Cyr61 induces gastric cancer cell motility/invasion via activation of the integrin/nuclear factor-kappaB/cyclooxygenase-2 signaling pathway.

PURPOSE: Cysteine-rich 61 (Cyr61/CCN1) is involved in many different types of tumor development and progression. Nonetheless, the role of Cyr61 in human gastric cancer has not yet been fully characterized.Experimental design: We addressed the issue by immunohistochemical staining of 81 gastric adenocarcinoma specimens. Liposome-mediated transfection was used to introduce a Cyr61 expression vector into gastric cancer AGS cell lines. Transfectants were tested in invasion assay by a Boyden chamber. Furthermore, a cyclooxygenase-2 (COX-2) reporter assay and gel mobility shift assay were done to investigate the potential signal pathway of Cyr61. RESULTS: Patients with gastric adenocarcinoma whose tumor displayed high expression of Cyr61 correlated well with aggressive lymph node metastasis, more advanced tumor stage, histologic diffuse type, and early recurrence. Stable transfection of Cyr61 into the AGS cell line strongly enhanced its invasive activity. The overexpression of Cyr61 into AGS cells significantly increased the expression of COX-2 mRNA, protein, and enzymatic activity. Gel mobility shift assays further showed that the nuclear factor-kappaB (NF-kappaB) pathway was evidently activated in Cyr61-expressing AGS cells. Function-neutralizing antibody to alphavbeta3 but not alphavbeta5 effectively suppressed Cyr61-mediated NF-kappaB activation, COX-2 gene expression, and cell invasiveness. CONCLUSIONS: Cyr61 may contribute to the malignant progression of gastric cancer by promoting tumor cell motility/invasion through up-regulation of the functional COX-2 via an integrin alphavbeta3/NF-kappaB-dependent pathway.     

Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. RESULTS: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). CONCLUSION: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.     

药源性血液病(5)

药源性白细胞减少症(D-LP)和粒细胞缺乏症(D-AGC)1白细胞减少症和粒细胞缺乏症概念外周血白细胞(WBC)低于4ⅹ109/L时称为白细胞减少症(Leucopenia)。白细胞以中性粒细胞为主,中性粒细胞绝对计数(ANC)成人低于2ⅹ109/L,儿童低于1.5ⅹ109/L者称为粒细胞减少症(Neutropenia)。人的粒细胞数受多种因素影响,除遗传、环境因素外,尚可因病人的年龄、活动状态而不同。当ANC低于0.5ⅹ109/L时称为粒细胞缺乏症(Agranulocytosis)。引起粒细胞减少的病因很多,药源性粒细胞减少症是指特定药物通过不同机制引起ANC选择性减少或缺乏的病症。2病…     

树突状细胞与肿瘤免疫治疗的现状

恶性肿瘤严重威胁着人类的健康,且发病年龄趋向年轻化,以外科手术,辅助放、化疗及免疫治疗等综合治疗成为肿瘤治疗的发展方向.肿瘤的主动免疫治疗一直是肿瘤治疗研究的热点,其基本理论依据是通过调节或增强机体固有的内在性防御机制来抑制或杀伤肿瘤细胞,或通过抑制肿瘤细胞转化、促进恶性细胞分化来降低肿瘤的恶性程度.     

中医药治疗支气管哮喘48例

支气管哮喘属于祖国传统医学中"咳嗽"、"痰饮"、"哮喘"范畴,是临床常见病、多发病,该病难以根治且易反复发作.近年来中医药治疗哮喘有了较大的进步,我院收集近4年来的48例用中医辨证治疗的病案,效果较好,报道如下.     

可调控的胰岛素基因表达载体的构建及其体外表达研究

目的构建四环素调控的胰岛素基因表达载体 ,并研究其体外转移后的表达情况。方法通过基因重组技术构建胰岛素基因的四环素调控表达系统 ,用脂质体转移法导入成肌细胞 ,以不同浓度的强力霉素诱导 ,检测诱导后胰岛素原mRNA表达及胰岛素 /胰岛素原水平。结果RT PCR显示此基因能在真核细胞内表达。细胞培养液中胰岛素水平在加药 2 4h后开始增加 ,至第 7天仍在增加 ,撤药后迅速下降 ,至撤药后第 5天下降到基础水平。不同诱导药物浓度诱导的胰岛素产量明显不同 (P <0 .0 5 ) ,而细胞内和培养基中的胰岛素浓度无明显差异 (P >0 .0 5 )。结论单一四环素调控的胰岛素原表达系统能在真核细胞内表达 ,并呈现强力霉素浓度依赖性     

雌三醇有关物质的可能结构

采用LC-MSn和GC-MSn技术对雌三醇中有关物质的结构进行了初步鉴定.结果表明,存在2个主要杂质,可能为雌三醇的立体异构体.     

Both A chain and B chain of beta-bungarotoxin are functionally involved in the facilitation of spontaneous transmitter release in Xenopus nerve-muscle cultures.

In the present study, Xenopus nerve-muscle cultures were used to explore the functional roles of A chain (a phospholipase A(2) subunit) and B chain (a non-phospholipase A(2) subunit) of Bungarus multicinctus beta-bungarotoxin. It was found that beta-bungarotoxin induced an increment of the frequency of spontaneous synaptic currents (SSCs) in the nerve-muscle cultures. Modification of beta-bungarotoxin with pyridoxal-5'-phosphate or substitution of Ca(2+) with Ba(2+) in buffer abolished the phospholipase A(2) activity of beta-bungarotoxin and the facilitatory phase of SSC as well. Antibodies that were directed specifically against A chain or B chain effectively inhibited phospholipase A(2) activity, and as a consequence the SSC frequency was not greatly different from the control rate. These results suggest that both A and B chains are indispensable parts of beta-bungarotoxin for inducing the facilitation of SSC frequency with Xenopus nerve-muscle cultures.