ERCC1基因多态性对晚期胃癌患者奥沙利铂化疗敏感性的相关性

目的探讨切除修复交叉互补基因1(ERCC1)Asn118Asn C→Tr,s11615多态性与晚期胃癌患者对奥沙利铂为主方案一线化疗疗效的关系。方法 108例晚期胃癌患者采静脉血提取DNA,以real-time PCR法对ERCC1基因进行SNP分型。患者接受奥沙利铂为主方案化疗,观察疾病有效率及肿瘤进展时间(TTP),比较不同基因型与其有效率的关系。结果 108例入组患者总有效率为56.5%(61/108),其中ERCC1基因进行SNP分型,纯合基因型(C/C)与杂合基因型(C/T+T/T)在疾病有效组和无效组之间分布差异有统计学意义(P=0.005)。入组患者总中位TTP为6个月,C/T+T/T基因型患者中位TTP为6个月,与C/C中位TTP 7个月相比,差异有统计学意义(P=0.039)。结论 ERCC1 Asn118Asn基因多态性与晚期胃癌患者接受奥沙利铂为主方案一线化疗的临床疗效有相关性,有待进一步临床研究。     

DNA损伤修复、TP53、ABCB1基因单核苷酸多态性与NSCLC铂类药物疗效关系的研究进展

非小细胞肺癌(NSCLC)铂类药物的疗效与DNA损伤修复基因、抑癌基因等相关基因的单核苷酸多态性(SNPs)有关.在DNA损伤修复基因中,切除修复交叉互补基因1 rs11615、rs3212986、切除修复交叉互补基因5(ER-CC5)rs17655以及人类X射线交错互补修复基因3 rs861539的SNPs与NSCL...     

XRCC1在氧化应激诱导的DNA损伤及其修复过程中的作用及机制

<正>氧化应激诱导的DNA损伤可引起神经退行变、癌症和阿尔茨海默等疾病〔1〕。碱基切除修复(BER)是氧化应激引起的DNA损伤修复的主要形式,在BER和单链断裂修复通路中,X线修复交叉互补基因1(XRCC1)充当脚手架蛋白招募DNA修复蛋白参与DNA损伤位点的修复〔2〕。1 XRCC1的结构及其生物学特点XRCC1蛋白质分为三个功能域:(1)N末端功能域位于第     

DNA修复基因多态性与非小细胞肺癌患者含铂方案化疗预后的关系

目的探讨DNA修复基因ERCC1 C118T和XPD Lys751Gln单核苷酸多态性与含铂方案化疗非小细胞肺癌(NSCLC)患者临床预后的关系。方法选择经病理确诊为NSCLC的患者73例,在实施化疗前采取静脉血,提取DNA,行DNA测序,用PCR-RFLP方法检测ERCC1 C118T和XPD Lys751Gln基因型。所有患者均经含铂方案化疗,分析NSCLC患者ERCC1和XPD单核苷酸多态性与铂类化疗预后之间的关系。结果所有NSCLC患者中位生存期为18.0个月。ERCC1 CC型的中位总生存时间为19.803个月,CT型为15.993个月,TT型为16.233个月,CC型与CT、TT型间比较差异均有统计学意义(χ2=12.855,P=0.000;χ2=8.602,P=0.003)。XPD Lys751Gln只检测到A/A型、A/C型,A/A型的中位总生存时间为18.044个月,A/C型的中位总生存时间为18.075个月,两组间比较差异无统计学意义(χ2=0.034,P=0.854)。结论 DNA修复基因ERCC1C118T单核苷酸多态性与NSCLC患者铂类药物化疗后的生存期有关,在一定程度上可作为铂类药物化疗后生存期的预测指标。     

XRCC1与肺癌

X线修复交叉互补基因1(X-ray repair cross complementing 1,XRCC1)是一种重要的DNA修复基因,其编码的蛋白参与DNA单链断裂和碱基损伤修复,对维持细胞基因组的稳定性、预防肿瘤的发生有着重要的作用.本文对XRCC1基因的结构与功能以及基因多态性与肺癌易感性、肺癌放化疗疗效的关系的研究现状进行综述.     

