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Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc.Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction.Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance.Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.

IntroductionLung cancer is a leading cause of cancer incidence and death in the United States. Although most firefighters are fit and do not smoke, they are exposed to many known carcinogens during and in the aftermath of firefighting activities. Comprehensive epidemiologic investigations on lung cancer survival for both career and volunteer firefighters have not been undertaken.MethodsData from the Florida Cancer Data System (1981–2014) were linked with firefighter certification records from the Florida State Fire Marshal’s Office to identify all patients of this occupational group; lung cancer cause-specific survival data were compared with other occupational groups using Cox regression models with occupation as the main effect. Adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were calculated.ResultsOut of 210,541 male lung cancer cases diagnosed in Florida (1981–2014), 761 were firefighters (604 career, 157 volunteer). Lung cancer death was similar between volunteer (75.2%) and career firefighters (74.0%) but lower than non-firefighters (80.0%). Survival at 5 years was higher among firefighters (29.7%; career: 30.3%; volunteer: 27.4%) than non-firefighters (23.8%). In a multivariable model, compared with non-firefighters, firefighters have significantly higher cause-specific survival (aHR = 0.84; 95% CI: 0.77–0.91; p < 0.001). However, there were no significant survival differences between career and volunteer firefighters (1.14; 0.93–1.39; p = 0.213). In a separate multivariable model with firefighters as the comparator, other broad occupational groups had significantly lower cause-specific survival [white collar: 1.11 (1.02–1.21); blue collar: 1.15 (1.05–1.25); service: 1.13 (1.03–1.25); others/unknown: 1.21 (1.12–1.32); all p-values < 0.02].ConclusionLung cancer survival is significantly higher among firefighters compared with non-firefighters, but there is no significant difference between career and volunteer firefighters. Improved survival for firefighters might be due to a healthy worker effect, lower smoking prevalence relative to other worker groups, and possibly superior treatment adherence and compliance. Many firefighters are cross-trained as EMTs/paramedics and possess a level of medical knowledge that may favorably impact treatment engagement and better navigation of complex cancer care.

Abstract Supplemental oxygen (O2) therapy in preterm infants impairs lung development, but the impact of O2 on long‐term systemic vascular structure and function has not been well‐explored. The present study tested the hypothesis that neonatal O2 therapy induces long‐term structural and functional alterations in the systemic vasculature, resulting in vascular stiffness observed in children and young adults born preterm. Newborn Sprague‐Dawley rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) for 1 and 3 weeks. A subgroup exposed to 3 weeks hyperoxia was recovered in normoxia for an additional 3 weeks. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound and pressure myography. Aorta remodeling was assessed by collagen deposition and expression. Left ventricular (LV) function was assessed by echocardiography. We found that neonatal hyperoxia exposure increased vascular stiffness at 3 weeks, which persisted after normoxic recovery at 6 weeks of age. These findings were accompanied by increased PWV, aortic remodeling, and altered LV function as evidenced by decreased ejection fraction, cardiac output, and stroke volume. Importantly, these functional changes were associated with increased collagen deposition in the aorta. Together, these findings demonstrate that neonatal hyperoxia induces early and sustained biomechanical alterations in the systemic vasculature and impairs LV function. Early identification of preterm infants who are at risk of developing systemic vascular dysfunction will be crucial in developing targeted prevention strategies that may improve the long‐term cardiovascular outcomes in this vulnerable population.

Background c-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis. Methods High-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W–v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations. Results The microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner. Discussion Our study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation.