Experimental Biology and Medicine – serie

This book represents the proceedings of a Satellite Symposium of the XIth International Congress of Biochemistry on "Control of Membrane Fluidity" which was held on July 7, 1979 at the Charles H. Best Institute, University of Toronto, Toronto, Canada. The meeting was organized by M. Kates and A. Kuksis and was supported by the International Congress of Biochemistry. The purpose of the meeting was to review recent progress in many different areas of investigation bearing on the role of lipids in the structural and functional property of the cell membrane commonly referred to as fluidity. The aim was to emphasize the factors controlling membrane fluidity as studied in appropriate in vitro and in vivo experiments. The Symposium included invited review papers and short papers offered by discussants. In assem· bling the book no distinction has been made between the two types of presentations, nor has any significance been attached to the chronological order of their presentation in the Symposium. As a result it was possible to provide a much more coherent and continuous presentation than that available at the meeting.

In 1928, it was discovered that copper was essential for normal human metabolism. A decade later, in 1938, it was observed that patients with rheu­ matoid arthritis exhibited a higher than normal serum copper concentration that returned to normal with remission of this disease. Thirteen years later, it was found that copper complexes were effective in treating arthritic dis­ eases. The first report that copper complexes had antiinflammatory activity in an animal model of inflammation appeared twenty-two years after the dis­ covery of essentiality. In 1976, it was suggested that the active forms of the antiarthritic drugs are their copper complexes formed in vivo. This sugges­ tion has been confirmed and extended in the interim in over 200 recent publications. Individual biomedical scientists from many countries who have published in these areas recently saw a need for a meeting to exchange current re­ supporting new hypotheses. We search results and discuss the evidence met on the University of Arkansas Medical Sciences campus in Little Rock, Arkansas, August 10-13, 1981. Participants came from Australia, England, France, Germany, Israel, Italy, The Netherlands, Norway, Poland, Scotland, Sweden, Switzerland, Wales, Zimbabwe, and over twenty of the United States.

Methods in Protein Sequence Analysis contains an intensely prac­ tical account of all the new methodology available to scientists carrying out protein and peptide sequencing studies. Many of the striking advances in fields as diverse as immunology, cell motility, and neurochemistry have in fact been fueled by our ever more powerful ability to determine the sequences and structures of key proteins and peptides. It is our hope that the rich array of tech­ niques and methods for sequencing proteins discussed in this volume-methods that generate much of the information crucial to progress in modern biology-will now become accessible to all who can benefit from them. The papers of the present volume constitute the Proceedings of the IVth International Conference on Methods in Protein Se­ quence Analysis, which was held at Brookhaven National Labo­ ratory, Upton, NY, September 21-25, 1981. It was the most recent in a series of biennial conferences, the previous one having been held in Heidelberg, GFR, in 1979. The series was originated by Richard Laursen, and initially dealt with one aspect of the field, solid-phase sequencing. The scope of the meeting was very broad and among the many aspects of protein sequencing discussed were: instrumentation, strategy, chemicals, mass spectrometry, cleavage of proteins and separation of peptides, and solid, liquid, manual, and even "gas­ phase" sequencing.

The Fifth Ir Gene Workshop was held at the Chase-Park Plaza Hotel, St. Louis, MO, August 28-31, 1982; 240 scientists participated in the Workshop. The man­ uscripts compiled in this book describe the state of the art concerning Ir genes. Although the notion of Ir Genes: Past, Present, and Future has not been ad­ dressed specifically by each author, the reader is certain to get this flavor from the contributions. In this Preface, we have tried to summarize some of the salient ob­ servations and discussions from the Workshop. The mUltiple genes of the I region have been defined traditionally by serolog­ ical analysis of intra-H-2 recombinant mice and the pattern of immune responses to certain antigens developed by these recombinant mice. The application of sev­ eral new techniques, such as gene cloning and DNA sequencing, production of T and B cell hybridomas, and development of cloned T cell lines has changed this tradition and introduced a new phase into the analysis of the I region, Ia antigens, and Ir genes.

