Enolase-1 is a therapeutic target in endometrial carcinoma

ENO1 plays a paradoxical role in driving the pathogenesis of tumors. However, the clinical significance of ENO1 expression remains unclear and its function and modulatory mechanisms have never been reported in endometrial carcinoma (EC). In this study, ENO1 silencing significantly reduced cell glycolysis, proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo by modulating p85 suppression. This in turn mediated inactivation of PI3K/AKT signaling and its downstream signals including glycolysis, cell cycle progression, and epithelial-mesenchymal transition (EMT)-associated genes. These effects on glycolysis and cell growth were not observed after ENO1 suppression in normal human endometrial epithelial cells (HEEC). Knocking down ENO1 could significantly enhance the sensitivity of EC cells to cisplatin (DDP) and markedly inhibited the growth of EC xenografts in vivo. In clinical samples, EC tissues exhibited higher expression levels of ENO1 mRNA and protein compared with normal endometrium tissues. Patients with higher ENO1 expression had a markedly shorter overall survival than patients with low ENO1 expression. We conclude that ENO1 favors carcinogenesis, representing a potential target for gene-based therapy.     

白藜芦醇对大鼠脊髓损伤早期Bcl-2和Bax表达的影响

目的:探讨脊髓损伤后使用白藜芦醇对脊髓损伤早期Bcl-2和Bax表达的影响。方法:2004-06/09在武汉大学人民医院动物实验中心将62只SD健康成年雄性大鼠随机分成5组,据Allen's法制成中度脊髓损伤模型,术后立即腹腔注射白藜芦醇100mg/kg或甲基强的松龙(MPSS)100mg/kg;通过免疫组织化学染色观察脊髓损伤8,24及72h后白藜芦醇组脊髓Bcl-2和Bax表达的变化,并与MPSS组进行疗效对比。结果:与损伤组比较,Bcl-2表达在损伤后8h差异无显著性意义(P>0.05),显示白藜芦醇对损伤后的脊髓无干预作用,而24及72h后差异有显著性意义P<0.01),表明白藜芦醇能够增强Bcl-2表达,对(损伤后脊髓有明显作用;Bax表达在损伤后8及72h差异有显著性意义(P<0.05),其中24h时最为显著(P<0.01),表明白藜芦醇可抑制Bax表达,对损伤后的脊髓有干预作用;白藜芦醇与MPSS组间差异无显著性意义(P>0.05),即白藜芦醇对损伤后脊髓有相似作用。结论:白藜芦醇在脊髓损伤早期能够有效上调Bcl-2表达及下调Bax表达,对损伤后脊髓起保护作用。     

北京市血液透析的现状和存在问题

北京市血液透析质量控制和改进中心（Beijing Hemodialysis Quality Control ＆ Improvement Center,BJHDQCIC）自2002年12月成立以来,一直致力于北京市血液透析质量控制和改进工作.中心的宗旨为：规范血液透析中心的诊疗行为，统一质量标准，保证透析治疗安全，提高透析患者的生存质量。通过建立行业标准和定期检查，督促北京市各血液透析中心不断改善环境、透析用水质量、从业人员专业素质。[第一段]     

血小板活化因子及血小板膜糖蛋白与缺血性脑血管疾病

目的：血小板活化在血栓形成和脑血管疾病过程中具有重要意义。分析血小板活化因子-血小板膜糖蛋白在脑血管病发生发展过程中的变化水平，进一步揭示二者的关系。推动脑血管病的预防和诊治。 资料来源：应用计算机检索Medline数据库1990—01／2004—12有关检测血小板活化因子与脑血管疾病关系的文章，检索词“P1atelet activation，Platelet glycoprotein，Cerebral artefial thrombosis，Atherosclerosis”。并限定文章语言种类为English，观察对象为人类。同时应用计算机检索中国清华同方期刊网数据库1994—01／2004—12有关血小板活化与脑动脉硬化、脑血栓形成关系的文章，限定文章语言种类为汉语，检索词“血小板膜糖蛋白，脑动脉硬化。脑梗死”。 资料选择：对资料进行初审，选取符合要求的有关文献，并查找全文。纳入标准：①有关血小板膜糖蛋白的结构、检测原理及在血小板活化过程中如何作用的研究原著。②有关定量检测血小板膜糖蛋白对脑血管病的诊断预防有意义的研究原著。排除标准：文献中重复的研究和与本研究无关的其他种类血小板膜糖蛋白的文章。 资料提炼：共收集到64篇有关血小板活化因子的检测与脑血管病关系的文献。排除重复或无关血小板膜糖蛋白的研究．纳入19篇。血小板膜糖蛋白的结构及检测原理3篇，血小板活化与脑动脉硬化的关系1篇．血小板活化因子与脑血栓形成的关系12篇．血小板活化与心血管病的关系1篇．血小板膜糖蛋白受体拮抗剂的应用2篇。资料综合：在脑血管疾病发生发展过程中血小板活化起重要促进作用，由于动脉粥样硬化斑块的形成。促使血小板活化的因素无法逆转，使得血小板长期处于活化状态．临床抗凝治疗可能在一定程度上降低血小板的活化．但不能完全消除致活化因素的作用。活化的血小板与静息的血小板相比。其血小板膜糖蛋白发生显著变化。并在血小板膜上大量表达，成为活化血小板的分子标志物。随着血小板膜糖蛋白分子生物学研究的深入及血栓形成分子机制的阐明．新型血小板膜受体拮抗剂的合成将会取代或补充阿司匹林和溶栓剂的作用，推动脑血管疾病的预防和诊治。 结论：在血栓性疾病中，血小板活化起了关键作用．因此研究血小板活化作为脑血管内血栓形成和梗死的早期因素。准确测定其活化标志物GPⅡb／Ⅲa、GPⅠb和GMP-140对脑血管疾病发生的诊断、预防、治疗效果监测都有着重要意义。     

