Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

3 404例2型糖尿病患者视网膜病变患病率及其相关因素分析

目的 分析2型糖尿病（T2DM）患者视网膜病变（DR）患病率及其相关因素。方法 对3 404例2型糖尿病住院患者进行回顾性研究，根据眼科会诊结果，将患者分为3组，其中非DR组（A组/NDR组）2 562例，DR非增殖期组（B组/NPDR组）716例，DR增殖期组（C组/PDR组）126例。得出DR的患病率，比较3组患者之间临床资料及临床指标的异同，及其与DR的相关性。结果 2型糖尿病患者DR患病率达24.7%，与甘油三酯（OR=1.110，P=0.000）、糖化血红蛋白（HbA1c）（OR=1.087，P=0.000）、血尿酸（OR=1.003，P=0.000）、病程（OR=1.002，P=0.000）相关。结论 2型糖尿病患者DR患病率为24.7%，高血脂、高血糖、高尿酸血症、病程长为DR的独立危险因素。早期发现糖尿病、早期治疗糖尿病、积极控制血糖血脂血尿酸，对于减少DR的发生及延缓DR的发展意义重大。     

82例应力性骨折影像学诊断回顾性分析

目的：研究影像学在诊断应力性骨折中的应用。方法：选取2013年1月—2017年12月南京医科大学第一附属医院收治的82例保有影像学资料并诊断明确的应力性骨折患者作为研究对象，对患者影像学资料进行回顾性分析，并比较分析X线、CT、MRI对应力性骨折的诊断准确率及漏诊的原因。结果：82例应力性骨折患者的男女比例为1∶1.9，平均年龄为49.77岁；病变多累及下肢骨及中轴骨，胫骨为最常见累及部位；X线、CT、MRI的诊断准确率依次升高，X线、CT的初诊漏诊与MRI分级之间的关系无统计学意义；X线及CT图像中骨膜反应易被漏诊。结论：应力性骨折的影像学诊断应结合临床病史及好发部位，早期诊断应力性骨折首选MRI，注重X线及CT中骨膜反应及软组织情况以减少漏诊率。     

A benchmark dose study of prenatal exposure to di(2-ethylhexyl) phthalate and behavioral problems in children

IntroductionPrenatal exposure to di(2-ethylhexyl) phthalate (DEHP) has been reported to be associated with adverse effects on neurodevelopment that yield behavior syndromes in young children with an estimated median exposure lower than the currently recommended tolerable daily intake (TDI) and reference dose (RfD).ObjectivesOur aim was to derive the benchmark dose for prenatal exposure to DEHP for the neurodevelopmental health in children.MethodsA total of 122 mother-child pairs from the Taiwan Maternal and Infant Cohort Study were analyzed for the dose-response relationship between maternal exposure to DEHP and children's behavioral syndromes evaluated at 8 years (n = 122, 2009), 11 years (n = 96, 2012), and 14 years (n = 78, 2015) of age. We employed a multivariate regression model to assess the statistical associations between the estimated maternal average daily intake of DEHP and child's individual CBCL scores for boys and girls at each separate age, followed by a mixed model for all the children across three ages accounting for individual variations. We then employed structural equation models by combining the children's specific behavioral problem scores at different ages and obtained a simulated overall latent score in relation to maternal exposure. Based on the established dose-response relationship, we derived the benchmark dose (BMD) and the lower limit (BMDL).ResultsAssociations of maternal DEHP exposure (median 4.54$\mu g/kg\_bw/day$) with the Child Behavior Checklist (CBCL) scores were all significant, except for somatic complaints, adjusting for child's age, gender, IQ, and family income. The BMDL, given a benchmark response of 0.10 (0.05) and a background response of 0.05, was 6.01 (2.16) $\mu g/kg\_bw/day$for an integrated CBCL score.ConclusionsThe current TDI (RfD) of 50 (20) $\mu g/kg\_bw/day$ for DEHP might not protect pregnant women for their children from behavioral problems. There remains the lack of comparable toxicological data. Further investigations are needed.     