Cell growth, one of the most fundamental of biological processes, has long been among the least understood. On April 24-28, 1984 sci- entists convened from around the world in Canada's Banff National Park for The International Cell Cycle Society's 10th Conference. Their purpose was to evaluate recent developments in the field of cell prolif- eration and to explore the interrelationship between cell growth, de- velopment, and differentiation, and proliferative diseases such as can- cer. Growth, Cancer, and the Cell Cycle collects those conference papers that present the most recent advances in this field. The first section of the book is Gene Expression and Development During Growth. It examines the structure and function of chromatin, DNA unwinding proteins, and nonhistone nuclear proteins, then ex- plores transcriptional, translational, and post-translational regulation during the cell cycle and the interrelationship and coordinate regula- tion of cell growth, differentiation, and gene expression. The second section, Growth Activation and Dormancy, focuses upon the events that occur during the transition between active cell growth and proliferative quiescence.The role of DNA strand breaks, protein kinase activity, growth regulatory factors, and the cytoskeleton are examined. Section three discusses The Topology of the Cell Cycle. It reviews genetic approaches for determining the sequence of events and cau- sality relationships that comprise and coordinate the many separate processes involved in cell cycle progression and describes the use of multipara meter flow cytometry to characterize the mammalian cell cy- cle and intracellular metabolic and transitional growth states.

The Chilton Conference on Inositol and Phosphoinositides, held on January 9-11, 1984 at Southwestern Medical School, University of Texas Health Science Center, Dallas, Texas, was the third in a series of conferences on cyclitols and phosphoinositides. The first took place in 1968 in New York [Ann. New York Acad. Sci. (1969), 765,508-819] and the second was held in 1977 in East Lansing, Michigan [eyclitols and Phosphoinositides, Wells, W. W. and Eisenberg, F. , eds. , (1978) Academic press, New York, pp. 1-607. ] In the interim since the previous conference, not only has the pace of research in the field accelerated markedly, but the physiological importance of phosphoinositide metabolism has become apparent to an increasing number of investigators from diverse fields in the life sciences. Thus it seemed to us timely for both recent and established workers in this area, as well as others whose interests impinged on it, to meet in order to disseminate new information, to review, and perhaps arrive at, a consensus of our current understanding of the role of inositol and phosphoinositides, and to establish new directions for research for the next few years. The expansion of the field since the last meeting made it mandatory to restrict the scope of the topics covered at the conference, primarily to aspects dealing with mammalian systems. We sincerely regretted the exclusion of recent research on cyclitols and phosphoinositides in microbes and plants and hope that these areas will be included in future conferences.

Leukocyte culture conferences have a long pedigree. This volume records some of the scientific highlights of the 16th such annual con­ ference, and is a witness to the continuing evolution and popularity of leukocyte culture and of immunology. There is strong evidence of the widening horizons of immunology, both technically, with the obviously major impact of molecular biology into our understanding of cellular processes, and also conceptually. Traditionally, the 'proceedings' of these conferences have been published. But have the books produced really recorded the major part of the conference, the informal, friendly, but intense and some­ times heated exchanges that take place between workers in tackling very similar problems and systems and which are at the heart of every successful conference? Unfortunately this essence cannot be incorpo­ rated by soliciting manuscripts. For this reason, we have changed the format of publication, retaining published versions of the symposium papers, but requesting the workshop chairmen to produce a summary of the major new observations and areas of controversy highlighted in their sessions, as a vehicle for defining current areas of interest and debate. Not an easy task, as the workshop topics were culled from the abstracts submitted by the participants, rather than being on predefined topics. The unseasonal warmth in Cambridge was reflected in the atmos­ phere of the conference, the organization of which benefited from the administrative skills of Jean Bacon, Philippa Wells, Mr. Peter Irving, and Mrs.