Hypoxic Preconditioning Alleviates Ethanol Neurotoxicity: The Involvement of Autophagy

Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. A sublethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system neurodegenerative diseases. We have recently demonstrated that autophagy is a protective response to alleviate ethanol toxicity. A modest hypoxic preconditioning (1 % oxygen) did not cause neurotoxicity but induced autophagy (Tzeng et al. Free Radic Biol Med 49: 839–846, 2010). We, therefore, hypothesize that the modest hypoxic preconditioning may offer a protection against ethanol-induced neurotoxicity. We showed here that the modest hypoxic preconditioning (1 % oxygen) for 8 h significantly alleviated ethanol-induced death of SH-SY5Y neuroblastoma cells. Under the normoxia condition, cell viability in ethanol-exposed cultures (316 mg/dl for 48 h) was 49 ± 6 % of untreated controls; however, with hypoxic preconditioning, cell viability in the ethanol-exposed group increased to 78 ± 7 % of the controls (p < 0.05; n = 3). Bafilomycin A1, an inhibitor of autophagosome and lysosome fusion, blocked hypoxic preconditioning-mediated protection. Similarly, inhibition of autophagic initiation by wortmannin also eliminated hypoxic preconditioning-mediated protection. In contrast, activation of autophagy by rapamycin further enhanced neuroprotection caused by hypoxic preconditioning. Taken together, the results confirm that autophagy is a protective response against ethanol neurotoxicity and the modest hypoxic preconditioning can offer neuroprotection by activating autophagic pathways.     

Prediction of failure in vancomycin-treated methicillin-resistant Staphylococcus aureus bloodstream infection: a clinically useful risk stratification tool

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of bloodstream infection (BSI) and is often associated with invasive infections and high rates of mortality. Vancomycin has remained the mainstay of therapy for serious Gram-positive infections, particularly MRSA BSI; however, therapeutic failures with vancomycin have been increasingly reported. We conducted a comprehensive evaluation of the factors (patient, strain, infection, and treatment) involved in the etiology and management of MRSA BSI to create a risk stratification tool for clinicians. This study included consecutive patients with MRSA BSI treated with vancomycin over 2 years in an inner-city hospital in Detroit, MI. Classification and regression tree analysis (CART) was used to develop a risk prediction model that characterized vancomycin-treated patients at high risk of clinical failure. Of all factors, the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, with a cutoff point of 14, was found to be the strongest predictor of failure and was used to split the population into two groups. Forty-seven percent of the population had an APACHE-II score < 14, a value that was associated with low rates of clinical failure (11%) and mortality (4%). Fifty-four percent of the population had an APACHE-II score ≥ 14, which was associated with high rates of clinical failure (35%) and mortality (23%). The risk stratification model identified the interplay of three other predictors of failure, including the vancomycin MIC as determined by Vitek 2 analysis, the risk level of the source of BSI, and the USA300 strain type. This model can be a useful tool for clinicians to predict the likelihood of success or failure in vancomycin-treated patients with MRSA bloodstream infection.     

Selective targeting of checkpoint kinase 1 in tumor cells with a novel potent oncolytic adenovirus.

DNA-damage checkpoints are activated to arrest cells and promote survival upon genotoxic challenge. Efforts have been taken to target checkpoint kinase 1 (chk1; approved gene symbol CHEK1), a crucial checkpoint modulator, for therapeutic intervention. However, improvement of the potency and specificity of such therapeutics remains a major challenge. This prompted us to develop a novel chk1-targeting strategy by constructing a potent oncolytic adenovirus (M2). M2 was generated by combining two artificial features into a wild-type adenovirus type 5 genome. First, M2 was engineered with a 27-bp deletion in the E1A region to confer tumor-selective replication. Second, an antisense chk1 cDNA was substituted for viral E3 6.7K and gp19K genes. In this design, M2 exploited the adenovirus E3 promoters to express antisense chk1 cDNA in a viral replication-dependent fashion and preferentially silenced the chk1 gene in tumor cells. By virtue of combining oncolysis with chk1 targeting, M2 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M2, plus a low dose of cisplatin, cured 80% of orthotopic hepatic carcinoma mouse models that were otherwise resistant to cisplatin. These findings have directed us toward the development of novel oncolytic adenoviruses that will be potentially applicable to a wide range of molecular-based therapeutics.