Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner.

Primary tumours can establish long-range communication with distant organs to transform them into fertile soil for circulating tumour cells to implant and proliferate, a process called pre-metastatic niche (PMN) formation. Tumour-derived extracellular vesicles (EV) are potent mediators of PMN formation due to their diverse complement of pro-malignant molecular cargo and their propensity to target specific cell types (Costa-Silva et al., 2015; Hoshino et al., 2015; Peinado et al., 2012; Peinado et al., 2017). While significant progress has been made to understand the mechanisms by which pro-metastatic EVs create tumour-favouring microenvironments at pre-metastatic organ sites, comparatively little attention has been paid to the factors intrinsic to recipient cells that may modify the extent to which pro-metastatic EV signalling is received and transduced. Here, we investigated the role of recipient cell cholesterol homeostasis in prostate cancer (PCa) EV-mediated signalling and metastasis. Using a bone metastatic model of enzalutamide-resistant PCa, we first characterized an axis of EV-mediated communication between PCa cells and bone marrow that is marked by in vitro and in vivo PCa EV uptake by bone marrow myeloid cells, activation of NF-κB signalling, enhanced osteoclast differentiation, and reduced myeloid thrombospondin-1 expression. We then employed a targeted, biomimetic approach to reduce myeloid cell cholesterol in vitro and in vivo prior to conditioning with PCa EVs. Reducing myeloid cell cholesterol prevented the uptake of PCa EVs by recipient myeloid cells, abolished NF-κB activity and osteoclast differentiation, stabilized thrombospondin-1 expression, and reduced metastatic burden by 77%. These results demonstrate that cholesterol homeostasis in bone marrow myeloid cells regulates pro-metastatic EV signalling and metastasis by acting as a gatekeeper for EV signal transduction.

Core personal competencies important to entering students' success in medical school: what are they and how could they be assessed early in the admission process?

Assessing applicants' personal competencies in the admission process has proven difficult because there is not an agreed-on set of personal competencies for entering medical students. In addition, there are questions about the measurement properties and costs of currently available assessment tools. The Association of American Medical College's Innovation Lab Working Group (ILWG) and Admissions Initiative therefore engaged in a multistep, multiyear process to identify personal competencies important to entering students' success in medical school as well as ways to measure them early in the admission process. To identify core personal competencies, they conducted literature reviews, surveyed U.S and Canadian medical school admission officers, and solicited input from the admission community. To identify tools with the potential to provide data in time for pre-interview screening, they reviewed the higher education and employment literature and evaluated tools' psychometric properties, group differences, risk of coaching/faking, likely applicant and admission officer reactions, costs, and scalability. This process resulted in a list of nine core personal competencies rated by stakeholders as very or extremely important for entering medical students: ethical responsibility to self and others; reliability and dependability; service orientation; social skills; capacity for improvement; resilience and adaptability; cultural competence; oral communication; and teamwork. The ILWG's research suggests that some tools hold promise for assessing personal competencies, but the authors caution that none are perfect for all situations. They recommend that multiple tools be used to evaluate information about applicants' personal competencies in deciding whom to interview.