Drug–physiology interaction and its influence on the QT prolongation-mechanistic modeling study

The current study is an example of drug–disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology—ten Tusscher ventricular cardiomyocyte cell model—was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values with standard deviation (SD) for each reported study point were compared and differences were analyzed with Student’s t test (α?=?0.05). The simulated results reflected the QTc interval changes measured in patients, as well as their clinically observed interindividual variability. The QTc interval changes were highly correlated with the change in plasma potassium both in clinical studies and in the simulations (Pearson’s correlation coefficient?>?0.55). The results suggest that the modeling and simulation approach could provide valuable quantitative insight into the cardiological effect of the potassium and heart rate changes caused by electrophysiologically inactive, non-cardiological drugs. This allows to simulate and predict the joint effect of several risk factors for QT prolongation, e.g., drug-dependent QT prolongation due to the ion channels inhibition and the current patient physiological conditions.     

Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder

CCCTC‐binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow‐up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.     

社区常见恶性肿瘤筛查研究

目的探寻一种简便的恶性肿瘤初筛自查方法。方法将人体肿瘤分为三类:体表肿瘤约占15％;空腔脏器肿瘤占65％;深层实体脏器肿瘤20％。通过科普宣传教育,让群众学会自查体表部位肿瘤,每年用自查盒助查各空腔脏器有无微量出血,隐血阳性时,去医院进一步精查。北京部分大学选40～70岁居民1万人,分成试验组、对照组各5千人。结果试验四年后:试验组共查出79例癌,年平均癌检出率482.5人/10万,癌死亡率为12.2/10万;对照组癌死亡率206.2人/10万,两组有显著性差异。在癌症高发区,同时作扩大普查试验:广东四会市肿瘤所,在门诊普查1669人,检出25例癌,鼻咽癌占24例。1999～2000年,江苏省食管胃癌高发区,普查近8万人,检出480例癌。加上“九五”以前的普查统计,用秦氏自查盒已筛查431075人,检出1272例癌,癌前病变1万多例。结论试验证明该方案设计合理,在当前是一种最简便的恶性肿瘤初筛自查方法。     

ARL4C stabilized by AKT/mTOR pathway promotes the invasion of PTEN-deficient primary human glioblastoma

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency in primary human glioblastoma (GBM) is associated with increased invasiveness and poor prognosis with unknown mechanisms. Therefore, how loss of PTEN promotes GBM progression remains to be elucidated. Herein, we identified that ADP-ribosylation factor like-4C (ARL4C) was highly expressed in PTEN-deficient human GBM cells and tissues. Mechanistically, loss of PTEN stabilized ARL4C protein due to AKT/mTOR pathway-mediated inhibition of ARL4C ubiquitination. Functionally, ARL4C enhanced the progression of GBM cells in vitro and in vivo. Moreover, microarray profiling and GST pull-down assay identified that ARL4C accelerated tumor progression via RAC1-mediated filopodium formation. Importantly, targeting PTEN potently inhibited GBM tumor progression in vitro and in vivo, whereas overexpression of ARL4C reversed the tumor progression impaired by PTEN overexpression. Clinically, analyses with patients' specimens validated a negative correlation between PTEN and ARL4C expression. Elevated ARL4C expression but PTEN deficiency in tumor was associated with poorer disease-free survival and overall survival of GBM patients. Taken together, ARL4C is critical for PTEN-deficient GBM progression and acts as a novel prognostic biomarker and a potential therapeutic candidate. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

输尿管软镜碎石术围手术期肾彩色多普勒超声血流动力学评价

目的　彩用彩色多普勒超声（CDFI）对单发肾结石患者输尿管软镜碎石术围手术期肾血流动力学的评价。 方法　分析2016年7月至2018年6月共61例输尿管软镜碎石手术的单发肾结石患者,应用CDFI观察围手术期术侧肾叶间动脉血流参数,记录术前1 d、术后1 h内及术后5 d叶间动脉血流参数,并进行统计学分析。 结果　围手术期肾叶间动脉血流参数整体分析,收缩期峰值流速（Vmax）、舒张末期流速（Vmin）及阻力指数（RI）数值差异分别具有统计学意义（P<0.05）。与术前血流参数相比,术后1 h叶间动脉Vmax及Vmin均减低,RI增高（P<0.017）,术后5 d复查,Vmax及Vmin较术后1 h升高、RI较术后1 h减低（P<0.017）,与术前测值相比差异无统计学意义（P>0.017）。 结论　CDFI可以观察并量化输尿管软镜碎石术围手术期肾内动脉灌注,快速评价术侧肾血流动力学变化,手术后会出现短期、可逆性肾叶间动脉流速减低、RI增高。     

Size‐Stable Supramolecular Hyperbranched Polymer Vesicles for Redox‐Triggered Double‐Drug Release

Supramolecular polymer vesicles (SPVs) with stimuli‐responsive features are promising multifunctional nanocarriers; however, improving the stability and developing multiple‐drug‐loaded SPVs remain key issues in this field. In this work, cross‐linked supramolecular hyperbranched polymer vesicles (SHPVs) with redox‐responsiveness are first constructed based on an AB₂‐type macromonomer‐synthesized SHP. The obtained cross‐linked SHPVs exhibit much better size stability than those of non‐cross‐linked branched self‐assemblies, and higher double‐drug‐loading capacity compared with linear supramolecular polymer self‐assemblies. Particularly, these cross‐linked SHPVs exhibit a redox‐triggered, controlled double‐drug release behavior upon the addition of H₂O₂.