc. (Raritan, NJ) Patent Number: 6,506,553 Date filed: March 30, 1995 Abstract: A novel assay utilizing Epstein-Barr virus (EBV) specific peptides is disclosed. The assay is particularly useful for detecting early antigen antibodies in a blood sample from an individual having an EBV-associated disease, the disease preferably being infectious mononucleosis. Excerpt(s): This invention relates to Epstein-Barr virus (EBV) associated disease, and specifically to the use of EBV specific peptides for diagnosis of EBV-associated disease. Epstein-Barr virus (EBV) is a human herpesvirus which is endemic in all human populations. Most people are infected with the virus in early childhood and then carry the virus for life. If the initial infection is delayed until adolescence, infectious mononucleosis (IM) frequently results. IM is a self-limiting symptomatic disease with illness ranging from mild to severe. EBV is also linked with certain kinds of cancer. In the malarial belt of Africa, EBV is a contributory factor in the development of Burkitt's lymphoma (BL) and in South-East Asia, the virus is linked to the high incidence of undifferentiated nasopharyngeal carcinomas (NPC). EBV has also been shown to be associated with certain malignancies occurring in organ transplant recipients and in some patients with acquired immune deficiency syndrome (AIDS). Acute viral infection leads to the production of specific nuclear antigens (termed EBNA-I and EBNA-II), an "early antigen" (EA) complex, viral capsid antigens (VCA), and other associated molecules. The "early antigen complex" consists of the "early antigen-diffuse" (EA-D) and the "early antigen-restricted" (EA-R) antigens, based on their distribution in immunofluorescence assays. The antigens are distinguished by being localized in the cytoplasm plus nucleus (i.e. diffuse distribution) or in the cytoplasm only (i.e. restricted) and by their staining appearance in methanol-fixed cells. These EA antigens, with molecular weight 50-55 Kd, 17 Kd, and 85 Kd, respectively, are synthesized during the "lytic" phase of EBV infection and not in transformed lymphoblastoid cells. Antibodies reactive with the early antigens are present during acute EBV infection and then disappear as the virus enters a phase of latency. The reappearance of anti-EA antibodies signals viral reactivation and provides some insight to the possible role of this virus in diseases such as nasopharyngeal carcinoma and Burkitt's lymphoma. Web site: http://www.delphion.com/details?pn=US06506553__

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Oligonucleotide therapies for modulating the effects of herpesviruses Inventor(s): Crooke; Stanley T. (Carlsbad, CA), Draper; Kenneth G. (San Marcos, CA), Ecker; David J. (Carlsbad, CA), Mirabelli; Christopher K. (Encinitas, CA) Assignee(s): Isis Pharmaceuticals, Inc. (Carlsbad, CA) Patent Number: 6,310,044 Date filed: April 28, 1992

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Abstract: Compositions and methods are provided for the treatment and diagnosis of herpesvirus infections. In accordance with preferred embodiments, oligonucleotides are provided which are specifically hybridizable with RNA or DNA deriving from a gene corresponding to one of the open reading frames UL5, UL8, UL9, UL13, UL29, UL30, UL39, UL40, UL42 AND UL52 of herpes simplex virus type 1. The oligonucleotide comprises nucleotide units sufficient in identity and number to effect said specific hybridization. In other preferred embodiments, the oligonucleotides are specifically hybridizable with a translation initiation site; it is also preferred that they comprise the sequence CAT. Methods of treating animals suspected of being infected with herpesvirus comprising contacting the animal with an oligonucleotide specifically hybridizable with RNA or DNA deriving from one of the foregoing genes of the herpesvirus are disclosed. Methods for treatment of infections caused by herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, human herpes virus 6, Epstein Barr virus or varicella zoster virus are disclosed. Excerpt(s): This invention relates to therapies and diagnostics for herpesvirus infections. In particular, this invention relates to antisense oligonucleotide interactions with certain portions of herpesvirus RNA which have been found to lead to modulation of the activity of the RNA and, thus, to modulation of the effects of the viruses themseves. Approximately 500,000 new cases of genital herpes are reported each year, and it is estimated that 30 million Americans are affected by this currently incurable disease. Similarly, it is estimated that there is an annual incidence of 500,000 new cases of herpes simplex gingivostomatitis and at least 100 million Americans suffer from recurrent herpes labialis. Overall the prevalence of seropositive individuals in the general population is approximately 70-80%. Although recurrent herpes simplex virus infections are the most prevalent of all herpesvirus infections, there is a need to develop more specific forms of therapy for diseases such as herpes simplex encephalitis, keratoconjunctivitis, herpetic whitlow and disseminated herpes infections of neonates and immunocompromised hosts. The incidence of encephalitis is low (one case in 250,000 individuals per year), yet with existing therapy, the mortality rate is as high as 40% and approximately 50% of the survivors are left with severe neurological sequelae. Ocular infections are neither rare nor trivial. They are usually caused by HSV-1 and are a leading cause of blindness in many countries of the world. Herpetic whitlow is an occupational hazard of nurses, dentists and physicians which begins with erythema and tenderness of the distal segments of the fingers and is followed by coalescence and enlargement of the vesicles. An accompanying lymphangitis and lymphadenopathy of the draining lymphatics is a common feature. Neonatal HSV infection is usually encountered as a consequence of a child being born through an infected birth canal. The incidence of the disease is approximately 1 in 10,000 births. Mortality in babies with limited infection can be as high as 20% while mortality of neonates from disseminated infection, even with current therapy, can approach 75% and many survivors have significant neurological impairment. Web site: http://www.delphion.com/details?pn=US06310044__ •

Oligonucleotides with anti-Epstein-Barr virus activity Inventor(s): Mulder; Carel (Worcester, MA) Assignee(s): University of Massachusetts (Boston, MA) Patent Number: 5,837,854 Date filed: April 5, 1996

Patents 87

Abstract: Oligonucleotides that inhibit Epstein-Barr virus functions, pharmaceutical compositions containing such oligonucleotides, and methods of using these compositions to treat Epstein-Barr virus-associated diseases. Excerpt(s): This invention relates to oligonucleotides, pharmaceutical compositions containing such oligonucleotides, and methods of using these compositions for the treatment of pathology associated with Epstein-Barr virus infection. Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus which infects the majority of the population and is associated with disease and neoplasia. A double-stranded DNA virus of 172 kb, EBV can infect lymphocytes and epithelial cells. Infection of B lymphocytes with EBV results in their activation and proliferation. In most individuals, primary EBV infection occurs during childhood and does not result in clinical manifestations. If primary infection is delayed until adolescence, infectious mononucleosis (IM), a self-limiting proliferation of EBV-infected B cells, can result. Subsequent to primary infection, EBVinfected cells persist within the host for life. Low levels of infectious virus are produced by epithelial cells in most asymptomatic seropositive individuals. EBV-infected B cells are kept from proliferating out of control in vivo by a properly functioning immune system. In individuals who are immunosuppressed, however, EBV-infected cells can give rise to lymphoproliferative disorders leading to disease or neoplasia. Web site: http://www.delphion.com/details?pn=US05837854__ •

Peptide reagent enabling a primary Epstein-Barr virus infection to be detected by testing for the corresponding antibodies, and method for using this reagent Inventor(s): Brebant; Richard (Marcy-l'Etoile, FR), Drouet; Emmanuel (Corenc, FR) Assignee(s): L'Universite Joseph Fourier (St Martin d'Heres, FR) Patent Number: 6,337,180 Date filed: August 15, 1997 Abstract: The use of a peptide reagent for detecting the presence or absence of a primary Epstein-Barr virus infection in a patient by testing for IgM antibodies, recognizing said reagent, in a biological sample from the patient according to a per se known method based on the formation of at least one antigen-antibody complex, is disclosed. The reagent contains a peptide recognized by at least one antibody to a peptide having the sequence of formula (II): Leu Glu Ile Lys Arg Tyr Lys Asn Arg Val Ala Ser Arg Lys Cys Arg Ala Lys Phe Lys Gln. The reagent enables such a primary infection to be detected very early. Excerpt(s): The invention relates to the use of a peptide reagent enabling a primary Epstein-Barr virus infection to be detected, even at a very early stage, by testing in a biological sample for the possible presence of IgM antibodies that recognize the said reagent. The invention also relates to a method for detecting a primary Epstein-Barr virus infection using such a peptide reagent, as well as to a kit (detection set) enabling this method to be carried out. The Epstein-Barr virus (abbreviation: EBV) is known to be a virus capable of infecting human epithelial and lymphoid cells. It is established that this virus is the source of infectious mononucleosis (abbreviation: IMN). Primary infection occurs most often during childhood, generally asymptomatically, and the virus thereafter remains present in the body in the latent state. It is estimated generally that more than 95% of adult humans are infected with this virus. In some countries and/or in some social groups, it is possible for primary infection not to take place until the age of adolescence or in the young adult. Among these cases of late primary infection,

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approximately 50% are acute infections accompanied by symptoms of infectious mononucleosis (IMN). It is known, moreover, that, in some geographic regions, EBV is closely associated with certain cancers, in particular cancer of the nasopharynx and Burkitt's lymphoma. Web site: http://www.delphion.com/details?pn=US06337180__ •

Treatment of Epstein Barr infection Inventor(s): DeMarco; Charlene C. (462 S. Philadelphia Ave., Egg Harbor, NJ 08215) Assignee(s): none reported Patent Number: 6,107,303 Date filed: March 15, 1999 Abstract: A method of treating Epstein Barr virus infection in humans by administering a pharmaceutically effective amount of an antiviral agent selected from a group consisting of acyclovir, famciclovir, valacyclovir and a pharmaceutically acceptable salt thereof is provided. Excerpt(s): Epstein Barr Virus (EBV) is a herpesvirus that infects 95% of the population world wide. EBV is the causative agent for infectious mononucleosis and is also closely associated with nasopharyngeal carcinoma, Burkitt's Lymphoma in Africa and the growth of smooth-muscle tumors after organ transplants. The symptoms of the EBV invention includes fatigue, low grade fever, lymphadenopathy and sore throat. Some patients experience a more severe infection with splenomegaly. EBV takes a fulminant course in patients infected with HIV. In EBV infections, once the initial episode resolves, the virus becomes latent and can be reactivated later in life. A few EBV infections remain chronically active. To date, no effective treatment for EBV exists. Accordingly, a need for such a treatment is evident. This invention is directed to a method of treating mammals, including humans, infected with Epstein-Barr virus by administering to a mammal in need thereof of a pharmaceutically effective amount of acyclovir, famciclovir, valacyclovir or a pharmaceutically acceptable salt thereof. Web site: http://www.delphion.com/details?pn=US06107303__

Patent Applications on Epstein Barr Virus As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to Epstein Barr virus:

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This has been a common practice outside the United States prior to December 2000.

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Aminopyridine-containing thiourea inhibitors of herpes viruses Inventor(s): Bloom, Jonathan; (Nyack, NY), DiGrandi, Martin; (Piermont, NY), Dushin, Russell; (Garrison, NY), Lang, Stanley; (Carlsbad, CA), O'Hara, Bryan; (Norwood, NJ) Correspondence: American Home Products Corporation; Patent Law Department; Five Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20020026055 Date filed: March 12, 2001 Abstract: Compounds of the formula 1whereinA is heteroaryl;R.sub.9-R.sub.12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R, and R.sub.10 or R.sub.11 and R.sub.12 may be taken together to form aryl of 5 to 7 carbon atoms; W is O, NR, or is absent;G is aryl or heteroaryl; andX is a bond X is a bond, --NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; andJ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; andn is an integer from 1 to 6; or a pharmaceutical salt thereof, useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus. Excerpt(s): This application claims the benefit of U.S. Provisional Application Nos. 60/150,698, 60/155,240, 60/155,192, and 60/150,692, and U.S. Application Nos. 09/208,540, 09/208,164, 09/208,561 each of which was filed Dec. 9, 1998. These applications are herein incorporated by reference in their entireties. Eight viruses have been identified which are members of the family Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Each member of this family is characterized by an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of which houses the viruses' relatively large double-stranded DNA genome (i.e. approximately 80-250 kilobases). Members of the human alphaherpesvirus subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and varicella-zoster virus (VZV). The human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these herpesviruses is causally-related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R. J. 1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1996. Epstein-Barr Virus, p. 2397-2446. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); pneumonia and retinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.] and HHV7 [Frenkel, N., and Roffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven

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Publishers, Philadelphia, Pa.]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht, J.C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol. 71:418792, 1997]). HCMV is considered in more detail below. Following the primary infection, herpesviruses establish latency within the infected individual and remain there for the remainder of his/her life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA polymerase. HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Primary infection with HCMV is usually asymptomatic, although heterophile negative mononucleosis has been observed. The virus is horizontally transmitted by sexual contact, breast milk, and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences. HCMV remains in a latent state within the infected person for the remainder of his/her life. Cell-mediated immunity plays a central role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive persons. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Circulating epstein-barr virus DNA in the serum of patients with gastric carcinoma Inventor(s): Chan, Wing Yee; (Tuen Mun, CN), Lo, Yuk Ming Dennis; (Kowloon, CN), Ng, Kwok Wai; (Tai Po, CN) Correspondence: TOWNSEND AND TOWNSEND AND CREW, LLP; TWO EMBARCADERO CENTER; EIGHTH FLOOR; SAN FRANCISCO; CA; 94111-3834; US Patent Application Number: 20020192642 Date filed: January 25, 2002 Abstract: The present invention features methods for diagnosing, detecting, monitoring and determining the prognosis of gastric cancer, non-head and neck and lymphoid malignancies, and gastritis in a patient by detecting or measuring EBV DNA present in the serum or plasma of the patient. The present invention also features diagnostic kits comprising suitable reagents for detecting EBV DNA in the serum or plasma of a patient. Excerpt(s): This invention relates to the discovery that Epstein Barr virus may be found in the cell free fluid of a patient's blood and when such virus is found and the patient suffers from gastritis, that patient has a predisposition to progress from gastritis to gastric cancer. It is known that tumour-derived DNA can be released by cancer cells of a variety of tumours (Anker et al., Cancer Metastasis Rev. 18: 65-73 (1999)). Examples include oncogene mutations from pancreatic carcinoma (Anker et al., Gastroenterology. 112: 4-1120 (1997)), microsatellite alterations in lung cancer (Chen et al., Nature Medicine. 2: 3-1035 (1996)) and epigenetic changes from liver cancer (Wong et al., Cancer Res. 59: 3 (1999)). In addition, virus DNA has been found in the circulation of a number of cancers known to be associated with virus infection. Examples include Epstein-Barr virus (EBV) DNA from nasopharyngeal cancer (Mutirangura et al., Clin

