In order to better understand the molecular basis for the development of therapeutic resistance by prostate cancer, we have undertaken experimentation in which we genetically compared therapy resistant prostate cancer cells to therapy sensitive prostate cancer cells. As a result of this comparison, we have identified a novel gene product, previously referred to as T6 (now referred to as Protocadherin-PC) that is highly upregulated when prostate cancer cells are selected for resistance to apoptotic agents in vitro and when these cells are selected for hormonal resistance in vivo. This progress report describes our success in characterizing the human Protocadherin-PC gene and gene product and in describing the probable mechanism through which this protein increases therapeutic resistance of prostate cancer cells. As a result of these studies, we believe that prostate cancer progresses to the state of therapeutic resistance in a mechanistically similar manner to that of human colon cancer and melanoma.

This phase I project characterized a gene product initially referred to as "T6" that is upregulated when cultured prostate cancer cells were selected for an apoptosis-resistance phenotype. We have characterized this molecule and now call it protocadherin-PC. It is a very unusual species of protocadherin family molecules in that it is localized cytoplasmically instead of membrane-bound (like other members of this family) and we have shown that it binds to the wnt-signaling transcription factor, P-catenin, activating transcription from beta-catenin/TCF promotors. Thus, expression of protocadherin-PC in prostate cancer cells appears to activate the wnt signaling pathway in an analgous manner to which writ signaling is activated during progression of colon cancer or melanoma. We have also found that this unique protocadherin is encoded on the human Y chromosome and we have shown that the Y-chromosomal form of protocadherin-PC is highly upregulated in actual specimens of hormone-resistant prostate cancers in conjunction with activation of the writ- signaling pathway. Therefore, the results of this project suggest that activation of the wnt-signaling pathway by protocadherin-PC has an important role in the development of therapeutic resistance in prostate cancer patients.

This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

Knowledge about diagnostic procedures in melanoma has in creased rapidly within the past few years. Single tumor cells have been identified in normal tissue such as sentinel lymph nodes, as well as in bone marrow, peripheral blood, and other bodily fluids and cells, by molecular technologies. The introduction of polymerase chain reaction-based methods can be regarded as a prototype of this dramatic development towards molecular approaches in new diagnostic procedures. This fact opens up the possibility of clinical use in patients and of influencing treatment strategies. Considerable discrepancies have been described, how ever, in the success rates of these new techniques for the detec tion of minimal residual disease in cancer patients. Despite fav orable results reported by different groups of investigators, it will take several years to define the clinical and pathophysiological relevance of new diagnostic procedures. The 1st International Symposium "Minimal Residual Disease in Melanoma: Biology, Detection and Clinical Relevance of Microme tastases", held in September 1999 in Homburg/Saar, Germany, fo cused on recent developments in this particular area of cancer re search. The purpose of the meeting was to stimulate discussion and exchange of new data and ideas by renowned international scientists. The aim of this volume is to summarize major topics of basic research and clinical investigations presented by invited experts in this fascinating but still. controversial field of melanoma re search.

Providing a unique A-Z guide to antibodies for immunohistology, this is an indispensable source for pathologists to ensure the correct application of immunohistochemistry in daily practice. Each entry includes commercial sources, clones, descriptions of stained proteins/epitopes, the full staining spectrum of normal and tumor tissues, staining pattern and cellular localization, the range of conditions of immunoreactivity, and pitfalls of the antibody's immunoprofile, giving pathologists a truly thorough quick-reference guide to sources, preparation and applications of specific antibodies. Appendices provide useful quick-reference tables of antibody panels for differential diagnoses, as well as summaries of diagnostic applications. Expanded from previous editions with over forty new entries, this handbook for diagnostic, therapeutic, prognostic and research applications of antibodies is an essential desktop book for practicing pathologists as well as researchers, residents and trainees.

The formation of blood vessels is an essential aspect of embryogenesis in vertebrates. It is a central feature of numerous post-embryonic processes, including tissue and organ growth and regeneration. It is also part of the pathology of tumour formation and certain inflammatory conditions. In recent years, comprehension of the molecular genetics of blood vessel formation has progressed enormously and studies in vertebrate model systems, especially the mouse and the zebrafish, have identified a common set of molecules and processes that are conserved throughout vertebrate embryogenesis while, in addition, highlighting aspects that may differ between different animal groups. The discovery in the past decade of the crucial role of new blood vessel formation for the development of cancers has generated great interest in angiogenesis (the formation of new blood vessels from pre-existing ones), with its major implications for potential cancer-control strategies. In addition, there are numerous situations where therapeutic treatments either require or would be assisted by vasculogenesis (the de novo formation of blood vessels). In particular, post-stroke therapies could include treatments that stimulate neovascularization of the affected tissues. The development of such treatments, however, requires thoroughly understanding the developmental properties of endothelial cells and the basic biology of blood vessel formation. While there are many books on angiogenesis, this unique book focuses on exactly this basic biology and explores blood vessel formation in connection with tissue development in a range of animal models. It includes detailed discussions of relevant cell biology, genetics and embryogenesis of blood vessel formation and presents insights into the cross-talk between developing blood vessels and other tissues. With contributions from vascular biologists, cell biologists and developmental biologists, a comprehensive and highly interdisciplinary volume is the outcome.