Most complex biological systems, such as enzyme pathways, are effec­ tively controlled near the beginning of the process. There is increasing evidence that the same is true for the immune system, with the initial interactions between antigen, antigen-presenting cells, and T cells hav­ ing a paramount influence on the ensuing events. Thus, analysis of the early stages of the immune responses has been a preoccupation of many immunologists. This has been considerably aided by the capac­ ity to expand these early events, and 'immortalize' them as clones of T cells, for detailed analysis. The discovery by Morgan, Ruscetti, and Gallo (Science 193, 1007, 1976) of T-cell growth factor (now termed interleukin-2 or IL-2) has had a major impact in immunology that is far from over. The greater ease of handling murine tissues experimentally, with the availability of more precisely defined reagents such as inbred strains, has meant that, to date, most of the work on long-term T-cell cultures has been per­ formed in the mouse, as summarized by Fathman and Fitch (eds. , Iso­ lation, Characterization and Utilization of T Lymphocyte Clones, Aca­ demic Press, NY, 1982). However, the limitations of working with human tissues are counterbalanced by the great long-term importance of understanding disorders of human immune regulation, especially since it is becoming evident that these are far from rare. Immune deficiencies such as agammaglobulinemia and T-cell deficiencies are not common, but immune hyperresponsiveness occurring in allergy and allergiC diseases (e. g.

This book is based on the proceedings of the symposium entitled "Di­ rected Drug Delivery: A Multidisciplinary Problem," which was held in Lawrence, Kansas on October 17-19, 1984. The purpose of the sym­ posium and this book is to focus on the multidisciplinary nature of drug delivery. Development of a successful drug delivery system re­ quires contributions from various scientific disciplines, including pharmaceutical chemistry, analytical chemistry, medicinal chemistry, biochemistry, pharmacology, toxicology, and clinical medicine. The contents of this volume illustrate the importance of the various disci­ plines in identifying the problems and approaches for the develop­ ment of a rational and effective drug delivery system. Thus the infor­ mation provided herein will be of value not only to the pharmaceutical chemists who are responsible for dosage form design, but also to the pharmacokineticists, pharmacologists, and clinicians involved in bio­ logical evaluation of drug delivery systems. The volume should also be of interest to the analytical chemists who must provide technology to quantitcltively evaluate drug delivery. Additionally, this work will also interest the biochemists and medicinal chemists involved in drug dis­ covery, since the drug delivery system often plays a major role in determining the success or failure of a new drug entity. Each speaker at the symposium was requested to contribute a chapter reviewing the contribution of their major discipline to the de­ velopment of a successful drug delivery system.

In the past five years, a surprising and intense resurgence in interest in vitamins and other micronutrients and their role in health and dis­ ease has occurred. The recognition has emerged that vitamins not only are essential for life ·in that severe nutritional deficiencies occur in their absence, but that these compounds may also serve as natural inhibitors of cancer. Synthetic alterations of the basic vitamin A mole­ cule have also resulted in the production of compounds that are more potent as anticancer agents than the natural substance and may have substantial therapeutic activity as well. Whether other vita­ mins can be changed or altered to produce a better anticancer effect than the native compound has been little explored to date, but should be a fruitful pursuit for future study. In our concluding remarks to the First International Conference in 1982, we speculated that rapid advances in our understanding of vi­ tamins would occur in the next few years and that large-scale inter­ vention trials of vitamins as preventive agents in defined human pop­ ulations would be started. This anticipated generation of data on vitamins and their interactions has proceeded rapidly and the impor­ tance of interactions between vitamins and other micronutrients in the prevention setting has become better appreciated. Currently, more than 25 intervention trials with a variety of target populations using vitamins and other micronutrients have been started, but it re­ mains too early for meaningful analysis of the results to date.

For decades retroviruses have been riding the crest of a wave of experimental research directed toward the identification of an infectious agent of human neoplastic diseases. In the early 1970s, several scientists successfully demonstrated the presence of retroviruses in numerous animal species and proved their etiological role in some related diseases. Corresponding findings in humans were somewhat discouraging. Although financial support for this line· of research declined, a few dedicated retrovirologists survived and continued to collect more biological information and technological expertise that opened a new approach to the search for a human retrovirus. The rewards came with the discovery that the genes responsible for neoplastic transformation (oncogenes) are of cellular origin and can be shuttled about by retroviruses, and with the identification of a new family of Human T-cell Lymphotrophic retroViruses (HTLV) from patients with diseases ranging from leukemia to the acquired immunodeficiency syndrome (AIDS). An understanding of the role and significance of retroviruses in human pathology requires basic knowledge of the major animal systems studied. With this perspective in mind, we present here a survey that includes general overviews, minireviews on each animal system studied with selected experimental reports and, finally, a stimulating review of the field of human retrovirology by many of the pioneer scientists who created it. We are especially grateful to Profs. C. A. Romanzi and G. C. Schito for promoting the organization of the Symposium. On behalf of the Sym­ posium Committee, we thank E. Soeri, L. Casarino, G. P. Gesu, M.

