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'What is a nongenotoxic carcinogen?'This question recurred through­ out the Ernst Schering Research Foundation Workshop on nongeno­ toxic carcinogenesis, underlining the complexity of the topic. The clarity of the view that all carcinogens act by mutating DNA, origin­ ally advocated by Bruce Ames nearly 20 years ago, has been clouded by the increasing numbers of compounds which are not genotoxic but which nevertheless can cause cancer. There is an urgent need to in­ crease our understanding of these compounds so that their risks can be evaluated realistically and decisions made from a position of knowl­ edge and strength, rather than in fear of the unknown. A nongenotoxic carcinogen can be defined as a compound which causes cancer, but which does not cause damage to DNA as its primary biological activity. This negative definition covers a range of carci­ nogens acting through a variety of mechanisms. Such chemicals often produce tumours only in a single organ species, and there are a few common locations which are affected most often. For example, in male rats, certain carcinogens bind to az globulin to form a complex which 11 accumulates in the kidney tubular cells, which is followed by necrosis and compensatory cell proliferation leading the neoplasia. Other com­ mon mechanisms include hormonal imbalance resulting in thyroid tu­ mours or peroxisome proliferation resulting in liver cancer. These and other examples are studied in some detail in the papers of this book.

The annual research conference for 1996 of the American Institute for Cancer Re­ search was again held at the Loews L'Enfant Plaza Hotel in Washington, DC, August 29 and 30. The topic for this, the seventh in the series, was'Dietary Fat and Cancer: Genetic and Molecular Mechanisms.'Two separate presentations were given as the conference overview.'Fat and Cancer: The Epidemiologic Evidence in Perspective'noted that die­ tary fat can be saturated, largely from animal or dairy sources, or mono- or polyunsatu­ rated, mostly from plant sources. Unlike animal fats, fish contain relatively high levels of protective omega-3 fatty acids. Although the hypothesis that dietary fat is associated with cancer is plausible, the mechanisms involved are reasonable, and many animal studies support the hypothesis, there are many obstacles in any direct extrapolation to humans, in­ cluding imprecise measures of dietary fat intake, variability in individual diets, and spe­ cies variations. Despite these limitations, there is a weak positive correlation between colon cancer and dietary fat intake, but with substantial differences for various ethnic groups. In the case of breast cancer, there is substantial variation among countries and eth­ nic groups, but the overall evidence indicated an association with fat in the diet. Epidemiologic studies of dietary fat and prostate cancer are more consistent and most show a positive relationship. However, it was not clear which types of dietary fat were im­ plicated in the effect.

Most of the world's experts on prions met for a workshop in Erice in August 1996. The aim of the workshop was to discuss the fundamentals of the science ofprions. It was for­ tunate that so many could be present given the pressure that they were under because of the data presented in March 1996, indicating that Bovine Spongiform Encephalopathy, BSE or Mad Cow Disease, had penetrated the species barrier and was beginning to cause a new dis­ ease in humans--the new variant ofCreutzfeldt-Jakob Disease, nvCJD. This important and urgent subject became an additional major topic at the workshop. This is a book containing most of the talks plus the abstracts of those unable to find time to write up their talks. Almost all papers were written in the spring and summer of 1997 and contain material added after the workshop; thus Bob Will's paper on the new variant of cm contains data up to July 1997 and four contributions arrived in October 1997. In addition to the talks given at our workshop, there was a special joint session with the Planetary Emergencies Workshop where many distinguished scientists, including three Nobel laureates, discussed major issues affecting our planet. Six talks were given by us to this other workshop, five about prions, BSE, and nvCJD, and one on the broader issue of new epi­ demics by Luc Montagnier. Although most of the talks concerned research issues, there were a few special talks.

Although phosphorylation of proteins on tyrosine is relatively rare compared to phosphorylation on serine or threonine residues, the past two decades of research into PTP function have led to a great appreciation of the critical role PTPs have in regulating basic cellular processes. Among these important roles is the regulation of cellular signaling pathways related to metabolism. This volume contains chapters which highlight many aspects of PTP function in the context of metabolism. Given the growing obesity and diabetes epidemics in the United States and throughout the world, the desire to identify possible therapeutic targets for treatment of these diseases is a high priority. In many ways, PTPs may be attractive drug targets since they are amenable to targeting with small molecules; however many challenges abound in making PTP inhibitors.

For those like me who witnessed the beginning of the adventure of human mitochon­ drial pathology, one can only be astounded by the extent and unexpectedness of what the field has come to offer. Extent because nobody could have imagined the sheer size of the domain. Unexpectedness because hitherto it was impossible to imagine the clinical polymorphism that this pathology would represent. The starting point was clear. Initially, there was the exceptional, and for a long time unique, observation of euthyroidian hypermetabolism that Luft and colleagues analyzed remarkably in biochemical and clinical terms. Thereafter, there was the support provided by the electron microscopy studies of Afzelius, and the very first visualization of mitochondrial abnormalities. That was way back in 1958. A few years later, progress in the cytology and cytochemistry of skeletal muscle tissue was to provide the means of detecting such abnormalities by examining sections with light microscopy. The colorful term'ragged red fibers', coined by W. K. Engel, became uni­ versally accepted, and this typical aspect with Gomori trichrome stain was to throw light on the frequency with which these mitochondrial abnormalities could occur under pathological conditions which, until then, had remained a total mystery regard­ ing their mechanism: syndromes such as the ocular myopathies with their descending evolution and the oculocraniosomatic syndromes. We were at the beginning of the 1970s.

