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 -     

基于HMGB1/TLR4/NF-κB信号通路研究木兰脂素对急性鼻窦炎大鼠的治疗作用及机制

目的： 观察木兰脂素对急性鼻窦炎(ARS)大鼠的治疗作用，并探讨其通过高迁移率家族蛋白1/ Toll样受体4/核因子-κB(HMGB1/TLR4/NF-κB)信号通路的调控机制方法： 49只大鼠，随机取9 只作为正常组，40只用鼻窦腔内接种金黄色葡萄球菌法制备ARS模型，36只建模成功大鼠随机分为模型组、木兰脂素低剂量组、木兰脂素高剂量组、阳性组，各9只。木兰脂素低剂量组、木兰脂素高剂量组分别灌胃20、80 mg·kg^-1体质量的木兰脂素，模型组和正常组灌胃等体质量溶媒，阳性组灌胃40 mg·kg^-1 体质量左氧氟沙星，连续7 d。给药前、末次给药后1 h评估各组鼻窦炎症状评分；测定给药后各组血白细胞(WBC)计数及中性粒细胞占比，观察鼻窦黏膜病理组织学变化，检测鼻腔灌洗液中肿瘤坏死因子-α(TNF-α)、白介素(IL)-6水平及鼻黏膜中HMGB1、TLR4、NF-κB mRNA和蛋白表达情况结果： 给药后，木兰脂素低剂量组、高剂量组、阳性组的急性鼻窦炎症状评分及血WBC计数均低于模型组，但仍高于正常组，且木兰脂素高剂量组及阳性组均低于木兰脂素低剂量组，差异均有统计学意义(P＜0.05)，而木兰脂素高剂量组与阳性组比较，差异无统计学意义(P＞0.05)。与给药前比较，给药后木兰脂素低剂量组、高剂量组及阳性组急性鼻窦炎症状评分均降低(P＜0.05)，正常组及模型组给药前后无明显差异(P＞0.05)。与模型组比较，木兰脂素低剂量组、木兰脂素高剂量组、阳性组中性粒细胞占比均降低，且木兰脂素高剂量组低于木兰脂素低剂量组，阳性组低于木兰脂素高剂量组，差异均有统计学意义(P＜0.05)，而阳性组与正常组比较，差异无统计学意义(P＞0.05)。HE染色显示，模型组大鼠纤毛脱落、缺失、排列紊乱，黏膜上皮破损、变性，黏膜内及黏膜下可见大量炎症细胞浸润； 木兰脂素低剂量组、木兰脂素高剂量组及阳性组上述病理变化均减轻，且木兰脂素高剂量组和阳性组炎症反应减轻更为明显。与模型组比较，木兰脂素低剂量组、木兰脂素高剂量组、阳性组鼻腔灌洗液中 TNF-α、IL-6水平及鼻黏膜中HMGB1、TLR4、NF-κB mRNA和蛋白相对表达量均降低，但仍高于正常组，且木兰脂素高剂量组及阳性组均低于木兰脂素低剂量组，差异均有统计学意义(P＜0.05)，而木兰脂素高剂量组及阳性组比较，差异无统计学意义(P＞0.05)结论： 木兰脂素治疗ARS效果显著，可能通过HMGB1/TLR4/NF-κB信号通路抑制鼻黏膜炎症反应。     

特纳综合征患者骨质疏松的研究进展

特纳综合征(TS)是女性常见的性染色体异常疾病,与多种疾病共存。越来越多的证据表明TS患者有较高的骨质疏松患病率,本文就近年来TS中骨质疏松的危险因素及管理治疗的相关研究进展做一综述。     

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。     

PKP术中不同注入量高粘度骨水泥治疗骨质疏松性腰椎骨折的疗效分析

目的探讨经皮椎体后凸成形术（PKP）术中不同注入量高粘度骨水泥治疗骨质疏松性腰椎骨折（OLVF）的疗效及安全性。 方法前瞻性收集2016年9月至2018年9月本院OLVF患者150例，男84例，女66例，年龄（60±8）岁。依据随机数字表分为高量组、中量组、低量组，每组50例，高量组、中量组、低量组PKP术中高粘度骨水泥注入量分别为5.0~7.0 ml、3~4.9 ml、<3.0 ml，比较三组疗效及安全性。 结果150例患者获得满意随访，随访时间（19±7）个月。高量组、中量组、低量组手术时间、术中出血量比较，差异无统计学意义（P>0.05）；高量组和中量组术后3、6个月椎体前缘高度[（27.3±3.1）mm、（26.0±2.7）mm和（26.9±3.0）mm、（25.7±2.8）mm]明显高于低量组[（23.8±2.8）mm、（21.3±2.5）mm]，高量组和中量组术后3、6个月Cobb角及疼痛视觉模拟评分法（VAS）、Oswestry功能障碍指数问卷表（ODI）评分[（40.2±4.7）°、（41.5±4.8）°、（2.6±0.4）分、（1.6±0.3）分、（25.8±3.5）分、（26.9±3.5）分和（40.9±4.8）°、（42.1±4.8）°、（2.6±0.4）分、（1.6±0.3）分、（26.2±3.5）分、（27.2±3.7）分]明显低于低量组[（46.3±5.3）°、（47.8±5.6）°、（3.3±0.4）分、（2.3±0.4）分、（33.3±4.1）分、（34.3±4.2）分]，差异有统计学意义（F=25.371、18.914、29.334、22.457、34.276、30.217、29.364、20.071，均P<0.001）；高量组骨水泥渗漏率（28.00%）明显高于中量组和低量组（8.00%和4.00%），差异有统计学意义（χ²=10.241，P=0.005）。 结论PKP术中不同注入量高粘度骨水泥治疗OLVF的疗效及安全性存在一定的差异，其中注入中量（3~4.9 ml）高粘度骨水泥可获得良好的疗效及安全性，值得临床推广。     

