Department of Pathology
ResearchMembers of a department that has a century-long tradition of novel discoveries and therapeutic applications, our Pathology investigators press toward a better understanding of disease. The following is a selection of work that is currently underway. Daniel Perl, M.D.Neuropathology studies by Dr. Daniel Perl and coworkers have shown the extent and location of important protein accumulation that characterizes the earliest phases in the development of Alzheimer's disease. Studies have further demonstrated evidence for cellular damage to nerve cells produced by oxidative stress in both Alzheimer's disease and Parkinson's disease, suggesting a common pathway of degeneration for both disorders. In studies of ALS-parkinsonism-dementia complex of Guam, a unique degeneration of the nervous system seen in the natives of that island in the Western Pacific with features of Alzheimer's disease, Parkinson's disease, and ALS, or Lou Gehrig's disease, evidence has shown that the pathologic features encountered in the brain have changed over the past 30 years. These changes strongly suggest that the etiology of the condition is environmental in nature and that the new features result from alterations in exposure to a putative environmental etiologic agent. Andrew D. Bergemann, Ph.D.Axon guidance is critical to the correct development of the vertebrate nervous system. Workers in Dr. Andrew D. Bergemann's laboratory have made considerable progress towards an understanding of the molecular interactions underlying axon guidance. In particular, the observation of proteolytic processing of ephrin-B2, an axon guidance molecule, in response to oligomerization, suggests that it is a key regulatory step in the interaction of growing axons with their milieu. Thomas M. Fasy, M.D., Ph.D.Research in the laboratory of Dr. Thomas M. Fasy is largely focused on autoantibodies from patients with autoimmune and other diseases and inbred mouse models of autoimmune disease. Current work is focused on autoantibodies which bind cytokines or neuropeptides, especially pain-suppressing opioid peptides. Enkephalin-binding and nocistatin-binding autoantibodies have recently been identified. The possibility that some enkephalin-binding autoantibodies have catalytic (peptidase) activity capable of inactivating enkephalins is a major focus of current research. A separate ongoing project tests the hypothesis that immune status (especially, anti-tumor immunity and Th1/Th2 balance) can be modulated by nutritional interventions. Stave Kohtz, Ph.D.Cancer research in the laboratory of Dr. Stave Kohtz is directed at understanding how dysregulated expression of cyclin D1 in a certain B-cell neoplasm (Mantle cell lymphona; MCL)results in neoplastic growth. The median age for MCL is 50-60 years, and the survival rate is much shorter than it is for other low grade lymphomas. This research may suggest novel therapeutic avenues for treatment of MCL. In addition, studies of cyclin-dependent kinase (CDK) activity are being conducted in situ using antibodies directed at phosphorylated kinase substrates. This approach provides a more functionally significant view of kinase dysregulation in tumors than does simply staining for cyclin or CDK expression; it may eventually be used for early detection of neoplastic cells in situ, for differential diagnosis, and for prognosis. David Burstein, M.D.Dr. David Burstein and co-workers are developing new and novel tumor markers, all of which are key components of cancer-causing signal transduction pathways. Many signal transduction pathways consist of cascades of protein phosphorylations. Dr. Burstein's lab is adapting the use of phoshorylation-specific antibodies for immunohistochemical staining of tumors. Some of the phosphorylations correspond to oncogenic actions of protein kinases now being targeted by a new class of kinase-inhibitory drugs that are proving to be less toxic, more potent, and useful in designing individualized tumor therapy based upon the abnormalities found in each individual tumor. This contrasts with the currently used highly toxic and non-specific chemotherapy. (Two new kinase-inhibitory drugs, herceptin and STI-571, effective in breast cancer and chronic myelogenous leukemia, respectively, have been highly successful.) With Dr. DS Kohtz, his lab has developed a phosphorylation-specific anti-phospho-histone H1 tissue stain that allows visualization of cyclin-dependent kinase activity on tumor tissue sections. With Dr. R Haber, Endocrinology, Dr. Burstein