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Cancer Res. 4: 665-9 (1998); Lo et al., Cancer Res. 59: 1188-91 (1999)) and certain lymphomas (Lei et al., Br J Haematol. 111:239-46 (2000); Gallagher et al., Int J Cancer. 84: 442-8 (1999); Drouet et al., J Med Virol. 57: 383-9 (1999)), and human papillomavirus DNA from head and neck cancer (Capone et al., Clin Cancer Res. 6: 4171-5 (2000)). Recently, much interest has been focused on the presence of tumor-derived DNA in the plasma and serum of cancer patients (Chen, X. Q. et al., Nat. Med., 2:1033-1035 (1996); Nawroz, H. et al., Nat. Med., 2:1035-1037 (1996)). For virally-associated cancers, cell-free tumor-associated viral DNA has been detected in the plasma and serum of patients (Mutirangura, A. et al., Cancer Res., 4:665-669 (1998); Lo, Y. M. D. et al., Clin. Cancer Res., 59:1188-1191 (1999); Capone, R. B. Clin. Cancer Res., 6:4171-4175 (2000)). One important virus which has been associated with many types of malignancy is the Epstein-Barr virus (EBV) (Cohen, J. I. N. Engl. J Med., 343:481-492 (2000)). Epstein-Barr virus (EBV) is a human herpesvirus that infects the majority of the human population. EBV is commonly transmitted by saliva and established latent infection in B lymphocytes where it persists for the lifetime of the host. In this regard, circulating EBV DNA has been detected in the plasma and serum of patients with nasopharyngeal carcinoma (NPC) (Mutirangura, A. et al., Cancer Res., 4:665-669 (1998); Lo, Y. M. D. et al., Clin. Cancer Res., 59:1188-1191 (1999)) and certain lymphoid malignancies (Lei, K. I. et al., Br. J Haematol., 111:239-246 (2000); Drouet, E. et al., J. Med. Virol., 57:383-389 (1999); Gallagher, A. et al., Int. J. Cancer, 84:442-448 (1999)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition for and method of treatment using triterpenoids Inventor(s): Flore, Ornella; (New York, NY) Correspondence: Thomas A. O'Rourke; Wyatt, Gerber, Meller & O'Rourke; 99 Park Avenue; New York; NY; 10016; US Patent Application Number: 20020091158 Date filed: October 15, 2001 Abstract: Methods and compositions for treating Kaposi's sarcoma and Epstein Barr virus using a a therapeutic derivative of a triterpenoid acid and derivatives thereof are disclosed, Excerpt(s): Acquired Immunodeficiency Syndrome (AIDS) is one of the most significant infections to appear in recent history. This epidemic is not confined to a single segment of the population nor is its spread blocked by natural barriers or international boundaries. Millions have died in Africa and many more individuals are infected worldwide. In the United States more than 100,000 people have died and at least 1 million more are presently infected with the virus. Although there are some new drug treatments that are currently available for treating the disease, this pandemic shows no signs of abating. AIDS is a disease of an acquired immunodeficiency syndrome in humans caused by HIV. The first description of the disease was in 1981. Its causative agent, HIV, was discovered in 1983. As of 1993 it is estimated that about 13 million people were infected with HIV worldwide and this number has increased to about 21 million in 1996. See B. Jasny, Science, 260(5112), 1219 (1993) and P. Piot, Science, 272(5270), 1855 (1996). AIDS was first diagnosed in male homosexuals who exhibited a variety of infections of fungal (Candida albicans), protozoal (Pneumocystis carinii), and viral (Herpes zoster) origin. Many of these individuals also had an increased incidence of kaposi sarcoma and lymphoma. They had a depressed T helper/T suppressor

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lymphocyte cell ratio and an absence of delayed hypersensitivity responses. Collectively, these observations suggested a deficiency in cell-mediated immunity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for the treatment of viral disorders Inventor(s): Faller, Douglas V.; (Weston, MA) Correspondence: Ronald I. Eisenstein; NIXON PEABODY LLP; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20010009922 Date filed: January 8, 2001 Abstract: This invention relates to compositions and methods for the treatment of virus infections and other viral-associated disorders. Compositions comprise an inducing agent and an anti-viral agent. The inducing agent induces the expression of a cellular or viral product, such as viral thymidine kinase, increasing the sensitivity of proliferating cells to the anti-viral agent. Typical anti-viral agents are nucleoside analogs such as ganciclovir that inhibit viral replication. Methods involve administration of therapeutically effective amounts of the inducing agent with the anti-viral agent to destroy virus-infected cells. Viral infections that can be treated include infections by herpes viruses such as Kaposi's-associated herpes virus and Epstein-Barr virus, HIV infections and HTLV infections. These compositions and methods are particularly effective against episomal and latent infections in proliferating cells. Excerpt(s): This invention relates to compositions and methods for the treatment of viral disorders. Treatment involves administration of an inducing agent, to induce expression of a product in a virus-infected cell, and an anti-viral agent, that acts on the expressed product to destroy the virus-infected cell. A growing number of cellular disorders such as neoplastic malignancies have been found to contain viral genetic sequences or virus particles in the anomalous cells. For a large number of these disorders, the presence of the virus is believed to be causative or at least contributory instrument. Representative members of many of the known families of viruses have been found in such cells including members of the herpes family of viruses, the polyomaviruses and the hepatitis viruses. Epstein-Barr virus (EBV), a 172 kb herpes virus, is often found intimately associated with both mature and immature B cells and is believed to be involved to some degree in infectious mononucleosis, African Burkitt's lymphoma (BL) and nasopharyngeal carcinoma. EBV undergoes lytic replication after initial infection of oropharyngeal epithelia. The linear form genome is duplicated, packaged into the viral capsid and extruded from the cell by budding or lysis. One hundred viral proteins are synthesized during this lytic stage of the virus life cycle. In contrast, normal B cells incubated with EBV in vitro are efficiently immortalized and develop into continuously growing lymphoblastoid cell lines (LCIs). The cellular events that regulate these distinct outcomes are as yet unclear. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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EBV CTL epitopes Inventor(s): Burrows, Scott Renton; (Queensland, AU), Kerr, Beverley Mavis; (Queensland, AU), Khanna, Rajiv; (Queensland, AU), Misko, Ihor Stephan; (Queensland, AU), Moss, Denis James; (Queensland, AU) Correspondence: Steven L. Highlander, Esq.; FULBRIGHT & JAWORSKI L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20020150590 Date filed: August 1, 2001 Abstract: The present invention provides cytotoxic Epstein-Barr virus T-cell epitopes. These epitopes are QVKWRMTTL, VFSDGRVAC, VPAPAGPIV, TYSAGIVQI, LLDFVRFMGV, QNGALAINTF, VSSDGRVAC, VSSEGRVAC, VSSDGRVPC, VSSDGLVAC, VSSDGQ-VAC, VSSDGRVVC, VPAPPVGPIV, VEITPYEPIG, VEITPYEPTW, VELTPYKPTW, RRIYDLIKL, RKIYDLIEL and PYLFWLAGI. The present invention further provides vaccines including one or more of these epitopes, optionally with additional epitopes. Excerpt(s): The present invention relates to cytotoxic T-cell (CTL) epitopes within Epstein-Barr virus. The present invention also relates,to subunit vaccines including CTL epitopes. Epstein-Barr virus (EBV) is a gamma herpesvirus which establishes a latent lifelong infection in the host following acute infection (14, 15). While primary infection generally occurs in childhood without significant morbidity, adolescents and young adults may present with the symptoms of acute infectious mononucleosis (IM). The main feature of IM is a self-limiting lymphoproliferation involving both T and B cells accompanied by clinical symptoms such as fever and lymphadeiiopatlhy (52.53). Occasionally, the clinical symptoms persist and recur for extended periods after the initial infection. Episodic IM such as this has been described as chronic active EBV infection or, in some cases, severe chronic active EBV infection (35). EBV DNA has been detected in both serum and peripheral blood lymphocytes (PBL) during acute IM with the levels of detectable DNA gradually decreasing as the illness abates (21.22.58). Evidence for latent EBV infection includes the observation that spontaneous lymphoblastoid cell lines (LCLs), expressing latent proteins, can be regularly established from healthy immune individuals after explantation of either lymph node tissue (34) or fractionated B lymphocytes (59). Although latent EBV infection is usually asymptomatic, sequential studies have established that recrudescence of viral replication in the oral cavity may result in release of infectious virus (59). The exact site of persistence of the virus is uncertain, but the available evidence suggests that small lymphocytes in the circulation harbour the virus in a nonproductive episomal state (24). Accordingly, in asymptoinatic donors. EBV DNA is detectable by sensitive PCR analysis in PBL expressing the B-cell marker CD19(29, 55). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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ENHANCEMENT OF B CELL ACTIVATION AND IMMUNOGLOBULIN SECRETION BY CO-STIMULATION OF RECEPTORS FOR ANTIGEN AND EBV GP350/220 Inventor(s): LEES, ANDREW; (SILVER SPRING, MD), MOND, JAMES J.; (SILVER SPRING, MD) Correspondence: FINNEGAN HENDERSON FARABOW; GARRETT & DUNNER LLP; 1300 I STREET NW; WASHINGTON; DC; 20005 Patent Application Number: 20020119529 Date filed: June 10, 1999 Abstract: The present invention provides vaccine adjuvants comprising the Epstein Barr Virus glycoprotein 350/220 or naturally occurring variants thereof, a fusion protein comprising EBV Gp350/220 sequence which binds to the CR2 receptor, or a synthetically-derived fragment of Gp350/220 which retains the ability to bind to the CR2 receptor. The present invention further provides immunostimulatory compositions comprising an EBV Gp350/220 adjuvant sequence that binds the CR2 complex and at least one antigen of interest other than Gp350/220. Co-administration of the adjuvant with an antigen of interest, other than an antigen comprising EBV 350/220 sequence, enhances the immunogenicitiy of the antigen. In a preferred embodiment, the adjuvant is directly or indirectly covalently bound to an antigen of interest to form an immunogenic composition. In a most preferred embodiment of the composition, antibodies are elicited against at least one Gp350/220 epitope and against at least one epitope of the antigen. Excerpt(s): The present invention relates to the use of Epstein Barr Virus glycoprotein 350/220 (Gp350/220), and naturally-occurring or synthetically-derived fragments of Gp350/220 which retain the ability to bind to the CR2 receptor on B cells. The invention also relates to non-complement derived peptides that bind to the CR2 receptor as well complement-derived peptides and the hexapeptide LYNVEA. These proteins, peptides, and fragments can be used as vaccine adjuvants and as adjuvanting components of immunostimulatory compositions and vaccines. The invention also relates to the use of non-complement derived peptides that bind to the CR2 receptors, as well as complement derived peptides and the hexapeptide LYNVEA. Complement is the name given to a series of some 20 proteins which are activated by microbial invasion to form an important line of defense against infection. The most well-recognized complement functions are those leading to the osmotic lysis and/or phagocytosis of invading bacteria or parasites. Components in the cell walls of infectious organisms trigger the complex and interconnected pathways of the complement enzyme cascade. During this process the most abundant component, C3, is converted into an enzymatically active form and ultimately cleaved into a number of fragments such as C3a and a series of phagocytosis-promoting peptides including C3b and related peptides, iC3b, C3dg. C3a is an anaphylatoxin which triggers mast cells and basophils to release a host of chemotactic and inflammatory factors which both contribute to the activation of neutrophils and other phagocytic cells, and concentrate these cells at the site of microbial infection. C3b becomes covalently linked to the surface of the invading organism. The bound C3b interacts with the CR1 (CD35) receptors on the surface of the phagocytic cells. This interaction induces the activated phagocytes to engulf the microbes, which are then fused with cytoplasmic granules and destroyed. The destruction of invading microorganisms by phagocytic cells is an important part of cellular immunity.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Epstein barr virus induced genes Inventor(s): Birkenbach, Mark; (Tinley Park, IL), Kieff, Elliot; (Brookline, MA) Correspondence: WOLF GREENFIELD & SACKS, PC; FEDERAL RESERVE PLAZA; 600 ATLANTIC AVENUE; BOSTON; MA; 02210-2211; US Patent Application Number: 20020040133 Date filed: August 14, 2001 Excerpt(s): The present invention relates, in general, to Epstein Barr virus induced (EBI) genes. In particular, the present invention relates to DNA segments coding for EBI 1, EBI 2, or EBI 3 polypeptides; EBI 1, EBI 2, or EBI 3 polypeptides; recombinant DNA molecules; cells containing the recombinant DNA molecules; antisense EBI 1, EBI 2, or EBI 3 constructs; antibodies having binding affinity to an EBI 1, EBI 2, or EBI 3 polypeptide; hybridomas containing the antibodies; nucleic acid probes for the detection of the presence of Epstein Barr Virus; a method of detecting Epstein Barr virus in a sample; and kits containing nucleic acid probes or antibodies. Epstein-Barr Virus (EBV) is the cause of infectious mononucleosis, a benign proliferation of infected B lymphocytes (Henle, G., et al., Proc. Natl. Acad. Sci. USA 59(1):94-101 (1968)) and can also cause acute and rapidly progressive B lymphoproliferative disease in severely immune compromised patients or in experimental infection of tamarins (Miller, G., Fields Virol., 2nd ed., 1921-58 (1990)). Infection of human B lymphocytes, in vitro, results in expression of six virus encoded nuclear proteins (EBNAs) and two virus encoded membrane proteins (LMPs) (Kieff and Liebowitz, Fields Virol., 2nd ed., 1889-1920 (1990)), and in substantially altered cell growth (Nilsson and Klein, Adv. Cancer Res. 37(319):319-80 (1982)). EBV infected B lymphocytes recapitulate features of antigen stimulation in enlarging, increasing RNA synthesis, expressing activation antigens and adhesion molecules, secreting Ig and proliferating (Boyd, A. W., et al., J. Immunol. 134(3):1516-23 (1985); Gordon, J., et al., Immunology 58(4):591-5 (1986); Guy and Gordon, Intl. J. Cancer 43(4):703-8 (1989); Nilsson and Klein, Adv. Cancer Res. 37(319):319-80 (1982); Thorley-Lawson, D. A., et al., J. Immunol. 134(5):3007-12 (1985)). Unlike antigen stimulated B lymphocytes, EBV infected B lymphocytes continue to proliferate in vitro as immortalized lymphoblastoid cell lines (LCLs) (Nilsson, K., et al., Intl. J. Cancer 8(3):443-50 (1971)). EBV effects on lymphocytes have been studied by comparing the properties of EBV-negative [EBV(-)] Burkitt lymphoma (BL) cell lines and EBV-positive [EBV(+)] derivatives, infected by EBV, in vitro (Calender, A., et al., Proc. Natl. Acad. Sci. USA 84(22):8060-4 (1987); Ehlin-Henriksson, B., et al., Intl. J. Cancer 39(2):211-8 (1987); Nilsson and Klein, Adv. Cancer Res. 37(319):319-80 (1982); Rowe, M., et al., Intl. J. Cancer 37(3):367-73 (1986)). EBV(-) BL cells resemble proliferating centroblasts of germinal centers, characteristically expressing CD10, CD20, CD77 (BLA), class II antigen, and the carbohydrate recognized by peanut agglutinin (Calender, A., et al., Proc. Natl. Acad. Sci. USA 84(22):8060-4 (1987); Ehlin-Henriksson, B., et al., Intl. J. Cancer 39(2):211-8 (1987); Favrot, M. C., et al., Intl. J. Cancer 38(6):901-6 (1986); Gregory, C. D., et al., Intl. J. Cancer 42(2):213-20 (1988); Gregory, C. D., et al., J. Gen. Virol. 71:1481-1495 (1990); Gregory, C. D., et al., J. Immunol. 139(1):313-8 (1987); Rowe, M., et al., Intl. J. Cancer 37(3):367-73 (1986); Rowe, M., et al., Intl. J. Cancer 35(4):435-41 (1985)). Both EBV(-) BL cells and centroblasts lack surface IgD and antigens associated with early phases of mitogen stimulation in vitro, including CD23, CD39 and CD30. In general, EBV(+) BL cells closely resemble EBV infected primary B lymphocytes in not

