Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes.

Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at subnanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef-expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV-infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells.

Racial and Ethnic Disparities in Colorectal Cancer Screening and Outcomes.

Colorectal cancer (CRC) incidence and mortality vary by race and ethnicity in the United States, with the highest burden of disease among Black and American Indian/Alaska Native individuals. There are multiple contributors to these disparities, including lifestyle and environmental risk factors that result from adverse social determinants of health and are more prevalent in minority and medically underserved communities. In addition, participation in CRC screening, which is demonstrated to reduce CRC-related mortality, is lower in all racial/ethnic minority groups than for White individuals. Evidence-based efforts to reduce CRC disparities aim to increase screening uptake via multicomponent and culturally tailored interventions.

Knowledge and attitudes of lower Michigan primary care physicians towards dietary interventions: A cross-sectional survey.

Background: Dietary interventions are first-line therapies for the prevention and management of many chronic diseases, yet primary care physicians prescribe these interventions infrequently. Objectives: This study investigates primary care physicians' current knowledge and opinions regarding the delivery of dietary interventions. This work aims to identify modifiable barriers to prescribing dietary interventions to prevent and treat diet-related diseases. Methods: We designed and fielded an anonymous, cross-sectional survey of faculty and resident physicians across the Internal Medicine, Family Medicine, and Pediatrics departments in three academic and community hospitals in lower Michigan. Data were collected between January 15 and April 15, 2019. Self-rated knowledge and attitudes were measured on a 5-point Likert scale. Objective scores were calculated for each question as percentage answered correctly among all respondents. Objective knowledge scores were compared based on participants' years in practice. Results: Response rate was 23% (356 responses). The sample was 62.3% female and 75.3% non-Hispanic White, and 56.7% were age 40 or younger. Average objective knowledge score was 70.3% (±17.2) correct. Mean self-rated knowledge score was 2.51 (±0.96) on a scale of 1(Poor) - 5(Excellent). Overall agreement with a statement of importance of dietary interventions was 3.99 (±0.40) on a scale of 1 (strongly disagree) to 5 (strongly agree). A majority (91.7%) of respondents indicated they would like more opportunities to learn about the evidence supporting dietary interventions. Conclusions: Physicians desire to incorporate dietary interventions into their practice. Findings encourage the development of educational strategies to support dietary intervention use among primary care physicians.