discovered that the glucose transporter GLUT1 is an immunohistochemical tumor marker in a number of common epithelial malignancies. GLUT1 is induced in tumor cells by a hypoxia-sensing pathway. Tumor hypoxia has been shown to contribute to therapeutic failure and tumor progression. Dr. Burstein and colleagues have shown specific GLUT1 staining patterns to be indicative of tumor hypoxia, whereas other GLUT1 patterns are not. Two other important signal transduction pathway components being exploited as new tumor markers are p63, a p53-homologous protein that he and colleagues have shown to be useful in lung cancer diagnosis and other diagnostic applications; and the discovery that a specific tyrosine phosphatase (which opposes the action of tyrosine kinases) appears to function aberrantly in many common malignancies. This is consistent with the ability of tyrosine phosphatases to oppose the actions of tyrosine kinases, many of which activate oncogenic pathways. In addition to its applications in pathology, the molecular biology of this tyrosine phosphatase is being investigated, including its interaction with key oncogenic signal transduction pathways activated by tyrosine kinases jak-2, c-src, growth factor receptors, and others. Susan Morgello, M.D.The Manhattan HIV Brain Bank, established and directed by Dr. Susan Morgello, is an eight million dollar NIH-funded project focused on the neurologic, neuropsychologic, and neuropathologic manifestations of AIDS. Dr. Morgello and her staff at 4 major medical centers in New York (Mount Sinai, Beth Israel, Saint Luke's, and Roosevelt Hospital), have recruited a large cohort of advanced stage HIV -infected individuals who have agreed to be fluid and organ donors for the purposes of AIDS research. This program has supplied clinical information, tissue, and fluid samples to AIDS researchers across America and in Europe and Australia. The bank acts as a resource to the international AIDS research community, to facilitate direct investigations of HIV-related human disease. Additionally, research within the Manhattan HIV Brain Bank has led to the elucidation of causes of HIV-related mortality in the era of highly active antiretroviral therapies. Selected References:
David Zhang, M.D., Ph.DResearch in the Molecular Pathology Laboratory of Dr. David Zhang focused on the development of novel DNA amplification and detection methods and development of effective anticancer drugs. The technologies invented in his laboratory include the isothermal ramification amplification assay (RAM) and hybridization signal amplification assay (HSAM). Both technologies have been granted by the US Patent Office and licensed to Hamilton Thorne Biosciences, a biotechnology company based in Boston. RAM, unlike conventional polymerase chain reaction (PCR), can amplify DNA and RNA targets without the use of thermocycling. It is extremely sensitive and can detect as few as 10 molecules, which is as sensitive as PCR. HSAM is another detection technology based on the principles of nucleic acid hybridization and specific ligand interaction. This technology is simple and sensitive to identify DNA/RNA targets and proteins. These methods are currently under the development for the detection of certain microorganisms in the clinical samples and apply to in situ amplification, DNA arrays, and proteomics. In addition, Dr. Zhang's laboratory has identified several plants that have strong anticancer activities, including prostate, breast, and lung cancers in cultured cancer cells and in animals. Recent research from his laboratory demonstrated that the ingredients from the plants promote apoptosis and reduce proliferation of cancer cells. The target of the plant has been recently identified to be cyclo-oxygenase which is linked to many biological activities, such as carcinogenesis, inflammation, and cell proliferation. The ingredients from the plants may be used as a novel chemopreventative agent and/or adjuvant therapy for the treatment of cancer in the future. Ronald E. Gordon, Ph.D.Dr. Ronald E. Gordon's research is focused on elucidating the mechanisms involved in the development of pulmonary fibrosis in response to oxidant injury. In exploring these phenomena, he has developed an animal model system in which it is possible to prevent the development of fibrosis using prophylactic taurine treatment. His laboratory in collaboration with other laboratories looking at similar effects (Rutgers University and SUNY Institute for Basic Research) explores morphologic criteria and the molecular mechanisms involved in the natural history of the disease and prevention. Another focus of his research, which in many ways parallels that of lung fibrosis, is the mechanisms involved in the development of atherosclerosis. He has and continues to collaborate with numerous Physicians and researchers throughout the institution working to find treatment to prevent the development or stop the progression of this disease. Selected References:
Juan Gil, M.D. and Hai-Shan Wu, Ph.D.Drs. Juan Gil and Hai-Shan Wu are conducting studies on applicability of computerized image analysis technology to practical problems in Anatomic Pathology and Cytology. After clarifying the difficulties posed by fully automatic nuclear segmentation and its resolution by means of semiautomatical procedures, as well as statistical and non-statistical classificatory approaches, the current emphasis is on the quantitative characterization of nuclear chromatin texture by means such as fractal dimensions and autocorrelation factors. Chromatin texture has always been one of the prime factors considered by pathologists in their diagnostic work. It is hoped that the use of quantitative descriptors will increase the dependability and reproducibility of difficult cytologic and histologic classifications. Applications in Cytopathology are a priority. Additionally, the laboratory has initiated cooperative studies with scientists in the Department of Radiology aimed at participation in applications of low dose CAT scanning technology for lung cancer, with emphasis on problems related to random background noise. The group continues to offer support to numerous investigators in the School who have a need to obtain quantitation of aspects of their morphological studies. These studies have led to a high number of publications in recent years. Steven Dikman, M.D.In research related to kidney disease, Dr. Steven Dikman in conjunction with members of the Nephrology Division and the Recanti/Miller Transplant Institute, demonstrated a marked increased expression of chemokines, chemokine receptors and inducible costimulator, a newly recognized molecule involved in ongoing activation and T cell effector function, in patients with transplant glomerulopathy, a process that affects glomerular function in some long term kidney transplant patients. Targeting of chemokines or chemokine receptors may provide a means of treatment and prevention of transplant glomerulopathy. John T. Fallon, M.D., Ph.D.Cardiovascular research by Dr.
John T. Fallon is focused on why atherosclerotic plaques Robert Phelps, M.D.Dr. Robert Phelps is studying the effects of numerous dermatologic treatment modalities on the synthesis of collagens. This includes coblation, Nlite laser, Obaji peels, and TCA peels. He is also studying the morphology of elastic fibers in PXE and the effect of chelators on the histopathology and clinical features of the disease. Liane Deligdisch, M.D., Peter Schlosshauer, M.D. , and Tamara Kalir, M.D.In Gynecologic Pathology, Dr. Liane Deligdisch's ongoing research is the study of the effect of hormonal therapy on the endometrium, especially of Tamoxifen and hormone replacement therapy. Dr. Deligdisch in collaboration with Dr. Peter Schlosshauer is studying specimens from prophylactic oophorectomies performed on the high risk patients for ovarian carcinoma, histologically, morphometrically, and with a battery of tumor markers. This study is following a number of previous investigations on the early stages of ovarian cancer and precancerous (dysplastic) ovarian lesions. In the present study, molecular biology methods are correlated with histologic and morphometric findings. Dr. Tamara Kalir is investigating the etiology of ovarian cancer using a model system of cancers that arise in endometriosis. Maoxin Wu, M.D., Ph.D.Dr. Maoxin Wu, Director of Fine Needle Aspiration (FNA) Service, is the principle investigator of "Advanced Therapeutic Monitoring of Cancer Using Fine Needle Aspiration and Molecular Study". This project has been proved by IRB and is in the early phase of study. In collaboration with Dr. David Burstein, Dr. Wu has developed a useful tumor marker panel (p63 and TTF-1) for the differential diagnosis of poorly differentiated squamous cell carcinoma and small cell carcinoma of lung. The result has been presented in the recent IAP conference and received strongly positive comments. Dr. Wu is also collaborating with Dr. David Zhang in studying effects of Chinese herb medicine in stomach cancer. |