白介素1β基因多态性对质子泵抑制剂三联方案根除幽门螺杆菌疗效影响的Meta分析

目的 系统评价白介素1β（interleukin-1β,IL-1β）基因多态性与质子泵抑制剂三联方案根除幽门螺杆菌疗效的关系。方法 检索PubMed、Embase、CBM、CNKI、Wanfang data、CQVIP等数据库,收集IL-1β基因多态性（C-511T、T-31C）与质子泵抑制剂三联方案根除幽门螺杆菌感染的临床文献。根据纳入和排除标准筛选文献、评价和提取数据后,采用RevMan 5.3软件进行meta分析。结果 共纳入4篇文献,包含1 123例对象。Meta分析结果显示,IL-1β C-511T基因多态性中仅CC与TT基因型间质子泵抑制剂三联疗法的幽门螺杆菌根除率存在统计学差异（78.5%vs 92.1%,P<0.05）;CT与CC或TT基因型间幽门螺杆菌根除率无统计学差异（87.7%vs 78.5%,87.7%vs 92.1%）。IL-1β T-31C基因多态性中TT、TC与CC基因型间质子泵抑制剂三联疗法的幽门螺杆菌根除率无统计学差异（87.9%,84.6%,96.2%）。结论 IL-1β C-511T基因多态性可能影响质子泵抑制剂三联方案根除幽门螺杆菌的疗效。     

MDR1 C3435T基因多态性与肾移植患者他克莫司血药浓度关系的Meta分析

目的:系统评价多药耐药基因1(MDR1)C3435T基因多态性与肾移植患者他克莫司(FK506)血药浓度的关系,为器官移植术后免疫抑制剂的精准化治疗提供循证参考。方法:计算机检索数据库Embase、Science Direct、Pubmed、CNKI、Wan fang、Conchrane,Clinicaltrials.gov,检索年限为1990年1月至2016年10月,检索语种为中文和英文,收集有关MDR1C3435T基因多态性与肾移植患者FK506血药浓度关系的研究。对纳入的研究进行资料提取与质量评价。用Cochrane提供Revman 5.3软件进行Meta分析。结果:有8项研究纳入此次Meta分析,共827例患者。Meta分析结果显示,MDR1C3435T基因型中CT型患者在肾移植术后1周[MD=-16.93,95%CI(-27.67,-6.19),P=0.002]、1月[MD=-18.09,95%CI(-26.41,-9.78),P<0.0001]、6月[MD=-15.52,95%CI(-25.18,-5.85),P=0.002]时,血药浓度高于同期CC型患者;TT型患者在肾移植术后1周[MD=-30.76,95%CI(-53.04,-8.48),P=0.007]、1月[MD=-25.92,95%CI(-48.34,-3.51),P=0.02]、3月[MD=-33.77,95%CI(-48.74,-18.80),P <0.00001]、6月[MD=-22.25,95%CI(-32.97,-11.53),P<0.0001]、12月[MD=-22.74,95%CI(-42.76,-2.72),P=0.03]时,血药浓度高于同期CC型患者;TT型患者在肾移植术后3月[MD=-18.81,95%CI(-34.30,-3.33),P=0.002]时,血药浓度高于同期CT型患者。结论:MDR1C3435T基因多态性与FK506血药浓度/剂量存在相关性,且血药浓度的关系是携带者(CT型或者TT型)>非携带者(CC型)。在肾移植术后不同时期内,根据MDR1C3435T基因多态性与FK506血药浓度/剂量存在的相关性,做基因检测可以在短时间内达到有效血药浓度。由于纳入研究数量较少、样本量不大、该结论有待大样本、高质量研究进一步证实。     