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expressing CD10 or CD77 and in expressing early activation and differentiation markers, vimentin, Bac-1, Bcl-2, surface IgD and CD44 (Calender, A., et al., Proc. Natl. Acad. Sci. USA 84(22):8060-4 (1987); Ehlin-Henriksson, B., et al., Intl. J. Cancer 39(2):2118 (1987); Favrot, M. C., et al., Intl. J. Cancer 38(6):901-6 (1986); Gregory, C. D., et al., J. Gen. Virol. 71:1481-1495 (1990); Henderson, S., et al., Cell 65(7):1107-15 (1991); Rowe, M., et al., Intl. J. Cancer 37(3):367-73 (1986); Rowe, M., et al., EMBO J. 6(9):2743-51 (1987); Spira, G., et al., J. Immunol. 126(1):122-6(1981); Suzuki, T., et al., J. Immunol. 137(4):120813 (1986)). Experiments with single gene transfer into EBV(-) B lymphoma cells, or with specifically mutated EBV recombinants reveal that EBNA 2, LMP 1 and EBNA 3C are essential for lymphocyte growth transformation and alter cellular or viral gene expression. Expression of EBNA 2 alone in EBV(-) BL cell lines results in enhanced transcription of CD23, CD21 (Cordier, M., et al., J. Virol. 64(3):1002-13 (1990); Wang, F., et al., J. Virol. 64(S):2309-18 (1990); Wang, F., et al., Proc. Natl. Acad. Sci. USA 84(10):3452-6 (1987)), and c-fgr (Knutson, J. C., J. Virol. 64(6):2530-6 (1990)). EBNA 2 also transactivates the LMP promoters (Fahraeus, R., et al., Proc. Natl. Acad. Sci. USA 87(19):7390-4 (1990); Wang, F., et al., J. Virol. 64(7):3407-16 (1990)). Analysis of a series of EBNA 2 mutants indicates that the ability of EBNA 2 to transactivate gene expression is tightly linked to its essential role in cell growth transformation (Cohen, J. I., et al., J. Virol. 65(5):2545-54 (1991)). LMP 1 is also critical to EBV's effects on cell growth. LMP 1 transforms immortalized rodent fibroblasts (Baichwal and Sugden, Oncogene 2(5):461-7 (1988); Wang, D., et al., Cell 43:831-40 (1985) and induces vimentin, Bcl-2 and many of the activation markers and adhesion molecules that EBV induces in BL cells (Birkenbach, M., et al., J. Virol. 63(9):4079-84 (1989); Henderson, S., et al., Cell 65(7):110715 (1991); Wang, D., et al., J. Virol. 62(11):4173-84 (1988)). In EBV(-) BL cells, EBNA 3c induces higher level expression of CD21 (Wang, F., et al., J. Virol. 64(5):2309-18 (1990)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methylated, SmD homologous peptides, reactive with the antibodies from sera of living beings affected with systemic lupus erythematosus Inventor(s): Luhrmann, Reinhard Georg; (Marburg, DE), Meheus, Lydie; (Merelbeke, BE), Raymackers, Joseph; (Eke, BE), Union, Ann; (Aalter, BE) Correspondence: Patricia A. Kammerer; HOWREY SIMON ARNOLD & WHITE, LLP; 750 Bering Drive; Houston; TX; 77057-2198; US Patent Application Number: 20020165355 Date filed: January 24, 2002 Excerpt(s): The present invention relates to a method of producing certain peptides containing methylated arginines that are followed by a glycine residue and that constitute immunogenic determinants of antibodies present in sera from patients with systemic lupus erythematosus, or Epstein-Barr virus and wherein the methylation is a prerequisite for reacting with said antibodies. The invention also relates to the use of said peptides for diagnosis and treatment of systemic lupus erythematosus and related diseases, diseases in which Epstein-Barr virus has been implicated. Systemic lupus erythematosus is an autoimmune disease, in which the patient develops antibodies that react with many tissues of his own body. Dominant antibodies are directed against components of the cell nucleus, with epitopes that may be found in DNA, and in proteins that constitute small ribonucleoprotein particles (snRNPs). The first laboratory test ever devised for this disease was the LE (lupus erythematosus) cell test. This test has to be repeated many times, before it results in a positive reaction in about 90% of the

Patents 97

people with systemic lupus erythematosus. Also, the LE cell test is not specific for lupus, and can be positive in up to 20% of the people with rheumatoid arthritis, in some patients with other rheumatic conditions like Sjogren's syndrome or scleroderma, in patients with liver disease, and in persons taking drugs such as hydralazine and procainamide. The ANA test, which detects antibodies against nuclear antigens, is more specific for lupus than the LE test, and is positive in many patients that suffer from systemic lupus erythematosus. As with the LE test, a positive ANA is not diagnostic for lupus since the test may also be positive in people with scleroderma, dermatomyositis, rheumatoid arthritis, Sjogren's syndrome, in patients treated with certain drugs, or in patients suffering from infectious mononucleosis, liver disease, malaria etc. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel interleukin compositions and methods of use Inventor(s): Blazar, Beverly A.; (Providence, RI), Webb, Andrew C.; (Milton, MA) Correspondence: SALIWANCHIK LLOYD & SALIWANCHIK; A PROFESSIONAL ASSOCIATION; 2421 N.W. 41ST STREET; SUITE A-1; GAINESVILLE; FL; 326066669 Patent Application Number: 20010019713 Date filed: January 16, 2001 Abstract: A novel immunoregulatory factor, designated IL-X, is described which has been isolated from an Epstein-Barr virus (EBV) infected lymphoblastoid cell line. IL-X is a growth factor for EBV transformed human B lymphocytes and for murine helper T lymphocytes. Also taught are methods of raising antibodies to IL-X, and cloning of IL-X. Excerpt(s): This application is a continuation-in-part of co-pending application Ser. No. 08/026,132, filed Feb. 11, 1993. Epstein-Barr Virus (EBV) is a lymphotropic virus in humans that is closely associated with two malignancies, Burkitt's lymphoma, and nasopharyngeal carcinoma, as well as a lymphoproliferative disorder, infectious mononucleosis. Also, in recent years, several EBV-associated proliferative syndromes and malignancies have been described in the profoundly immunocompromised host. There are two main types of EBV carrying B lymphocyte lines, i.e., Burkitt's Lymphoma derived (BL) and lymphoblastoid (normal lymphocyte) derived cell line (LCL). BL lines, which are derived from malignant cells in tumor biopsies, are monoclonal, usually aneuploid with a specific chromosomal translocation, bear a characteristic glycoprotein pattern, and are tumorigenic in nude mice. The LCL lines are derived from normal B cells, are polyclonal, have a normal diploid karyotype, a glycoprotein pattern similar to stimulated normal B cells, and do not grow when explanted subcutaneously into nude mice. LCLs, however, do grow in nude mice when inoculated intracerebrally, suggesting that immunological restriction is important in controlling outgrowth of EBVcarrying cells, even in a xenogeneic host. Reports of polyclonal outgrowths of karyotypically normal EBV-carrying cells in immunodeficient individuals confirm this observation (Houweling, A., P. J. Eisen, A. J. Eb [1980] Virology 105:537; Rassoulzadegan, M., M. Binetriy, F. Cuzin [1982] Nature 300:713; Treisman, R., V. Novak, J. Favoloro, R. Kamen [1981] Nature 292:595; Giovanella, B., K. Nilsson, L. Zech, O. Yim, G. Klein, J. S. Stehlin [1979] Int. J. Cancer 24:103). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Peptides and nucleic acid sequences related to the epstein barr virus Inventor(s): Middeldorp, Jaap M.; (Oss, NL), van Grunsven, Wouterus M.J.; (Oss, NL) Correspondence: MYERS BIGEL SIBLEY & SAJOVEC; PO BOX 37428; RALEIGH; NC; 27627; US Patent Application Number: 20020169286 Date filed: December 21, 2001 Abstract: The present invention relates to peptides immunochemically reactive with antibodies to the Epstein-Barr virus (EBV), nucleic acid sequences encoding these peptides, monoclonal antibodies against these peptides, cell lines capable of producing monoclonal antibodies and anti-idiotype antibodies. The invention also relates to recombinant vector molecules comprising a nucleic acid sequence according to the invention and host cells transformed or transfected with these vector molecules. The invention is further concerned with immunological reagents and methods for the detection of EBV or anti-EBV antibodies and a method for the amplification and detection of Epstein Barr viral nucleic acid. Excerpt(s): EBV is an ubiquitous human herpes virus that was first discovered in association with the African (endemic or e) form of Burkitt's lymphoma (BL). Subsequently the virus was also found associated with nasopharyngeal carcinoma (NPC) and was shown to be the causative agent of infectious mononucleosis (IM). Infection usually occurs during early childhood, generally resulting in a subclinical manifestation, occasionally with mild symptoms. Infection during adolescence or adulthood, however, can give rise to IM characterized by the presence of atypical lymphocytes in the periphery. The bulk of these lymphocytes are T lymphocytes; however, included in their number are a small population of B lymphocytes infected by EBV. The infection of B lymphocytes may also be accomplished in vitro. Such cells become transformed and proliferate indefinitely in culture and have been referred to as "immortalized", "latently infected" or "growth transformed". As far as is known, all individuals who become infected with EBV remain latently infected for life. This is reflected by the lifelong continuous presence of small numbers of EBV-genome positive transformed B-cells among the circulating peripheral blood lymphocytes and the continuous but periodic shedding of virus in the oropharynx. In the vast majority of cases EBV infection results in a lymphoproliferative disease that may be temporarily debilitating, but is always benign and self-limiting. In certain immunosuppressed individuals, however, the result can be full-blown malignancy. This occurs in individuals who are immuno-suppressed intentionally, particularly children receiving organ transplants who are treated with cyclosporine A, or opportunistically, as in the case with individuals infected with HIV, or genetically, as in the case of affected males carrying the XLP (x-linked proliferative syndrome) gene. In these cases the resulting malignancies derive from the polyclonal proliferation of EBV-infected B cells. In addition, in such patients uncontrolled epithelial replication of the virus is detectable in lesions of oral hairy leukoplakia. Thus, the immune response plays a central role in the control of EBV infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Production of therapeutic proteins in transgenic cereal crops Inventor(s): Altosaar, Illimar; (Ottawa, CA), Dudani, Anil; (Ottawa, CA), Ganz, Peter; (Orleans, CA), Sardana, Ravinder; (Ottawa, CA), Tackaberry, Eilleen; (Ottawa, CA) Correspondence: Mr. W. Charles Kent; Ridout & Maybee LLP; 19th Floor; 150 Metcalfe St.; Ottawa; ON; K2P 1P1; CA Patent Application Number: 20030159182 Date filed: August 29, 2002 Abstract: There is provided a herpes virus vaccine produced in in the seeds of a cereal crop and a method of producing the vaccine. The method comprises: a) obtaining a nucleic acid sequence encoding a herpes virus antigen; b) introducing the nucleic acid sequence into cereal plant tissue competent to form seeds; c) permitting said cereal plant tissue to develop; and, d) directing preferential expression of the antigen encoded by the nucleic acid sequence in seeds formed by the cereal plant tissue. Herpes viruses antigens of particular interest include all or antigenic portions of gB (from human cytomegalovirus ("HCMV")), gH (from HCMV), and gD (from herpes simplex virus 1 or 2), as well as antigens from Epstein Barr virus and varicello-zoster virus-8. Envelope glycoproteins from herpes viruses are antigens of interest. Cereal crops of particular interest include rice, wheat, oats, barley, and corn. Vaccines produced according to the invention are very stable and may be administered by a variety of routes, including injection and contact with mucosal membranes, such as by oral administration in purified or unpurified form. Excerpt(s): Human cytomegalovirus ("HCMV") is a widely distributed member of the herpes virus family that is transmitted by blood and other body secretions. In immunocompromised individuals such as AIDS patients, organ transplant recipients and low weight pre-term infants, the virus can cause severe and/or lethal disease, while congenital infection may result in damage to the central nervous system. The HCMV encoded glycoprotein B complex ("gB") is a transmembrane protein of 907 amino acids (for the prototype Towne strain) which is initially synthesized in infected cells as a 105 kDa non-glycosylated polypeptide. In normal infected mammalian host cells, the gB polypeptide undergoes post-translational glycosylation, cleavage of the N-terminal 24 amino acid signal peptide, oligomerization and folding which take place in the endoplasmic reticulum of the cell, where it is transiently associated with a membranebound chaperonin. This results in transport of a 150 kDa gB precursor to the Golgi complex where further carbohydrate modifications occur and the polypeptide is proteolytically cleaved to yield products of 116 kDa and 58 kDa which are disulfide linked. Both species are targets for neutralizing and non-neutralizing antibodies, each representing both continuous and discontinuous epitopes. A phosphorylation site is located in the cytoplasmic tail and may be important for correct intracellular trafficking. The sequence of gB (Towne) is reported in Spaete et al., Virology 167(1), 207 (1988), Pub. Med. Acc. No. M22343. Mammalian immune responses are highly specific and sensitive to even minor differences between potential antigenic sites. Thus, changes to the posttranslational modification of an antigen such as gB will have the potential to render it unsuitable for use as a vaccine against infection by the native organism. Plant seeds are an ideal organ for the targeted synthesis of heterologous proteins. However, where the proteins of interest are of non-plant origin, numerous technical challenges arise in the production and recovery of useful transgenic proteins. In particular, differences in posttranslational modification and transport may render plant-produced proteins unsuitable for some uses in mammals.