非小细胞肺癌ERCC1和Rad51表达与铂类药物化疗疗效的关系

用免疫组化SP法检测53例非小细胞肺癌(NSCLC)患者铂类药物化疗后的核苷酸切除修复交叉互补组1(ERCC1)和DNA损伤修复蛋白(Rad51)的表达情况,分析ERCC1和Rad51的表达与患者中位生存时间(MST)和中位无病生存时间(DFT)的关系.结果:ERCC1和Rad51的阳性表达率分别为42.8%、57.5%,其阳性表达与患者的性别、年龄、肿瘤组织学类型、分期及分化程度无关(P>0.05).单一ERCC1阴性或Rad51阴性的患者MST和DFT均明显长于ERCC1阳性或Rad51阳性的患者(P均<0.05).两种蛋白均阳性表达者的MST、DFT分别短于两蛋白阴性表达者(P均<0.05).认为ERCC1和Rad51的联合检测可以预测NSCLC患者术后铂类药物辅助化疗的疗效.     

结肠癌患者谷胱甘肽巯基转移酶P1(GSTP1)基因多态性与奥沙利铂敏感性和中医证型的相关性研究

背景结肠癌属于发病率均较高的癌症,化疗仍是其只要治疗手段,奥沙利铂作为第三代铂类化疗药物在治疗肠癌方面有较好的的疗效,但受基因易感性的影响,不同基因型的人群对药物的敏感性不同,因而治疗效果也有较大差异.目的探究结肠癌患者谷胱甘肽巯基转移酶P1(Glutathione S-transferase pi 1, GSTP1)基因多态性与奥沙利铂敏感性和中医证型的相关性.方法选取我院2015-01/2020-06结肠癌患者246例,均行奥沙利铂方案化疗,化疗前检测GSTP1基因Ile105Val位点多态性,化疗3个周期后评价疗效.比较不同化疗疗效患者临床资料、GSTP1基因型分布情况,分析奥沙利铂化疗疗效的影响因素,并统计结肠癌患者中医证型分布情况,评价GSTP1基因型与中医证型、证素的关系.结果GSTP1基因Ile105Val位点存在多态性,符合哈迪-温伯格(Hardy-Weinberg)遗传平衡定律检验,具有人群代表性(P0.05). 246例结肠癌患者经奥沙利铂方案化疗3个周期后,总有效率为43.90%(108/246).临床分期Ⅳ期、中高分化、淋巴结转移、GSTP1基因型AG、GG是结肠癌患者奥沙利铂化疗效果的重要影响因素(P0.05). 118例结肠癌患者中医证型分布情况:瘀毒内阻型脾肾阳虚型气血双亏型湿热蕴结型肝肾阴虚型.瘀毒内阻型、气血双亏型患者GSTP1基因型分布比较,差异有统计学意义(P0.05);不同GSTP1基因型分布患者中医证型分布比较,差异有统计学意义(P0.05);不同GSTP1基因型患者中医病位证素脾、肺、肾分布差异有统计学意义(P0.05).结论结肠癌患者GSTP1基因多态性与奥沙利铂敏感性、中医证型均存在一定相关性,因此检测GSTP1基因多态性,有助于评价患者接受以奥沙利铂为基础药物化疗的治疗效果,判断中医证型,从而为结肠癌个体化治疗提供科学指导.     

PARP1在氧化应激诱导的DNA损伤及其修复过程中的作用

<正>活性氧自由基(ROS)在代谢或炎症过程中定期产生,它的产生与抗氧化防御不平衡形成了氧化应激。氧化应激导致DNA损伤和促进炎症反应~(〔1,2〕)。聚腺苷酸二磷酸核糖聚合酶-1(PARP1)作为DNA损伤的分子感受器,在氧化应激诱导DNA损伤时被激活,活化的PARP1介导碱基切除修复复合物参与受损DNA的修复。1 PARP1的结构及其功能1.1 PARP1的结构PARP1基因位于染色体1q41-42区,有     

切除修复交叉互补基因1与铂类耐药

切除修复交叉互补基因1（excision repair cross-completion1,ERCC1）是DNA修复的重要因子之一,而DNA修复参与了铂类药物耐药的形成,ERCC1表达增高和其多态性均与铂类耐药有关,用药物干预或基因封闭技术抑制ERCC1表达能在一定程度上逆转铂类耐药。     