骨肉瘤患者3种基因多态性与大剂量甲氨蝶呤不良反应相关性的Meta分析

目的:系统评价骨肉瘤患者亚甲基四氢叶酸还原酶(MTHFR)、还原性叶酸载体1(RFC1)、多药耐药基因1(MDR1)基因多态性对大剂量甲氨蝶呤不良反应的影响,为大剂量甲氨蝶呤临床个体化用药提供循证参考。方法:计算机检索Medline、Embase、clinical trials.gov、中国知网、万方数据和中国生物医学文献数据库,收集MTHFR C677T/A1298C、RFC1 G80A、MDR1 C3435T不同基因多态性与大剂量甲氨蝶呤不良反应相关性的队列研究,对符合纳入标准的临床研究进行资料提取后,采用纽卡斯尔-渥太华量表进行质量评价后,采用Rev Man 5.3、Microsoft Excel 2016对大剂量甲氨蝶呤相关不良反应(血液毒性与骨髓抑制、肝毒性、肾毒性、口腔黏膜炎、消化道毒性、整体不良事件)发生率等结局指标进行Meta分析与描述性分析。结果:共纳入8项队列研究,合计608例患者。报告MTHFR C677T、MTHFR A1298C、RFC1 G80A、MDR1 C3435T多态性相关的结局指标分别有6、5、4、2项。Meta分析与描述性分析结果表明,MTHFR C677T多态性与G3-4腎毒性[TT/CT vs.CC:OR=12.35,95%CI(3.28,46.42),P<0.001]、G3-4口腔黏膜炎[T vs.C:OR=2.04,95%CI(1.06,3.93),P=0.03]、口腔黏膜炎[TT vs.CT/CC:OR=2.27,95%CI(1.20,4.27),P=0.01]、肾毒性(P<0.05)的发生风险显著相关;MTHFR A1298C多态性与G3-4肝毒性、G3-4肾毒性、G3-4口腔黏膜炎有关,但均无显著相关性(P>0.05);RFC1 G80A多态性与血液毒性、肝毒性、肾毒性、消化道毒性均无显著相关性(P>0.05);MDR1C3435T多态性与口腔黏膜炎有显著相关性(P<0.05),与血液毒性、肝毒性均无显著相关性(P>0.05)。结论:MTHFR C677T突变可能导致大剂量甲氨蝶呤不良反应发生风险增加,MTHFR A1298C多态性与大剂量甲氨蝶呤不良反应无显著相关性,RFC1 G80A或MDR1 C3435T多态性与大剂量甲氨蝶呤不良反应的研究较少,相关性尚不明确。     

MDR1 C3435T基因多态性与胃溃疡患者治疗相关性分析

目的 分析MDR1 C3435T基因多态性与胃溃疡患者治疗的相关性.方法 回顾性分析2010年10月至2015年10月来我院就诊的胃溃疡患者共80名,其中Hp阳性患者47例,另选取80例健康体检者作为对照组,测定两组入选对象MDR1 C3435T基因多态性,比较不同基因型胃溃疡患者治疗后Hp阳性率和耐药率.结果 观察组(Hp阳性)患者3435TT基因型频率和T等位基因频率均明显高于观察组(Hp阴性)和对照组(P＜0.05);观察组(Hp阴性)患者3435TT基因型频率和T等位基因频率亦均明显高于对照组(P＜0.05).治疗后3435TT基因型患者Hp阳性率和耐药率均明显高于C3435T和CC3435基因型患者(P＜0.05).结论 MDR1 C3435T基因多态性与胃溃疡患者的治疗具有相关性,3435TT基因型患者较难根除Hp,耐药性较强.     

