Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

双源CT多定量参数对胃癌的诊断价值及与HER2的相关性

目的:探讨门脉期双源CT多个定量参数与胃腺癌病理分化程度及HER2的相关性。方法: 回顾性分析2018年7月至2019年4月间于陕西省人民医院行双源CT双能量扫描的48例经胃镜活检(21例)或手术病理证实（27例）的胃腺癌及30例正常胃的影像学资料，其中27例HER2指标明确，通过西门子第二代双源CT扫描获得静脉期双能量图像，利用syngo.via软件获得曲线斜率、门脉期碘浓度、标准化碘浓度；将患者分为胃腺癌与正常胃壁组，高、中、低分化胃腺癌组，HER2阳性组（+，++，+++）与HER2阴性组（-）。统计学方法采用Kappa一致性检验、ROC曲线法、两独立样本t检验及方差分析。结果:活检与术后病理结果具有较强的一致性（Kappa系数为0.701），两者无明显差异；胃腺癌与正常胃壁两组间能谱曲线斜率（1.35±0.24、2.19±0.71）及标准化碘浓度（0.31±0.079、0.54±0.157）均具有统计学意义（P<0.05），曲线下面积分别为0.992、0.919；低分化、中分化及高分化胃腺癌能谱曲线斜率值（3.07±0.67，2.63±0.57，2.01±0.39）组间及组内差异均具有统计学意义（P<0.05），低分化、中分化及高分化胃腺癌门脉期标准化碘浓度(0.60±0.167，0.52±0.089，0.36±0.039)组间差异具有统计学意义（P<0.05），中分化组与低分化组差异无统计学意义（P>0.05），高分化组与中、低分化组均具有统计学差异（P<0.05）。HER2阳性组与阴性组的能谱曲线斜率及标准化碘浓度值无统计学差异（P>0.05）。结论:能谱曲线斜率及门脉期标准化碘浓度值有助于对胃腺癌进行诊断并推测病理分化程度；双源CT定量参数与免疫组化指标HER2无相关性。     

Noncoding telomeric repeat‐containing RNA inhibits the progression of hepatocellular carcinoma by regulating telomerase‐mediated telomere length

Telomeric repeat‐containing RNA (TERRA) is closely involved in the regulation of telomere length, which plays critical roles in tumorigenesis. However, the biological significance of TERRA in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we found that HCC cells show a frequent downregulation of TERRA and its positive regulator TTAGGG repeat binding factor‐1 (TRF1), whereas the negative regulator TTAGGG repeat binding factor‐1 (TRF2) was upregulated. We found that TERRA, TRF1, and TRF2 contributed to poor prognosis of HCC patients. Importantly, we found that the downregulation of TERRA significantly promoted HCC cell growth and metastasis in vitro and in vivo, whereas the upregulation of TERRA showed an opposite effect. Mechanistically, downregulation of TERRA significantly increased telomerase activity and promoted telomere elongation. Moreover, the inhibitory effects of TERRA overexpression on the growth and metastasis of HCC cells were reversed by treatment with TA‐65 that activates telomerase activity. In contrast, the protumor effect of TERRA downregulation was reversed by treatment with TMPyP4 that inhibits telomerase activity. Our findings reveal that TERRA plays a critical role in HCC cell growth and metastasis, indicating that TERRA is a potential therapeutic target for HCC.     

脑血管畸形致脑出血患者手术治疗效果观察

目的分析脑血管畸形致脑出血患者应用手术治疗的临床疗效。方法纳入本院2018年1月—2020年1月收治的60例脑血管畸形致脑出血患者,随机分组(每组样本容量共计30例),参照组给予保守治疗,观察组给予手术治疗,对比两组临床疗效、治疗前、治疗1月后NIHSS评分、住院时间。结果临床总有效率观察组(93.33%)明显高于参照组(63.33%),观察组治疗1月后NIHSS评分明显低于参照组,观察组住院时间明显比参照组短,差异均具有统计学意义(P<0.05)。结论脑血管畸形致脑出血患者采纳手术治疗,可有效减轻患者神经功能受损情况,缩短治疗时间。     

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin‐Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)‐induced G1/S cell‐cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF‐induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal‐regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c‐Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP‐1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate‐bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage‐independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage‐independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR‐Akt‐p70S6K and mTOR‐Akt‐GSK3β‐AP‐1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2‐Akt‐p70S6k signaling pathway.     

从湿论治慢性静脉功能不全刍见

慢性静脉功能不全是常见的周围血管疾病。文章在梳理历代中医辨证思路的基础上,结合现代医学的认识和临床观察,分别从湿的来源、湿在慢性功能不全疾病中的具体体现和治疗3个方面来探讨本类疾病与湿的关系。认为湿作为本病的重要致病因素和病理产物,贯穿于本病的始终,与本病的形成密不可分,在治疗上应注重对湿的辨析,明确其性质、来源、病证特点等,选用多法以祛湿。     

Effects of exercise dose and type during breast cancer chemotherapy on longer-term patient-reported outcomes and health-related fitness: A randomized controlled trial

The Combined Aerobic and Resistance Exercise (CARE) Trial compared different types and doses of exercise performed during breast cancer chemotherapy. Here, we report the longer-term follow-up of patient-reported outcomes, health-related fitness and exercise behavior at 6, 12 and 24 months postintervention. A multicenter trial in Canada randomized 301 breast cancer patients initiating chemotherapy to thrice weekly, supervised exercise consisting of a standard dose of 25–30 min of aerobic exercise (STAN; n = 96), a higher dose of 50–60 min of aerobic exercise (HIGH; n = 101) or a combined dose of 50–60 min of aerobic and resistance exercise (COMB; n = 104) performed for the duration of chemotherapy (median of 17 weeks). Primary outcomes were patient-reported outcomes including quality of life, cancer-related symptoms and psychosocial outcomes. Secondary outcomes were objective health-related fitness (assessed at 12 months only) and self-reported exercise behavior. A total of 269 (89.4%) participants completed patient-reported outcomes at all three follow-up time points and 263 (87.4%) completed the health-related fitness assessment at 12-month follow-up. COMB was significantly superior to (i) STAN for sleep quality at 6-month follow-up (p = 0.027); (ii) HIGH for upper body muscular endurance at 12-month follow-up (p = 0.020); and (iii) HIGH for meeting the resistance exercise guideline at 6-month follow-up (p = 0.006). Moreover, self-reported meeting of the combined exercise guideline during follow-up was significantly associated with better patient-reported outcomes and health-related fitness. Performing combined exercise during and after breast cancer chemotherapy may result in better longer-term patient-reported outcomes and health-related fitness compared to performing aerobic exercise alone.