1. Senior Research Staff

Michael Benninger, M.D., Chair
Maria Worsham, Ph.D.

2. Research Summaries

Principal Investigator: Worsham, Maria J., Ph.D.
Molecular Modeling of Diagnosis and Prognosis in HNSCC (NIH R01 1DE01599001)

Head and neck squamous cell carcinoma (HNSCC) carries a high mortality rate despite advances in chemotherapy and radiation therapies. This is due mainly to the highly heterogeneous nature of the disease, both morphologically and genetically. A current shortcoming in the diagnosis, prognosis, and treatment of HNSCC is a lack of methods that adequately address the complexity and diversity of the disease. A major objective of the proposed research is to develop a detailed molecular fingerprint of HNSCC tumor tissues that is linked to clinical information. Diagnostic and prognostic marker systems based on single parameters have generally proven inadequate. Thus, multiparametric methods, which rely on many pieces of information, are ideally suited to the grouping of tumor subtypes and the identification of specific patterns of disease progression and clinical outcomes. Our goal is to accomplish a multivariable comprehensive genome-wide molecular blueprint of HNSCC integrated with clinical risk factors in order to refine patient diagnosis and prognosis to aid in the clinical management of patients at the earliest disease stages. We will interrogate an evidence-based panel of gene loci implicated in head and neck cancer, many of which are distributed along critical pathways utilized by HNSCC cells. The molecular targets to be investigated using a novel assay will be done in an epidemiologically well-characterized cohort of 1000 primary HNSCC derived from a large, multi-ethnic, primary care patient population diagnosed by surgical biopsies in the Henry Ford Health System from 1986-2003, and followed from 5-22 years. This approach should yield a validated multivariable genetic blueprint for diagnosis and prognosis analogous to or even more powerful than TNM-staging, permitting more accurate grouping of tumor subtypes, more accurate distinction of prognostic groups, and better prediction of effective treatment strategies.

1. Senior Research Staff

Evelyn Barrack, Ph.D.
David Burks, M.D.
Jagadananda Ghosh, Ph.D.
Mani Menon, M.D., Chairman
Sivagnanam Thamilselvan, Ph.D.
Prem Veer Reddy, Ph.D., Associate Director for Research

2. Research Summaries

Principal Investigator: Burks, David, M.D.
Interstitial Cystitis Clinical Research Network (NIH NIDDK (U01DK065213)

 Interstitial cystitis is a chronic debilitating disease characterized by urinary frequency, urgency and bladder pain. Despite the first descriptions of this disease by Guy Hunner in 1914, it still remains "The Great Enigma." The disease continues to defy a consensus definition, a definable pathophysiology or a reliably effective treatment. Multiple theories of pathogenesis have spawned a myriad of mostly ineffective treatments. Many physicians either doubt, or are unaware of the existence of this disease causing significant delay in diagnosis for many patients, especially men and children, where the disease is most poorly characterized. Since 1987 the NIH has begun a systematic, evidence-based effort to define interstitial cystitis determine its biochemical and clinical characteristics and evaluate novel therapies. Beginning with the NIDDK Workshop and Consensus Conference, the definition of interstitial cystitis has evolved from a restrictive instrument used for research papers, to a more inclusive criteria developed by the Interstitial Cystitis Data Base Group. The Interstitial Cystitis Clinical Trials Group proved that a collaborative multi-center group could recruit patients into rigorous, novel treatment protocols. The major objective of this grant is to develop the Interstitial Cystitis Clinical Research Network to continue the evolution in characterizing this disease. We propose evaluating a novel therapy, IPD-1151T, an immune system modulator with possible efficacy in interstitial cystitis patients. A published pilot study showed significant improvement in symptom scores with minimal side effects. The ICCRN will work in collaboration with the Chronic Prostatitis Clinical Research Network to investigate interstitial cystitis as a subset of chronic pelvic pain disorders of the bladder. A coordinated effort to develop common patient evaluation and treatment protocols, will allow an overarching analysis of these urologic pain syndromes.

Principal Investigator: Thamilselvan, Sivagnanam, Ph.D.
Urolithiasis and Peroxidative Injury (R01DK056249)

