Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action,Pharmacology, Safety,and Efficacy

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

AQP3 Increases Intercellular Cohesion in NSCLC A549 Cell Spheroids through Exploratory Cell Protrusions

Tumor cell aggregation is critical for cell survival following the loss of extracellular matrix attachment and dissemination. However, the underlying mechanotransduction of clustering solitary tumor cells is poorly understood, especially in non-small cell lung cancers (NSCLC). Here, we examined whether cell surface protrusions played an important role in facilitating the physical contact between floating cells detached from a substrate. We employed poly-2-hydroxyethyl methacrylate-based 3D culture methods to mimic in vivo tumor cell cluster formation. The suprastructural analysis of human NSCLC A549 cell spheroids showed that finger-like protrusions clung together via the actin cytoskeleton. Time-lapse holotomography demonstrated that the finger-like protrusions of free-floating cells in 3D culture displayed exploratory coalescence. Global gene expression analysis demonstrated that the genes in the organic hydroxyl transport were particularly enriched in the A549 cell spheroids. Particularly, the knockdown of the water channel aquaporin 3 gene (AQP3) impaired multicellular aggregate formation in 3D culture through the rearrangement of the actomyosin cytoskeleton. Moreover, the cells with reduced levels of AQP3 decreased their transmigration. Overall, these data indicate that cell detachment-upregulated AQP3 contributes to cell surface protrusions through actomyosin cytoskeleton remodeling, causing the aggressive aggregation of free-floating cells dependent on the property of the substratum and collective metastasis.     

Collective reflection strategy for moderating conformity tendency and promoting reflective judgment performance

Reflective judgement is crucial for medical-related practitioners in dealing with controversial issues. However, the conformity phenomenon is likely to occur and interfere with reflective judgement learning during interactive activities. Effective strategies are required to moderate the conformity behaviour tendency (CBT) and improve reflective judgement performance (RJP). This study demonstrates two significant results: (a) Compared with the guided self-reflection learning strategy, the online collective reflection (OCR) learning strategy effectively weakened the learners' general CBT while dealing with professional controversial issues; and (b) a significantly negative correlation between the RJP achieved and the change of CBT in online environment was detected in the OCR group. The implications and potential applications in higher education were discussed. Further studies are needed to confirm the long-term effects and the extending application to other professional studies.     

Efficacy of alpha-cypermethrin and thiamethoxam against Trogoderma granarium Everts (Coleoptera: Dermestidae) and Tenebrio molitor L. (Coleoptera: Tenebrionidae) on concrete

Laboratory bioassays were conducted to evaluate alpha-cypermethrin and thiamethoxam for the control of adults, small larvae and large larvae of the khapra beetle Trogoderma granarium, and the yellow mealworm beetle Tenebrio molitor, on concrete. Factors such as dose (0.025 and 0.1 mg alpha-cypermethrin or thiamethoxam/cm²), exposure interval (1, 3 and 7 d), and formulation (alpha-cypermethrin SC and thiamethoxam WG) were evaluated. Apart from immediate assessment at end of exposure, an assessment of delayed mortality was performed with the survivors of the 7-d exposure by removing them from the treated substrate and keeping them on untreated surfaces for 7 more days. After the 7-d exposure, more T. granarium adults were dead on dishes treated with alpha-cypermethrin than with thiamethoxam. Small larvae were generally less susceptible than adults. After 7 d, small larval mortality reached 64.4% for alpha-cypermethrin, while for thiamethoxam it was <6%. Large T. granarium larvae were more tolerant than the small ones. Delayed mortality of T. granarium adults was generally high for both insecticides and doses, and ranged between 43.3 and 63.3% of those that were still alive immediately after the 7-d treatment. For both larval categories, delayed mortality was higher for larvae that had been previously exposed to alpha-cypermethrin, than with thiamethoxam. For T. molitor, after the 7-d exposure, significantly more adults were dead on dishes treated with alpha-cypermethrin than with thiamethoxam. For small larvae mortality was 38.9% at the lowest thiamethoxam dose, but in the other cases ranged between 88.9 and 95.6%. In the case of large larvae, the overall mortality was low in all tested combinations. Regarding delayed mortality of this species, it remained at low levels, for both adults and small larvae. Our results indicate that T. molitor was more susceptible than T. granarium in both insecticides tested, but alpha-cypermethrin was more effective than thiamethoxam.     

