Methodology of a multispecialty outpatient Obesity Treatment Research Program.

Despite the large number of U.S. adults who overweight or obese, few providers have ready access to comprehensive lifestyle interventions, the cornerstone of medical obesity management. Our goal was to establish a research infrastructure embedded in a comprehensive lifestyle intervention treatment for obesity. The Obesity Treatment Research Program (OTRP) is a multi-specialty project at Mayo Clinic in Rochester, Minnesota designed to provide a high intensity, year-long, comprehensive lifestyle obesity treatment. The program includes a nutritional intervention designed to reduce energy intake, a physical activity program and a cognitive behavioral approach to increase the likelihood of long-term adherence. The behavioral intervention template incorporated the Diabetes Prevention Program and the Look AHEAD trial materials. The OTRP is consistent with national recommendations for the management of overweight and obesity in adults, but with embedded features designed to identify patient characteristics that might help predict outcomes, assure long-term follow up and support various research initiatives. Our goal was to develop approaches to understand whether there are patient characteristics that predict treatment outcomes.

Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling.

BACKGROUND AND AIMS: Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis. METHODS: In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation. RESULTS: After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor. CONCLUSION: Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.