中国人群中CYP2C19基因多态性对质子泵抑制剂三联疗法根除幽门螺杆菌疗效影响的Meta分析

目的：系统评价中国人群中药物代谢酶CYP2C19基因多态性与质子泵抑制剂三联疗法根除幽门螺杆菌疗效的关系,为临床治疗提供循证参考。方法：检索PubMed、Embase、CBM、CNKI、WanFang data、CQVIP等数据库,收集CYP2C19基因多态性与质子泵抑制剂三联疗法根除幽门螺杆菌感染的临床文献。根据纳入和排除标准筛选文献、评价和提取数据后,采用RevMan 5.3和Stata 13.1软件进行Meta分析。结果：共纳入12篇文献,包含1 851例对象。Meta分析结果显示：不考虑质子泵抑制剂类型,CYP2C19强代谢型（EM）、中间代谢型（IM）与弱代谢型（PM）的幽门螺杆菌根治率存在统计学差异[EM vs. IM：OR=0.57,95%CI（0.36,0.88）,P<0.05;EM vs. PM：OR=0.39,95%CI（0.25,0.59）,P<0.05;IM vs. PM：OR=0.54,95%CI（0.35,0.86）,P<0.05]。亚组分析表明含奥美拉唑的三联方案中,EM型幽门螺杆菌根治率明显低于IM型[OR=0.21,95%CI（0.11,0.39）,P<0.05],同样结果也发生在EM与PM之间[OR=0.12,95%CI（0.04,0.35）,P<0.05],但IM型与PM型间无差异。其他质子泵抑制剂如埃索美拉唑、兰索拉唑、雷贝拉唑等未发现上述差异。结论：中国人群中CYP2C19基因多态性可能影响奥美拉唑三联疗法根除幽门螺杆菌的疗效,但不影响埃索美拉唑、兰索拉唑、雷贝拉唑等质子泵抑制剂的根除效果。     

亚洲人群MDR1 C3435T基因多态性与肾移植患者他克莫司血药浓度关系的Meta分析

目的:系统评价亚洲人群多药耐药基因1(MDR1)C3435T基因多态性与肾移植患者他克莫司(FK506)血药浓度的关系,以为临床治疗提供循证参考。方法:计算机检索Pub Med、ELSEVIER、Cochrane图书馆、EBSCO、中国生物医学文献数据库、中国期刊全文数据库、万方数据库,收集有关亚洲人群MDR1 C3435T基因多态性与肾移植患者FK506血药浓度关系的研究,提取资料并进行质量评价后,采用Rev Man 5.2统计软件进行Meta分析。结果:共纳入8篇文献,包含826例患者。Meta分析结果显示,MDR1 C3435T基因型中TT型携带者在肾移植术后6个月[MD=-26.49,95%CI(-31.26,-21.72),P<0.000]、12个月[MD=-8.70,95%CI(-13.81,-3.60),P<0.000]时FK506血药浓度/剂量值高于同期CT型携带者;CT型携带者在肾移植术后6个月[MD=-17.44,95%CI(-21.10,-13.77),P<0.000]、12个月[MD=-15.13,95%CI(-21.92,-8.33),P<0.000]时FK506血药浓度/剂量值高于同期CC型携带者。结论:亚洲人群肾移植术后FK506血药浓度/剂量值与MDR1 C3435T基因型相关,且TT型>CT型>CC型。由于纳入研究数量较少、样本量不大,该结论有待大样本、高质量的研究进一步证实。     

MTHFR C677T基因多态性与孤独症谱系障碍易感性关系的Meta分析 #br#

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因多态性与孤独症谱系障碍（ASD）易感性的关系。方法 检索中国知网、万方数据、PubMed、Embase、Proquest、Web of science等数据库,收集MTHFR C677T基因多态性与ASD 关联的病例对照研究,检索时间至2020年6月30日。应用Stata 14.0软件进行Meta分析。结果 共纳入16篇文献, 其中病例组2 149例,对照组2 251例。Meta分析结果显示在等位基因模型（T vs. C,OR=1.51,95%CI：1.15~1.99,P= 0.003）、显性模型（TT+CT vs. CC,OR=1.67,95%CI：1.21~2.29,P=0.002）中,MTHFR C677T多态性与ASD发生具有相关 性。而在隐性模型（TT vs. CT+CC,OR=1.20,95%CI：0.82~1.76,P=0.340）和纯合子模型（TT vs. CC,OR=1.43,95%CI： 0.92~2.22,P=0.113）中MTHFR C677T多态性与ASD易感性无关。种族亚组分析显示,高加索人MTHFR C677T多态 性仅在显性模型（OR=1.30,95%CI：1.04~1.63,P=0.024）中与 ASD 发生相关,而亚洲人在等位基因模型（OR=1.85, 95%CI：1.13~3.01,P=0.014）和显性模型（OR=1.99,95%CI：1.18~3.36,P=0.010）中和 ASD 发病有关。 结论MTHFR C677T基因多态性与ASD易感性相关。     