RPLU、FURL及PCNL治疗输尿管上段嵌顿性结石的疗效研究

目的探讨后腹腔镜切开取石术（retroperitoneal laparoscopic lithotomy，RPLU）、输尿管软镜碎石清石术（lithotripsy with flexible ureteroscope，FURL）及经皮肾镜碎石清石术（percutaneous nephrolithotomy，PCNL）种不同方法治疗输尿管上段嵌顿性结石的疗效，以明确直径大于1.5 cm的输尿管上段嵌顿性结石的最佳处理方案。 方法回顾性分析159例输尿管上段嵌顿性结石，收集其术前术中资料，按术式不同分为RPLU组56例、FURL组55例、PCNL组48例。对手术时间、术后住院时间、结石清除率、术后并发症等数据进行统计学分析。 结果FURL组手术时间和术后住院时间明显短于RPLU组和PCNL组，差异均有统计学意义（P＜0.05）。RPLU组术后3 d和术后1个月的结石清除率（100%，100%）稍高于FURL组（90.9%，94.5%）和PCNL组（93.8%，93.8%），3组患者术后无严重并发症出现，差异均无统计学意义（P＞0.05）。 结论3种不同手术方法治疗嵌顿性输尿管上段结石均安全有效，FURL组手术时间及住院时间更短，患者术后恢复更快，更具有优势。     

控制性低中心静脉压在原发性肝癌伴肝炎后肝硬化患者腹腔镜肝切除中的应用

背景与目的:在肝脏切除手术中采用控制性低中心静脉压(CLCVP)技术可有效减少肝断面出血,然而,低中心静脉压(CVP)所产生的相对低血压和潜在低灌注可能造成不良影响,这使其推广应用受到一定程度的限制。本研究探讨CLCVP技术在原发性肝癌伴肝炎后肝硬化患者腹腔镜肝切除手术中的应用效果和安全性。方法:回顾性分析2017年4月—2019年3月在安徽医科大学第一附属医院肝胆胰外科行全腹腔镜解剖性肝切除手术的44例原发性肝癌伴肝炎后肝硬化患者临床资料,所有患者均接受同一组医生手术,其中24例患者术中采用CLCVP技术(观察组),另外20例患者术中未采用CLCVP对照组(对照组),分析并比较两组术前、术中、术后的相关临床资料。结果:两组患者术前资料包括性别、年龄、BMI、Child分级、肝硬化程度、肝肾功能指标差异均无统计学意义(均P0.05)。两组手术均顺利完成,无围手术期死亡病例。观察组术中、术后均未见低CVP相关气栓、肝肾损伤等并发症。与对照组比较,观察组术中动脉收缩压、CVP明显降低,手术时间与肝门阻断时间明显缩短、术中出血和手术输血率明显降低,但术中乳酸指标明显升高(均P0.05)。两组的术后出血、感染、胸腔积液、胆汁漏的发生率以及肝肾功能指标、拔管时间、住院时间方面均无统计学差异(均P0.05),但观察组患者术后引流量多于对照组(P0.05);两组术后复发率亦无统计学差异(P0.05)。结论:在做好术前肝功能评估和术中密切观测患者灌注指标的前提下,CLCVP技术对肝炎后肝硬化患者腹腔镜肝切除手术是安全可靠的,虽然低CVP会使机体灌注减少,机体无氧代谢增强,乳酸含量增高,但对肝肾功能及肝癌的复发无明显影响,而且较低的CVP能够有效减少术中出血量和输血量,缩短手术时长和肝门阻断时间,降低长时间缺血缺氧对肝脏的打击。总之,在无严重心、肺、脑、肾基础疾病的肝炎后肝硬化患者腹腔镜肝切除手术中,CLCVP是一种值得推荐的控制肝断面出血技术。     

The key role of macrophage depolarization in the treatment of COPD with ergosterol both in vitro and in vivo

Macrophages are the most abundant immune cells in the lung, which play an important role in COPD. The anti-inflammatory and anti-oxidation of ergosterol are well documented. However, the effect of ergosterol on macrophage polarization has not been studied. The objective of this work was to investigate the effect of ergosterol on macrophage polarization in CSE-induced RAW264.7 cells and Sprague-Dawley (SD) rats COPD model. Our results demonstrate that CSE-induced macrophages tend to the M1 polarization via increasing ROS, IL-6 and TNF-α, as well as increasing MMP-9 to destroy the lung construction in both RAW264.7 cells and SD rats. However, treatment of RAW264.7 cells and SD rats with ergosterol inhibited CSE-induced inflammatory by decreasing ROS, IL-6 and TNF-α, and increasing IL-10 and TGF-β, shuffling the dynamic polarization of macrophages from M1 to M2 both in vitro and in vivo. Ergosterol also decreased the expression of M1 marker CD40, while increased that of M2 marker CD163. Moreover, ergosterol improved the lung characters in rats by decreasing MMP-9. Furthermore, ergosterol elevated HDAC3 activation and suppressed P300/CBP and PCAF activation as well as acetyl NF-κB/p65 and IKKβ, demonstrating that HDAC3 deacetylation was involved in the effect of ergosterol on macrophage polarization. These results also provide a proof in immunoregulation of ergosterol for therapeutic effects of cultured C. sinensis on COPD patients.