This book has been developed from its earlier and far less formal presentment as the proceedings of a symposium entitled The Biochemistry of S-Adenosylmethionine as a Basis for Drug Design that was held at the Solstrand Fjord Hotel in Bergen, Norway on June 30-July 4, 1985. The purpose of the symposium was to bring together scientists from various disciplines (biochemistry, pharmacology, virology, immunology, chemistry, medicine, and so on) to discuss the recent advances that have been made in our understanding of the biological roles of S­ adenosylmethionine (AdoMet) and to discuss the feasibility of utilizing AdoMet-dependent enzymes as targets for drug design. Thus the information provided herein will be of value not only to basic scientists involved in elucidating the role of AdoMet in biology, but also to medicinal chemists who are using this basic knowledge in the process of drug design. The volume should also be of interest to pharmacologists and clinicians involved in biological evaluation of potential therapeutic agents arising from the efforts of the biochemists and medicinal chemists. Each plenary speaker at the symposium was requested to submit a chapter reviewing recent contributions of their discipline to our base of knowledge about the biological role of AdoMet. Topics covered in this volume include protein and phospholipid methylations (Section A), nucleic acid methyl­ ations (Section B), the regulation of AdoMet, S-adenosylhomocysteine, and methylthioadenosine metabolism (Section C), clinical aspects of AdoMet (Section D), and the design, synthesis, and biological evaluation of trans­ methylation inhibitors (Section E).

This book encompasses the proceedings of a conference held at Trinity College, Oxford on September 21-25, 1985 organized by a committee comprised of Drs. M. Crumpton, M. Feldmann, A. McMichael, and E. Simpson, and advised by many friends and colleagues. The immune response gene workshops that took place were based on the need to understand why certain experimental animal strains were high responders and others were low responders. It was assumed that identification of the immune response (Ir) genes and definition of their products would explain high and low responder status. Research in the ensuing years has identified the Ir gene products involved in antibody responses as the la antigens, or MHC Class II antigens. These proteins are now well defined as members of the immunoglobulin gene superfamily, and their domain structure is known. Epitopes have been defined by multiple mono­ clonal antibodies and regions of hypervariability identified. Their genes have been identified and cloned. The basic observation of high and low responsive­ ness to antigen is still not understood in mechanistic terms, however, at either the cellular or molecular level. This is because the rate of progress in immune regulation has been far slower than in the molecular biology of the MHC Class II antigens. This is not surprising, since immune regulation is a very complex field at the crossroads of many disciplines.

"Methods in Protein Sequence Analysis 1986" offers an account of a rapidly developing area of protein research. Scientists from major laboratories throughout the world here report their latest findings and authoritative interpretations, as well as all the laboratory details needed to work productively with the powerful new techniques that are pushing the field's frontiers so rapidly ahead.

In 1928, it was discovered that copper was essential for normal human metabolism. Ten years later, 1938, it was observed that patients with rheumatoid arthritis had a higher than normal serum copper concentration, which returned to normal wi th remission of this disease. Thirteen years later, it was found that copper complexes were effective in treating arthritic diseaseS. The first report that copper complexes had antiinflammatory activity in an animal model of in­ flammation appeared twenty-two years after the discovery of essen­ tiality. In 1976, it was suggested that the active forms of the anti­ arthritic drugs are their copper complexes formed in vivo. This suggestion was confirmed and extended in the interim with over 1000 recent publications, and many of these were addressed in the proceed­ ings of our first symposium, published in 1982. The present symposium was organized to present new normal physiological, nutritional, and biochemical aspects of essential metal­ loelement metabolism as well as variations in metabolism associated with disease states. In addition new data concerning antimicrobial, antiinflammatory, antiulcer, anticancer, anticarcinogenic, analgesic, and radioprotectant activities of copper complexes were presented. These activities are consistent with the notion that they represent the facilitation of normal copper-dependent metabolic processes in dis­ ease states. The presentations and interactive discussions that fol­ lowed are contained in these proceedings. John R. J. Sorenson Dedication These proceedings are dedicated to those who made this truly memorable scientific and social Arkansas experience possible.

