临床分离大肠埃希菌耐药性分析及I型整合子研究

目的了解临床分离大肠埃希菌对常用抗菌药物的耐药状况;研究整合子在大肠埃希菌中的分布情况,探讨其与大肠埃希菌耐药性之间的相关性。方法收集广东省3所医院2010-2012年分离的大肠埃希菌,采用K B纸片扩散法进行药敏试验;聚合酶链反应（PCR）法扩增3类整合子整合酶基因和整合子可变区,测序分析整合子所携带的耐药基因盒类型。结果共收集156株大肠埃希菌,其对青霉素类、头孢菌素类、氟喹诺酮类、氨基糖苷类和磺胺类等的大多数抗菌药物的耐药率＞50%;耐药率＜10%的抗菌药物有头孢哌酮/舒巴坦（0）、亚胺培南（3.85%）、头孢替坦（4.35%）、厄他培南（7.69%）和哌拉西林/他唑巴坦（8.97%）;I类整合子的检出率为57.69%（90/156）,多重耐药菌与非多重耐药菌的整合子检出率分别为66.00%（66/100）和64.71%（22/34）,两组比较,差异无统计学意义（P＞0.05）,但分别与敏感菌组（9.09%,2/22）相比,差异均有统计学意义（P＜0.01）。所检出的整合子可变区分为9种类型,大部分都含有aadA和dfrA耐药基因盒。结论大肠埃希菌整体耐药情况严重;I类整合子在临床分离大肠埃希菌中分布广泛,并与大肠埃希菌的耐药性关系密切,主要介导对氨基糖苷类、磺胺类、β 内酰胺类等多种抗菌药物的耐药性。     

长春碱增加班马鱼肿瘤耐药基因abcb4的表达

目的通过研究长春碱(VBL)对斑马鱼早期发育过程中abcb4肿瘤耐药基因表达的影响,为进一步建立抗肿瘤药物多药耐药筛选的斑马鱼模型奠定重要的实验基础。方法将长春碱稀释成不同浓度梯度的药液,在受精后0.5~1.5 h的斑马鱼胚胎上完成药物暴露实验,计算出长春碱IC_(50)的数值。设置长春碱为实验组,胚胎培养液为空白对照组,分别作用于受精后0.5~1.5 h的斑马鱼胚胎,观察受精后24~120 h的斑马鱼胚胎发育情况,记录死亡、孵化及畸形的胚胎数目;收集不同组别的斑马鱼胚胎,通过实时荧光定量PCR和胚胎整体原位杂交的方法,检测斑马鱼胚胎中abcb4基因的表达量。结果计算出长春碱在斑马鱼胚胎中的IC_(50)为3.08μmol/L;与对照组比较,实验组的斑马鱼胚胎abcb4基因的mRNA水平明显升高(P0.05);通过胚胎整体原位杂交的方法,在受精后120 h斑马鱼胚胎的小肠部位发现有abcb4基因阳性杂交信号,且实验组斑马鱼胚胎在脑和心脏部位发现abcb4基因阳性杂交信号。结论长春碱能明显增加斑马鱼早期胚胎中abcb4肿瘤耐药基因的表达水平,提示使用斑马鱼可以复制肿瘤耐药模型。     

芪竹方对结肠癌耐药株HCT-8/V及肝癌耐药株Bel/Fu细胞耐药体外逆转作用的观察

[目的]研究芪竹方对结肠癌耐药株HCT-8/V、肝癌耐药株Bel/FU体外逆转作用.[方法]血清药理法制备芪竹方含药血清,MTT法检测芪竹方及其含药血清对HCT-8/V及Bel/FU细胞耐药逆转作用.[结果]芪竹方250 μg/ml、50μg/ml、芪竹方20％含药血清、10％含药血清均可逆转HCT-8/V细胞的耐药性（P＜0.05）,其逆转倍数分别为14.65、6.20、6.53、3.01;芪竹方及其含药血清对Bel/FU细胞耐药性无逆转作用.[结论]芪竹方可体外逆转结肠癌耐药细胞株HCT-8/V耐药性,而对Bel/FU细胞无体外逆转作用.     

Changing patterns and trends of multidrug-resistant tuberculosis at referral centre in Northern India: A 4-year experience

Purpose: India has a high burden of drug-resistant tuberculosis (TB), although there is little data on multidrug-resistant tuberculosis (MDR-TB). Although MDR-TB has existed for long time in India, very few diagnostic laboratories are well-equipped to test drug sensitivity. The objectives of this study were to determine the prevalence of MDR-TB, first-line drug resistance patterns and its changing trends in northern India in the 4 years. Materials and Methods: This was a prospective study from July 2007 to December 2010. Microscopy, culture by Bactec460 and p-nitro-α-acety lamino-β-hydroxypropiophenone (NAP) test was performed to isolate and identify Mycobacterium tuberculosis (M. tb) complex (MTBC). Drug sensitivity testing (DST) was performed by 1% proportional method (Bactec460) for four drugs: Rifampicin, isoniazid, ethambutol and streptomycin. Various clinical and demographical profiles were evaluated to analyse risk factors for development of drug resistance. Results: We found the overall prevalence rate of MDR-TB to be 38.8%, increasing from 36.4% in 2007 to 40.8% in 2010. we found that the prevalence of MDR-TB in new and previously treated cases was 29.1% and 43.3% (P < 0.05; CI 95%). The increasing trend of MDR-TB was more likely in pulmonary TB when compared with extra-pulmonary TB (P < 0.05; CI 95%). Conclusions: we found a high prevalence (38.8%) of MDR-TB both in new cases (29.1%) and previously treated cases (43.3%).This study strongly highlights the need to make strategies for testing, surveillance, monitoring and management of such drug-resistant cases.     