PARP-1:一个肿瘤治疗的新靶点

聚腺苷酸二磷酸核糖转移酶-1[poly(ADP- ribose)polymerase-1,PARP-1]是存在于真核细胞中催化聚ADP核糖化的细胞核酶,他参与的聚ADP核糖化是真核细胞中蛋白质翻译后的重要修饰方式之一．PARP-1在DNA修复和细胞凋亡中发挥至关重要的作用．PARP-1的缺失使细胞对DNA损伤因子易感,可能参与肿瘤的发生．体外和体内研究表明抑制PARP-1 则可降低DNA修复功能,增强放疗和化疗对肿瘤的治疗效果．目前PARP-1抑制剂已进入抗肿瘤药物Ⅰ期临床研究,PARP-1有望成为肿瘤治疗的一个新靶点．     

1-Naphthyl isocyanate and 1-naphthylamine as metabolites of 1-naphthylisothiocyanate

Abstract: The importance of the bioactivation of 1-naphthylisothiocyanate was studied. Forty minutes after 1-naphthylisothiocyanate administration to rats, bile was collected over a 2.5-h period; the liver was then excised and homogenized. 1-naphthylisothiocyanate and its metabolites in bile and liver of rats were identified and quantified using coupled gas chromatography-mass spectrometry. Three main compounds were found in all 1-naphthylisothiocyanate-treated animals. They were identified as 1-naphthyl isocyanate, 1-naphthylamine and the parent compound, 1-naphthylisothiocyanate. When rats were given cycloheximide, which attenuates 1-naphthylisothiocyanate toxicity, 30 min before 1-naphthylisothiocyanate (300 mg/kg), 1-naphthyl isocyanate concentration was significantly lower than in rats receiving only 1-naphthylisothiocyanate. The appearance of 1-naphthylamine was also inhibited by cycloheximide, although not to the same extent as 1-naphthyl isocyanate. On the other hand, phenobarbital, which potentiates 1-naphthylisothiocyanate hepatotoxicity, enhanced 1-naphthyl isocyanate and 1-naphthylamine formation. It is suggested that 1-naphthyl isocyanate, 1-naphthylamine and the highly reactive sulfur released from 1-naphthylisothiocyanate might be involved in the hepatotoxic effect of 1-naphthylisothiocyanate.     

Cytochrome 1A1 and 1B1 gene diversity in the Zanzibar islands

Amodiaquine (AQ) is a 4‐aminoquinoline widely used in the treatment of malaria as part of the artemisinin combination therapy (ACT). AQ is metabolised towards its main metabolite desethylamodiaquine mainly by cytochrome P450 2C8 (CYP2C8). CYP1A1 and CYP1B1 play a minor role in the metabolism but they seem to be significantly involved in the formation of the short‐lived quinine‐imine. To complete the genetic variation picture of the main genes involved in AQ metabolism in the Zanzibar population, previously characterised for CYP2C8, we analysed in this study CYP1A1 and CYP1B1 main genetic polymorphisms. The results obtained show a low frequency of the CYP1A1*2B/C allele (2.4%) and a high frequency of CYP1B1*6 (approximately 42%) followed by CYP1B1*2 (approximately 27%) in Zanzibar islands. Genotype data for CYP1A1 and CYP1B1 show a low incidence of fast metabolisers, revealing a relatively safe genetic background in Zanzibar’s population regarding the appearance of adverse effects.     

甲型H1N1与季节性H1N1流感病毒血凝素基因比较分析

目的分析泰安市2008～2009年度季节性流感与2009年度甲型H1N1流感病原学检测结果 ,比较季节性H1N1与甲型H1N1血凝素基因变异情况。方法选择国家级流感监测哨点医院以及暴发疫情的疫点,采集流感样病例的鼻咽拭子标本,通过RealtimePCR进行病毒检测,用MDCK细胞进行病毒分离,通过RT-PCR扩增血凝素HA1片段的基因并测序,利用生物信息学进行序列分析。结果 2008～2009年共检测鼻咽拭子标本283份,分离出流感病毒33株,分离阳性率为11.67%,其中季节性H1N1亚型31株。2009年5月1日～12月31日,检测鼻咽拭子标本996份,流感核酸检测阳性417份,阳性率为41.86%,其中甲型H1N1337份,季节性H1N1亚型1份。6株季节性H1N1病毒均在多个氨基酸位点上发生变异,与疫苗株A/Brisbane/59/2007(H1N1)比较,有11个位点发生了突变,其中5个位点位于抗原决定簇上;测序成功的6株甲型H1N1病毒在多个氨基酸位点发生变异,与疫苗株A/California/07/2009(H1N1)比较,有6个位点发生突变,其中1个位点位于抗原决定簇的B区。结论 2008～2009年度季节性H1N1为优势株,甲流暴发后,甲型H1N1成为绝对优势毒株。季节性H1N1分离株有多处氨基酸替换,抗原决定簇B区变异频繁;甲型H1N1病毒分离株的基因有变异,但关键位点第222位仍为D(天冬氨酸),与疫苗株相比抗原决定簇的关键位点变化不大。     