Since its discovery as the cause of infectious mononucleosis in 1964, the Epstein-Barr virus (EBV) has been etiologically implicated in an increasing number of human diseases. Generally considered the first human oncogenic virus because of a number of studies linking it with Burkitt's lymphoma and nasopharyngeal carcinoma (NPC), as well as its documented oncogenicity in nonhuman primates, EBVhas served as a model for identifying subsequent candidate oncogenic viruses and the stimulus for Evans' revision of the Henle-Koch postulates to accommodate the problems in proving viral oncogenicity in humans. Research on the role of EBV in human cancer was particularly en­ hanced (a) by the pioneering work of Werner and Gertrude Henle, and (b) by the coordinated efforts of the Special Virus Leukemia Program and its successors, the Special Virus Cancer Program and the Virus Cancer Program of the National Cancer Institute (NCI). Initiated by Dr. Frank J. Rauscher, who subsequently became director of the Ncr and is now Vice-President of the American Cancer Society, and expanded by Dr. John B. Moloney, whose contributions to cancer research were honored at this Second International Symposium on EBV and Associated Malignant Diseases, these NCI contract-sup­ ported programs brought together investigators from all over the world to participate in a joint effort to unravel the mystery of EBV behavior and pathogenicity. It was these programs that gave us the opportunity to work with such outstanding people as Professor Yohei Ito, to whom this book is dedicated.

This volume contains the proceedings of an International Sympo- sium on the Biology and Pharmacology of Tumor Cell Differentiation- held on June 29-July I, 1986 at the University of Tromso, Norway. The objective of this meeting was to bring together scientists from various disciplines to discuss recent advances in the understanding of tumor cell differentiation and to bridge the gap between experimental findings and clinical application of new knowledge. Thus the infor- mation will be of value not only to basic scientists involved in mol- ecular and cell biology, but also to pharmacologists and clinicians trying to develop the concept of tumor cell differentiation as a thera- peutic modality. Each plenary speaker and selected poster presenters were requested to submit a comprehensive, up-to-date review of recent contributions to their disciplines related to differentiation and: hematopoietic factors and leukemic cells in culture~ vitamin deriva- tives and polyamines; nucleosides and methylation; and cell interac- tions.

The Fifth International Lymphokine Workshop was convened in Clearwater Beach, Florida, January 11-15, 1987. The theme chosen for the meeting was 'The Molecular Basis of Lymphokine Action," which reflected the opinion of the organizers as to how far the field had moved since the first Lymphokine Workshop only eleven years ago. As was evident at the last Lymphokine Workshop held in 1985, the contribution of molecular biology, particularly in the cloning of lymphokine genes, continues to play an important role in clarifying the structure of lymphokines, providing recombinant (read "pure") proteins for biological studies, and suggesting directions for studies of the molecular basis of lymphokine activity. The most recent lymphokines to yield to molecular cloning meth­ odology were the B-cell growth and differentiation factors, in partic­ ular BSF-1 or, as it is sometimes termed, interleukin 4. One of the surprises from this research is the broad spectrum of activities that can be attributed to this molecule, aside from its effects on B-cells, thus perhaps justifying its being called an interleukin. The interleukin 2 symposium demonstrated that even in a well-established research area, controversy and excitement can continue, when evidence was presented by several investigators indicating the presence of a second "converter" protein that changes the affinity of the now classical Tac antigen from a low to a high affinity IL-2 receptor.

