Genetic toxicity assessment using liver cell models: past,present, and future

ABSTRACT

Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment.     

The Relationship between College Graduate’s Dual Self-Consciousness and Job Search Clarity: The Mediating Role of Perceived Stress

The aim of the study was to explore the relationship between college graduates’ dual self-consciousness, job search clarity and perceived stress, and reveal the mediating role of perceived stress between dual self-consciousness and job search clarity. In this study, 467 college graduates were investigated using the Dual Self-Consciousness Scale, Job Search Clarity Scale, and Perceived Stress Scale. After controlling for gender, age, and region, the results revealed that: (1) private self-consciousness has a significant positive predictive effect on job search clarity; (2) perceived stress has a significant negative predictive effect on job search clarity; (3) perceived stress plays partial mediation effects between private self-consciousness and job search clarity; (4) perceived stress plays complete mediation effects between public self-consciousness and job search clarity; (5) perceived stress has suppressing effects between public self-consciousness and job search clarity.     

急性心肌梗死静脉溶栓药物研究现状及进展

1986年,GISSI研究首次表明,采用链激酶静脉溶栓治疗能降低ST段抬高急性心肌梗死（AMI）患者的死亡率,并可以与冠状动脉内溶栓治疗相媲美,为AMI的治疗和预后带来了革命性的转变.     

(加味)柴芍承气汤对重症急性胰腺炎及其并发症的作用

目的探讨(加味)柴芍承气汤对重症急性胰腺炎(SAP)及其并发症的防治作用。方法65例SAP患者分为中药组35例,对照组30例。2组的内科治疗相同,中药组一经确诊即予柴芍承气汤加味银杏叶治疗,每剂煎成100~150m l,自鼻胃管内注入或口服,每日2~3次,直至患者腹痛缓解、腹胀基本消失、肠鸣恢复。分别观察2组患者治疗72 h后的PaO2、SaO2肾功能、脑病、局部并发症情况、腹痛缓解时间、肠鸣恢复时间、病死率,以及血清中血小板活化因子(PAF)、肿瘤坏死因子(TNF-α)、白介素-1(IL-1)水平变化。结果治疗72 h后中药组与对照组低氧血症的发生率分别为45.71%、73.73%,P<0.05;肾损害、脑病、局部并发症发生率以及病死率均低于对照组,但无统计学差异;腹痛缓解时间、肠鸣恢复时间均优于对照组(P<0.05);中药组血清中PAF、TNF-α、IL-1水平显著降低(P<0.01),而对照组则无明显变化。结论该汤剂对SAP及其并发症有较好的防治作用。抑制细胞因子或炎症介质可能是该汤剂治疗SAP的重要机制。     

盐酸戊乙奎醚用于全麻术前减少腺体分泌的研究

目的评价盐酸戊乙奎醚作为全麻术前用药减少腺体分泌的有效性与安全性。方法本研究采用多中心随机双盲平行对照观察。298例全麻病人随机分为三组,术前分别肌肉注射阿托品、盐酸戊乙奎醚或注射用水,测定注射后30min唾液分泌量。用视觉模拟评分(VAS)方法测定口干程度,记录不良反应。结果给药后30min,阿托品、盐酸戊乙奎醚和注射用水组唾液分泌量分别较给药前变化(-17·64±19·53)、(-22·30±21·04)和(2·71±19·46)mg。VAS阿托品、盐酸戊乙奎醚组用药后明显增加。给药后30min,阿托品、盐酸戊乙奎醚和注射用水组HR分别较给药前变化(1·65±8·82)、(-4·30±7·01)和(-0·54±6·49)次/分。观察期间无严重不良反应。结论盐酸戊乙奎醚作为全麻术前用药,可明显减少唾液分泌,无HR增快,无明显不良反应。     

人Uroplakin Ⅱ启动子用于靶向性基因治疗膀胱癌的实验研究

目的探讨利用人UroplakinⅡ(hUPⅡ)启动子进行靶向性基因治疗膀胱癌的可能性。方法将hUPⅡ启动子和肿瘤坏死因子-α(TNF-α)克隆到腺病毒载体Ad5中,构建重组体pAd-hUPⅡ-TNF。转染细胞293后产生复制缺陷型的重组腺病毒,感染膀胱癌细胞系BIU-87,检测TNF-α对BIU-87细胞体外生物学行为及体内成瘤性的影响。结果成功构建pAd-hUPⅡ-TNF重组腺病毒载体,转染细胞293获得复制缺陷型重组腺病毒。BIU-87细胞经重组腺病毒感染后可产生高浓度的TNF-α,并降低BIU-87的生长速度。感染腺病毒的BIU-87培养液可抑制L929细胞的生长。裸鼠原位膀胱肿瘤动物模型实验结果表明膀胱灌注重组腺病毒48h后,裸鼠尿液含高浓度的TNF-α,4周后腺病毒组膀胱重量和体积明显低于对照组(P<0.01)。结论hUPⅡ启动子TNF-α为治疗基因的重组腺病毒可特异性使膀胱癌细胞系BIU-87产生高浓度的TNF-α,并降低BIU-87和L929细胞的生长速度。重组腺病毒可使裸鼠尿内含高浓度的TNF-α,并可抑制裸鼠原位膀胱肿瘤动物模型膀胱癌细胞的成瘤性。