Weight-based discrimination and medication adherence among low-income African Americans with hypertension: how much of the association is mediated by self-efficacy?

OBJECTIVES: Much of the excessive morbidity and mortality from cardiovascular disease among African Americans results from low adherence to anti-hypertensive medications. Therefore, we examined the association between weight-based discrimination and medication adherence. METHODS: We used cross-sectional data from low-income African Americans with hypertension. Ordinal logistic regression estimated the odds of medication non-adherence in relation to weight-based discrimination adjusted for age, sex, education, income, and weight. RESULTS: Of all participants (n = 780), the mean (SD) age was 53.7 (9.9) years and the mean (SD) weight was 210.1 (52.8) lbs. Reports of weight-based discrimination were frequent (28.2%). Weight-based discrimination (but not weight itself) was associated with medication non-adherence (OR: 1.94; 95% CI: 1.41-2.67). A substantial portion 38.9% (95% CI: 19.0%-79.0%) of the association between weight-based discrimination and medication non-adherence was mediated by medication self-efficacy. CONCLUSION: Self-efficacy is a potential explanatory factor for the association between reported weight-based discrimination and medication non-adherence. Future research should develop and test interventions to prevent weight-based discrimination at the societal, provider, and institutional levels.

The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.

PURPOSE: To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). EXPERIMENTAL DESIGN: PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined. RESULTS: In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50) = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013). CONCLUSIONS: These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment.

Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.