Despite its universality in human female aging, the menopause and its biology are not completely understood. New biologic mechanisms by which sex hormones may be detrimental or confer protection are continually being discovered. We are now starting to understand that the role of the estrogen receptor is not identical in all tissues. Important nongenomic effects for sex hormones have also been described. Hormone replacement therapy (HRT) has produced effects on health risks: some are reduced, some are increased, and the rest remain uncertain. HRT is being used by an increasing number of women to alleviate climacteric symptoms in the perimenopausal period and to prevent osteoporosis and cardiovascular disease later. Positive effects on Alzheimer's disease and dementia on the one hand, and an increase in venous thrombosis on the other, are currently being reported by several groups. Both the preventive benefits and the risk of breast cancer seem to be linked to long-term and current use. HRT requires further testing through specific clinical trials, currently underway in the United States, before confident recommendations may be made about the full range of benefits and risks.

Now in its second year, Progress in Cell Cycle Research was conceived to serve as an up to date introduction to various aspects of the cell division cycle. Although an annual review in any field of scientific investigation can never be as current as desired, especially in the cell cycle field, we hope that this volume will be helpful to students, to recent graduates considering a de1liation in subject and to investigators at the fringe of the cell cycle field wishing to bridge frontiers. An instructive approach to many subjects in biology is often to make comparisons between evolutionary distant organisms. If one is willing to accept that yeast represent a model primitive eukaryote, then it is possible to make some interesting comparisons of cell cycle control mechanisms between mammals and our little unicellular cousins. By and large unicellular organisms have no need for intracellular communication. With the exception of the mating phenomenon in S. cerevisiae and perhaps some nutritional sensing mechanisms, cellular division of yeast proceeds with complete disregard for neighbourly communication. Multicellular organisms on the other hand, depend entirely on intracellular communication to maintain structural integrity. Consequently, elaborate networks have evolved to either prevent or promote appropriate cell division in multicellular organisms. Yet, as described in chapter two the rudimentary mechanisms for fine tuning the cell division cycle in higher eukaryotes are already apparent in yeast.

I have been privileged to witness and participate in the great growth of knowledge on chemical carcinogenesis and mutagenesis since 1939 when I entered graduate school in biochemistry at the University of Wisconsin­ Madison. I immediately started to work with the carcinogenic aminoazo dyes un­ der the direction of Professor CARL BAUMANN. In 1942 I joined a fellow graduate student, ELIZABE1H CAVERT, in marriage and we soon commenced a joyous part­ nership in research on chemical carcinogenesis at the McArdle Laboratory for Cancer Research in the University of Wisconsin Medical School in Madison. This collaboration lasted 45 years. I am very grateful that this volume is dedi­ cated to the memory of Elizabeth. The important and varied topics that are reviewed here attest to the continued growth of the fields of chemical car­ cinogenesis and mutagenesis, including their recent and fruitful union with viral oncology. I feel very optimistic about the application of knowledge in these fields to the eventual solution of numerous problems, including the detection and estimation of the risks to humans of environmental chemical carcinogens and re­ lated factors.

I have been privileged to witness and participate in the great growth of knowledge on chemical carcinogenesis and mutagenesis since 1939 when I entered graduate school in biochemistry at the University of Wisconsin­ Madison. I immediately started to work with the carcinogenic aminoazo dyes un­ der the direction of Professor CARL BAUMANN. In 1942 I joined a fellow graduate student, ELIZABETH CA VERT, in marriage and we soon commenced a joyous part­ nership in research on chemical carcinogenesis at the McArdle Laboratory for Cancer Research in the University of Wisconsin Medical School in Madison. This collaboration lasted 45 years. I am very grateful that this volume is dedi­ cated to the memory of Elizabeth. The important and varied topics that are reviewed here attest to the continued growth of the fields of chemical car­ cinogenesis and mutagenesis, including their recent and fruitful union with viral oncology. I feel very optimistic about the application of knowledge in these fields to the eventual solution of numerous problems, including the detection and estimation of the risks to humans of environmental chemical carcinogens and re­ lated factors.

In all organs of the body, proteases have critical roles to play both in normal development and functioning and in disease states. The brain is no exception to this, with proteases having emerging roles in synaptic plasticity, memory, neurodegenerative disorders such as Alzheimer's, Parkinson's and prion diseases, ischemia and traumatic brain injury, inflammatory and infectious diseases, and tumor progression. Proteases in the Brain brings together a wide range of topics under this central theme and highlights the large number of proteases involved in these normal and disease processes. Proteases in the Brain reviews the role and regulation of proteases in, Alzheimer's disease, brain ischemia and traumatic brain injury, human glioma, inflammatory and infectious diseases of the central nervous system, metabolism of the prion protein, modulating synaptic activity, multiple sclerosis, neuronal plasticity and memory consolidation, Parkinson's disease, processing, conversion and inactivation of neuropeptides. Proteases in the Brain is a timely and useful source of information both for those well-versed in the role of proteases in the brain, and for those who are beginning to realize the important role of this family of enzymes in brain function and dysfunction.