化妆品功效评价(Ⅵ)——化妆品人体功效评价的实验设计

概述了化妆品人体功效评价实验设计的概念、基本要素和基本原则,介绍了常用实验设计类型和实验设计要点,提供了人体功效评价实验方案设计的思路,有助于提高研究者制定实验设计方案的水平。     

人纤维蛋白原对急诊外伤致创伤性凝血病疗效及相关因素分析

目的:探讨人纤维蛋白原(fibrinogen，FIB)对急诊创伤性凝血病患者的临床疗效及相关因素。方法:将2015年6月至2018年6月本院收治的100例严重创伤患者纳入本研究，根据是否创伤性凝血病分为凝血病组(80例)和非凝血病组(20例)。比较凝血病组和非凝血病组患者收住后第1个24 h的急性生理和慢性健康评分(acute physiology and chronic health evaluation II，APACHE II)、创伤严重程度评分(injury severity score，ISS)、低体温及低灌注发生率等指标。采用Logistic多因素回归方法分析严重创伤患者发生创伤性凝血病的相关因素。将80例创伤性凝血病患者随机分为观察组(40例)和对照组(40例)。对照组按照常规诊疗措施治疗，观察组在对照组处理基础上给予人FIB，比较治疗前后观察组和对照组的凝血功能指标，及治疗后的临床用血量、住院时间及病死率。结果:与治疗前相比，治疗后观察组和对照组的凝血酶原时间(prothrombin time，PT)、活化部分凝血活酶时间(activated partial thromboplastin time，APTT)及D-二聚体水平降低(P<0.05)，FIB水平明显升高(P<0.05)。观察组的红细胞(red blood cell，RBC) 输注量、新鲜冰冻血浆(fresh frozen plasma，FFP)输注量、重症加强护理病房(intensive care unit，ICU)时间及病死率均明显低于对照组，差异具有统计学意义(P<0.05)。创伤性凝血病患者PT>18 s(r=0.623，P=0.024)、APTT>60 s(r=0.722，P=0.018)、凝血酶时间(thrombin time，TT)>15 s(r=0.719，P=0.033)与ISS评分呈正相关。碱缺失(base deficit，BD)≥6(OR=3.678，95%CI=1.065～9.417)、格拉斯哥评分(Glasgow coma scale，GCS)≤8(OR=5.299，95%CI=1.122～8.711)和血小板(platelet，PLT)计数(OR=0.982，95%CI=0.971～0.996)是严重创伤患者发生创伤性凝血病的独立预测因素。结论:人FIB可有效改善创伤性凝血病患者的凝血功能，降低病死率、缩短ICU时间，创伤性凝血病与创伤严重程度、合并休克、低体温和重型颅脑损伤存在一定的相关性。     

Using a multicultural lens to understand illnesses among Haitians living in America.

Currently, ethnic and racial minority individuals represent a large proportion of the U.S. population, and researchers expect that they will represent the majority of the population by 2050. This shift in U.S. demographics calls for a greater awareness and integration of cultural issues into the assessment and treatment of ethnically and linguistically diverse clients. This article examines the unique beliefs and manifestations of illnesses among Haitians in connection with the American Psychological Association's (APA, 2002) Multicultural Guidelines. The authors use a common culture-bound syndrome, Séizisman, to illustrate the cultural beliefs, assessment, and treatment of illnesses among Haitians. In so doing, they demonstrate how to incorporate the APA Multicultural Guidelines into treatment with clients of diverse cultural and racial backgrounds. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

智能组合式充电机的开发与研制

针对集中供电式地震勘探仪器在地震勘探作业中对电瓶充电的特殊要求，我们研制出一种智能组合式充电机。文中阐述了智能式充电机的设计原理，介绍了其性能指标及使用效果。