Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome.

OBJECTIVE: Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome. APPROACH AND RESULTS: Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs. CONCLUSIONS: Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.

miR-29b participates in early aneurysm development in Marfan syndrome.

RATIONALE: Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-ß (TGF-ß) signaling. Although TGF-ß blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-ß causes aneurysms remain ill-defined. OBJECTIVE: We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS. METHODS AND RESULTS: Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-ß, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-ß blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies. CONCLUSIONS: We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

Self-efficacy Toward a Healthcare Career Among Minority High School Students in a Surgical Pipeline Program: A Mixed Methods Study.

OBJECTIVE: While many barriers to healthcare careers exist for URM students, a strong sense of self-efficacy may help mitigate these obstacles. This study explores how URM high school students describe their academic challenges and compares their descriptions across self-efficacy scores. DESIGN: We conducted a convergent mixed methods study of URM high school students. Students completed a validated self-efficacy questionnaire and participated in semi-structured focus group interviews to discuss their approach to academic challenges, goal setting, and achievement. The primary outcome was academic, social, and emotional self-efficacy, measured using the Self-Efficacy Questionnaire for Children. We separated participants into high and low self-efficacy groups based on scores in each domain. Using thematic analysis, we identified and compared common themes associated with academic challenges and goal setting. SETTING: Surgical exposure pipeline program sponsored by Stanford University Department of Surgery PARTICIPANTS: Low-income, high academic achieving URM high school students interested in science, technology, engineering and mathematics, and/or healthcare careers. RESULTS: Thirty-one high school students completed the focus groups and self-efficacy questionnaire. Most students scored in the high self-efficacy group for at least one domain: 65% for academic self-efficacy, 56% for social self-efficacy, and 19% for emotional self-efficacy. Four emergent themes highlighted participants' perspectives toward educational success: fulfillment in academic challenges, focus on future goals, failing forward, and asking for help. Compared to students with low self-efficacy scores, students in the high-scoring self-efficacy groups more often discussed strategies and concrete behaviors such as the importance of seeking support from teachers and peers and learning from failure. CONCLUSIONS: Students in high self-efficacy groups were more comfortable utilizing approaches that helped them succeed academically. Additional efforts are needed to bolster student self-efficacy, particularly in students from URM backgrounds, to increase diversity in medical schools.

A comparison of provider perspectives on cultural competency training: A mixed methods study.

BACKGROUND: We aimed to identify differences in training among colorectal cancer physicians and advanced practice providers with high and low cultural competency METHODS: Using explanatory sequential mixed methods, we surveyed providers and dichotomized into high and low cultural competency (CC) groups, conducted qualitative interviews, and analyzed verbatim transcripts using deductive and inductive codes to compared findings across groups using a joint display. RESULTS: Fifty-four of 92 providers (59%) responded; 10 respondents from each group (20/36 invited) completed semi-structured interviews about previous CC trainings. Low CC providers' training included explanations of cultural differences that, in practice, improved awareness and utilization of communication tools, but they also desired decision-making tools and cultural exposure. High CC providers' training included action-oriented toolkits. In practice, they admitted failures, improved communication, and attributed patient behaviors to external factors. High CC providers desired performance evaluations. CONCLUSIONS: Behaviorally-oriented CC training offered a robust foundation for culturally competent care.

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.