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Head & Neck Oncology
Microvascular Reconstruction
Thyroid/Parathyroid Surgery

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Biorepository

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Mass Spectrometry

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Cancer is marked by uncontrolled proliferation and inappropriate survival of damaged cells in the body. Many processes used to direct the proper growth, differentiation and cell death of tissues in the developing embryo are identical to the genetic pathways that are perturbed in the cancerous state. Recently, an abundant class of non-coding RNAs, microRNAs (miRNAs), has been implicated to function as tumor suppressor genes and oncogenes and is often dysregulated in human cancers. Little is known regarding how these molecules contribute to cellular transformation and tumor formation. MiRNAs are small ~22 nucleotide single-stranded RNAs that negatively regulate expression of their gene targets. Animal miRNAs bind to complementary sequences located in the 3’ untranslated region (3’ UTR) of their target protein-coding messenger RNAs (mRNAs), resulting in translational inhibition and/or mRNA degradation.

Dr. Kerscher is very interested in studying the role miRNAs play in controlling developmental events and how this relates to cancer progression. The lab employs the simple roundworm, Caenorhabditis elegans, an organism easily grown and studied in the laboratory and amenable to genetic manipulation, to characterize the biological function of novel miRNA genes. Specifically, the lab focuses on the lin-4 and let-7 miRNA families, which they have found to direct important developmental processes such as cell-fate specification and gonad formation. The lin-4 and let-7 miRNAs are highly conserved across animal phylae and provide a unique opportunity to apply knowledge gained in the nematode to elucidate the mechanisms of human disease.

Faculty

The focus of my research is on AIDS pathogenesis, neuroAIDS and the study of monocyte maturation, infection and traffic. The goals of these studies are to define the role of macrophages in the central nervous system, and monocytes and CD8+ T lymphocytes outside the brain, contributing to pathogenesis of disease. Much of this work is done in non-human primate models.
We have described target cells infected in the CNS, their turnover and replacement by cells from the blood and bone marrow, and emerging subpopulations of monocytes that expand with disease. While investigating a pathogenic role of activated/infected monocytes in the induction of brain infection and inflammation, we are currently working on immunologic agents that selectively target SIV and HIV infected, activated monocyte/macrophages. We use the CD8 lymphocyte depletion and rapid AIDS model to study the consequences of monocyte/macrophage activation and traffic, the role of viral sequences within SIV that may drive CNS disease.

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Data Management

Specimen Procurement

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Keywords:  MicroRNA biology, Cancer Research, Lung cancer and biology, Cancer genomics, Molecular study of oncogene mechanism, Oncogenic signaling, Cancer cell metabolism, and Finding new uses of old drugs.

I. MicroRNAs and mechanism of lung cancer genes

Oncogenes activated via gene amplification have a proven track record of being amenable to invention of new anti-cancer therapies. We and others discovered a recurrent amplified region in lung cancer genomes. This amplicon contains the TTF-1 gene (thyroid transcription factor 1 or known as NKX2-1) which is essential for lung development and morphogenesis. We are interested in mapping the interconnection between TTF-1 and microRNAs to afford novel entry points to investigate TTF-1-linked lung biology. Using a variety of experimental approaches, our laboratory is the first to discover the two types of TTF-1-linked microRNAs – an upstream microRNA that directly regulates TTF-1 expression and downstream microRNAs that are regulated by TTF-1. Currently, we are investigating the biology of these interactions between microRNAs and a lung cancer/development gene.

II. New uses of old drugs

In order to minimize the exorbitant costs and risks of de novo drug discovery and development, our strategy is to use off-patent marketed small molecule drugs as the starting point of drug discovery efforts, i.e. repurposing/repositioning an old drug for a new use. Medications that have come off patent are affordable for patients and have well documented biological, toxicological, and pharmacokinetic studies associated with them. Consequently, functional screening of such “old drugs” may readily yield chemicals for immediate clinical trials. Furthermore, “off-label” prescribing allows physicians to innovate with treatments based on emerging research data. Towards this end, we are conducting a multitude of cell-based screens to uncover new utilities of “old drugs” in fighting cancers. This line of research entails a highly translational goal in sight.  Although cancer is the focal point of our work, our approach is in principle transplantable and could be used to discover novel therapeutic strategies to treat other diseases. There are approximately 9990 drugs known to clinical medicine. Each drug should be considered an information-rich entity that merits exploration especially as treatment of orphan diseases.

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Staff

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Proteomics, Malaria, Cancer

Dr. Nyalwidhe is interested in the application of functional, expressional and structural proteomics approaches to the study of human diseases with emphasis on infectious diseases and cancer. This includes research on human malaria caused by Plasmodium falciparum, a variety of other infectious agents, prostate cancer and viral-induced carcinomas, in addition to other forms of cancer.

