Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.

BACKGROUND: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice. METHODS: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin- cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed. RESULTS: E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin-, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth. CONCLUSIONS: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+ cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.

Medical students' perceived educational needs to prevent and treat childhood obesity.

BACKGROUND: Medical schools are challenged to incorporate more prevention-based education into curricula, offering an opportunity to revisit approaches to nutrition education. The objective of this study was to explore United States (US) medical students' understanding of childhood obesity, specifically barriers to childhood obesity prevention and treatment and students' perceived educational deficits. METHODS: The research team conducted phone interviews with 78 3rd- and 4th-year medical students, representing 25 different medical schools across the US. Using a semi-structured interview guide, researchers asked students to describe the etiology of childhood obesity and reflect on where they acquired knowledge of the etiology and what additional resources they would need to treat obese children. Using a phenomenological approach to analysis, researchers identified five dominant emergent themes. RESULTS: Student-perceived barriers to childhood obesity prevention and treatment in clinical care included student-centered (e.g., lack of knowledge), patient-centered (e.g., lack of access), and healthcare system-centered barriers (e.g., limited time). Students requested more applicable nutrition information and counseling skills relevant to preventing and treating childhood obesity; however, they tended to identify others (e.g., parents, schools), rather than themselves, when asked to describe how childhood obesity should be prevented or treated. DISCUSSION: To provide students with an understanding of their role in preventing and treating childhood obesity, US medical schools need to provide students with childhood obesity-specific and general nutrition education. To build their self-efficacy in nutrition counseling, schools can use a combination of observation and practice led by skilled physicians and other healthcare providers. Increasing students' self-efficacy through training may help them overcome perceived barriers to childhood obesity prevention and treatment.

Nutrition education among low-income older adults: a randomized intervention trial in Congregate Nutrition sites.

Nutritional well-being among older adults is critical for maintaining health, increasing longevity, and decreasing the impact of chronic illness. However, few well-controlled studies have examined nutritional behavior change among low-income older adults. A prospective, controlled, randomized design examined a five session nutrition education module delivered to limited-resource older adults (N = 703) in Congregate Nutrition sites by Cooperative Extension agents. Experimental group participants were significantly more likely than control group participants to increase multivitamin use, to increase calcium supplement use, to read labels of dietary supplements, to carry a supplement and/or medication list, and to discuss such use with their health care professional. The study addresses weaknesses in the literature by using a theoretically derived education component, implementing the intervention within a setting regularly used by low-income older adults, employing randomized assignment to intervention and control conditions, and using hierarchical linear modeling to deal with "nested" data.

Antioxidants and prevention of chronic disease.

The generation of reactive oxygen species (ROS) and other free radicals (R) during metabolism is a necessary and normal process that ideally is compensated for by an elaborate endogenous antioxidant system. However, due to many environmental, lifestyle, and pathological situations, excess radicals can accumulate, resulting in oxidative stress. Oxidative stress has been related to cardiovascular disease, cancer, and other chronic diseases that account for a major portion of deaths today. Antioxidants are compounds that hinder the oxidative processes and thereby delay or prevent oxidative stress. This article examines the process of oxidative stress and the pathways by which it relates to many chronic diseases. We also discuss the role that endogenous and exogenous antioxidants may play in controlling oxidation and review the evidence of their roles in preventing disease.