治伤巴布剂对大鼠急性软组织损伤模型P38MAPK、AKT信号通路的影响＊

目的 观察治伤巴布剂对急性软组织损伤（acute soft tissue injury， ASTI）模型p38丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、丝/苏氨酸蛋白激酶（AKT）信号通路的影响，探讨治伤巴布剂干预ASTI的可能作用机制。方法 将40只雄性SD大鼠按照随机数字表法分为正常对照组、模型对照组、治伤巴布剂组、p38MAPK信号通路抑制剂组、AKT信号通路抑制剂组，每组8只。除正常对照组外，其余四组均予以左侧后肢小腿ASTI造模。造模成功后，治伤巴布剂组于标记部位立即予治伤巴布剂（修剪成1.5x3cm大小）外敷，并用胶布固定；其余四组均予等剂量赋形剂（修剪成1.5×3 cm大小）外敷处理，胶布固定；持续外敷，共持续24 h。p38MAPK信号通路抑制剂组在造模前30 min予腹腔注射p38MAPK信号通路抑制剂SB203580（400 μg/kg/天）1次；AKT信号通路抑制剂组在造模前30 min予腹腔注射AKT信号通路抑制剂perifosine（20 mg/kg/天）1次。分别于0（造模前）、2h、4h、8h、12h、24h测量受伤小腿肌肉处的周长，并计算肌肉肿胀率（muscle swelling rate，MSR）。24 h药物干预结束后，采用颈椎脱臼法处死大鼠。后将左侧后肢小腿损伤中心部位进行取材，分成三份。一部分用于观察组织病理学形态变化；一部分用于逆转录聚合酶链反应（RT-PCR）检测核因子-κB（nuclear factor kappa-B，NF-κB）p65 mRNA、肿瘤坏死因子-α（TNF-α）mRNA、白细胞介素-1β（IL-1β）mRNA表达水平；剩下部分用酶联免疫吸附试验（ELISA）法检测骨骼肌组织TNF-α、IL-1β含量水平及蛋白质免疫印迹（Western-blot）法测定p38MAPK、AKT、NF-κB p65、核因子抑制蛋白α（inhibitor kappa B alpha， IκBα）表达水平。结果 与正常对照组相比，模型对照组MSR显著增加（P<0.01）；病理形态学上，骨骼肌组织可见大面积肌细胞排列紊乱，肌细胞变性坏死，间质内可见红细胞聚集及大量炎症细胞浸润；骨骼肌组织TNF-α、IL-1β含量水平显著升高（P<0.01）；磷酸化p38MAPK（p-p38）/总p38MAPK（t-p38），磷酸化-AKT（p-AKT）/总-AKT（t-AKT）明显升高（P<0.01），NF-κB p65及NF-κB p65mRNA表达水平明显升高（P<0.01）。与模型对照组相比，治伤巴布剂组MSR在治疗第8 h、12 h、24 h显著下降（P<0.01），且在治疗第24 h，其MSR较p38MAPK、AKT信号通路抑制剂组下降更明显（P<0.05）；病理学评分显著下降（P<0.01），且较p38MAPK、AKT信号通路抑制剂组下降更显著（P<0.05）；骨骼肌组织TNF-α、IL-1β含量水平明显下降（P<0.01），且较p38MAPK、AKT信号通路抑制剂组更显著（P<0.05）；p-p38/t-p38及p-AKT/t-AKT明显下降（P<0.01），NF-κB p65及NF-κB p65 mRNA表达水平显著下降（P<0.01），且较p38MAPK、AKT信号通路抑制剂组在降低NF-κB p65及NF-κB p65 mRNA相对表达值方面更显著（P<0.01）。结论 治伤巴布剂可能同时对p38MAPK、AKT信号通路产生了一定的抑制作用，引起NF-κB活性下调，NF-κB p65蛋白的表达下调，进而引起骨骼肌组织TNF-α、IL-1β炎性细胞因子含量水平下调，减轻ASTI炎症反应，从而改善ASTI。