类风湿关节炎患者转运蛋白基因多态性与甲氨蝶呤疗效及不良反应的相关性研究

目的探讨类风湿关节炎（RA）患者还原型叶酸载体（RFC-1）基因G80A及三磷酸腺苷结合盒转运体B1（ABCB1）基因C3435T单核苷酸多态性（SNP）与甲氨蝶呤（MTX）疗效与不良反应的相关性。方法采用实时荧光定量聚合酶链反应（FQ-PCR）法检测136例单用MTX的RA患者RFC-1基因G80A及ABCB1基因C3435T多态性,并与MTX治疗疗效和不良反应相关分析。结果 RFC-1基因G80A及ABCB1基因C3435T多态性与MTX治疗RA的不良反应无明显相关性（P〉0.05）;RFC-1基因G80A多态性与MTX治疗RA的疗效无明显相关（P〉0.05）,而ABCB1基因C3435T的多态性与疗效相关,携带有CC基因型的患者MTX疗效明显优于携带有TT或CT基因型的患者。CT和CC比较,（P=0.015,OR=4.189,95%CI为1.314~13.353）;TT和CC比较,（P=0.02,OR=5.941,95%CI为1.320~26.739）。结论 ABCB1基因C3435T多态性可能对RA患者应用MTX的疗效有预测作用。     

中国人群亚甲基四氢叶酸还原酶C677T多态性与急性淋巴细胞白血病关系的Meta分析

目的:探讨中国人群亚甲基四氢叶酸还原酶基因(MTHFR)C677T位点多态性与急性淋巴细胞白血病(ALL)易感性和甲氨蝶呤(MTX)化疗时毒副反应的关系。方法:检索以中国人群为研究对象ALL组和对照组MTHFR基因C677T位点多态性的OR值或RR值为效应指标的相关文献,符合入选标准的文献,应用RevMan 5.0软件对研究结果进行异质性检验和效应值合并,并进行敏感性分析和偏倚评估。结果:纳入MTHFR基因C677T位点多态性与ALL的文献共7篇,共计病例824例,对照1090例。TT+CT vs CC:固定效应模型OR=0.76,95%CI:0.63～0.91;随机效应模型OR=0.70,95%CI:0.52～0.93,TT vs CC+CT:固定效应模型OR=0.90,95%CI:0.70～1.15;随机效应模型OR=0.93,95%CI:0.53～1.61,漏斗图基本对称。MTHFR基因C677T位点多态性与MTX的毒副反应的文献共3篇,共计病例138例。TT+CT vsCC:固定效应模型OR=2.65,95%CI:1.28～5.49;随机效应模型OR=2.96,95%CI:0.66～13.32,TT vsCC+CT:固定效应模型OR=2.68,95%CI:1.14～6.29;随机效应模型OR=3.31,95%CI:0.57～19.21。结论:MTHFR基因677C→T突变对ALL的发生起着保护作用。MTHFR基因TT基因型与ALL的发生无显著的相关性。MTHFR基因多态性与MTX治疗的毒副反应无显著的相关性。更可靠的结论尚需大样本进行进一步研究。     

111例心衰患者的 MDR1 和CYP3A 基因多态性与地高辛血药浓度的相关性研究

目的：观察中国贵州地区汉族心衰患者中MDR1C3435T、CYP3A4＊18B和CYP3A5＊3等位基因多态性对地高辛血药浓度的影响。方法：收集111名中国贵州地区汉族心衰患者的血样与地高辛治疗药物浓度监测（TDM）数据,通过PCR-RFLP法分析患者的MDR1C3435T、CYP3A4＊18B及CYP3A5＊3基因型,分析每个基因的多态性对地高辛血药浓度的影响。结果：70岁以上患者MDR1各基因型组中,野生纯合子（CC）组、突变杂合子（CT）组、突变纯合子（TT）组的地高辛血药浓度依次增高。CC组和CT组较TT组的地高辛血药浓度差异有统计学意义（P〈0.05）;CYP3A4和CYP3A5各基因型组之间的地高辛血药浓度差异均无统计学意义（P〉0.05）。结论：MDR1C3435T等位基因突变可使地高辛血药浓度提高;而CYP3A4＊18B和CYP3A5＊3等位基因突变对地高辛的血药浓度无明显影响。     