Specific biomolecular interactions occur in practically every bio- logical process, usually involving macromolecules such as proteins and nucleic acids. Thus, it is not surprising that great attention has been devoted by biologists, chemists, and physical chemists to the general phenomenon of macromolecular recognition in order to gain a better understanding of the principles, forces, and energetics that de- termine the often remarkable specificities of such interactions as those of enzymes and their substrates and inhibitors, antibodies with anti- gens, hormones with their receptors, and DNA with drugs. These studies have allowed the unraveling of some basic principles of mol- ecular recognition, such as complementarity, specificity, and dynam- ics of the interacting species, and at the same time have led to development of analytical and separation techniques based on bio- logical specificity (e. g. , affinity chromatography and other bioaffinity methods).This volume was assembled to address current research and developing ideas in biomolecular recognition through the contribu- tions presented at the Conference on "Mechanisms of Recognition in Biological Macromolecules" held in Siena, Italy, September 4-6,1986. The Conference was cosponsored by the National Research Council of Italy, the Italian Biochemical Society, the University of Siena, and the International Interest Group in Biorecognition Technology.

Hepatic Encephalopathy (HE) is a neuropsychiatric disorder resul t- ing from liver failure. HE may be associated with fulminant (acute) hepatic failure or chronic liver disease with portal-systemic shunting. The latter condition is characterized neuropathologically by astro- cytic rather than neuronal changes (Alzheimer Type II astrocytosis). The former is frequently accompanied by cerebral edema. Several hypotheses have been proposed to explain the pathogene- sis of HE. These include: 1. A toxic action of a substance (or substances) such as ammonia on brain function 2. A deficit of cerebral energy metabolism 3. Neurotransmitter changes, and, more recently 4. The role of "endogenous benzodiazepines. " This volume summarizes the results of a symposium held in Val David, Quebec from October 3D-November I, 1988, that was devoted to an evaluation of the evidence for and against the various hypothe- ses of HE. Data from studies in patients, in experimental (animal) models of HE, and in cultured cell preparations were discussed. In addition, a review of available approaches to the treatment and man- agement of HE was included.The therapeutic use of lactulose, anti- biotics, dietary treatment, and branched-chain amino acid treatments were included, as well as the results of preliminary studies of the therapeutic use of the benzodiazepine antagonist, flumazenil. Roger F. Butterworth, PhD Gilles Pomier Layrargues, MD v Acknowledgments The symposium was made possible by the generous financial assistance of: Hoffman-La Roche Ltd.

Epstein-Barr virus (EBV) is one of the most widespread human viruses, with over 80% of the general population exposed by young adulthood, as determined by antibody studies. Initial infection usu­ ally occurs during childhood or the teenage years. It is clear that, de­ pending on the age of the recipient, clinical manifestations of the primary infection can vary. It has been known for 20 years that EBV is the etiologic agent of acute infectious mononucleosis (IM) and is also closely associated with African Burkitt's lymphoma (BL) and naso­ it is a pharyngeal carcinoma (NPC). There is increasing evidence that factor in the etiology of B-celllymphomas, which arise at a high fre­ quency in immunodeficient populations. EBV may also contribute to the development of autoimmune disease. Thus, this virus continues to attract world-wide attention. The major target cell for EBV infection has now been conclusively identified as the complement receptor-type 2 (CR2), the Cd/Cdg 3 3 receptor on B lymphocyte. It is apparent, however, that other cells also can become infected by EBV, such as epithelial cells in the parotid gland and other epithelial cells in the upper respiratory tract. This might help account for the EBV-assodated carcinomas of the upper respiratory tract. The first in a series of international symposia on EBV -associated diseases focused primarily on Burkitt's-type lymphomas or on NPC (Kyoto 1977; Dusseldorf 1980; Kuala Lumpur 1982) and emphasized mainly the clinical elements of these diseases. Subsequent symposia (Loutraki, 1984; St.