PD-1/PD-L1抑制途径与自身免疫性糖尿病

PD-1(CD279)是一种负性协同刺激分子,属于CD28超家族成员,呈诱导性表达于活化的T、B和自然杀伤细胞表面.PD-L1(B7-H1,CD274)和PD-L2(B7-DC,CD273)是PD-1的两个配体.PD-1和PD-L1相互作用可以使活化的自身反应性T细胞获得负性信号,抑制其对自身抗原持续的免疫应答.若PD...     

Expression and significance of ICAM-1 and its counter receptors LFA-1 and Mac-1 in experimental acute pancreatitis of rats

AIM: To investigate the role of intercellular adhesion molecule-1 (ICAM-1) and its counter receptors LFA-1 and Mac-1 in acute pancreatitis (AP). METHODS: SD rats were allocated to AP group and control group randomly (25 rats each). AP was induced by infusion of 5% chenodeoxycholic acid into the pancreatic duct, followed by ligation of pancreatic duct. The rats were sacrificed at 1, 3, 6, 12 and 24 h after induction of pancreatitis. Five rats were sacrificed at one time point in the two groups before the blood and specimens from pancreas and lung were obtained. Serum amylase and ascitic fluid were measured at each time point. Expression of ICAM-1 at different time points was assessed by immunohistochemistry in pancreas and lung, and the expression of LAF-1 and Mac-1 on neutrophils at different time points was detected by flow cytometer. RESULTS: Induction of AP was confirmed by the serum levels of amylase and histological studies. The expression of ICAM-1 in pancreas increased significantly than that in the control group at all time points (P < 0.05 or P < 0.01), as well as the expression in lung except at 1 h. The expression of LFA-1 and Mac-1 on neutrophil in blood increased significantly in AP group than that in control group at several time points (P < 0.05 ox P < 0.01). The amount of ascitic fluid and serum amylase level of AP group increased significantly than that of control group at all time points (P < 0.05 or P < 0.01). Parallel to these results, a significant neutrophil infiltration was found in pancreas and lung tissues of AP group rats. CONCLUSION: Our findings suggest the important role for ICAM-1, LFA-1 and Mac-1 in mediating the development of AP from a local disease to a systemic illness. Upregulation of ICAM-1, LFA-1, Mac-1 and subsequent leukocyte infiltration appear to be significant events of pancreatic and pulmonary injuries in AP.     

Genetic link with cholelithiasis among pediatric SCA Tunisian patients: Examples of UGT1A1, SLCO1A2 and SLCO1B1

Aims and background: Hyperbilirubinemia is often observed in chronic hemolysis and results in the formation of pigment cholelithiasis that could be increased by the presence of defected enzymes involved in the bilirubin metabolism. Indeed, this is the first report that interested in the study of polymorphisms in genes encoded for enzymes involved in the bilirubin metabolism: rs 4149056 of SLCO1B1 and rs4149000 of SLCO1A2 in combination with rs8175347 and rs887829 of UGT1A1 in order to find a correlation between the polymorphisms studied and the presence of gallstones in a population of sickle cell anemia (SCA) pediatric Tunisians.

Material and methods: Our study involved 102 unrelated Tunisian subjects. All SCA patients are children (less than 16 years old) and were characterized by hyperbilirubinemia and 52 of them have cholelithiasis. The polymorphisms of the candidate genes were analyzed for all subjects by PCR/sequencing. Genotype and allele frequencies between cases and controls were compared using Pearson's chi-square test with a significance threshold of P?<?0.05 (compare 2, version 1.02).

Results: The novelty of this report is that children carrying the combined genotype of the rs studied: (TA7TA7)/TT/TC/GA have a higher risk to develop gallstones (P?=?0.0027, RR?=?18.27 (20.0061–915.28)).

Conclusion: Altogether our data provide the implication of UGT1A1 and SLCO1A2 in sickle cell anemia-related cholelithiasis.     