100 Epstein Barr Virus

Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Quantitative epstein barr virus PCR rapid assay Inventor(s): Green, Pamela A.; (Cincinnati, OH), Witte, David P.; (Cincinnati, OH) Correspondence: FROST BROWN TODD, LLC; 2200 PNC CENTER; 201 E. FIFTH STREET; CINCINNATI; OH; 45202; US Patent Application Number: 20030175684 Date filed: February 13, 2002 Abstract: The present invention provides novel compositions comprising Epstein-Barr virus-specific oligonucleotides that are useful as primers to amplify particular regions of the genome during enzymatic nucleic acid amplification. The invention also provides a rapid, sensitive and specific method for the detection and quantitation of the virus which may be present in a clinical specimen, using the virus-specific primers and enzymatic nucleic acid amplification; hybridization of amplified target sequences, if present, with one or more Epstein-Barr virus-specific oligonucleotide probes which are labeled with a detectable moiety; and detection of the detectable moiety of labeled oligonucleotide probe hybridized to amplified target sequences of Epstein-Barr virus DNA. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application Serial No. 60/268,439, filed Feb. 13, 2001, which application is hereby incorporated by reference in its entirety. The invention relates generally to novel compositions and methods for detecting the presence of viruses that frequently infect humans and are associated with the development of human disease. More particularly, the invention is directed to an accurate and sensitive method for the diagnosis and quantitation of Epstein-Barr virus infection using specific oligonucleotides as primers to amplify particular regions of the genome of the virus sought to be detected in a clinical specimen. Epstein-Barr virus-specific oligonucleotides may be used in the subsequent detection of the amplified regions of DNA. Epstein-Barr virus (EBV), a human herpes virus, is ubiquitous in humans. Antibodies to polypeptides of the virus are present in over 80% of human serum samples from the United States and in even higher percentages from populations in Asia and Africa. Although it is prevalent throughout the world, the consequences of EBV infection vary among different populations. The virus is responsible for of infectious mononucleosis, a benign proliferation of infected B-lymphocytes, in Western countries and is implicated in Burkitt's lymphoma in Africa and nasopharyngeal carcinoma (NPC) in Asia. EBV can also cause acute and rapidly progressive B lymphoproliferative disease in severely immune compromised patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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VIRUS VACCINES Inventor(s): HACKETT, CRAIG S.; (WALLINGFORD, CT), SMITH, GALE EUGENE; (WALLINGFORD, CT), VOLVOVITZ, FRANKLIN; (WOODBRIDGE, CT), VOZNESENSKY, ANDREI I.; (WEST HARTFORD, CT), WILKINSON, BETHANIE E.; (HIGGANUM, CT) Correspondence: FROMMER LAWRENCE & HAUG; 745 FIFTH AVENUE- 10TH FL.; NEW YORK; NY; 10151; US Patent Application Number: 20020071848 Date filed: January 22, 1999 Abstract: Improved mammalian virus vaccines are combinations that contain an immunogenic amount of inactivated virus, such as influenza virus, Herpes varicella virus, measles virus, Epstein Barr virus, respiratory syncytial virus, parainfluenza 3, Herpes simplex type 1 virus, and Herpes simplex type 2 virus, and an immunogenic amount of a purified recombinant envelope protein from the virus, or a fragment or precursor of the protein. Alternatively, they contain either inactivated virus and/or envelope protein antigens and an adjuvant such as granulocyte-microphage colony stimulating factor. One embodiment of an influenza vaccine is prepared by combining inactivated virus, preferably three strains of the virus, and hemagglutinin, preferably a combination of respective hemagglutinins for each of the three strains present. In another embodiment, an influenza vaccine is prepared by combining inactivated virus, again preferably three strains of the virus, and neuraminidase, preferably a combination of respective neuraminidase for each of the three strains present. In a third embodiment, the vaccine contains inactivated virus and both hemagglutinin and neuraminidase, preferably using three strains of each. Granulocyte-macrophage colony stimulating factor is, optionally, added to these embodiments. Excerpt(s): This invention relates to improved virus vaccines for influenza, Herpesviruses, and the like. Immunization to protect against communicable disease is one of the most successful and cost-effective practices of modern medicine. Smallpox has been completely eliminated by vaccination, and the incidence of many other dreaded diseases such as polio and diphtheria has been drastically reduced through immunization programs. However, vaccines, especially those based on the use of inactivated viruses, vary in effectiveness. For example, while the currently licensed influenza vaccine is reportedly over 80% efficacious in young adults, it is only approximately 60% efficacious in adults 65 years of age and older, and less than 50% effective in children under 2 years of age. The recently licensed chicken pox vaccine is reportedly approximately 70% efficacious, and there are currently no effective vaccines against many important viral diseases including those caused by respiratory syncytial virus, parainfluenza 3 virus, Rotavirus and the human immunodeficiency virus. In some cases licensed inactivated viral vaccines may cause adverse reactions which have prevented their use at the higher dosages needed to improve efficacy. Inactivated virus vaccines confer protection by stimulating immune responses to proteins found in the free virus. Antibodies to the mature envelope proteins found on free virus may be optimal in blocking the initial events of infection (such as virus binding to a cell receptor and attachment and entry into a cell) following exposure to a virus, but may be suboptimal once a virus has entered a cell. Once infected, the cells and the cell-associated immature virions contain precursors to the mature envelope proteins. These precursor proteins may stimulate more optimal immune responses for stemming the spread of infection and preventing clinical illness when the body's first line of defense, antibodies to free virus, does not completely prevent all virus from infecting cells.


Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with Epstein Barr virus, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “Epstein Barr virus” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on Epstein Barr virus. You can also use this procedure to view pending patent applications concerning Epstein Barr virus. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON EPSTEIN BARR VIRUS Overview This chapter provides bibliographic book references relating to Epstein Barr virus. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on Epstein Barr virus include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Chapters on Epstein Barr Virus In order to find chapters that specifically relate to Epstein Barr virus, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and Epstein Barr virus using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “Epstein Barr virus” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on Epstein Barr virus: •

AIDS and Related Conditions Source: in Little, J.W., et al. Dental Management of the Medically Compromised Patient. 5th ed. St. Louis, MO: Mosby, Inc. 1997. p. 325-356. Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $48.00 plus shipping and handling. ISBN: 0815156340. Summary: A working knowledge of the multitude of compromised health states is essential for dental professionals, as the majority of medically compromised patients need or want oral health care. This chapter on AIDS and related conditions is from a text that provides the dental practitioner with an up to date reference work describing the dental management of patients with selected medical problems. After an introductory section that covers definitions, morbidity and mortality statistics, and geographic factors, the authors discuss incidence and prevalence, etiology, pathophysiology and


complications, signs and symptoms (clinical presentation and laboratory findings), the medical management of patients with AIDS, managing opportunistic infections (cytomegalovirus, herpes viruses, Epstein Barr virus, human papillomavirus), and the dental management of this population. Dental considerations include the prevention of medical complications, patient evaluation, treatment planning considerations, and common oral complications in patients with AIDS, including candidiasis, Kaposi's sarcoma, hairy leukoplakia, aphthous lesions (canker sores), HIV periodontal disease, salivary gland disease, and lymphadenopathy. 18 figures. 16 tables. 108 references.

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CHAPTER 7. PERIODICALS AND NEWS ON EPSTEIN BARR VIRUS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover Epstein Barr virus.

News Services and Press Releases One of the simplest ways of tracking press releases on Epstein Barr virus is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “Epstein Barr virus” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to Epstein Barr virus. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “Epstein Barr virus” (or synonyms). The following was recently listed in this archive for Epstein Barr virus: •

Social status does not explain lymphoma risk linked to infectious mononucleosis Source: Reuters Medical News Date: May 02, 2002


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DiaSorin receives FDA approval for Epstein Barr Virus assay technology Source: Reuters Medical News Date: July 01, 1999

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Trinity's Epstein Barr virus markers grow to five Source: Reuters Medical News Date: August 06, 1998

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Incstar's Epstein Barr Virus Test Approved Source: Reuters Medical News Date: June 29, 1995 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “Epstein Barr virus” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “Epstein Barr virus” (or synonyms). If you know the name of a company that is relevant to Epstein Barr virus, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.

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BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “Epstein Barr virus” (or synonyms).

Academic Periodicals covering Epstein Barr Virus Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to Epstein Barr virus. In addition to these sources, you can search for articles covering Epstein Barr virus that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

11

These publications are typically written by one or more of the various NIH Institutes.


•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.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 citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

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

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

12

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). 13 See http://www.nlm.nih.gov/databases/databases.html.


•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The 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 “Epstein Barr virus” (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 19707 70 613 320 0 20710

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 “Epstein Barr virus” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

15

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.

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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 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: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

19 Adapted 20

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 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.

117

APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on Epstein Barr virus can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internetbased services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to Epstein Barr virus. 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 Epstein Barr virus. 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 “Epstein Barr virus”:


•

Other guides Epstein Barr and Mononucleosis http://www.nlm.nih.gov/medlineplus/tutorials/epsteinbarrandmonoloader.html Hemorrhagic Fevers http://www.nlm.nih.gov/medlineplus/hemorrhagicfevers.html Herpes Simplex http://www.nlm.nih.gov/medlineplus/herpessimplex.html Infection Control http://www.nlm.nih.gov/medlineplus/infectioncontrol.html Infectious Mononucleosis http://www.nlm.nih.gov/medlineplus/infectiousmononucleosis.html Influenza http://www.nlm.nih.gov/medlineplus/influenza.html Viral Infections http://www.nlm.nih.gov/medlineplus/viralinfections.html

Within the health topic page dedicated to Epstein Barr virus, the following was listed: •

General/Overview Epstein Barr and Mononucleosis http://www.nlm.nih.gov/medlineplus/tutorials/epsteinbarrandmonoloader.html Epstein-Barr Virus and Infectious Mononucleosis Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/diseases/ebv.htm Mononucleosis Source: American Academy of Family Physicians http://familydoctor.org/handouts/077.html Mononucleosis Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00352

•

Diagnosis/Symptom Mono Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/mono/test.html Neck Swelling: Self-Care Flowcharts Source: American Academy of Family Physicians http://familydoctor.org/flowcharts/514.html

•

Children Infectious Mononucleosis Source: Nemours Foundation http://kidshealth.org/parent/infections/bacterial_viral/mononucleosis.html

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What's Mono? Source: Nemours Foundation http://kidshealth.org/kid/talk/qa/mono.html •

Latest News Mononucleosis Ups Risk for HIV Infection Source: 11/25/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14831 .html

•

Organization National Center for Infectious Diseases http://www.cdc.gov/ncidod/index.htm National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/

•

Teenager Mononucleosis Source: Nemours Foundation http://kidshealth.org/teen/infections/common/mononucleosis.html On the Teen Scene: When Mono Takes You Out of the Action Source: Food and Drug Administration http://www.fda.gov/fdac/features/1998/398_mono.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. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Epstein-Barr Virus and Infectious Mononucleosis Summary: Epstein-Barr virus, frequently referred to as EBV, is a member of the herpesvirus family and one of the most common human viruses. Source: Centers for Disease Control and Prevention, U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6978


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 Epstein Barr virus. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •


•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to Epstein Barr virus. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with Epstein Barr virus. 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 Epstein Barr virus. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at

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http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “Epstein Barr virus” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “Epstein Barr virus”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “Epstein Barr virus” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “Epstein Barr virus” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.22

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

22

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.


libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)23: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

23

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/


•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/


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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

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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/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on Epstein Barr virus: •

Basic Guidelines for Epstein Barr Virus Infectious mononucleosis (CMV) Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000568.htm Infectious mononucleosis (EB) Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000591.htm

•

Signs & Symptoms for Epstein Barr Virus Ataxia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003198.htm Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm


Drowsiness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003208.htm Enlarged liver Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Enlarged lymph nodes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003097.htm Enlarged spleen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003276.htm Facial swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003105.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Jaundice Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003243.htm Loss of appetite Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003121.htm Malaise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm Muscle aches Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Muscular aches Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Neck stiffness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Rapid heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Seizures Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm

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Sensitivity to light Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003041.htm Shortness of breath Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Skin rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Sore throat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003053.htm Swollen lymph glands Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003097.htm Tiredness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm •

Diagnostics and Tests for Epstein Barr Virus Aldolase Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003566.htm Anti-smooth muscle antibody Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003531.htm AST Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003472.htm Blood differential Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Chemistry panel Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003468.htm Coombs' test, direct Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003344.htm Cryoglobulins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003555.htm Febrile/cold agglutinins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003549.htm Heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003399.htm Immunoelectrophoresis - serum Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003541.htm


Immunofluorescence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003521.htm LDH Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003471.htm LDH isoenzymes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003499.htm Leukocyte alkaline phosphatase Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003651.htm Monospot test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003454.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Quantitative immunoglobulins (nephelometry) Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003545.htm Rheumatoid factor Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003548.htm T(thymus derived) lymphocyte count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003516.htm •

Nutrition for Epstein Barr Virus Fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm

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Background Topics for Epstein Barr Virus Acute Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002215.htm Analgesics Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002123.htm Antigen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002224.htm Enzyme Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002353.htm Exudate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002357.htm

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Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Malignancy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002253.htm Palpation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002284.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.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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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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EPSTEIN BARR VIRUS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [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] Acyclovir: Functional analog of the nucleoside guanosine. It acts as an antimetabolite, especially in viruses. It is used as an antiviral agent, especially in herpes infections. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] 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] 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] 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]


Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adverse Effect: An unwanted side effect of treatment. [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] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agammaglobulinemia: An immunologic deficiency state characterized by an extremely low level of generally all classes of gamma-globulin in the blood. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Agglutinins: Substances, usually of biological origin, that cause cells or other organic particles to aggregate and stick to each other. They also include those antibodies which cause aggregation or agglutination of a particulate or insoluble antigen. [NIH] Agonists: Drugs that trigger an action from a cell or another drug. [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] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH]

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Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-helix: One of the secondary element of protein. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] 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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [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] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. [NIH] Anaplastic large cell lymphoma: A rare agressive form of lymphoma (cancer that begins in cells of the lymphatic system) that is usually of T-cell origin. [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] Anergy: Absence of immune response to particular substances. [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] 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] Antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. [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] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Antiviral Agents: Agents used in the prophylaxis or therapy of virus diseases. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase;

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binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] 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] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arginine butyrate: A substance that is being studied as a treatment for cancer. [NIH] Arteries: The vessels carrying blood away from the heart. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU] 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] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that


produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Basal 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] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Bed Rest: Confinement of an individual to bed for therapeutic or experimental reasons. [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] 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]

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Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [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] 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] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] 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 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 transfusion: The administration of blood or blood products into a blood vessel. [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 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 Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] 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] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] 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] 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]

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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] 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] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] 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 Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [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] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU]


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] 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] 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] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chickenpox: A mild, highly contagious virus characterized by itchy blisters all over the body. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] 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] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] 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] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH]

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Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] 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] Coliphages: Viruses whose host is Escherichia coli. [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] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Communicable disease: A disease that can be transmitted by contact between persons. [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] Complementarity Determining Regions: Three regions (CDR1, CDR2 and CDR3) of amino acid sequence in theimmunoglobulin variable region that are highly divergent. Together the CDRs from the light and heavy immunoglobulin chains form a surface that is complementary to the antigen. These regions are also present in other members of the immunoglobulin superfamily, for example, T-cell receptors (receptors, antigen, T-cell). [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, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [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] 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] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] 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] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH]

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Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Cooperative group: A group of physicians, hospitals, or both formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer treatments often require many more people than a single physician or hospital can care for. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [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]


Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] 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] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoplasmic Granules: Condensed areas of cellular material that may be bounded by a membrane. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Defective Viruses: Viruses which lack a complete genome so that they cannot completely replicate or cannot form a protein coat. Some are host-dependent defectives, meaning they can replicate only in cell systems which provide the particular genetic function which they lack. Others, called satellite viruses, are able to replicate only when their genetic defect is complemented by a helper virus. [NIH] 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

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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]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dilatation: The act of dilating. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [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] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duct: A tube through which body fluids pass. [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] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] EBV: A DNA virus of the herpes group discovered in cultures of Burkitt's lymphoma cells. EBV is the cause of infectious mononucleosis, and it has an integration site on human chromosome 14. [NIH] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] 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

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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] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [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] Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [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] Endotoxin: Toxin from cell walls of bacteria. [NIH] Enhancers: Transcriptional element in the virus genome. [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]

Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]

for

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] 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] Epidemiological: Relating to, or involving epidemiology. [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] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of

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antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Epstein: Failure of the upper eyelid to move downward on downward movement of the eye, occurring in premature and nervous infants. [NIH] Epstein-Barr virus: EBV. A common virus that remains dormant in most people. It has been associated with certain cancers, including Burkitt's lymphoma, immunoblastic lymphoma, and nasopharyngeal carcinoma. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Induratum: A type of panniculitis characterized histologically by the presence of granulomas, vasculitis, and necrosis. It is traditionally considered to be the tuberculous counterpart of nodular vasculitis, but is now known to occur without tuberculous precedent. It is seen most commonly in adolescent and menopausal women, is initiated or exacerbated by cold weather, and typically presents as one or more recurrent erythrocyanotic nodules or plaques on the calves. The nodules may progress to form indurations, ulcerations, and scars. [NIH]

Erythema Multiforme: A skin and mucous membrane disease characterized by an eruption of macules, papules, nodules, vesicles, and/or bullae with characteristic "bull's-eye" lesions usually occurring on the dorsal aspect of the hands and forearms. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estrogen: One of the two female sex hormones. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excisional: The surgical procedure of removing a tumor by cutting it out. The biopsy is then examined under a microscope. [NIH] Excisional biopsy: A surgical procedure in which an entire lump or suspicious area is removed for diagnosis. The tissue is then examined under a microscope. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation,


visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [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. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Free Radical Scavengers: Substances that influence the course of a chemical reaction by ready combination with free radicals. Among other effects, this combining activity protects pancreatic islets against damage by cytokines and prevents myocardial and pulmonary perfusion injuries. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU]

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Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [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 Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. [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] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by


such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germinal Center: The activated center of a lymphoid follicle in secondary lymphoid tissue where B-lymphocytes are stimulated by antigens and helper T cells (T-lymphocytes, helperinducer) are stimulated to generate memory cells. [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] Glandular fever: A highly contagious disease of rodents caused by Pasteurella (Francisella) tularensis which may infect farm animals. It is spread mechanically either by flies or ticks, or by direct inoculation. It is characterized by fever and tubercle-like nodule formations. [NIH] Glial Fibrillary Acidic Protein: An intermediate filament protein found only in glial cells or cells of glial origin. MW 51,000. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] 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] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH]

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Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulomas: Small lumps in tissues caused by inflammation. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Helix-loop-helix: Regulatory protein of cell cycle. [NIH] Helper Viruses: Viruses which enable defective viruses to replicate or to form a protein coat by complementing the missing gene function of the defective (satellite) virus. Helper and satellite may be of the same or different genus. [NIH] Hemagglutinins: Agents that cause agglutination of red blood cells. They include antibodies, blood group antigens, lectins, autoimmune factors, bacterial, viral, or parasitic blood agglutinins, etc. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [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]


Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemosiderin: Molecule which can bind large numbers of iron atoms. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis Viruses: Any of the viruses that cause inflammation of the liver. They include both DNA and RNA viruses as well viruses from humans and animals. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatomegaly: Enlargement of the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Genitalis: Herpes simplex of the genitals. [NIH] Herpes Simplex Encephalitis: An inflammatory disease of the skin or mucous membrane characterized by the formation of clusters of small vesicles. [NIH] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [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]

Histiocytosis: General term for the abnormal appearance of histiocytes in the blood. Based on the pathological features of the cells involved rather than on clinical findings, the histiocytic diseases are subdivided into three groups: Langerhans cell histiocytosis, nonLangerhans cell histiocytosis, and malignant histiocytic disorders. [NIH] Histology: The study of tissues and cells under a microscope. [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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Hospitals, Public: Hospitals controlled by various types of government, i.e., city, county, district, state or federal. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Housekeeping: The care and management of property. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is

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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] Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent. [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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] 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] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [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] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH]


Idiotype: The unique antigenic determinant in the variable region. [NIH] Immortal: Stage when the mother cell and its descendants will multiply indefinitely. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunization Programs: Organized services to administer immunization procedures in the prevention of various diseases. The programs are made available over a wide range of sites: schools, hospitals, public health agencies, voluntary health agencies, etc. They are administered to an equally wide range of population groups or on various administrative levels: community, municipal, state, national, international. [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunoblastic Lymphadenopathy: A disorder characterized by proliferation of arborizing small vessels, prominent immunoblastic proliferations and amorphous acidophilic interstitial material. Clinical manifestations include fever, sweats, weight loss, generalized lymphadenopathy and frequently hepatosplenomegaly. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunoglobulin Variable Region: That region of the immunoglobulin (antibody) molecule that varies in its amino acid sequence and composition, confers the antigenic specificity, and

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is thought to comprise the binding site for the antigen. It is located at the N-terminus of the Fab fragment of the immunoglobulin. It includes hypervariable regions (complementarity determining regions) and framework regions. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Immunotoxin: An antibody linked to a toxic substance. Some immmunotoxins can bind to cancer cells and kill them. [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] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a


specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infectious Mononucleosis: A common, acute infection usually caused by the Epstein-Barr virus (Human herpesvirus 4). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage

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requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravenous: IV. Into a vein. [NIH] 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]

Involution: 1. A rolling or turning inward. 2. One of the movements involved in the gastrulation of many animals. 3. A retrograde change of the entire body or in a particular organ, as the retrograde changes in the female genital organs that result in normal size after delivery. 4. The progressive degeneration occurring naturally with advancing age, resulting in shrivelling of organs or tissues. [EU] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill


cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kaposi: A tumor characterized by development, essentially in men, of violet red patches and nodules on the skin. This disease also affects deeper organs. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] 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.

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[NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH]


Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphadenopathy: Disease or swelling of the lymph nodes. [NIH] Lymphangitis: Inflammation of a lymphatic vessel or vessels. Acute lymphangitis may result from spread of bacterial infection (most commonly beta-haemolytic streptococci) into the lymphatics, manifested by painful subcutaneous red streaks along the course of the vessels. [EU] 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] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocyte Transformation: Morphologic alteration of small lymphocytes in culture into large blast-like cells able to synthesize DNA and RNA and to divide mitotically. It is induced by interleukins, mitogens such as phytohemagglutinins, and by specific antigens. It may also occur in vivo, as in graft rejection and chronic myelogenous leukemia. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphomatoid Granulomatosis: An angiocentric and angiodestructive lymphoreticular proliferative disorder primarily involving the lungs. Histologically it simulates malignant lymphoma and in some cases may progress to lymphoma. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphoproliferative Disorders: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU]

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Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Measles Virus: The type species of morbillivirus and the cause of the highly infectious human disease measles, which affects mostly children. [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] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Melanin: The substance that gives the skin its color. [NIH]


Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] 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] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it

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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] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] 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] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Mononucleosis: The presence of an abnormally large number of mononuclear leucocytes (monocytes) in the blood. The term is often used alone to refer to infectious mononucleosis. [EU]

Morbillivirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have hemagglutinin but not neuraminidase activity. All members produce both cytoplasmic and intranuclear inclusion bodies. MEASLES VIRUS is the type species. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat


(lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [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] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] 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

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stimulation of 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] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Nidation: Implantation of the conceptus in the endometrium. [EU] 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 Matrix: The fibrogranular network of residual structural elements within which are immersed both chromatin and ribonucleoproteins. It extends throughout the nuclear interior from the nucleolus to the nuclear pore complexes along the nuclear periphery. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleocapsid: A protein-nucleic acid complex which forms part or all of a virion. It consists of a capsid plus enclosed nucleic acid. Depending on the virus, the nucleocapsid may correspond to a naked core or be surrounded by a membranous envelope. [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH]


Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] 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] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncology: The study of cancer. [NIH] Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [NIH]

Orf: A specific disease of sheep and goats caused by a pox-virus that is transmissible to man and characterized by vesiculation and ulceration of the lips. [NIH]

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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] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Ornithine Decarboxylase: A pyridoxal-phosphate protein, believed to be the rate-limiting compound in the biosynthesis of polyamines. It catalyzes the decarboxylation of ornithine to form putrescine, which is then linked to a propylamine moiety of decarboxylated Sadenosylmethionine to form spermidine. EC 4.1.1.17. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Oropharynx: Oral part of the pharynx. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] 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] 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] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Panniculitis: General term for inflammation of adipose tissue, usually of the skin, characterized by reddened subcutaneous nodules. [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] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Peanut Agglutinin: Lectin purified from peanuts (Arachis hypogaea). It binds to poorly differentiated cells and terminally differentiated cells and is used in cell separation techniques. [NIH] Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [NIH] Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and

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covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] 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] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylate: 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] Photoreceptors: Cells specialized to detect and transduce light. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]


Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Phytohemagglutinins: Mucoproteins isolated from the kidney bean (Phaseolus vulgaris); some of them are mitogenic to lymphocytes, others agglutinate all or certain types of erythrocytes or lymphocytes. They are used mainly in the study of immune mechanisms and in cell culture. [NIH] Picornavirus: Any of a group of tiny RNA-containing viruses including the enteroviruses and rhinoviruses. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [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] Pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Polychlorinated Biphenyls: Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants. [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] 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

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tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Population Control: Includes mechanisms or programs which control the numbers of individuals in a population of humans or animals. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] 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] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] 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 central nervous system lymphoma: Cancer that arises in the lymphoid tissue found in the central nervous system (CNS). The CNS includes the brain and spinal cord. [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] Procainamide: A derivative of procaine with less CNS action. [NIH] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH]


Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] 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] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [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

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proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] 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] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [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]

Putrescine: A toxic diamine formed by putrefaction from the decarboxylation of arginine and ornithine. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] 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, 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] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [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] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] 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] Reading Frames: The sequence of codons by which translation may occur. A segment of mRNA 5'AUCCGA3' could be translated in three reading frames, 5'AUC. or 5'UCC. or 5'CCG., depending on the location of the start codon. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH]

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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] 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] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [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 failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Replicon: In order to be replicated, DNA molecules must contain an origin of duplication and in bacteria and viruses there is usually only one per genome. Such molecules are called replicons. [NIH] Respiratory syncytial virus: RSV. A virus that causes respiratory infections with cold-like symptoms. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [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] 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] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhadinovirus: A genus of the family Herpesviridae, subfamily Gammaherpesvirinae, infecting New World primates. Herpesvirus 2, Ateline is the type species. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribonucleoproteins: Proteins conjugated with ribonucleic acids (RNA) or specific RNA. Many viruses are ribonucleoproteins. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Rod: A reception for vision, located in the retina. [NIH] Saimiri: A genus of the family Cebidae consisting of four species: S. boliviensis, S. orstedii (red-backed squirrel monkey), S. sciureus (common squirrel monkey), and S. ustus. They inhabit tropical rain forests in Central and South America. S. sciureus is used extensively in research studies. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH]

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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] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Scleroproteins: Simple proteins characterized by their insolubility and fibrous structure. Within the body, they perform a supportive or protective function. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] 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] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Senescence: The bodily and mental state associated with advancing age. [NIH] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serology: The study of serum, especially of antigen-antibody reactions in vitro. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] 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]


Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small 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]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for 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] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH]

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Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermidine: A polyamine formed from putrescine. It is found in almost all tissues in association with nucleic acids. It is found as a cation at all pH values, and is thought to help stabilize some membranes and nucleic acid structures. It is a precursor of spermine. [NIH] Spermine: A biogenic polyamine formed from spermidine. It is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at all pH values. Spermine is associated with nucleic acids, particularly in viruses, and is thought to stabilize the helical structure. [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] 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] Splenomegaly: Enlargement of the spleen. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Squamous: Scaly, or platelike. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Stasis: A word termination indicating the maintenance of (or maintaining) a constant level; preventing increase or multiplication. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [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]


Steroids: Drugs used to relieve swelling and inflammation. [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] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stringency: Experimental conditions (e. g. temperature, salt concentration) used during the hybridization of nucleic acids. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] 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] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] 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] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH]

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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] Synchrony: The normal physiologic sequencing of atrial and ventricular activation and contraction. [NIH] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [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] 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 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] Thioredoxin: A hydrogen-carrying protein that participates in a variety of biochemical reactions including ribonucleotide reduction. Thioredoxin is oxidized from a dithiol to a disulfide during ribonucleotide reduction. The disulfide form is then reduced by NADPH in a reaction catalyzed by thioredoxin reductase. [NIH] Thiourea: A photographic fixative used also in the manufacture of resins. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), this substance may reasonably be anticipated to be a carcinogen (Merck Index, 9th ed). Many of its derivatives are antithryoid agents and/or free radical scavengers. [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]


Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Ticks: Blood-sucking arachnids of the order Acarina. [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] Tonsils: Small masses of lymphoid tissue on either side of the throat. [NIH] Topical: On the surface of the body. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH]

Dictionary 189

Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [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] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] 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 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] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccine adjuvant: A substance added to a vaccine to improve the immune response so that less vaccine is needed. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Varicella: Chicken pox. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricular: Pertaining to a ventricle. [EU] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU]

Dictionary 191

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] Vial: A small bottle. [EU] Vimentin: An intermediate filament protein found in most differentiating cells, in cells grown in tissue culture, and in certain fully differentiated cells. Its insolubility suggests that it serves a structural function in the cytoplasm. MW 52,000. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viral Vaccines: Suspensions of attenuated or killed viruses administered for the prevention or treatment of infectious viral disease. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Virus Activation: The mechanism by which latent viruses, such as genetically transmitted tumor viruses or prophages of lysogenic bacteria, are induced to replicate and are released as infectious viruses. It may be effected by various endogenous and exogenous stimuli, including B-cell lipopolysaccharides, glucocorticoid hormones, halogenated pyrimidines, ionizing radiation, ultraviolet light, and superinfecting viruses. [NIH] Virus Diseases: A general term for diseases produced by viruses. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] 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] Voluntary Health Agencies: Non-profit organizations concerned with various aspects of health, e.g., education, promotion, treatment, services, etc. [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] Xenograft: The cells of one species transplanted to another species. [NIH] Xeroderma Pigmentosum: A rare, pigmentary, and atrophic autosomal recessive disease affecting all races. It is manifested as an extreme photosensitivity to ultraviolet light as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yellow Fever: An acute infectious disease primarily of the tropics, caused by a virus and transmitted to man by mosquitoes of the genera Aedes and Haemagogus. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