脂蛋白脂肪酶外显子9基因突变研究

目的 :筛查国人脂蛋白脂肪酶 (LPL)外显子9基因突变和Ser447→stop突变频率 ,并探讨该突变对血脂水平的影响。方法 :依血脂测定结果 ,将169例分为高甘油三酯血症组(HTG组 ) ,48例和正常甘油三酯组(对照组 )121例 ,利用聚合酶链反应 -单链构象多态性和聚合酶链反应 -限制性片段长度多态性分析技术对待测人群的LPL基因外显子9及其相邻内含子区域进行突变筛查 ,并对典型单链构象电泳图谱携带者进行PCR产物测序。结果 :在169例中检出1例Ser447→stop突变纯合子 ,50例Ser447→stop杂合子 ,未检出其它位点的突变 ;HTG组的Ser447→stop突变检出率 (25.0 % ,12/48)明显低于对照组 (31.4 % ,38/121) ,HTG组的Stop447 等位基因频率(12.5% )明显低于对照组 (16.5% ),两组比较差别均有统计学意义(P<0.01)。结论 :我国人群中LPL外显子9突变种类单一 ,Ser447→stop是一高频率的多态性位点 ,Stop447等位基因可能有轻微的降低血浆甘油三酯的作用。     

Gene therapy of cancer

Gene therapy was initially thought of as a means to correct single gene defects in hereditary disease. Since then, cancer has become the most important indication for gene therapy in clinical trials. In the foreseeable future, the best way to achieve reasonable intratumoral concentrations of a transgene with available vectors will be direct intratumoral injection with or without the help of various techniques such as endoscopy or computed tomography guidance. At present, viral and nonviral methods of gene transfer are used either in vivo or ex vivo/in vitro. The most important viral vectors currently used in clinical trials are retroviruses, adenoviruses, adeno-associated viruses and herpes viruses. However, none of them satisfies all the criteria of an ideal gene therapeutic system, and vectors with only minimal residues of their parent viruses (gutless vectors) and completely synthetic viral vectors are gaining importance. Nonviral methods of gene therapy include liposomes, injection of vector-free (naked) DNA, protein-DNA complexes, delivery by gene gun, calcium-phosphate precipitation, electroporation and intracellular microinjection of DNA. The first clinical trial of human gene therapy was performed in 1990 and since then more than 5000 patients have been treated worldwide in over 400 clinical protocols. Side effects were rare and mostly mild in all of these studies and expression of the transgene was demonstrated in patients in vivo. Despite anecdotal reports of therapeutic responses in some patients, there is still no unequivocal proof of clinical efficacy of most approaches to gene therapy in cancer, primarily due to very low transduction and expression efficacy in vivo of available vectors. Strategies for gene therapy of cancer can be subdivided into four basic concepts: 1) strengthening of the immune response against a tumor, 2) repair of cell cycle defects caused by loss of tumor suppressor genes or inappropriate activation of oncogenes, 3) suicide gene strategies and 4) inhibition of tumor angiogenesis. Gene marker studies and gene protection of normal tissue are also discussed.     

Gene therapy of atherosclerosis

Atherosclerosis and related diseases are the leading cause of death in Western world. The disease process begins with the formation of fatty streaks already during the first decade of life but does not manifest clinically until several decades later. Gene therapy is a potential new way to target multiple factors playing a role in the development and progression of atherosclerosis. A great number of genes involved in the development of atherosclerosis have been identified and have been tested both in vitro and in vivo as potential new targets for therapy. Pre-clinical experiments have shown the feasibility and safety of several gene therapy applications for the treatment of atherosclerosis and clinical trials have also provided evidence for the applicability of gene therapy for the treatment of cardiovascular diseases. In this review we discuss vectors and potential gene therapy approaches for intervention and therapy of atherosclerosis.     