甲型H1N1流感合并肺炎的临床特点分析

目的通过对甲型H1N1流感合并肺炎的临床特点的分析。方法分析2009年月10月-2010年3月在我院入住的29例甲型H1N1流感合并肺炎患者的临床表现、实验室检查及胸部CT等资料。结果本组病例男性16例,女性13例。3例妊娠,13例合并有基础疾病。所有病例均有流感样前驱症状,呼吸道主要症状为发热、干咳少痰,严重者气短、呼吸困难、咯血。合并细菌感染时咯脓痰。肺部听诊无啰音或少啰音,合并哮喘时有哮鸣音,合并细菌感染时可有湿啰音。实验室检查65%白细胞不高或降低,41%心肌酶升高,58.6%存在低氧血症,35%呼吸衰竭。影像学表现多种多样：65.5%主要为单侧或双侧棉团样、团片样边界模糊高密度渗出影伴肺实变,其内见充气支气管征,病变沿支气管血管束分布。轻症及早期较局限,重症者及晚期病变融合呈双肺多发弥漫性改变。少数呈大叶及小叶性肺炎表现。预后大多良好,病死率6.9%。主要死亡原因为呼吸衰竭及大咯血。结论甲型H1N1流感合并肺炎是以甲型H1N1流感病毒肺炎为主要疾病的多种肺炎构成。甲型H1N1流感病毒肺炎临床表现具有流感病毒肺炎共性特点,其影像学表现有一定特征性。     

Notch-1与Jagged-1蛋白在大肠癌组织中的表达及其意义

目的探讨Notch-1与Jagged-1蛋白在大肠癌组织中的表达及其与临床病理特征的关系。方法应用免疫组织化学PV-9000二步法检测大肠癌组织、癌旁组织及癌远端组织中Notch1与Jagged-1蛋白的表达,并分析Notch1与Jagged-1蛋白表达与临床病理参数的关系。结果Notch-1、Jagged-1蛋白在大肠癌中表达的阳性率明显高于癌旁组织及癌远端组织（P〈0．05）;大肠癌中Jagged-1蛋白表达强度与肿瘤组织学分级、Dukes分期及淋巴结转移密切相关（r=0．355、0．385、0．248,P均〈0．05）。大肠癌中Notch-1蛋白与Jagged-1蛋白表达呈正相关（r=0．305,P〈0．05）。结论Notch．1及Jagged-1蛋白可能在大肠癌发生发展中起重要作用。     

Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin

Abstract:  Administration of melatonin to rodents decreases the incidence of tumorigenesis initiated by benzo[ a ]pyrene or 7,12-dimethylbenz[ a ]anthracene, which requires bioactivation by cytochrome P450 enzymes, such as CYP1A1, CYP1A2 and CYP1B1, to produce carcinogenic metabolites. The present study tested the hypothesis that melatonin is a modulator of human CYP1 catalytic activity and gene expression. As a comparison, we also investigated the effect of melatonin on the catalytic activity of CYP2A6, which is also a procarcinogen-bioactivating enzyme. Melatonin (3–300 μ m ) decreased 7-ethoxyresorufin O -dealkylation catalyzed by human hepatic microsomes and recombinant CYP1A1, CYP1A2 and CYP1B1, whereas it did not affect coumarin 7-hydroxylation catalyzed by hepatic microsomes or recombinant CYP2A6. Melatonin inhibited CYP1 enzymes by mixed inhibition, with apparent K _i values (mean ± S.E.M.) of 59 ± 1 (CYP1A1), 12 ± 1 (CYP1A2), 14 ± 2 (CYP1B1) and 46 ± 8 μ m (hepatic microsomes). Additional experiments indicated that melatonin decreased benzo[ a ]pyrene hydroxylation catalyzed by hepatic microsomes and CYP1A2 but not by CYP1A1 or CYP1B1. Treatment of MCF-10A human mammary epithelial cells with melatonin (up to 300 μ m ) did not affect basal or benzo[ a ]pyrene-inducible CYP1A1 or CYP1B1 gene expression. Consistent with this finding, melatonin did not influence reporter activity in aryl hydrocarbon receptor-dependent pGudluc6.1-transfected MCF-10A cells treated with or without benzo[ a ]pyrene, as assessed in an in vitro cell-based luciferase reporter gene assay. Overall, melatonin is an in vitro inhibitor of human CYP1 catalytic activity, and it may be useful to develop potent analogues of melatonin as potential cancer chemopreventive agents that block CYP1-mediated chemical carcinogenesis.