193

INDEX A Abdomen, 135, 142, 163, 165, 175, 185, 186, 191 Abdominal, 135, 163, 173, 174 Aberrant, 20, 43, 135 Acceptor, 135, 165, 173, 188, 189 Acquired Immunodeficiency Syndrome, 49, 63, 91, 135 Actin, 17, 135 Acute leukemia, 75, 135 Acute lymphoblastic leukemia, 73, 135 Acute lymphocytic leukemia, 4, 135 Acyclovir, 4, 5, 39, 88, 90, 135, 155 Adaptability, 135, 143 Adenosine, 135, 159, 175 Adenovirus, 42, 135 Adipose Tissue, 135, 173 Adjuvant, 94, 101, 135, 155 Adolescence, 27, 83, 85, 87, 98, 135 Adrenal Cortex, 136, 178 Adverse Effect, 136, 184 Affinity, 38, 45, 95, 136, 139, 165, 167, 184 Affinity Chromatography, 45, 136 Agammaglobulinemia, 36, 136 Agar, 136, 176 Agglutinins, 131, 136, 157 Agonists, 39, 136 Algorithms, 136, 141 Alkaline, 132, 136, 142 Alkaline Phosphatase, 132, 136 Alkylating Agents, 136, 190 Alleles, 83, 136, 165 Allogeneic, 31, 73, 74, 136, 157 Allogeneic bone marrow transplantation, 74, 136 Alpha Particles, 136, 180 Alpha-1, 5, 137 Alpha-helix, 84, 137, 164 Alternative medicine, 106, 137 Amino Acid Sequence, 54, 137, 138, 146, 155, 160 Amino Acids, 53, 99, 137, 145, 155, 172, 174, 176, 179, 182, 189, 190 Amino-terminal, 10, 137 Amplification, 98, 100, 137 Anaesthesia, 137, 162 Anal, 4, 137 Analog, 135, 137, 154, 155

Analogous, 137, 188 Analytes, 118, 137 Anaphylatoxins, 137, 146 Anaplastic, 74, 137 Anaplastic large cell lymphoma, 74, 137 Anatomical, 137, 151, 161, 183 Anemia, 137, 167, 169 Anergy, 46, 137 Animal model, 19, 28, 39, 42, 46, 56, 137 Annealing, 138, 176 Anogenital, 7, 138 Antibacterial, 138, 185 Antibiotic, 82, 138, 142, 185, 187 Antibody therapy, 15, 62, 138 Anticoagulant, 138, 179 Antigen-Antibody Complex, 87, 138, 145 Antigen-presenting cell, 138, 149 Antihypertensive, 138, 159 Anti-inflammatory, 138, 156, 174 Antimetabolite, 135, 138, 154 Antineoplastic, 136, 138, 154, 159 Antioxidant, 138, 173 Antiviral, 4, 6, 18, 53, 56, 77, 78, 88, 90, 135, 138 Antiviral Agents, 6, 138 Anus, 137, 138, 139, 142 Aponeurosis, 139, 155 Apoptosis, 8, 15, 17, 20, 25, 47, 60, 139 Applicability, 12, 139 Aqueous, 139, 140, 148 Arachidonic Acid, 139, 178 Arginine, 40, 77, 137, 139, 173, 179 Arginine butyrate, 40, 77, 139 Arteries, 139, 141, 147, 165, 168 Assay, 11, 16, 18, 59, 83, 85, 100, 106, 139, 160 Astrocytes, 24, 139 Asymptomatic, 37, 46, 87, 90, 93, 139 Ataxia, 73, 129, 139, 187 Atrial, 139, 187 Attenuated, 139, 149, 191 Atypical, 3, 98, 139, 162 Auditory, 13, 139 Autoantibodies, 26, 37, 53, 139, 140 Autoantigens, 25, 26, 139, 140 Autoimmune disease, 26, 43, 96, 140, 169 Autoimmunity, 25, 26, 140 Autologous, 16, 32, 55, 140


Axillary, 21, 140 B Bacteria, 68, 94, 138, 140, 152, 153, 166, 168, 176, 179, 180, 181, 184, 185, 186, 188, 190, 191 Bacterial Infections, 82, 140 Bacteriophage, 35, 140, 176, 188 Basal Ganglia, 139, 140, 155 Basal Ganglia Diseases, 139, 140 Base, 4, 21, 140, 149, 155, 164, 187 Basophils, 94, 140, 157, 165 Bed Rest, 5, 140 Benign, 10, 20, 25, 82, 83, 95, 98, 100, 140, 155, 157, 170, 180, 191 Benign tumor, 25, 140 Beta-Galactosidase, 39, 47, 140 Bilateral, 140, 182 Bile, 140, 155, 159, 165 Binding Sites, 10, 140 Bioavailable, 40, 141 Biochemical, 9, 17, 30, 35, 37, 47, 48, 49, 136, 138, 141, 154, 156, 164, 187 Biochemical reactions, 141, 187 Biological therapy, 141, 157 Biomarkers, 57, 141 Biopsy, 5, 6, 11, 57, 141, 153 Biopsy specimen, 6, 11, 141 Biosynthesis, 8, 139, 141, 173, 178 Biotechnology, 59, 106, 113, 141 Biotin, 141, 172 Bladder, 141, 169, 178 Blastocyst, 141, 146, 151, 173, 176, 189 Blood pressure, 138, 141, 143, 159, 169, 184 Blood transfusion, 21, 141 Blood vessel, 141, 143, 144, 151, 166, 168, 184, 186, 187, 190 Blot, 34, 141, 172 Body Fluids, 141, 150, 184, 189 Bone Marrow, 20, 32, 41, 46, 57, 72, 75, 135, 141, 142, 144, 148, 160, 166, 169, 186 Bone Marrow Transplantation, 72, 75, 142 Bowel, 137, 142, 149, 163 Bowel Movement, 142, 149 Brachytherapy, 142, 163, 164, 180, 192 Branch, 127, 142, 148, 166, 174, 185, 187 Broad-spectrum, 57, 142 Buccal, 142, 166 C Calcium, 142, 145, 184 Candidiasis, 104, 142 Candidosis, 142 Capsid, 85, 92, 142, 171, 191

Carbohydrate, 95, 99, 142, 156, 177 Carbon Dioxide, 142, 148, 176 Carcinogen, 142, 187 Carcinogenesis, 21, 142 Carcinogenic, 136, 142, 162, 172, 178, 190 Cardiac, 28, 143, 151, 152, 170 Cardiovascular, 14, 27, 143 Cardiovascular disease, 14, 27, 143 Case report, 6, 63, 143, 145 Case series, 17, 143, 145 Case-Control Studies, 72, 143 Catabolism, 8, 143 Causal, 22, 143, 183 Cause of Death, 143, 148 Cell Cycle, 8, 26, 34, 44, 143, 147, 157 Cell Death, 51, 52, 139, 143, 170 Cell Differentiation, 44, 143, 184 Cell Division, 140, 143, 148, 157, 169, 176, 183 Cell proliferation, 12, 20, 49, 52, 58, 143, 163, 184 Cell Size, 143, 154 Cell Survival, 33, 143, 157 Central Nervous System, 62, 90, 99, 143, 155, 157, 169, 172, 177 Cerebellar, 139, 143, 181 Cerebral, 139, 140, 143, 144, 147, 152, 167 Cerebrovascular, 140, 143, 144, 187 Cerebrum, 143, 144, 189 Chemokines, 37, 52, 144 Chemotactic Factors, 144, 146 Chemotaxis, 37, 144 Chemotherapy, 4, 30, 53, 82, 144 Chickenpox, 82, 144 Cholera, 144, 183 Cholesterol, 140, 144, 147, 150, 159, 165 Chorioretinitis, 144, 182 Choroid, 144, 181, 182 Chromatin, 23, 45, 139, 144, 152, 171 Chromosomal, 20, 24, 41, 44, 97, 137, 144, 176, 182, 183, 187 Chromosome, 22, 45, 144, 150, 164, 165, 183, 187, 189 Chronic, 4, 13, 28, 38, 39, 43, 93, 144, 149, 162, 165, 166, 183, 186, 187 Chronic myelogenous leukemia, 144, 166 CIS, 9, 58, 144, 181 Clamp, 35, 144 Clinical Medicine, 13, 68, 144, 177 Clinical Protocols, 55, 144 Clinical study, 18, 145

Index 195

Clinical trial, 7, 32, 40, 55, 77, 78, 113, 145, 147, 148, 179, 180 Clone, 37, 145 Cloning, 19, 37, 42, 51, 97, 141, 145 Codon, 145, 155, 180 Coliphages, 140, 145 Collagen, 145, 154, 155 Combinatorial, 19, 145 Communicable disease, 101, 145 Complement, 10, 14, 15, 17, 19, 32, 94, 137, 145, 146, 155, 164, 167 Complementarity Determining Regions, 146, 161 Complementary and alternative medicine, 71, 76, 146 Complementary medicine, 71, 146 Complementation, 32, 146 Complete remission, 4, 146, 181 Complete response, 15, 146 Computational Biology, 113, 146 Conception, 146, 154 Concomitant, 5, 146 Cones, 73, 146, 182 Congestion, 146, 153 Conjugated, 146, 171, 182 Conjunctiva, 146, 162, 164 Connective Tissue, 142, 145, 146, 155, 166, 168, 182, 183, 186, 187 Constitutional, 146, 182 Contamination, 24, 146 Contraindications, ii, 146 Control group, 27, 147 Convulsions, 147, 150, 177 Cooperative group, 41, 147 Coordination, 147, 169 Cornea, 147, 164, 192 Coronary, 143, 147, 168 Coronary heart disease, 143, 147 Coronary Thrombosis, 147, 168 Corpus, 147, 178 Corpus Luteum, 147, 178 Cortex, 139, 147, 181 Cortical, 24, 147, 187 Corticosteroids, 4, 147, 156 Crossing-over, 147, 180 Cultured cells, 9, 24, 147 Curative, 147, 187 Cutaneous, 38, 63, 72, 142, 147, 166, 175 Cyclic, 147, 178 Cyclin, 39, 52, 147 Cyclin-Dependent Kinases, 39, 147 Cyclosporine, 84, 98, 148

Cysteine, 144, 148, 151 Cytogenetics, 41, 148, 183 Cytokine, 7, 33, 57, 84, 148 Cytomegalovirus, 4, 6, 14, 27, 32, 35, 40, 86, 89, 99, 104, 148, 155 Cytomegalovirus Infections, 148, 155 Cytoplasm, 17, 85, 139, 140, 148, 152, 157, 171, 182, 191 Cytoplasmic Granules, 94, 148 Cytotoxic, 8, 12, 15, 28, 30, 41, 43, 51, 53, 55, 56, 61, 62, 82, 83, 84, 93, 148, 161, 180, 184 Cytotoxicity, 15, 28, 42, 84, 148 D Databases, Bibliographic, 113, 148 Death Certificates, 11, 148 Decarboxylation, 148, 173, 179 Decidua, 148, 176 Defective Viruses, 148, 157 Degenerative, 148, 158 Deletion, 28, 36, 72, 139, 148 Dementia, 135, 148 Denaturation, 149, 176 Dendrites, 149, 171 Dendritic, 15, 18, 31, 41, 43, 64, 149 Dendritic cell, 15, 18, 31, 41, 43, 64, 149 Density, 149, 150, 154, 165 Dentists, 86, 149 Depolarization, 149, 184 Deuterium, 149, 159 Diagnostic procedure, 81, 106, 149 Diffusion, 149, 162 Digestion, 140, 142, 149, 163, 165, 186 Digestive system, 79, 149, 169 Digestive tract, 149, 184 Dilatation, 149, 177 Dilution, 30, 149 Diphtheria, 101, 149 Diploid, 97, 146, 149, 176 Direct, iii, 15, 22, 25, 29, 31, 35, 47, 131, 144, 149, 156, 159, 181 Disease Progression, 149, 191 Disparity, 30, 149 Dissociation, 136, 149 Distal, 29, 86, 150, 179 Dorsal, 150, 153, 177 Dorsum, 150, 155 Drive, ii, vi, 6, 50, 58, 67, 96, 103, 150 Drug Interactions, 150 Duct, 150, 182 Dyes, 140, 150, 154, 171 Dyslipidemia, 28, 150


E Eclampsia, 150, 177 Edema, 150, 177 Effector, 12, 15, 17, 18, 31, 56, 145, 150 Effector cell, 15, 31, 150 Efficacy, 12, 19, 29, 31, 39, 101, 150 Effusion, 46, 72, 150 Electrolyte, 150, 184 Electrons, 138, 140, 150, 163, 173, 180 Emaciation, 135, 151 Embryo, 47, 141, 143, 151, 162, 168, 185 Embryo Transfer, 47, 151 Embryology, 48, 151 Enamel, 151, 164 Encephalitis, 40, 86, 151 Encephalitis, Viral, 151 Endemic, 58, 85, 98, 144, 151, 167 Endocarditis, 142, 151 Endocrine System, 151, 170 Endometrium, 148, 151, 168, 171, 189 Endopeptidases, 151, 179 Endothelial cell, 14, 151, 187 Endothelium, 14, 151, 152 Endothelium, Lymphatic, 151 Endothelium, Vascular, 151, 152 Endotoxin, 152, 189 Enhancers, 27, 152 Environmental Exposure, 152, 172 Environmental Health, 112, 114, 152 Environmental Pollutants, 152, 176 Enzymatic, 54, 100, 142, 145, 147, 152, 176, 181 Enzyme-Linked Immunosorbent Assay, 59, 152 Eosinophils, 152, 157, 165 Epidemic, 91, 152 Epidemiological, 37, 152 Epidermis, 152, 164 Epinephrine, 152, 190 Epithelial, 6, 18, 32, 44, 61, 84, 87, 98, 148, 152, 158 Epithelial Cells, 18, 32, 44, 61, 87, 152, 158 Epithelium, 151, 152, 173, 192 Epitope, 55, 63, 94, 152 Erythema, 4, 5, 86, 153 Erythema Induratum, 5, 153 Erythema Multiforme, 4, 153 Erythrocytes, 137, 142, 153, 176, 181 Esophagus, 149, 153, 175, 186 Estrogen, 21, 153 Ether, 72, 153 Eukaryotic Cells, 153, 161, 171, 173

Excisional, 5, 153, 192 Excisional biopsy, 5, 153 Excitation, 153, 154 Exhaustion, 153, 167 Exogenous, 18, 153, 155, 191 External-beam radiation, 153, 164, 180, 192 Extracellular, 10, 51, 57, 139, 146, 153, 154, 184 Extracellular Matrix, 146, 153, 154 Extraction, 4, 153 Eye Infections, 135, 153 F Family Planning, 113, 154 Fat, 5, 21, 28, 132, 135, 139, 142, 147, 154, 165, 169, 176, 182, 184 Fatigue, 88, 130, 154 Fatty acids, 154, 178 Febrile, 4, 131, 154, 167 Fetus, 47, 90, 154, 176, 177, 185, 190 Fibroblasts, 54, 96, 154 Flow Cytometry, 20, 154 Fludarabine, 30, 154 Fluorescence, 154 Fluorescent Dyes, 154 Fluorouracil, 82, 154 Fold, 8, 22, 154 Free Radical Scavengers, 154, 187 Fungus, 142, 154 G Galactosides, 140, 155 Gallbladder, 135, 149, 155 Ganciclovir, 19, 40, 53, 56, 77, 90, 92, 155 Ganglia, 4, 140, 155, 170 Ganglion, 39, 155, 172, 192 Gangrenous, 155, 183 Gas, 142, 149, 155, 159, 190 Gastric, 32, 62, 90, 155 Gastrin, 155, 158 Gastritis, 90, 155 Gelatin, 155, 156 Gels, 11, 155 Gene Expression, 8, 9, 18, 24, 37, 39, 42, 46, 48, 58, 96, 155 Gene Rearrangement, 20, 54, 155 Gene Targeting, 54, 155 Genetic Code, 155, 171 Genetic Counseling, 14, 155 Genetic Engineering, 24, 141, 145, 155 Genetic testing, 156, 176 Genetics, 12, 25, 26, 28, 33, 34, 38, 42, 49, 56, 58, 148, 156

