Search

Abstract Background Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS −/− and HCT 116 ASNS +/+ cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice. Results ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS −/− xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth. Conclusions Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.

US medical schools increasingly seek ways to reduce costs and improve productivity. One aspect of this effort has been the development of performance-based incentives for individual faculty. A myriad of such plans exist. Typically, they incentivize clinical revenue generation but vary widely in how teaching, investigation, and administrative contributions are recognized. In Pathology at Yale, we have developed a transparent metrically driven approach that recognizes all missions and allows faculty significant control over their career path. Although some metrics derive from traditional measures such as workload relative value units and one’s level of grant support, the key concept underpinning our approach is to define one’s contributions not in terms of the revenue generated, but rather on the effort devoted to each of our missions, benchmarked against national or local standards. Full-time faculty are paid a competitive rank-based salary and are expected to contribute at least 100% effort in support of the school’s missions: clinical, research, education, administration, and professional service. Metrics define the effort assigned to each activity. Faculty achieving greater than 100% effort receive bonus compensation in proportion to their excess effort. By codifying explicitly how such effort is recognized into a single metric (% effort), we achieve a process that better aligns the professional and personal goals of faculty with the aims of the school. To facilitate its implementation, we have developed a web-based software platform called SWAY (Standardized Workload Analysis at Yale) that enables faculty to monitor their progress and record their activities in real time.

Objective: Evidence suggests that physical activity whilst pregnant is beneficially associated with maternal cardiometabolic health and perinatal outcomes. It is unknown if benefits extend to objective markers of the neonate condition at birth. This study investigated associations of maternal pregnancy physical activity with cord blood pH. Methods: Cord blood pH was measured when clinically indicated in a subgroup of Born in Bradford birth cohort participants ('n' = 1,467). Pregnant women were grouped into one of four activity categories (inactive/somewhat active/moderately active/active) based on their self-reported physical activity at 26–28 weeks gestation. Linear regression was used to calculate adjusted mean differences in cord blood pH, and Poisson regression was used to quantify relative risks for moderate cord blood acidaemia (pH < 7.10), across physical activity groups. Results: More than half of pregnant women (52.0%) were inactive, one-fifth were somewhat active (21.7%), fewer were moderately active (14.6%) and active (11.7%), respectively. Pregnancy physical activity was favourably associated with higher cord blood pH. Compared to neonates of inactive women, there was some evidence that neonates of women who were at least somewhat active in pregnancy had lower relative risk of moderate cord blood acidaemia (for arterial blood: relative risk = 0.70 (95% confidence interval 0.48–1.03)). Conclusions: Modest volumes of mid-pregnancy maternal physical activity do not appear to adversely influence cord blood pH and may enhance the neonate condition at birth.