Alcohol abuse throughout the world is associated with serious social and medical implications. Problems such as intoxication, tol­ erance, and development of physical dependence have been well recognized. The central nervous system and the liver are especially affected. There is little doubt that alcohol abuse can result in organ damage, which in turn leads to deleterious health consequences to the individual. Understanding ethanol action presents a special and functional diver­ challenge because of its molecular simplicity sity. In fact, the ability for alcohol to disrupt cellular function is at­ tributed to its cellular injury without regard to an apparent specific mechanism of action. Nevertheless, the key to an effective treatment to this problem is through research into understanding the mechan­ isms underlying how ethanol interacts with cells and membranes. This book is the result of a cooperative effort among scientists from many nations who met in a symposium in Taipei, Taiwan, ROC, July 1988. The focus of this book is on experimental ap­ proaches to better understand the molecular mechanisms of ethanol on the biological system. These recent advances in the examination of the alcohol effects on cellular function are divided into four sec­ tions. The first section addresses specific actions of ethanol on the central nervous system. The second section is directed to the use of cell cuI tures in ethanol research and the usefulness of cell cultures in examination of the effects of ethanol in vitro.

During the last 10 years, the role of specific nutrients in cancer prevention and cancer treatment has been the subject of intense basic, preclinical, and clinical research. At present, the major focus of nutri­ tional oncology is on the mechanisms of carcinogenesis and their modification by nutrients and on cancer prevention studies in animals and humans. Some human epidemiological studies have confirmed the hypothesis, developed on animals, that there is an inverse relation­ ship between the intake and/or level of !3-carotene, vitamin A vita­ min E, or vitamin C and the risk of cancer, whereas others have shown no such relationship. This is not unexpected, since the protective effect of individual nutrients may be too small to be detected by epidemiological methodologies in which a single vitamin or mineral is considered as one variable. Conclusive evidence regarding the role of nutrients in human cancer prevention will come from a well­ designed human intervention study using one or more nutrients in a population that has a high risk of developing cancer. The involvement of specific nutrients in the regulation of protooncogene expression has just begun. Also, some of the results of human intervention trials are beginning to yield interesting results. A large number of interna­ tional scientists from various disciplines, including cell biology, mo­ lecular biology, nutritional oncology, epidemiology, and public health, reviewed and discussed their most recent findings. The following topics were emphasized: 1. Mechanisms of carcinogenesis; 2.

The Epstein-Barr virus continues to be the focus of much worldwide attention as a significant pathogen for a variety of human diseases, including certain types of cancer. In the new Epstein-Barr Virus and Human Disease 1990, special attention is given to investigations of the various genes responsible for the different manifestations caused by viral infection, as well as to promising new research that may yield clues to how cancer develops from a normal cell. In the present volume, renowned experts from many countries offer up-to-date information and insights into the fast-paced field of EBV research, including: nasopharyngeal carcinoma lymphoproliferative diseases molecular aspects of EBV molecular genetics of EBV pathobiology of EBV-related diseases immunology of EBV-related disorders future trends in EBV research. Epstein-Barr Virus and Human Disease 1990 is an essential resource for everyone concerned with either the experimental or clinical aspects of EBV virology, immunology, pathology, molecular biology, oncology, and related fields.

The role of carcinogenic agents in the deveolopment of human cancers is now being defined using a variety of human cells as experi­ mental model systems. A workshop on "neoplastic transformation in human cell systems in vitro: mechanisms of carcinogenesis" was held at the Georgetown University Medical Center, Washington, DC, on April 25-26, 1991. The aims of the workshop were to present the state-of-the­ art in the transformation of human cells in culture, as well as to provide insight into the molecular and cellular changes involved in the conver­ sion of normal cells to a neoplastic state of growth. The following topics were closely related to the theme of the workshops: 1. Derivation of in vitro model systems (epithelial, fibroblastic, and hematopoietic). 2. Factors modulating cellular transformation. 3. Usefulness of defined in vitro model systems for viral, chemical, and radiation carcinogenesis. 4. Multistep nature of human cell carcinogenesis. 5. Role of activated and suppressor oncogenes in neoplastic trans­ formation. The workshop was organized by J. S. Rhim and A. Dritschilo (cochairmen), G. Jay, J. little, M. McCormick, R Tennant, and R R Weischelbaum. There were 32 speakers, 30 poster presentations, and about 190 participants.