Index 197

Genital, 86, 156, 163 Genotype, 11, 156, 175 Germinal Center, 20, 21, 54, 62, 95, 156 Gestation, 156, 174, 176, 185 Gland, 104, 136, 156, 166, 167, 173, 178, 183, 186, 188 Glandular fever, 50, 156 Glial Fibrillary Acidic Protein, 24, 156 Glomerular, 156, 181 Glucocorticoid, 156, 191 Glucose, 156, 157, 162 Glycine, 96, 156 Glycoprotein, 32, 72, 94, 97, 99, 156, 167, 187, 189 Glycosidic, 156, 170, 172 Glycosylation, 99, 156 Goats, 156, 172 Gonadotropin, 47, 156 Governing Board, 156, 177 Grade, 15, 17, 21, 88, 157 Graft, 30, 55, 157, 158, 161, 166 Graft Rejection, 157, 161, 166 Grafting, 12, 157, 161 Granule, 157, 182 Granulocytes, 157, 164, 184, 191 Granulomas, 153, 157 Growth factors, 47, 157 H Half-Life, 31, 82, 157 Haptens, 136, 157 Headache, 130, 157, 162 Heart attack, 143, 157 Helix-loop-helix, 37, 157 Helper Viruses, 42, 157 Hemagglutinins, 101, 157 Hematopoietic Stem Cells, 36, 157 Hemoglobin, 137, 153, 157, 164 Hemorrhage, 5, 157, 158, 186 Hemosiderin, 5, 158 Hepatitis, 27, 92, 158, 162 Hepatitis Viruses, 92, 158 Hepatocytes, 158 Hepatomegaly, 158, 162 Hereditary, 13, 158, 175 Heredity, 155, 156, 158 Herpes Genitalis, 89, 158 Herpes Simplex Encephalitis, 86, 158 Herpes virus, 4, 6, 13, 18, 35, 46, 82, 83, 86, 89, 92, 98, 99, 100, 104, 158 Herpes Zoster, 82, 158 Heterogeneity, 136, 158 Histiocytosis, 5, 158

Histology, 158, 174 Homologous, 19, 90, 96, 136, 147, 155, 158, 183, 187, 189 Hormonal, 4, 158 Hormone, 17, 147, 152, 155, 158, 162, 168, 178, 182, 184, 188 Horseradish Peroxidase, 152, 158 Hospitals, Public, 158, 160 Housekeeping, 24, 47, 158 Human papillomavirus, 91, 104, 158 Humoral, 36, 157, 159 Humour, 159 Hybrid, 17, 24, 36, 42, 51, 145, 159, 172 Hybridization, 86, 100, 159, 171, 172, 186 Hybridomas, 72, 95, 159 Hydralazine, 97, 159 Hydrogen, 89, 135, 140, 142, 149, 159, 165, 169, 171, 173, 179, 187 Hydrolysis, 140, 159, 170, 175, 176, 179 Hydroxyurea, 8, 159 Hypercholesterolemia, 150, 159 Hyperlipidemia, 150, 159 Hyperplasia, 6, 159 Hypersensitivity, 92, 159, 182 Hypertension, 143, 157, 159, 177 Hyperthermia, 4, 159 Hypertriglyceridemia, 150, 159 Hypertrophy, 159 Hypoxanthine, 24, 159 I Id, 69, 75, 118, 120, 126, 128, 159 Idiotype, 98, 160 Immortal, 56, 58, 160 Immune Complex Diseases, 138, 160 Immune function, 21, 33, 36, 160, 161 Immune Sera, 160 Immune system, 4, 21, 27, 33, 41, 51, 78, 87, 138, 140, 141, 150, 160, 161, 166, 167, 169, 170, 175, 190, 191 Immunity, 15, 18, 20, 38, 43, 90, 92, 94, 135, 160, 188 Immunization, 29, 101, 160, 161 Immunization Programs, 101, 160 Immunoassay, 152, 160 Immunoblastic Lymphadenopathy, 47, 160 Immunocompromised, 4, 52, 82, 86, 97, 99, 160 Immunocompromised Host, 86, 97, 160 Immunodeficiency, 4, 5, 11, 18, 29, 36, 51, 91, 101, 135, 160 Immunofluorescence, 85, 132, 160


Immunogenic, 12, 94, 96, 101, 160 Immunoglobulin, 8, 20, 36, 138, 146, 160, 169 Immunoglobulin Variable Region, 20, 160 Immunologic, 30, 57, 78, 136, 144, 160, 161, 180 Immunosuppressant, 136, 154, 161 Immunosuppressive, 6, 30, 33, 156, 160, 161 Immunosuppressive Agents, 6, 161 Immunosuppressive therapy, 161 Immunotherapy, 12, 13, 30, 31, 41, 43, 51, 55, 74, 141, 161 Immunotoxin, 74, 161 Impairment, 13, 86, 139, 154, 161, 168 Implant radiation, 161, 163, 164, 180, 192 Implantation, 48, 146, 161, 171, 173 In situ, 9, 14, 16, 161 In Situ Hybridization, 9, 14, 161 In vivo, 9, 10, 12, 15, 19, 20, 23, 25, 27, 28, 31, 33, 34, 35, 36, 38, 41, 42, 43, 44, 45, 47, 53, 54, 55, 87, 161, 166 Incision, 161, 163 Incubated, 92, 161 Incubation, 161, 164 Incubation period, 161, 164 Indicative, 161, 174, 190 Induction, 8, 9, 15, 20, 40, 42, 43, 46, 53, 84, 161 Infarction, 147, 162, 168 Infectious Mononucleosis, 20, 26, 45, 46, 49, 50, 59, 60, 61, 62, 63, 64, 65, 68, 75, 78, 83, 85, 87, 88, 89, 92, 93, 95, 97, 98, 100, 105, 118, 119, 150, 162, 169 Infiltration, 162, 177, 192 Influenza, 6, 27, 101, 118, 162 Infusion, 30, 40, 162, 189 Initiation, 23, 34, 86, 162, 188 Inlay, 162, 181 Insight, 15, 18, 22, 23, 33, 57, 85, 162 Insulator, 162, 170 Insulin, 28, 162 Insulin-dependent diabetes mellitus, 162 Interleukin-1, 33, 84, 162, 163 Interleukin-10, 33, 163 Interleukin-2, 15, 163 Interleukins, 52, 161, 163, 166 Intermittent, 163, 165 Internal radiation, 163, 164, 180, 192 Interstitial, 142, 160, 163, 164, 181, 192 Intestine, 142, 163, 164, 186 Intoxication, 163, 192

Intracellular, 43, 51, 52, 99, 162, 163, 168, 178, 184 Intracellular Membranes, 163, 168 Intraperitoneal, 15, 163 Intrathecal, 25, 163 Intravenous, 19, 162, 163 Intrinsic, 35, 45, 136, 163 Invasive, 16, 21, 160, 163 Involution, 27, 163 Ion Channels, 139, 163 Ionizing, 136, 152, 163, 180, 191 Ions, 140, 149, 150, 159, 163 Irradiation, 53, 163, 192 J Joint, 28, 164, 187 K Kaposi, 35, 46, 49, 50, 52, 82, 89, 91, 92, 104, 164 Karyotype, 97, 164 Kb, 87, 92, 112, 164 Keratin, 39, 164 Keratoconjunctivitis, 86, 164 Kinetic, 35, 163, 164 L Labile, 145, 164 Large Intestine, 149, 163, 164, 180, 184 Latency, 9, 18, 20, 30, 33, 34, 35, 37, 40, 44, 48, 49, 50, 51, 58, 84, 85, 90, 164 Lectin, 164, 168, 174 Lentivirus, 25, 164 Lesion, 18, 164, 165, 184 Lethal, 15, 99, 164 Leucine, 9, 164 Leucocyte, 137, 164, 166 Leukemia, 4, 19, 47, 75, 77, 144, 165 Leukocytes, 15, 140, 142, 144, 152, 157, 163, 165, 171, 175, 189 Leukocytosis, 49, 165 Leukoplakia, 4, 5, 6, 18, 26, 45, 84, 98, 104, 165 Library Services, 126, 165 Life cycle, 22, 58, 92, 165 Ligands, 10, 36, 165 Ligation, 46, 165 Linkage, 14, 25, 26, 165 Linkage Disequilibrium, 14, 165 Lipid, 162, 165, 170, 173 Lipid Peroxidation, 165, 173 Lipophilic, 165, 176 Lipopolysaccharides, 165, 191 Lipoprotein, 150, 165, 191

Index 199

Liver, 24, 90, 97, 130, 135, 139, 140, 141, 148, 149, 155, 158, 165, 190 Liver cancer, 90, 165 Localization, 45, 68, 165 Localized, 16, 85, 149, 162, 165, 176, 183 Long-Term Care, 31, 165 Loop, 165 Low-density lipoprotein, 150, 165 Luciferase, 39, 166 Lupus, 25, 26, 96, 166, 187 Lymph, 4, 17, 21, 37, 78, 86, 88, 93, 104, 130, 131, 140, 151, 159, 160, 162, 166 Lymph node, 4, 17, 21, 37, 78, 93, 130, 140, 166 Lymphadenopathy, 86, 88, 104, 160, 162, 166 Lymphangitis, 86, 166 Lymphatic, 137, 151, 162, 166, 168, 185, 188 Lymphatic system, 137, 166, 185, 188 Lymphoblastic, 166 Lymphoblasts, 135, 166 Lymphocyte, 17, 18, 20, 37, 41, 42, 45, 52, 54, 56, 58, 84, 92, 96, 97, 132, 135, 138, 166, 167 Lymphocyte Count, 132, 135, 166 Lymphocyte Transformation, 17, 45, 166 Lymphocytic, 4, 166 Lymphoid, 7, 20, 30, 37, 40, 44, 83, 87, 90, 91, 138, 147, 156, 164, 166, 177, 188 Lymphomatoid Granulomatosis, 74, 166 Lymphoproliferative Disorders, 15, 35, 46, 77, 87, 166 Lytic, 35, 38, 44, 48, 49, 51, 53, 85, 92, 166, 183 M Macrophage, 57, 101, 162, 167 Macrophage Colony-Stimulating Factor, 57, 167 Major Histocompatibility Complex, 31, 167 Malaria, 97, 167 Malaria, Falciparum, 167 Malaria, Vivax, 167 Malignancy, 7, 23, 50, 51, 57, 83, 91, 98, 133, 167, 174 Malignant tumor, 34, 167, 169 Manifest, 29, 167 Mastitis, 167, 183 Measles Virus, 101, 167 Mediate, 17, 23, 51, 167 Mediator, 163, 167

MEDLINE, 113, 167 Melanin, 167, 175, 190 Membrane Proteins, 54, 95, 168 Memory, 18, 20, 43, 50, 58, 149, 156, 168 Meninges, 143, 168 Menopause, 168, 177 Menstrual Cycle, 168, 178 Mental Disorders, 79, 168 Mentors, 14, 168 Mercury, 154, 168 Mesenchymal, 24, 167, 168 Mesoderm, 168, 189 Metabolite, 168, 178 Methanol, 85, 168 Methyltransferase, 36, 168 MI, 61, 133, 168 Mice Minute Virus, 168, 174 Microbiology, 14, 20, 33, 35, 42, 45, 58, 139, 168 Microorganism, 168, 174, 191 Migration, 24, 168 Mitochondrial Swelling, 168, 170 Mitosis, 139, 169 Mobility, 37, 169 Modification, 45, 99, 155, 169 Monitor, 169, 171 Monoclonal, 7, 12, 38, 46, 53, 57, 62, 71, 72, 97, 98, 159, 164, 169, 180, 182, 192 Monoclonal antibodies, 7, 46, 98, 169, 182 Monocyte, 167, 169 Mononuclear, 31, 49, 61, 162, 167, 169, 189 Morbillivirus, 167, 169 Morphological, 151, 154, 169 Mucinous, 155, 169 Mucins, 169, 182 Mucosa, 166, 169, 186 Mucositis, 169, 188 Multiple Myeloma, 47, 169 Multiple sclerosis, 43, 169 Mutagenesis, 53, 170 Mutagens, 170 Myalgia, 162, 170 Myelin, 24, 169, 170 Myocarditis, 149, 170 Myocardium, 168, 170 N Naive, 13, 20, 43, 54, 170 Nasal Mucosa, 162, 170 Nasopharynx, 88, 170 NCI, 1, 42, 79, 111, 144, 170 Necrosis, 5, 139, 153, 162, 168, 170, 183 Need, 3, 15, 22, 38, 86, 88, 103, 121, 170


Neoplasia, 87, 170 Neoplasm, 49, 63, 170, 183, 190 Neoplastic, 16, 24, 92, 159, 166, 170, 172 Nerve, 4, 139, 149, 155, 167, 170, 172, 177, 183, 186, 189, 192 Nervous System, 143, 167, 170, 171, 186 Neural, 23, 24, 159, 170 Neuraminidase, 101, 169, 170 Neuroblastoma, 12, 170 Neuroendocrine, 38, 170 Neuronal, 40, 171 Neurons, 24, 149, 155, 171, 187 Neuroretinitis, 171, 182 Neutrons, 136, 163, 171, 180 Neutrophils, 5, 94, 157, 165, 171 Nidation, 151, 171 Nuclear, 9, 17, 34, 45, 63, 83, 85, 95, 97, 140, 151, 153, 155, 170, 171 Nuclear Matrix, 45, 171 Nuclear Pore, 171 Nuclear Proteins, 95, 171 Nuclei, 136, 151, 156, 169, 171, 172, 179 Nucleic acid, 11, 56, 84, 95, 98, 99, 100, 142, 155, 159, 161, 170, 171, 172, 185, 186 Nucleic Acid Hybridization, 159, 171 Nucleic Acid Probes, 95, 171 Nucleocapsid, 89, 171 Nucleolus, 171, 182 Nucleoproteins, 171 Nucleus, 85, 96, 139, 140, 144, 147, 148, 149, 152, 153, 169, 171, 172, 179, 186, 187 O Ocular, 39, 86, 172 Odds Ratio, 22, 172, 181 Ointments, 172, 174 Oligonucleotide Probes, 100, 172 Oligosaccharides, 170, 172 Oncogene, 52, 54, 90, 96, 172 Oncogenic, 46, 54, 164, 172 Oncology, 19, 41, 61, 62, 63, 74, 172 Oncolysis, 172 Oncolytic, 19, 172 Open Reading Frames, 52, 86, 164, 172 Opportunistic Infections, 104, 135, 172 Optic Nerve, 171, 172, 181, 182 Oral Health, 103, 172 Oral Manifestations, 3, 172 Orf, 47, 172 Organelles, 148, 173 Ornithine, 8, 173, 179 Ornithine Decarboxylase, 8, 173 Orofacial, 3, 173

