800 Zorn Avenue Vamc Dept. Of Emergency Medicine
Louisville KY 40206
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License #: 01060927A
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Is retinol binding protein 4 a link between adiposity and cancer? - Hormone molecular biology and clinical investigation
Retinol binding protein 4 (RBP4) is synthesized in the liver where it binds vitamin A, retinol, and transports it to tissues throughout the body. It has been shown in some studies that the level of circulating RBP4 increases with body mass, and the protein has been implicated as a mediator in the development of insulin resistance and the metabolic disease. Adipose tissue serves as another site of RBP4 synthesis, accounting for its designation as an adipokine. In addition to its function as a transport protein, RBP4 serves as a signaling molecule which, by binding to the membrane receptor STRA6, triggers downstream activation of pro-oncogenic pathways including JAK2/STAT3/5. Taken together, available information suggests the possibility that RBP4 may be a link between obesity and cancer.
IL-33 activates tumor stroma to promote intestinal polyposis. - Proceedings of the National Academy of Sciences of the United States of America
Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.
Understanding graft-versus-host disease. Preliminary findings regarding the effects of exercise in affected patients. - Exercise immunology review
Advances in this century regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) have led to an expanding population of long-term survivors, many of whom suffer severe side effects, particularly those related to graft-versushost disease (GVHD), a potentially multi-systemic disorder caused by immunoeffector donor lymphocytes that destroy host tissues. The GVHD, especially in its chronic form (cGVHD), generates considerable morbidity and compromises the physical capacity of patients. We have reviewed the main pathophysiological aspects of the disease as well as the data available on the effects of exercise in GVHD, based on animal and human patient research. Although exercise training as an adjunct therapy to improve health outcomes after allo-HSCT shows promise (particularly, this lifestyle intervention can improve physical fitness and possibly immune function while attenuating fatigue), there is a need for more randomized control trials that focus specifically on GVHD.Copyright Â© 2015 International Society of Exercise and Immunology. All rights reserved.
Comprehensive geriatric assessment in the older cancer patient: coming of age in clinical cancer care. - Clinical practice (London, England)
Cancer care at the extremes of life, in the young and the old, is characterized by unique issues associated with pediatrics and geriatric medicine, accentuated by the special vulnerabilities of these groups. In response to these needs, the field of pediatric oncology has been well honed to deal with the special problems associated with juvenile cancer patients. While most adult oncologists consider themselves well prepared to deal with older cancer patients, the current expansion of the geriatric population - their variable levels of fitness, frailty and vulnerability, the fact that cancer is primarily a disease of older adults, the significant expansion of agents and approaches to treat cancer, as well as their resultant toxicities and complications - has led to the development of specialized geriatric oncologists. Moreover, the special characteristics and needs of these patients have led to the evolution of new guidelines for evaluation, management and the conduct of research in older patients with cancer.
Combined use of vitamin D3 and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice. - Cancer prevention research (Philadelphia, Pa.)
Vitamin D3 and metformin are widely used in humans for regulating mineral metabolism and as an antidiabetic drug, respectively; and both of them have been shown to have chemopreventive effects against various tumors. This study was designed to investigate the potential synergistic chemopreventive effects of vitamin D3 and metformin against the development of early colon neoplasia in two models. The first model was a 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon cancer rat model and the second, a DMH-dextran sodium sulfate (DSS)-induced colitis-associated colon neoplasia mouse model. Compared with either vitamin D3 or metformin alone, combined use of vitamin D3 and metformin showed more pronounced effect in reducing the numbers of aberrant crypt foci (ACF) and tumor in the colon. The most prominent inhibitory effects were observed in the vitamin D3 medium dose (100 IU/kg/d) and metformin medium dose (120 mg/kg/d) combination group. Furthermore, our results showed that enhancement of metformin's chemopreventive effects by vitamin D3 was associated with downregulation of S6P expression, via the AMPK (IGFI)/mTOR pathway. In addition, enhancement of vitamin D3's chemopreventive effects by metformin was associated with inhibition of the protein expressions of c-Myc and Cyclin D1, via the vitamin D receptor/Î²-catenin pathway. These findings show that the combined use of vitamin D3 and metformin exhibits synergistic effects against the development of early colon neoplasia. They suggest that the combined use of vitamin D3 and metformin may represent a novel strategy for chemoprevention of colorectal cancer.Â©2014 American Association for Cancer Research.
Physical inactivity and low fitness deserve more attention to alter cancer risk and prognosis. - Cancer prevention research (Philadelphia, Pa.)
