Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Impact and Predictors of Noncircular Left Ventricular Outflow Tract Shapes on Estimating Aortic Stenosis Severity by Means of Continuity Equations

Determining aortic stenosis (AS) severity is clinically important. Calculating aortic valve (AV) area by means of the continuity equation assumes a circular left ventricular outflow tract (LVOT). The full impact of this assumption in calculating AV area is unknown. Predictors of noncircular LVOT shape in patients with AS are undefined.In 109 adult patients with AS who underwent multiplanar transesophageal echocardiography, we calculated AV area by means of the standard continuity method and by a modified method involving planimetric LVOT area.We found 54 circular, 37 horizontal-oval, 8 vertical-oval, and 10 irregular LVOTs. Area derived by direct planimetry correlated better with the modified than the standard continuity method (r=0.89 vs r=0.85; both P=0.0001). Valve areas of patients with mild, moderate, or severe AS by planimetry were more often mischaracterized with use of the standard than modified method (29 vs 18; P <0.0001). Horizontal-oval AV area derived by planimetry (1.28 ± 0.55 cm²) was underestimated by the standard method (1.05 ± 0.47 cm²; P=0.001), but not by the modified method. Congenital AV morphology and low cardiac index were the only multivariate predictors of horizontal-oval shape. Low cardiac index was the only predictor of noncircular shape.More than half our patients with AS had noncircular LVOTs. Using the modified method reduces mischaracterizations of AS severity. Congenital AV morphology and low cardiac index predict horizontal-oval or noncircular shape. These data suggest the value of direct LVOT measurement to calculate AS severity in patients who have congenital AV or a low cardiac index.     

LC-MS/MS法测定人血浆中布康唑浓度的不确定度评定

目的：评定LC-MS/MS法测定人血浆中布康唑浓度的不确定度。方法：分析测定过程中不确定度的来源，包括对照品的称量、仪器误差、标准溶液的配制、含药血浆样品的配制、血浆样品的处理、标准曲线的拟合、基质效应、重复性等，评定各来源分量的不确定度，计算合成不确定度和扩展不确定度。结果：人血浆中低（60.0 pg·mL^-1）、中（600.0 pg·mL^-1）、高（6 400.0 pg·mL^-1）浓度布康唑的扩展不确定度分别为5.62，63.90，626.26 pg·mL^-1（k=2，P=95%）。结论：LC-MS/MS法测定人血浆中布康唑浓度的不确定度主要由基质效应、血浆样品的处理（提取回收率），仪器误差、重复性（精密度）引入。     

Moving Toward Empirically Based Standardization in the Diagnosis of Delayed Ejaculation

BackgroundCriteria for delayed ejaculation (DE) rely on a long ejaculation latency (EL) time, lack of control/advancement regarding ejaculation, and associated bother/distress; yet, few studies have investigated these criteria in men who indicate the desire to ejaculate sooner during partnered sex.AimTo help standardize criteria for DE by better understanding characteristics of men who desire to ejaculate sooner during partnered sex in terms of their EL, reported ejaculatory control, and level of bother/distress, as well as their perceptions of typical and ideal ELs for men in general and of ELs for men with premature ejaculation (PE).MethodsA total of 572 men recruited through social media responded to an online survey regarding their EL, as well as typical, ideal, and PE ELs of men in general. They also rated (i) their ability to control and/or advance ejaculation and (ii) their level of associated bother/distress. 4 comparison groups were then established: men with probable DE (with [DE1] and without [DE2] ejaculatory control issues), a reference group with no ejaculatory disorders, and men who identified as having PE.OutcomesTo demonstrate differences in EL, ejaculatory control, and bother/distress between men with delayed ejaculation and the control and PE reference groups.ResultsELs for men with probable DE were twice as long as those with no ejaculatory disorders. When probable DE men were further subdivided into DE2 and DE1, differences were greater for the DE2 group. DE2 men also differed significantly from the reference group on ejaculatory control/advancement but not on bother/distress. Both DE and reference groups differed from the PE group.Clinical ImplicationsUsing both EL and ejaculatory control are useful in distinguishing men with delayed ejaculation from men without delayed ejaculation.Strengths & LimitationsA sizable sample drawn from a multinational population powered the study, whereas the use of social media for recruitment limited the generalizability of findings.ConclusionBoth EL and ejaculatory control differentiate men with probable DE from a control reference group having no ejaculatory disorders. Differences in bother/distress did not emerge as significant. Implications for diagnosing men with DE are presented.Rowland DL, Cote-Leger P. Moving Toward Empirically Based Standardization in the Diagnosis of Delayed Ejaculation. J Sex Med 2020;17:1896–1902.     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

艾尔巴韦/格拉瑞韦治疗慢性丙型肝炎患者疗效初步观察

目的 初步探讨应用艾尔巴韦/格拉瑞韦治疗慢性丙型肝炎(CHC)患者的疗效。方法 2017年3月~2018年3月仙桃市第一人民医院感染病科收治的CHC患者82例,被随机分为对照组41例和观察组41例,分别给予聚乙二醇干扰素-α联合利巴韦林治疗和艾尔巴韦/格拉瑞韦治疗,两组均连续治疗24周。采用RT- PCR法检测血清 HCV RNA,采用全基因序列测定法行病毒基因分型。比较两组早期病毒学应答(EVR)、治疗结束时病毒学应答(ETVR)和持续病毒学应答(SVR)。结果 在治疗结束时,观察组血清丙氨酸氨基转移酶(ALT)水平为(47.9±19.7)U/L,显著低于对照组【(63.5±21.2)U/L,P<0.05】,天冬氨酸氨基转移酶(AST)水平为(55.5±22.3)U/L,显著低于对照组【(81.3±25.8)U/L,P<0.05】;观察组EVR、ETVR和SVR分别为48.8%、63.4%和70.7%,与对照组的41.5%、53.7%和65.8%比,无统计学差异(P>0.05);18例观察组非HCV Ⅰ型感染者EVR、ETVR和SVR分别为88.9%、94.4%和88.9%,显著高于同组23例HCV Ⅰ型感染者(分别为52.2%、60.9%和52.2%, P<0.05),而与对照组15例非HCV Ⅰ型感染者比,无统计学差异(分别为86.7%、93.3%和73.3%, P>0.05);观察组SVR₁₂为87.8%(36/41),显著高于对照组的73.2%(30/41,P<0.05)。结论 应用直接抗病毒(DAA)药物艾尔巴韦/格拉瑞韦治疗CHC患者近期疗效达到,但远期疗效似优于标准治疗方案, 值得临床进一步验证。