CCTS: Pilot Grants

Basal cell carcinoma is the most common human cancer, affecting 3 out of 10 Caucasians. If excised early enough, it rarely leads to life-threatening consequences. Because it frequently appears on the face, the surgical treatments aim to preserve as much of the surrounding skin while removing the cancer. The current surgical techniques for treatment of basal cell carcinoma are time consuming and not cost effective. We have shown that Raman microscopy may be used to distinguish cancer from surrounding benign tissues. Our preliminary research suggests that this technique is very accurate at detecting cancer cells but must be optimized to be suitable for the operating room. The aim of this proposal is to bring Raman spectroscopic analysis within a useful timeframe to detect the cancer signature spectrum of a tumor. This project will develop the methods and provide data validation to show that removal of tumor, indicated by spectroscopy, corresponds to the clinical gold standard, histology.

Voluntary Medical Male circumcision (VMMC) is an effective strategy to reduce the risk of HIV acquisition in heterosexual men. Observational data and randomized controlled trails (RCTs) conducted in Africa suggest that the procedure reduces the risk of HIV acquisition by 50-76% in heterosexual males. VMMC has also been shown to reduce the incidence of other sexually transmitted infections , including herpes simplex virus type 2 and human papilloma virus (HPV) in men, and Chlamydia, trichomonas vaginalis , bacterial vaginosis and HPV in their female partners.

The results of the RCT’s are generating an increased demand for safe and affordable MC services in areas of moderate-to-high HIV prevalence where the MC rates are low. Latin America is a region where circumcision of males is uncommon. In the Dominican Republic (DR), which is the focus of this study, a 2007 nationwide household survey found that only 13.7% of men between the ages of 15-59 were circumcised. The prevalence of HIV in the DR is 0.8% nationwide but reaches 3.2% in high risk areas.

Previous studies conducted by our team have shown that 67 % of sexually active men in the Altagracia Province would be willing to be circumcised provided that education is provided about the benefits of the procedure. The objectives of the proposed study are to conduct a pilot introduction of MC in a selected population of high risk men at two areas of high prevalence of HIV in the DR. The study will include: developing culturally appropriate materials about the benefits of MC, assessing the uptake, safety (adverse event rate), patient satisfaction, and train providers and build capacity on VMMC in the DR. In addition, we will assess risk behaviors before and after VMMC and build key partnerships with the Ministry of Health of the DR and other stakeholders.

Hepatocellular carcinoma (HCC) is one of the most frequently encountered malignancies in the world, and one of the most fatal cancers in human. However, currently pharmacological intervention does not provide satisfactory cure. Therefore, new treatments, diagnosis, and prognosis are highly desirable. In particular diagnostic tools for liver cirrhosis, which could be a pre-malignant condition are not defined. The mitochondrial high affinity hexokinase 2 (HK2) that catalyzes the first committed step in glycolysis is highly expressed in HCC. Normal hepatocytes express only the low affinity hexokinase (glucokinase (GK)) but during the tumorigenesis process there is a switch from the expression of GK to the expression of HK2. Thus, in HCC cells there is high level of HK2 expression, whereas GK expression is silenced. The highly glycolytic HCC cells are therefore dependent on HK2. In a survey of 312 patient samples we found a strong correlation between high level of HK2 expression, dysplasia, and carcinoma. In the course of these studies we found also a correlation between HK2 expression and the onset of cirrhosis. Thus, the ultimate goals of this grant application are to examine the feasibility of HK2 inhibition for HCC therapy, and to use HK2 as a diagnostic or prognostic marker for liver cirrhosis and HCC.

Alzheimer's disease (AD) the leading cause of dementia in the elderly and a rapidly growing epidemic, particularly in the United States as the "baby boomers" reach the age of onset for AD. Advancing our understanding of disease onset and progression, as well as the best pathways to intervene for its prevention and treatment, is critical to overcoming this growing health care burden. Currently, there is no cure and therapy for AD is limited to symptomatic treatment because relatively little is known about the biological underpinnings of the disease. Our lab focuses on understanding the structural and functional interactions between proteins known to contribute to AD-induced neuronal death, apolipoprotein (apoE) and amyloid-beta (Ab). The leading hypothesis is that Ab is the proximal cause for neurodegeneration. AD risk increases with human apoE4 and decreases with apoE2, compared to apoE3. While apoE4 associates with extracellular plaques, apoE isoform-specific effects on the soluble and intraneuronal Ab components of Ab pathology are unknown. We developed unique transgenic mice to determine effects of apoE isoforms on the Ab pathology characteristic of AD. Preliminary data show significant and novel results, including recapitulation of human AD pathology.

Loss of dentition correlates with risk for oral cancer. A leading cause for loss of dentition is periodontal disease found in gums and jaw bones. We hypothesize that bacteria found in early gum disease migrate to tongue and floor of mouth areas. After exposure to alcohol, tobacco products, and a diet of refined simple sugars, resident and migratory bacteria attach, increase growth and produce a cancer causing chemical, acetaldehyde. DNA damage and abnormal growth of more primitive oral mucosa cells occurs. This study will provide exploratory data that will require validation in a larger and longer study to show gum disease and its treatment can affect acetaldehyde cell damage and reduce expected changes leading to oral cancer in oral mucosa.

The enzyme arylsulfatase B removes sulfate groups from complex carbohydrates which accumulate in the cystic fibrosis, a chronic disease characterized by severe respiratory symptoms. Thick secretions accumulate in the lungs of patients with cystic fibrosis (CF), impairing their air exchange and leading to chronic infection. In previous studies, we found that activity of the enzyme arylsulfatase B (ASB) was reduced in CF lung cells and increased when the genetic defect in CF was corrected. This project is designed to determine the activity of ASB in cells from children with CF and to test the effect of ASB on lung secretions from children with CF. ASB replacement therapy is safely and effectively used clinically in a different genetic disease (MPS VI), and this study will help to determine if ASB therapy may become a viable therapeutic option in CF.

Millions of type 1 diabetes (T1D) patients worldwide must have daily insulin injections to survive. However, it is not a cure; it does not halt the persistent autoimmune response. Recently, we have developed a new technology that treatment with autologous cord blood stem cells (CB-SC)-modulated CD4+CD62L+ regulatory T cells (Tregs) can reverse T1D, not only by controlling the autoimmunity but also by promoting beta-cell regeneration leading to the restoration of euglycemia in a diabetic mouse model. Thus, these findings provide a new approach for the treatment of T1D. Based on our current pre-clinical studies, we hypothesize that CB-SC can modulate the immune functions of CD4+CD62L+ Tregs of T1D patients. Thus, the Aims of this project are: 1) To determine the molecular mechanisms by which CB-SC modulate the function of T1D patient-derived CD4+CD62L+ Tregs; 2) To determine the molecular and cellular mechanisms underlying the formation of “TGF-beta1 rings” in pancreatic islets of humanized diabetic NOD-scid IL2R gamma (null) mice. Completion of this project may lead to open up new avenue for using cord blood stem cell-modulated Tregs to treat T1D in clinic.