The Resistance Arteries is focused on the general issue of the regulatory pathways in resistance arteries and comprises a selection of timely overviews and up-to-date research studies presented at the 4th International Symposium on Resistance Arteries. These small vessels act as major controllers of blood pressure, blood flow, and its distribution, and are involved in a variety of pathological conditions. Vascular diameter is influenced by a host of factors, some extrinsic to the smooth musc1e cells and some intrinsic. One will find contributions in nearly all of the five themes by which the book is organized; these address intra-and extracellular interactions, and membrane receptor pathways using vascular beds as diverse as the brain, he art, lung, kidney, and skin. Basic physiological studies are inc1uded; these examine: growth fac- tors, vasoactive endothelium-derived nitric oxide, the impacts of flow and stretch, myogenic mechanisms, calcium regulation by protein kinase C, and signal transduction pathways of the vascular smooth musc1e cell membrane receptors.Not only are tissues from appropriate animal models exploited in most of these reports, but many reflect the current increase in the use of human tissue to elucidate vascular alterations of function and morphology in hypertension, atherosclerosis, and ischemia. Noteworthy among the many techniques used are: membrane permeabilization with toxins, fura-2 for calcium determination, single cell electrophysiology, and the application of confocal microscopy to isolated, living vessels.

Nutrients in Cancer Prevention and Treatment contains articles that were presented by leading researchers and physicians in the field of nutritional oncology. Most of the previous conference proceedings on Nutrition and Cancer have dealt primarily with the issue of the role of nutrients in cancer prevention. This is logical because enormous quantities of laboratory and epi­ demiologic data have been published on the topic. Nutrients in Cancer Prevention and Treatment also contains several studies on the role of diet and vitamins in cancer treat­ ment. There are very few books that have reviewed laboratory and clinical studies and the role of vitamins in cancer treatment. There are preliminary data suggesting that daily supplementa­ tion with high doses of certain vitamins in combination with conventional therapeutic agents may enhance their growth inhibitory effects on tumor cells, and may protect normal tissues against some of their toxic effects. This book is unique in the sense that several articles have discussed the mechanisms of action of individual vitamins on cellular and molecular parameters. It is very exciting to note that some of the vitamins inhibit protein kinase C activity, increase the production of certain growth factors, and modulate the expression of a number of oncogenes. These studies, at least in part, offer rationales for the cancer protective effects of vitamins.

Experimental and clinical investigators join forces to explain our current understanding of lactoferrin. Drawing on many disciplines, the front-line authorities writing here define the known structural features of lactoferrin and describe in detail several of its physiological functions. These include the role of lactoferrin in killing bacteria, and its involvement in cell growth and proliferation, in the modulation of immune function, and in iron absorption. Particular attention is given to lactoferrin functions in the regulation of normal and diseased states. New knowledge of the molecular biology of lactoferrin is also included, along with discussions of commercially viable large-scale production techniques and important new industrial applications. This comprehensive, multidisciplinary work should open the door to the greatly expanded use of lactoferrin as a bioactive reagent in foods and pharmaceuticals. Lactoferrin: Interactions and Biological Functions offers a comprehensive, multidisciplinary view of our present knowledge of lactoferrin. The book should open the way to the expanded use of lactoferrin as a bioactive reagent in foods and pharmaceuticals.

The Fifth Ir Gene Workshop was held at the Chase-Park Plaza Hotel, St. Louis, MO, August 28-31, 1982; 240 scientists participated in the Workshop. The man­ uscripts compiled in this book describe the state of the art concerning Ir genes. Although the notion of Ir Genes: Past, Present, and Future has not been ad­ dressed specifically by each author, the reader is certain to get this flavor from the contributions. In this Preface, we have tried to summarize some of the salient ob­ servations and discussions from the Workshop. The mUltiple genes of the I region have been defined traditionally by serolog­ ical analysis of intra-H-2 recombinant mice and the pattern of immune responses to certain antigens developed by these recombinant mice. The application of sev­ eral new techniques, such as gene cloning and DNA sequencing, production of T and B cell hybridomas, and development of cloned T cell lines has changed this tradition and introduced a new phase into the analysis of the I region, Ia antigens, and Ir genes.