Gene Transfer And Models Of Gene Therapy For The Myocardium

1. Gene transfer into the myocardium can be achieved through direct injection of plasmid DNA or through the delivery of viral vectors, either directly or through the coronary vasculature. Direct DNA injection has proven extremely valuable in studies aimed at characterizing the activities of promoter elements in cardiac tissue and for examining the influence of the pathophysiological state of the myocardium on expression of transferred foreign genes. 2. Viral vectors, in particular adenoviruses and adeno-associated virus, are capable of transfecting genetic material with high transduction efficiencies and have been applied to a range of model systems for in vivo gene transfer. Efficient gene transfer has been achieved into the coronary vessels and surrounding myocardium by intracoronary infusion of adenovirus. 3. Because the immunogenicity of viral vectors can limit transgene expression, much attention has been paid to strategies for circumventing this, including the development of new modified adenovirus and adeno-associated virus vectors that do not elicit significant inflammatory responses. While cellular transplantation may prove valuable for the repair of myocardial tissue, confirmation of its value awaits establishment of a functional improvement in the myocardium following cell grafting. 4. Because gene transfer into the myocardium can now be achieved with high efficiency in the absence of significant inflammatory responses, the ability to regulate foreign gene expression in response to an endogenous disease phenotype will enable the development of new effective viral vectors with direct clinical applicability for specified therapeutic targets.     

Gene trap mutagenesis

Our ability to genetically manipulate the mouse has had a great impact on medical research over the last few decades. Mouse genetics has developed into a powerful tool for dissecting the genetic causes of human disease and identifying potential targets for pharmaceutical intervention. With the recent sequencing of the human and mouse genomes, a large number of novel genes have been identified whose function in normal and disease physiology remains largely unknown. Government-sponsored multinational efforts are underway to analyze the function of all mouse genes through mutagenesis and phenotyping, making the mouse the interpreter of the human genome. A number of technologies are available for the generation of mutant mice, including gene targeting, gene trapping and transposon, chemical or radiation-induced mutagenesis. In this chapter, we review the current status of gene trapping technology, including its applicability to conditional mutagenesis.     

甲胎蛋白基因表达调控及其在肝癌基因治疗中的应用

甲胎蛋白(alpha-fetaprotein,AFP)是一类胚胎中清蛋白样载体蛋白,在正常成人组织中很难检测到,恶性病变时又有大量产生,常被用作检测肝细胞癌变的指标。AFP基因调控区包括一系列顺式作用元件,特异的反式作用因子直接或间接地调控AFP基因的表达,其基因调控主要在转录水平上。AFP基因表达与肝癌发生中涉及到的某些原癌基因的表达相关。目前,基于对AFP基因表达调控的认识,可以构建出特定表达载体,应用于肝癌的靶向基因治疗。     

Analysis of Microglial Gene Expression

Microglia are the tissue macrophage of the central nervous system (CNS) and their activation is among the earliest signs of CNS dysfunction and disease. Because microglia express many macrophage markers, they are presumed to act primarily as effectors of CNS inflammation and destruction. While such responses are beneficial to the extent that they destroy CNS pathogens, these responses do have the potential to have neurotoxic outcomes. Consequently, therapies for many CNS neurodegenerative and inflammatory diseases have been directed at suppressing microglial function.There is evidence to suggest that microglia play an important role during CNS development and maintenance of CNS function that may go beyond simple defense against pathogens. Molecular analysis of microglial phenotypes and function has revealed three striking findings: (i) that microglia are a unique CNS-specific type of tissue macrophage; (ii) that they are highly heterogeneous within the healthy CNS; and (iii) that microglial responses are exquisitely tailored to specific regions of the CNS and specific pathological insults. We suggest that ubiquitous suppression (rather than targeted manipulation) of microglial function may fail to fully ameliorate CNS pathology and may even ultimately promote maladaptive outcomes.