Sedentary lifestyle is associated with elevated cancer risk whereas regular physical activity (PA) and high cardiorespiratory fitness (CRF) have the opposite effect, with several biologic mechanisms mediating such associations. There is a need for lifestyle interventions aimed at increasing the PA levels and CRF of the general population and particularly cancer survivors. Furthermore, provocative data suggest a dose-dependent benefit of increasing levels of PA and/or CRF against cancer risk or mortality. Thus, current PA guidelines (â‰¥150 min/wk of moderate-to-vigorous PA) may not be sufficiently rigorous for preventing cancer nor for extending cancer survivorship. Research targeting this issue is urgently needed. Promoting regular PA along with monitoring indicators of CRF and adiposity may provide powerful strategies to prevent cancer in populations, help patients with cancer more effectively deal with their disease and enhance secondary prevention programs in those who are affected by cancer.Â©2014 American Association for Cancer Research.
Race, age, and obesity disparities in adult physical activity levels in breast cancer patients and controls. - Frontiers in public health
Physical activity has been shown to be inversely associated with breast cancer recurrence and survival. Although physical activity is known to decline with age, rates of change in physical activity have not been well characterized in breast cancer patients and subgroups with known disparities in breast cancer survival, especially in minorities, the elderly, and the obese. We evaluated moderate and strenuous physical activity from high school through diagnosis in 1,220 breast cancer patients, and from high school to recruitment in 935 controls. We compared the proportion of patients and controls meeting the American Cancer Society (ACS) guidelines for physical activity and differences in declines in level of physical activity by race, age, and obesity. At diagnosis, only 33.2% of breast cancer patients met the ACS physical activity guidelines. Only 13.2, 24.7, and 30.5% of African-American (AA), obese, and older (â‰¥65â€‰years) patients met the guidelines, respectively. Controls showed slightly higher rates, with 36.4% overall, 23.7% of AA, 29.0% of obese, and 32.4% of older women meeting the guidelines. AA patients were less likely to meet guidelines compared to White patients (pâ€‰<â€‰0.0001). Obese patients were less likely to meet guidelines compared to non-obese (pâ€‰<â€‰0.0001). We found that both moderate and strenuous physical activity declined after high school in patients and controls. AA patients reported steeper declines in strenuous (pâ€‰=â€‰0.0027), and total (pâ€‰=â€‰0.0009) physical activity compared to Whites. Obese patients reported steeper declines in total physical activity compared to non-obese (pâ€‰=â€‰0.022). Differences in average slopes of declines in physical activity were not observed by age. Our results suggest that strategies and programs to encourage women to maintain recommended levels of physical activity after high school are needed. Furthermore, breast cancer patients, particularly AA and obese patients, should be targeted to help reduce disparities.
A prospective randomized wait list control trial of intravenous iron sucrose in older adults with unexplained anemia and serum ferritin 20-200 ng/mL. - Blood cells, molecules & diseases
Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05Â±55.48 m in the immediate intervention group and decreased a mean 11.45Â±49.46 m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39Â±0.46 g/dL in the immediate intervention group and declined a mean 0.39Â±0.85 g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.Published by Elsevier Inc.
Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer. - BMC systems biology
To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, ApcMin/+, we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of ApcMin/+ vs. wild-type littermates, kept on low vs. high-fat diet. Label-free mass spectrometry was used to quantify untargeted plasma and acyl-CoA liver compounds, respectively. Differences in contrasts of interest were analyzed statistically by unsupervised and supervised modeling approaches, namely Principal Component Analysis and Linear Model of analysis of variance. Correlation between plasma metabolite concentrations and polyp numbers was analyzed with a zero-inflated Generalized Linear Model.Plasma metabolome in parallel to promotion of tumor development comprises a clearly distinct profile in ApcMin/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in ApcMin/+ mice on high-fat diet revealed associations between polyp formation and plasma metabolic compounds including those involved in amino-acids metabolism as well as nicotinamide and hippuric acid metabolic pathways. Finally, we also show changes in liver acyl-CoA profiles, which may result from a combination of ApcMin/+-mediated tumor progression and high fat diet. The biological significance of these findings is discussed in the context of intestinal cancer progression.These studies show that high-throughput metabolomics combined with appropriate statistical modeling and large scale functional approaches can be used to monitor and infer changes and interactions in the metabolome and genome of the host under controlled experimental conditions. Further these studies demonstrate the impact of diet on metabolic pathways and its relation to intestinal cancer progression. Based on our results, metabolic signatures and metabolic pathways of polyposis and intestinal carcinoma have been identified, which may serve as useful targets for the development of therapeutic interventions.
Obesity and cancer pathogenesis. - Annals of the New York Academy of Sciences
Overweight and obesity have reached pandemic levels on a worldwide basis and are associated with increased risk and worse prognosis for many but not all malignancies. Pathophysiologic processes that affect this association are reviewed, with a focus on the relationship between type 2 diabetes mellitus and cancer, lessons learned from the use of murine models to study the association, the impact of obesity on pancreatic cancer, the effects of dietary fats and cholesterol on cancer promotion, and the mechanisms by which the intestinal microbiome affects obesity and cancer.Â© 2014 New York Academy of Sciences.
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