Urolithiasis is a major health problem in the United States, and the incidence and frequency of these stone appears to be increasing in this country. The prevalence of urinary tract stone disease is estimated to be 2-20 per 10,000. Chances of recurrence within 10 years are nearly 60%. The current cost to the nation for treating kidney stones is approximately $2.39 billion/year. Treatment program includes medications, open surgery, percutaneous techniques and extracorporeal shock wave lithotripsy. Despite recent advances in treatment, stone recurrence can be reduced by only 50%. Our working hypothesis is that free radical induced cell injury is central to the process of urolithiasis and that prevention of injury will prevent calcium oxalate nucleation, retention and deposition. Hyperoxaluria and calcium oxalate crystalluria are often associated with increased excretion of tubular marker enzymes, a finding consistent with damage to renal tubular cells. Moreover, these changes are observed even in the absence of crystalluria, suggesting oxalate induced membrane damage is not solely to injury produced by calcium oxalate crystals. We are the first to demonstrate the molecular mechanism of oxalate induced free radical production and first to demonstrate that the binding of calcium oxalate crystals in renal tubular membranes occurs via peroxidative injury. The oxidant and antioxidant balance is therefore a critical determinant of cell sensitivity to free radical injury and a major impact on the magnitude of stone crystal nucleation on the injured renal tubular epithelium and the development of stone nidus. We propose to test this hypothesis in an animal model and renal epithelial cells in culture. Hyperoxaluria is induced in male rats. In cell culture experiments, renal epithelial cells are exposed to oxalate and/or calcium oxalate monohydrate crystals. The effect of antioxidants on these experimental models will be tested. These studies will provide valuable information on the importance of antioxidants and, whether antioxidants offer promise as a therapeutic agent for recurrent stone formers.

1. Senior Research Staff

Henry Lim, M.D., Chairman
Henry Wong, M.D., Ph.D.

2. Research Summaries

Mycosis fungoides (MF) is a cutaneous malignancy of skin homing, memory, CD4+ T cells. This is a disease with diverse clinical presentations and a chronic progressive course. As the disease progresses to later stages, there is increasing tumor burden with more extensive skin involvement, causing generalized erythroderma or redness with systemic involvement. When the abnormal T cells enter the circulation, it is known as Sezary disease. To gain a better understanding of this complex cutaneous malignancy, we have taken a molecular approach, initially focusing our studies on T cells from Sezary patients since there are abundant tumor cells in the peripheral blood. From analysis of peripheral blood mononuclear cells (PBMC) from patients with Sezary disease, we have identified profound cytokine gene expression defects in tumor T cells in patients with Sezary disease. To further study the etiology for gene expression abnormalities, we have taken a gene expression profiling approach, hypothesizing that there are extensive gene expression differences between normal T cells and Sezary T cells that account for their molecular and clinical phenotype. Using high-density Affymetrix oligonucleotide microarrary profiling of total RNA from purified T cells from normal individuals and from MF (Sezary) patients, we have discovered genes that are highly expressed by greater than 30-fold in Sezary T cells, as well as genes that are preferentially loss that are expressed in normal memory T cells. In this proposal, we will focus on a set of genes that are highly expressed in MF-Sezary T cells, as these may yield insight into this disease and may lead to improve diagnosis. The aim of this grant is: 1. To validate the MF-Sezary genes in MF patients. 2. To determine the stage of disease that the expression of these abnormal genes first become detectable in affected tissue. 3. To study whether the expression of these genes are altered by therapy in vitro and in vivo.

1. Senior Research Staff

Scott Dulchavsky, M.D., Chairman
Subhash C. Gautam, Ph.D.
Daniel Reddy, M.D.

2. Research Summaries

• Specific Aim 1:  Develop just-in-time training methodologies which incorporate a brief ultrasound familiarization training with robust computer based training enhancement at the point of care to allow complex ultrasound examinations to be completed with remote expert guidance or autonomously by the non-physician crew-member.
• Specific Aim 2:  Develop an intuitive ultrasound image cataloging system which incorporates ground acquired ultrasound whole body images with predictive micro-gravity functionality for medical operational use.  A mathematical coupling model will be developed based on existing ground/in-flight ultrasound data which will allow microgravity associated morphometric and topographic changes to predicted.  The catalog will allow ground based crew-member organ system images to be acquired and stored in an enhanced format for medical operations personnel to use for medical diagnosis in space.
•  Specific Aim 3:  Access the ability of non-physician crew medical officer (CMO) analogs to acquire and interpret complex ultrasound examinations using cue cards and computer based proficiency enhancement autonomously or with remote guidance.

Principal Investigator: Reddy, Daniel, M.D.
Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) (NIH- R01N538384, subcontract)

Stroke is the third most common cause of death in North America.  Approximately 600,000 new strokes are reported annually.  It is the leading cause of disability on the United States.  The purpose of this study is to contrast the efficacy of Carotid Artery Stenting (CAS) versus Carotid Artery Endacarterectomy (CEA) in preventing stroke, myocardial infarction, and death during a 30 day peri-procedural period, and ipsilateral to the study artery over the follow-up period, in patients with symptomatic extracranial carotid stenosis.  This is a two phase study a Non-randomized lead-in credentialing phase with about 20 subjects/interventionalist to be followed by a randomized phase.  This is a prospective, randomized parallel, two-arm, multi-center trial, with blinded end points.  Approximately 110 centers will participate.