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.     

缺血性卒中和短暂性脑缺血发作的二级预防指南的新认识

2006年2月,美国卒中协会主办的国际卒中大会和当月出版的Stroke颁布了新的卒中和短暂性脑缺血发作(transient ischemic attack,TIA)二级预防指南[1,2]。新指南撰写委员会主席、美国哥伦比亚大学Sacco教授强调,与以前的指南[3,4]相比,新指南有了新的改进,它是一个以充分和完整证     

Hippocampal damage and cytoskeletal disruption resulting from impaired energy metabolism

To determine if impaired energy metabolism might contribute to some aspects of Alzheimer disease (AD), including the vulnerability of the CA1 region of the hippocampal formation and the altered cytoskeleton evident in neurofibrillary tangles, we examined the effects of metabolic poisons on neuronal damage and cytoskeletal disruption in the hippocampal formation. Intrahippocampal injection of 3-nitropropionic acid (3-NP) and malonic acid resulted in neuronal death, particularly in CA1. Cytoskeletal disruption included loss of dendritic MAP2, but sparing of axonal τ. MK-801 (a noncompetitive NMDA receptor antagonist) did not atenuate the lesions produced by intrahippocampal injection of malonate. MK-801, however, was effective against intrastriatal malonate. Acute systemic 3-NP resulted in neuronal damage and cytoskeletal disruption in the CA1 region of the hippocampal formation, including an extensive loss of MAP2 immuno-reactivity, but sparing of τ. The neuronal loss in CA1 was delayed as compared to striatum. Chronic intraventricular infusion of 3-NP produced a different pattern of neuronal damage. Loss of τ-1 immuno-reactivity was observed in CA3 and CA1 s. oriens, whereas MAP2 immunostaining was preserved. These results demonstrate that chronic and acute administration of metabolic inhibitors produce distinct patterns of neuronal damage and cytoskeletal disruption. The results further suggest a differential involvement of the NMDA receptor in malonate-induced neuronal damage in striatum as compared to the hippocampus. The pattern of neuronal damage and cytoskeletal disruption observed following acute metabolic impairment resembled some aspects of neurofibrillary pathology in AD, but did not result in τ hyperphosphorylation.     

在膀胱肿瘤并发前列腺增生症患者中采用同次施行膀胱肿瘤切除术和保留尿道粘膜前列腺切除术探讨

目的 探讨膀胱肿瘤并前列腺增生症患者同期施行膀胱肿瘤切除术和保留尿道粘膜前列腺切除术的可行性.方法 对同期施行经尿道膀胱肿瘤切除术及保留尿道粘膜前列腺切除术的16例膀胱癌合并前列腺增生症患者的临床资料进行了回顾性分析.结果 该组患者均顺利康复,无明显合并症,术后复诊,随访时间2～4年,3例出现肿瘤复发.结论 同期施行膀胱肿瘤切除术和保留尿道粘膜前列腺切除术,安全、效果肯定,值得基层医院推广应用.     

33例肺上沟癌的临床特点及放疗疗效

目的　探讨肺上沟癌的临床特点及放疗疗效和不良反应。方法　回顾性分析 3 3例肺上沟癌住院病人的临床特征和常规放疗的疗效。结果　肺上沟癌占原发性支气管肺癌的 2 9% ,常见症状为 :患侧肩、背和上肢疼痛 ( 78 8% ) ,后 1,2 ,3肋骨或椎骨破坏( 5 7 6% ) ,Horner’s综合征 ( 3 6 7% ) ;少见的症状为 :咳嗽 ( 2 7% ) ,咯血 ( 9% ) ;中位生存期为 8 4月 ;1,3 ,5年生存率分别为 3 5 6% ,12 3 % ,4 6% ;放疗反应可耐受。结论　肺上沟癌相当少见 ,其临床特征基本符合pancoast综合症 ,本病预后差 ,但放疗可缓解疼痛 ,提高生存质量。     

论我国医患冲突成因及和谐关系构建

目前我国医患之间的矛盾与冲突，实质上是新时期我国社会矛盾在卫生工作中的具体表现，反映了社会群体在经济状况、价值取向、角色意识、道德水平、法律法规等多方面的矛盾与冲突。和谐医患关系应是构建我国和谐社会的内容之一。和谐医患关系的构建需要完善的社会医疗保障体系建立、国家卫生行政管理加大、财政补偿合理投入、医疗服务质量提高、医学知识教育普及与提高、媒体理性传播、社会大众道德控制水平提升，法律法规完善等全方位的努力，有赖于医事主体双方及全社会的关注与通力改善。