Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

RWMAs in critically ill patients with non-obstructed coronary arteries

Introduction

Left ventricular (LV) dysfunction is estimated to occur in 10%–25% of the general intensive care unit (ICU) population and is frequently seen as regional wall motion abnormalities (RWMAs). Although RWMA is mostly attributed to myocardial ischemia or infarction, some studies have suggested that nonischemic RWMA might also be prevalent. We sought to establish that RWMA can be seen in critically ill patients with normal coronary arteries and to explore reasons for RWMA in this population.

Methods

In this retrospective study, data from the hospital angiography register and the ICU register were collated between 2012 and 2019. Patients were identified who underwent angiography in conjunction with their ICU stay and had RWMA on echocardiography. Patients were divided into either those with non-obstructed or those with obstructed coronary arteries. Cardiac magnetic resonance imaging (cMRI) examinations were reviewed if they had been performed on patients with non-obstructed coronaries.

Results

We identified 53 patients with RWMA and non-obstructed coronary arteries and 204 patients with RWMA and obstructed coronary arteries. Patients with non-obstructed coronary arteries were more often female, younger, and had fewer cardiovascular risk factors. They less commonly had ST elevation, but more frequently had T-wave inversion or serious arrhythmias. Troponin levels were higher in patients with obstructed coronary arteries, but NT-proBNP was similar between the groups. There were no differences in risk-adjusted 90-day mortality between patients with non-obstructed versus obstructed coronary arteries (OR 1.21, [95% CI 0.56–2.64], p = .628). In those with non-obstructed coronary arteries, follow-up echocardiography was available for 38 patients, of whom 30 showed normalization of cardiac function. Of the 14 patients with non-obstructed coronary arteries on whom cMRI was performed, 7 had a tentative diagnosis of Takotsubo syndrome or myocardial stunning; 4 had a myocardial infarction (preexisting in 3 cases); 1 patient had acute myocarditis; 1 patient had post-myocarditis; and 1 patient was diagnosed with dilated cardiomyopathy.

Conclusion

RWMA can be seen to occur in critically ill patients in the absence of coronary artery obstruction. Several conditions can cause regional hypokinesia, and cMRI is useful to evaluate the underlying etiology.     

Correction: Thrombotic and bleeding events,mortality, and anticoagulant use among 546,656 hospitalized patients with COVID‑19 in the United States: a retrospective cohort study

Journal of Thrombosis and Thrombolysis -     

Dectin-2受体介导宿主抵抗烟曲霉菌感染的研究

目的探讨C型凝集素受体Dectin-2在烟曲霉菌感染中的作用及机制。方法用紫外线灭活的烟曲霉菌膨胀态分生孢子刺激野生型(wild type, WT)和Dectin-2缺失(Clec4n-/-)小鼠骨髓来源的巨噬细胞(bone marrow derived macrophages, BMDMs)。刺激20min及40min后，利用Western印迹法检测BMDMs中脾酪氨酸激酶(spleen tyrosine kinase, Syk)和核转录因子κB抑制因子(inhibitor-κB, IκBα)的磷酸化水平。刺激16h后，利用酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测BMDMs细胞上清液中IL-6、TNF-α和IL-12p40的水平。另一方面，利用压舌感染的方法在WT和Clec4n-/-小鼠中构建烟曲霉菌肺部感染模型。感染2d后，统计小鼠整个肺脏荷菌量，并检测肺脏匀浆液中IL-6和IL-12p40水平。结果体外试验提示，烟曲霉菌刺激后，Dectin-2缺失的BMDMs中Syk和IκBα的磷酸化水平及IL-6、TNF-α和IL-12p40水平显著下降(P＜0.05)。体内试验发现，烟曲霉菌感染后，Dectin-2缺失小鼠中肺脏荷菌量显著升高(P＜0.05)，肺脏匀浆液内IL-6、IL-12p40水平显著降低(P＜0.05)。结论C型凝集素受体Dectin-2激活烟曲霉菌诱导的NF-κB信号通路并介导促炎细胞因子的产生，可在小鼠肺烟曲霉菌病动物模型中发挥保护性作用。     

基于网络药理学和分子对接技术探讨黄芪干预腹膜纤维化的机制

目的 运用网络药理学方法及分子对接技术探讨黄芪干预腹膜纤维化的可能机制。方法 利用中药系统药理学数据库及分析平台(TCMSP)检索黄芪的主要化学成分及靶点,并补充文献报道相关药理作用的成分作为潜在活性成分。以"peritoneal fibrosis"为关键词分别在OMIM、Genecards获取目前已知的与腹膜纤维化相关的疾病靶点,后取两者的交集靶点;对交集基因通过STRING数据库与Cytoscape 3.7.2软件构建"药物-成分-靶点-疾病"网络及蛋白互作(PPI)网络并筛选核心网络。基于R软件使用Bioconductor生物信息软件对核心靶点进行GO及KEGG富集分析,最终采用AutoDock软件将主要有效成分与核心靶点进行分子对接,得出其结合能力。结果 筛选出20个黄芪活性成分及文献报道有相关药理作用4个, 457药物作用靶点,与674个腹膜纤维化病靶点取交集,得到86个共同靶点。GO功能富集分析提示黄芪拮抗腹膜纤维化主要参与了蛋白激酶B信号转导的调节、细胞对化学的应激反应、炎症反应的调节等通路; KEGG通路富集分析主要涉及调控肿瘤、磷脂酰肌醇-3-羟激酶-蛋白激酶B(PI3K-Akt)、晚期糖基化终末产物/晚期糖基化终末产物受体(AGE-RAGE)、人类巨细胞病毒感染、HIF-1信号通路等;分子对接结果显示关键靶点与活性成分具有较好的结合能力。结论 黄芪治疗腹膜纤维化的分子机制,可能与抑制炎症及氧化应激反应、调节多种信号通路等相关。     

Measuring Psychological Inflexibility of Suicidal Thoughts: The Acceptance and Action Questionnaire for Suicidal Ideation (AAQ-SI)

Cognitive Therapy and Research - Despite interest in psychological inflexibility as a marker of suicide risk, no measure of psychological inflexibility specific to SI exists. The present study...     

371名大学生微信朋友圈人格、自我呈现策略与情绪表达的关系

目的 探究大学生微信朋友圈人格、自我呈现策略和情绪表达间的关系。方法 采用社交网络自我呈现策略问卷、艾森克人格问卷简式量表、伯克利情绪表达问卷,对随机抽取的371名大学生进行调查。结果 ⑴外倾型人格总分与真实自我呈现策略总分呈正相关(r=0.170,P=0.001),与正性情绪表达呈正相关(r=0.166,P=0.001),与情绪表达强度呈正相关(r=0.184,P=0.001),真实自我呈现策略与正性情绪表达呈正相关(r=0.239,P=0.001)。⑵真实自我呈现策略在外倾型人格与正性情绪表达的关系中存在部分中介效应。结论 371名大学生的外倾型人格、真实自我呈现策略与正性情绪表达关系密切,真实自我呈现策略在外倾型人格与正性情绪表达的关系中存在部分中介效应。     

Education Outcomes of Children Born Late Preterm: A Retrospective Whole-Population Cohort Study

Maternal and Child Health Journal - Early life exposures can have an impact on a child’s developmental trajectory and children born late preterm (34–36 weeks gestational age)...