The focus is on the mechanisms of interaction between infectious pathogens and their host cells, the mechanism of metastasis in cancer and the analysis of the proteome of human body fluids to identify clinically useful biomarkers for the diagnosis and prognosis of disease. Dr. Nyalwidhe is also using molecular biology and different mass spectrometry techniques in analyzing, monitoring and quantifying post-translational modifications in proteins to determine their influence in the progression and outcome of disease.

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Surgical oncology, Pancreatic/liver/biliary cancer, gastrointestinal cancer, melanoma, sarcoma, breast cancer 

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Faculty

Project I: Regulated Proteolysis in K-RAS-Mediated Tumorigenesis and Metastasis in human cancers

Dr. Tang's laboratory studies the RAS signal transduction pathway using multiple model organisms/systems including Drosophila, transgenic mice, human cancer cell lines and human cancer tissue specimens. As oncogenic RAS promotes the genesis of many human cancers, how best to contravene activated RAS signaling has been an intense area of investigation in the field of cancer biology for the past 30 years. Seven-In-Absentia (SINA), an E3 ubiquitin ligase, is an essential downstream component of the Drosophila RAS signal transduction pathway. The human homologue of SINA, SIAH, is a member of this evolutionarily highly conserved family of RING finger E3 ubiquitin ligases; however, the roles and regulation of SIAH-dependent proteolysis are not well understood in the context of RAS signal transduction in mammalian systems.

Dr. Tang's lab has accumulated evidence demonstrating the importance of proper SIAH function in mammalian K-RAS signaling. We show that by inhibiting the enzymatic activity of SIAH, and thus SIAH-mediated proteolysis, RAS-mediated neoplastic transformation and tumorigenesis can be effectively blocked in human cancer cells [Can Res 67(24):1798-810, 2007; JNCI 100(22):1606-29, 2008]. Furthermore, SIAH-deficient cells have reduced MAPK signaling, suggesting that SIAH might be involved in aberrant K-RAS signaling through a regulatory feedback loop mechanism. Thus, these studies provide an initial glimpse into the significance of the SIAH E3 ubiquitin ligase-regulated proteolysis in the K-RAS pathway during tumor initiation, progression and oncogenesis in human pancreatic cancer, lung cancer, invasive and metastatic breast cancer and hormonal-refractory prostate cancer.

Advancing understanding of the role of SIAH E3 ligases in K-RAS signaling and, more importantly, the potential to target SIAH as a novel new anti-K-RAS and anti-cancer target in the treatment of the most aggressive and the deadliest forms of human cancers represent exciting steps forward in the fields of K-RAS signaling, cancer biology and cancer therapy. Ultimately, we hope such SIAH-based anti-cancer therapies will lead to novel and efficacious treatments for human cancer patients, especially the ones with metastatic diseases.

Project II:   Innate Immunity and Cellular Defense

To understand how a host cell differentiates a pathogenic microbe from a nonpathogenic microorganism is a fundamental question in biology. Drosophila has an innate immune system that is similar to humans but is devoid of the complication of the adaptive immune system. We use the Drosophila as the model organism to study the molecular mechanism of how innate immunity is activated upon pathogen recognition. We found that the structural integrity of the sentinel receptors/innate sensors is modulated during infection and inflammation. We hypothesize that proteases release that is common during pathogen-host antagonism may provide an important cue for the host to distinguish a pathogenic versus a nonpathogenic microorganism. We are using transgenic fly models to demonstrate that protease release after pattern recognition provides a "tissue damage" signal that could alert host cells to the onset of endogenous tissue damage and exogenous pathogen invasion.

Project III:   Genetic Screens for Anti-Cancer Drug Resistance 

The development drug/chemical resistance is a recurring problem. There is an important need for us to understand the mechanisms by which drug/chemical resistance is acquired in multicellular organisms and cancers. We will carry out genetic screens in Drosophila for resistance to several key anticancer drugs that are prone to develop resistance. This effort, coupled with genomic and microarray analyses, should help to identify the alterations of key signaling pathways that could forecast and predict drug resistance development.

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Professor of Medicine/Pathology/Neurobiology, Director of Research and Neuroendocrine Unit

Medical Education:

MD : 1960
South Africa University Cape Town Medicine

Residency:

Surgery/Internal Medicine
Johannesburg General Hospital
Internal Medicine
Johannesburg General Hospital
Internal Medicine/Pediatrics
Baragwanath Hospital

Fellowship:

Endocrinology
University of Cape Town

Board Certifications:

Internal Medicine

Affiliations:

Fellow, American College of Physicians

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Histology Lab

Research Scholar

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Resident