Oropharynx, 98, 173 Osmosis, 173 Osmotic, 94, 169, 173 Ovary, 147, 173, 186 Overall survival, 21, 173 Overexpress, 9, 173 Ovum, 147, 148, 156, 165, 173, 178, 189 Ovum Implantation, 173, 189 Oxidation, 135, 138, 165, 173 Oxidative Stress, 28, 72, 173 P Palate, 170, 173 Palliative, 173, 187 Pancreas, 135, 141, 149, 162, 173, 189 Pancreatic, 5, 90, 154, 173 Panniculitis, 5, 153, 173 Papillomavirus, 173 Paraffin, 21, 174 Parasitic, 157, 174 Partial remission, 174, 181 Particle, 174, 188 Parvovirus, 6, 168, 174 Patch, 165, 174 Pathogen, 11, 28, 32, 46, 90, 161, 174 Pathogenesis, 5, 13, 14, 15, 18, 22, 26, 28, 38, 47, 48, 49, 50, 52, 54, 57, 174 Pathologic, 18, 22, 25, 139, 141, 142, 147, 159, 174 Pathologic Processes, 139, 174 Pathophysiology, 103, 174 Peanut Agglutinin, 95, 174 Pedigree, 25, 26, 174 Peer Review, 14, 67, 174 Peptide, 25, 31, 49, 50, 54, 55, 83, 87, 99, 151, 164, 174, 176, 178, 179 Pericardium, 174, 187 Perinatal, 27, 174 Periodontal disease, 104, 174 Peripheral blood, 15, 20, 31, 50, 59, 61, 62, 93, 98, 174 Peritoneal, 163, 174, 175 Peritoneal Cavity, 163, 175 Peroxidase, 53, 165, 175 Peroxide, 165, 175 Petroleum, 174, 175 Phagocyte, 167, 175 Phagocytosis, 94, 175 Pharmacologic, 39, 157, 175, 188 Pharynx, 162, 170, 173, 175 Phenotype, 8, 9, 21, 26, 55, 146, 175 Phenyl, 89, 175 Phenylalanine, 175, 190

Index 201

Phorbol, 68, 175 Phospholipases, 175, 184 Phospholipids, 154, 165, 175 Phosphorus, 142, 175 Phosphorylate, 53, 175 Phosphorylation, 99, 147, 175 Photoreceptors, 146, 175 Photosensitivity, 175, 192 Physiologic, 20, 141, 157, 168, 175, 178, 180, 187 Physiology, 14, 47, 51, 176 Phytohemagglutinins, 166, 176 Picornavirus, 71, 176 Placenta, 47, 176, 178 Plants, 142, 156, 164, 176, 188, 189 Plaque, 4, 176 Plasma, 40, 90, 91, 138, 151, 155, 157, 169, 176, 180, 191 Plasma cells, 138, 169, 176 Plasmid, 34, 38, 45, 176, 190 Platelet Activation, 176, 184 Pleated, 164, 176 Polychlorinated Biphenyls, 22, 176 Polymerase, 4, 5, 11, 16, 35, 37, 90, 138, 176 Polymerase Chain Reaction, 4, 5, 11, 16, 37, 176 Polymorphism, 11, 176 Polypeptide, 95, 99, 137, 145, 159, 176, 179, 192 Polysaccharide, 138, 177 Population Control, 57, 177 Posterior, 137, 139, 144, 150, 173, 177 Postmenopausal, 21, 177 Postnatal, 177, 185 Postsynaptic, 177, 184 Post-translational, 99, 177 Potentiates, 162, 177 Potentiation, 177, 184 Practice Guidelines, 114, 177 Preclinical, 40, 177 Precursor, 99, 101, 139, 150, 152, 175, 177, 178, 185, 190 Predisposition, 27, 90, 177 Preeclampsia, 48, 177 Prenatal, 151, 177 Prevalence, 21, 26, 27, 86, 103, 172, 177 Primary central nervous system lymphoma, 20, 74, 177 Probe, 16, 23, 100, 172, 177 Procainamide, 97, 177 Procaine, 177 Prodrug, 19, 53, 178

Progeny, 20, 178 Progesterone, 21, 178 Prognostic factor, 7, 21, 178 Progression, 10, 26, 37, 44, 138, 147, 178 Progressive, 14, 95, 100, 143, 149, 157, 163, 170, 176, 178, 181, 190 Promoter, 34, 35, 39, 47, 48, 178 Prophylaxis, 138, 178, 190 Proportional, 152, 178 Prostaglandin, 4, 39, 178 Prostaglandins A, 178 Prostate, 141, 178, 189 Protease, 28, 178 Protease Inhibitors, 28, 178 Protein C, 12, 44, 51, 94, 137, 140, 145, 148, 157, 164, 165, 179, 190, 191 Protein Conformation, 137, 164, 179 Protein S, 139, 141, 155, 179, 182, 187 Proteinuria, 169, 177, 179 Proteolytic, 137, 145, 179 Protocol, 11, 18, 19, 28, 41, 55, 56, 58, 78, 179 Protons, 136, 159, 163, 179, 180 Protozoa, 168, 179 Protozoal, 91, 179 Proximal, 29, 150, 179 Public Policy, 113, 179 Publishing, 4, 6, 59, 179 Putrescine, 173, 179, 185 Pyridoxal, 173, 179 Q Quaternary, 30, 179 Quiescent, 20, 179 R Race, 16, 164, 168, 179 Radiation, 4, 152, 153, 154, 159, 160, 163, 180, 191, 192 Radiation therapy, 153, 163, 164, 180, 192 Radioactive, 157, 159, 161, 163, 164, 169, 171, 172, 180, 190, 192 Radioisotope, 172, 180 Radiolabeled, 164, 180, 192 Radiotherapy, 142, 164, 180, 192 Randomized, 150, 180 Reactivation, 4, 6, 18, 21, 38, 39, 49, 85, 90, 180 Reactive Oxygen Species, 28, 180 Reading Frames, 52, 180 Reagent, 87, 166, 180 Recombinant, 16, 17, 20, 31, 32, 42, 46, 51, 84, 95, 98, 101, 180, 190 Recombination, 18, 19, 20, 29, 45, 155, 180


Reconstitution, 36, 180 Rectum, 139, 142, 149, 155, 164, 178, 180 Recur, 93, 180 Red blood cells, 153, 157, 181 Red Nucleus, 139, 181 Reductase, 181, 187 Refer, 1, 142, 145, 158, 165, 169, 170, 171, 181, 191 Refraction, 181, 185 Refractory, 30, 181 Regeneration, 180, 181 Regimen, 28, 144, 150, 181 Relative risk, 11, 181 Remission, 30, 63, 72, 181 Renal failure, 60, 181 Replicon, 24, 42, 181 Respiratory syncytial virus, 101, 181 Response rate, 15, 181 Restoration, 36, 180, 181 Retina, 144, 146, 171, 172, 181, 182 Retinal, 149, 172, 181 Retinitis, 40, 89, 182 Retrograde, 163, 182 Retroviral vector, 36, 52, 182 Retrovirus, 24, 46, 47, 49, 71, 182 Rhadinovirus, 90, 182 Rheumatism, 182 Rheumatoid, 28, 97, 132, 182 Rheumatoid arthritis, 28, 97, 182 Rhinitis, 182, 183 Ribonucleoproteins, 171, 182 Ribonucleoside Diphosphate Reductase, 159, 182 Ribose, 45, 135, 182 Ribosome, 71, 182, 189 Risk factor, 21, 57, 181, 182 Rituximab, 15, 62, 182 Rod, 144, 182 S Saimiri, 49, 182 Saliva, 90, 91, 182 Salivary, 104, 148, 149, 182 Salivary glands, 148, 149, 182 Sarcoma, 35, 46, 49, 50, 52, 63, 82, 90, 91, 104, 183 Satellite, 148, 157, 183 Schizoid, 183, 192 Schizophrenia, 183, 192 Schizotypal Personality Disorder, 183, 192 Scleroderma, 97, 183 Scleroproteins, 164, 183 Sclerosis, 43, 169, 183

Screening, 6, 145, 183 Secretion, 159, 162, 163, 169, 183 Segregation, 180, 183 Senescence, 27, 183 Septicaemia, 183 Sequencing, 11, 37, 176, 183, 187 Sequester, 57, 183 Serologic, 57, 65, 160, 183 Serology, 57, 59, 183 Serotypes, 42, 183 Serous, 151, 183 Serum, 37, 43, 54, 90, 91, 93, 100, 131, 137, 145, 156, 160, 165, 180, 183, 189 Sex Characteristics, 135, 183 Shedding, 39, 98, 184 Shock, 184, 189 Side effect, 136, 141, 184, 188 Signal Transduction, 10, 26, 29, 30, 41, 49, 64, 184 Signs and Symptoms, 5, 104, 181, 184 Skeletal, 144, 169, 184 Skeleton, 135, 164, 178, 184 Skull, 184, 187 Small intestine, 77, 158, 163, 184 Smooth muscle, 131, 137, 184, 186 Sneezing, 184 Sodium, 40, 184 Soft tissue, 141, 184 Solvent, 168, 173, 184 Soma, 184, 185 Somatic, 54, 135, 159, 169, 185 Specialist, 120, 185 Species, 99, 136, 152, 159, 164, 167, 168, 169, 174, 179, 180, 182, 185, 186, 189, 192 Specificity, 12, 16, 38, 51, 53, 55, 56, 83, 136, 151, 160, 185 Spectrum, 28, 30, 33, 37, 54, 185 Sperm, 144, 185 Spermidine, 8, 173, 185 Spermine, 8, 185 Spinal cord, 139, 143, 144, 155, 163, 168, 170, 177, 185 Spleen, 130, 148, 166, 185 Splenomegaly, 64, 88, 162, 185 Spontaneous Abortion, 84, 185 Squamous, 7, 185 Staging, 7, 185 Stasis, 5, 185 Statistically significant, 22, 185 Steel, 144, 185 Stem Cells, 36, 48, 136, 185 Steroids, 147, 156, 186

Index 203

Stimulus, 150, 153, 163, 164, 186 Stomach, 135, 149, 153, 155, 158, 175, 184, 185, 186 Strand, 45, 176, 186 Streptococci, 166, 186 Stress, 4, 28, 38, 45, 173, 177, 182, 186 Stringency, 44, 186 Stroke, 79, 112, 143, 186 Stromal, 36, 186 Stromal Cells, 36, 186 Subacute, 162, 186 Subclinical, 98, 162, 186 Subcutaneous, 5, 150, 155, 166, 173, 186 Subspecies, 185, 186 Substance P, 168, 180, 183, 186 Substrate, 45, 152, 170, 186 Suppression, 8, 21, 27, 72, 186 Suppressive, 27, 73, 186 Survival Rate, 173, 186 Symptomatic, 4, 5, 85, 186 Symptomatic treatment, 4, 5, 186 Synaptic, 184, 187 Synchrony, 44, 187 Systemic, 5, 25, 26, 39, 96, 141, 142, 149, 152, 160, 162, 164, 180, 183, 187, 188, 192 Systemic lupus erythematosus, 26, 96, 160, 187 T Telangiectasia, 73, 187 Telomere, 45, 187 Temporal, 9, 187 Tetracycline, 24, 47, 187 Thalamic, 139, 187 Thalamic Diseases, 139, 187 Therapeutics, 14, 34, 40, 187 Thermal, 150, 171, 176, 187 Thioredoxin, 35, 187 Thiourea, 89, 187 Thrombin, 179, 187 Thrombomodulin, 179, 187 Thrombosis, 179, 186, 187 Thymidine, 19, 40, 92, 188 Thymidine Kinase, 19, 40, 92, 188 Thymus, 132, 160, 166, 188 Thyroid, 53, 188, 190 Ticks, 156, 188 Tissue Culture, 188, 191 Tonsils, 21, 68, 188 Topical, 39, 174, 188 Toxaemia, 177, 188 Toxic, iv, 8, 53, 136, 148, 149, 152, 160, 161, 168, 176, 179, 188

Toxicity, 150, 168, 188 Toxicology, 73, 114, 188 Toxins, 71, 138, 151, 162, 169, 188 Trachea, 175, 188 Traction, 144, 188 Transcriptase, 182, 188 Transcription Factors, 9, 41, 51, 188 Transduction, 28, 36, 47, 51, 184, 188 Transfection, 9, 29, 44, 141, 188 Transfer Factor, 160, 188 Transferases, 156, 189 Transfusion, 189 Transgenes, 24, 25, 28, 47, 189 Translation, 86, 180, 189 Translational, 9, 31, 41, 55, 99, 189 Translocate, 52, 189 Translocation, 8, 52, 97, 189 Transmitter, 139, 163, 167, 189 Transplantation, 6, 7, 13, 24, 61, 62, 151, 160, 167, 189 Trauma, 4, 140, 157, 170, 187, 189 Trophoblast, 47, 141, 189 Tropism, 32, 42, 189 Tubercle, 156, 189 Tuberculosis, 5, 166, 189 Tuberous Sclerosis, 24, 189 Tumor marker, 141, 189 Tumor Necrosis Factor, 12, 28, 47, 51, 189 Tumor suppressor gene, 24, 189 Tumor-derived, 91, 189 Tumorigenic, 56, 97, 190 Tumour, 73, 90, 155, 172, 190 Tyrosine, 12, 36, 190 U Ulceration, 172, 190 Unconscious, 159, 190 Uracil, 40, 82, 190 Urea, 173, 190 Uremia, 181, 190 Uterus, 147, 148, 151, 178, 190 V Vaccination, 31, 43, 101, 190 Vaccine, 15, 31, 48, 94, 99, 101, 135, 179, 190 Vaccine adjuvant, 94, 190 Vagina, 142, 190 Vaginitis, 142, 190 Varicella, 3, 6, 82, 86, 89, 101, 190 Vascular, 5, 25, 28, 49, 144, 151, 152, 162, 176, 190 Vasculitis, 153, 190 Vasodilator, 159, 190


VE, 18, 190 Vector, 19, 24, 29, 39, 42, 71, 98, 188, 190 Vein, 163, 171, 183, 190 Venous, 5, 179, 190 Ventricular, 187, 190 Vertebrae, 4, 185, 190 Vesicular, 158, 190 Vestibular, 14, 191 Vestibule, 191 Veterinary Medicine, 113, 191 Vial, 32, 191 Vimentin, 96, 191 Viral Load, 4, 13, 16, 38, 191 Viral Vaccines, 101, 191 Viral vector, 16, 19, 191 Virion, 171, 191 Virus Activation, 73, 191 Virus Diseases, 138, 191 Viscera, 185, 191 Visceral, 5, 191

Vitro, 8, 15, 18, 19, 23, 29, 31, 34, 35, 36, 37, 41, 43, 44, 45, 47, 53, 55, 56, 58, 92, 95, 98, 151, 161, 176, 183, 188, 191 Voluntary Health Agencies, 160, 191 W Warts, 158, 191 White blood cell, 78, 135, 138, 144, 161, 162, 165, 166, 167, 169, 176, 191 Windpipe, 175, 188, 191 Withdrawal, 18, 192 X Xenograft, 138, 192 Xeroderma Pigmentosum, 39, 192 X-ray, 10, 53, 57, 154, 163, 171, 180, 192 X-ray therapy, 164, 192 Y Yeasts, 142, 154, 175, 192 Yellow Fever, 14, 192 Z Zoster, 3, 6, 82, 86, 89, 91, 99, 192 Zymogen, 179, 192

Index 205


Index 207


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