Genetic and epigenetic alterations of the EGFR and mutually independent association with BRCA1, MGMT,and RASSF1A methylations in Vietnamese lung adenocarcinomas

Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.     

Pump Speed Optimization in Patients Implanted With the HeartMate 3 Device

Background

Pump speed optimization in patients implanted with a ventricular assist device represents a major challenge during the follow-up period. We present our findings on whether combined invasive hemodynamic ramp tests and cardiopulmonary exercise testing (CPX) can help optimize patient management.

Left Ventricular Systolic Dysfunction and Cardiovascular Outcomes in Tetralogy of Fallot: Systematic Review and Meta-analysis

BackgroundAlthough there are robust data about the pathophysiology and prognostic implications of left ventricular (LV) systolic dysfunction in patients with acquired heart disease, similar prognostic data about LV systolic dysfunction are sparse in the tetralogy of Fallot (TOF) population. The purpose of this study was to perform a meta-analysis of all studies that assessed the relationship between LV ejection fraction (LVEF) and cardiovascular adverse events (CAEs) defined as death, aborted sudden death, or sustained ventricular tachycardia.MethodsWe used random-effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsOf the 1,809 citations, 7 studies with 2,854 patients (age 28 ± 4 years) were included. During 5.6 ± 3.4 years' follow-up, there were 82 deaths, 17 aborted sudden cardiac deaths, and 56 sustained ventricular tachycardia events. Overall, CAEs occurred in 5.1% (144 patients). As a continuous variable, LVEF was a predictor of CAE (HR 1.29, 95% CI, 1.09-1.53, P = 0.001) per 5% decrease in LVEF. Similarly, LVEF < 40% was also a predictor of CAE (HR 3.22, 95% CI, 2.16-4.80, P < 0.001).ConclusionsLV systolic dysfunction was an independent predictor of CAE, and we observed a 30% increase in the risk of CAE for every 5% decrease in LVEF, and a 3-fold increase in the risk of CAE in patients with LVEF <40% compared with other patients. These findings underscore the importance of incorporating LV systolic function in clinical risk stratification of patients with TOF and the need to explore new treatment options to address this problem.     

Coronary Artery Disease Manifestations in HIV: What,How, and Why

Understanding why persons with human immunodeficiency virus (HIV) have accelerated atherosclerosis and its sequelae, including coronary artery disease (CAD) and myocardial infarction, is necessary to provide appropriate care to a large and aging population with HIV. In this review, we delineate the diverse pathophysiologies underlying HIV-associated CAD and discuss how these are implicated in the clinical manifestations of CAD among persons with HIV. Several factors contribute to HIV-associated CAD, with chronic inflammation and immune activation likely representing the primary drivers. Increased monocyte activation, inflammation, and hyperlipidemia present in chronic HIV infection also mirror the pathophysiology of plaque rupture. Furthermore, mechanisms central to plaque erosion, such as activation of toll-like receptor 2 and formation of neutrophil extracellular traps, are also abundant in HIV. In addition to inflammation and immune activation in general, persons with HIV have a higher prevalence than uninfected persons of traditional cardiovascular risk factors, including dyslipidemia, hypertension, insulin resistance, and tobacco use. Antiretroviral therapies, although clearly necessary for HIV treatment and survival, have had varied effects on CAD, but newer generation regimens have reduced cardiovascular toxicities. From a clinical standpoint, this mix of risk factors is implicated in earlier CAD among persons with HIV than uninfected persons; whether the distribution and underlying plaque content of CAD for persons with HIV differs considerably from uninfected persons has not been definitively studied. Furthermore, the role of cardiovascular risk estimators in HIV remains unclear, as does the role of traditional and emerging therapies; no trials of CAD therapies powered to detect clinical events have been completed among persons with HIV.     

中医院校预防医学课程思政的教学改革和实践

“课程思政”是当前高等教学中加强大学生思想政治教育的主要途径之一。本文通过探索中医院校“预防医学”课程思政的建设,从教学内容、教学方法、教学团队建设、考核方式四个方面论述了专业知识传授和思政教育育人的有机融合,在教学中实施“知识传授”与“价值引领”同向同行,培养德术兼备的“卓越医生”。     

Trade-offs between acquired and innate immune defenses in humans

Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology.     

亚慢性硝酸钇暴露对雌性大鼠学习记忆能力的影响

目的：观察稀土化合物硝酸钇[Y（NO₃）₃]亚慢性（90 d）暴露对大鼠学习记忆能力的影响，并探究其可能的机制，为全面评估稀土元素钇的健康风险提供科学依据。方法：选用刚离乳（PND21）SD雌性大鼠，根据质量随机分为4组，分别为对照组（ddH₂O），Y（NO₃）₃低剂量组[10 mg/（kg·d）]、中剂量组[40 mg/（kg·d）]和高剂量组[160 mg/（kg·d）]，每组15只。连续灌胃受试物90 d后进行旷场实验、高架十字迷宫实验、转棒实验、Morris水迷宫实验。水迷宫检测后，每组取5只雌鼠心脏原位灌注，进行脑组织病理学检查。每组剩余10只雌鼠摘取脑组织，紫外分光光度计检测雌鼠大脑皮质和海马中谷氨酸（Glu）的含量；Western blot检测海马组织中N-甲基-D-天冬氨酸（NMDA）受体蛋白表达情况。结果：与对照组相比，硝酸钇90 d暴露后，转棒实验中160 mg/（kg·d）剂量组大鼠在棒时间、在棒圈数、掉落速度明显升高（P<0.05）。在Morris水迷宫定位航向实验第4天时，40、160 mg/（kg·d）剂量组大鼠逃避潜伏期明显降低（P<0.05）；Morris水迷宫空间探索实验中，40 mg/（kg·d）剂量组大鼠穿越平台次数、目标象限游泳时间明显增加（P<0.05）；160 mg/（kg·d）剂量组穿越平台次数、进入目标象限次数、目标象限游泳时间明显增加（P<0.05）；160 mg/（kg·d）剂量组大鼠东北、东南、西南象限的逃避潜伏期明显低于西北象限的逃避潜伏期（P<0.05）。160 mg/（kg·d）剂量组大鼠海马中Glu含量和NMDA受体NR1含量均明显低于对照组（P<0.05）。40和160 mg/（kg·d）剂量组大鼠海马中NMDA受体NR2A含量明显低于对照组（P<0.05）。结论：硝酸钇亚慢性（90 d）暴露可以引起雌性大鼠空间学习记忆能力增强；硝酸钇可能通过降低海马组织神经元细胞外Glu含量，抑制NMDA受体激活，增强雌性大鼠的空间学习记忆能力。