LRP与MRP在乳腺癌组织中的表达及意义

目的研究乳腺癌组织中肺耐药蛋白（LRP）、多药耐药相关蛋白（MRP）的表达及其意义。方法应用流式细胞术检测51例乳腺癌组织中LRP及MRP的表达情况,分析其与患者年龄、肿瘤大小、腋窝淋巴结转移及雌激素受体（ER）、孕激素受体（PR）表达状态等因素的关系,并探讨两者表达的相关性。结果LRP、MRP相对表达水平（用荧光强度表示）分别为0.46±0.84、1.51±1.57;除MRP与肿瘤大小相关外,两者与患者年龄、腋窝淋巴结转移、激素受体等均无相关性;乳腺癌组织中LRP与MRP表达水平间存在高度正相关（r=0.434,P=0.004）。结论部分乳腺癌具有原发性耐药,多药耐药表型隐含在乳腺癌组织中,不受化学药物的诱导,与恶性表型同时发生,且不受疾病发展的影响;MRP与肿瘤细胞增殖能力有一定关系,在肿瘤的发展过程中起重要作用;LRP似未参与乳腺癌的多药耐药机制,但与MRP在引起乳腺癌耐药方面具很大的协同性。     

Ibalizumab治疗耐多药HIV-1感染的研究进展

[摘要]　Ibalizumab是一种人源化免疫球蛋白G4单克隆抗体，其在阻断HIV-1进入CD4+ T淋巴细胞的同时，可保持人体正常免疫功能。鉴于此，临床逐步将ibalizumab与其他抗反转录病毒药物联合应用于治疗耐多药HIV-1感染，相关研究已经取得了较大进展。目前，ibalizumab是第一个被美国FDA批准用于治疗HIV-1感染的单克隆抗体，有望成为治疗耐多药HIV-1感染的新选择。本文综述了ibalizumab治疗成人耐多药HIV-1感染的药理学特性及临床疗效，为耐多药HIV-1感染的治疗提供参考。     

P-gp在乳腺黏液腺癌中的表达及意义

目的 探讨P-糖蛋白(P-gp)表达与乳腺黏液腺癌组织生物学行为及其预后的关系. 方法采用免疫组化SP法检测P-gp在41例乳腺黏液腺癌组织中的表达情况.结果 单纯型乳腺黏液腺癌组织P-gp表达阳性率明显低于混合型(P＜0.05);P-gp表达强度及阳性率与肿瘤的黏液量呈负相关(P＜0.05);P-gp表达与肿瘤大小、淋巴结转移情况及临床分期显著相关(P＜0.05).结论 单纯型乳腺黏液腺癌P-gp呈低水平表达,混合型乳腺黏液腺癌P-gp呈高水平表达;P-gp的表达是判断乳腺黏液腺癌预后的指标之一,并可能成为混合型乳腺黏液腺癌治疗的重要靶点.     

Sensitization of ABCB1 overexpressing cells to chemotherapeutic agents by FG020326 via binding to ABCB1 and inhibiting its function

The effectiveness of chemotherapeutic treatment is usually limited by the overexpression of adenosine triphosphate binding cassette (ABC) transporters, which mediate multidrug resistance (MDR) by acting as efflux pumps to remove chemotherapeutic agents from MDR cancer cells. Thus, the inhibition of ABC transporters may represent a promising strategy to reverse MDR. This study was to characterize the actions of FG020326, a newly synthesized triaryl-substituted imidazole derivative, to reverse MDR in vitro and in vivo. FG020326 significantly potentiated the cytotoxicity of paclitaxel, doxorubicin, and vincristine in the ABCB1 (P-glycoprotein, P-gp) overexpressing cells KBv200 and MCF-7/adr, but not in the ABCB1 negative parental cell lines KB and MCF-7. However, FG020326 did not alter the cytotoxicity of the aforementioned drugs in ABCC1 (MRP1), ABCC4 (MRP4), ABCG2 (BCRP) and LRP overexpressing cell lines, KB-CV60, NIH3T3/MRP4-2, S1-M1-80 and SW1573/2R120, respectively. FG020326, following p.o. administration, was present in concentrations sufficient for reversal of MDR in mice. The co-administration of FG020326 with paclitaxel or vincristine significantly enhanced the antitumor activity of these drugs without significantly increasing toxicity in the mice bearing the KBv200 cell xenografts. In addition, FG020326, at concentrations that reversed MDR, did not significantly affect the activity of CYP3A4 or alter the pharmacokinetic profile of paclitaxel after co-administration with paclitaxel. FG020326 produced a significant concentration-dependent displacement of [³H]azidopine and inhibition of efflux of drug from cells. Furthermore, FG020326 was co-localized with ABCB1 in cell membranes. Hence, FG020326 is characterized as a third generation MDR modulator that holds great promise for the treatment of cancer patients with ABCB1-mediated MDR.     

基于调控细胞凋亡的肿瘤化疗增敏策略

肿瘤多药耐药(multidrug-resistance,MDR)是肿瘤治疗中面临的一大难题。肿瘤对化疗药物产生耐药性的机制十分复杂,除癌细胞膜药物外排泵(Pgp等)过度表达所致外,细胞凋亡敏感性的异常变化也是其主要机制之一。文章综述了肿瘤凋亡通路异常改变引起耐药性的研究进展以及通过调整紊乱的凋亡通路克服MDR的策略。     

多药耐药肿瘤的联合用药

现就近2年的文献报道,总结了基于逆转多药耐药的抗肿瘤联合用药的相关信息,主要从多药耐药的发生机制、联合用药的规则方案、药物互相作用的主要靶点、当今研究的联合用药临床研究进展和此类联合用药的发展趋势等方面做一综述。