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糖原合酶激酶3β和腺瘤性结肠息肉病蛋白在气道上皮细胞机械损伤修复过程的时空分布

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生理学报 2007年第2期59卷 197-203页

作者：朱敏李建莎田丹马燕李娜萍吴人亮华中科技大学同济医学院病理学系卫生部呼吸系统疾病重点实验室武汉430030

为了探讨糖原合酶激酶3β(glycogen synthase kinase 3β,GSK3β)和腺瘤性结肠息肉病(adenomatous polyposis coli, APC)蛋白在气道上皮细胞(airway epithelial cells,AECs)损伤和修复中的作用,我们采用机械划线损伤的方法建立体外气道... 详细信息

为了探讨糖原合酶激酶3β(glycogen synthase kinase 3β,GSK3β)和腺瘤性结肠息肉病(adenomatous polyposis coli, APC)蛋白在气道上皮细胞(airway epithelial cells,AECs)损伤和修复中的作用,我们采用机械划线损伤的方法建立体外气道上皮损伤修复模型,采用Western blot、免疫荧光双标共聚焦成像和免疫沉淀的方法观察损伤修复过程中APC蛋白和GSK3β在AECs中表达及分布的动态变化。结果显示:(1)用Western blot方法观察到划线损伤0．5 h后即有GSK3β磷酸化增强(Ph达到高峰(Ph(Ph开始下降,而GSK3β总量大致保持一致。(2)在免疫荧光双标共聚焦成像实验中,划线损伤0 h组APC蛋白主要表达于胞浆,而划线损伤6 h后APC蛋白主要聚集于损伤前沿区的迁移活跃细胞。(3)免疫共沉淀的实验结果显示,划线损伤0 h时GSK3B和APC蛋白能共同沉淀,但在划线损伤6 h之后,两者发生了分离。以上结果表明:划线损伤后AECs立即启动修复过程,此时GSK3B的活性被抑制,促使APC蛋白游离出来;游离出来的APC蛋白则与微管正极结合,增加了微管的稳定性,从而调节细胞骨架运动,促进气道上皮的损伤修复。

关键词：糖原合酶激酶3β 腺瘤性结肠息肉病蛋白气道上皮细胞损伤修复

基于“时空特点”探讨电针预处理对脑缺血大鼠钠钙交换体1的影响

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针灸临床杂志 2024年第1期40卷 61-67页

作者：宁文华李礼张宝瑜杨沙张丽丽樊小农沈燕张亚男王舒天津中医药大学第一附属医院天津300381 国家中医针灸临床医学研究中心天津300381 天津市针灸学重点实验室天津300381 国家中医药管理局脑病针刺疗法重点研究室天津300381 天津市中医药研究院附属医院天津300120

目的:观察电针预处理对永久性脑缺血大鼠不同时相、不同缺血区域钠钙交换体1(NCX1)表达的影响,并探讨其可能机制。方法:84只雄性SD大鼠随机分为假手术组、模型组和电针组,每组再分0、1、2和24 h亚组,每亚组各7只。电针刺激大鼠“百会”... 详细信息

目的:观察电针预处理对永久性脑缺血大鼠不同时相、不同缺血区域钠钙交换体1(NCX1)表达的影响,并探讨其可能机制。方法:84只雄性SD大鼠随机分为假手术组、模型组和电针组,每组再分0、1、2和24 h亚组,每亚组各7只。电针刺激大鼠“百会”、双侧“内关”和“三阴交”,疏密波,频率2/15 hz,强度1 ma,每次20 min,连续5 d。于末次电针后2 h采用线栓法制备大鼠永久性脑缺血模型,通过免疫组化染色及Western Blot观察电针预处理对不同时相(0、1、2和24 h)、不同缺血区域(缺血区、非缺血区)皮层NCX1阳性细胞数及蛋白表达的调控模式。结果:缺血区,3组间0 h时相NCX1蛋白表达差异无统计学意义(P>0.05);模型组NCX1蛋白表达于1、2和24 h均低于同时相假手术组,差异具有统计学意义(Ph、2 h显著高于同时相模型组差异具有统计学意义(Ph降至最低,与同时相模型组,差异无统计学意义(P>0.05)。非缺血区,3组间0 h时相NCX1蛋白表达比较差异无统计学意义(P>0.05);与同时相假手术组比较,模型组NCX1蛋白表达于2 h、24 h显著降低,差异具有统计学意义(Ph、24 h时NCX1蛋白表达,与同时相模型组比较,差异具有统计学意义(Ph、2 h NCX1蛋白及非缺血区2 h、24 h NCX1蛋白表达,可能是其脑保护作用的途径之一。

关键词：电针预处理脑缺血耐受钠钙交换体

基于磷脂酰肌醇-3激酶/蛋白激酶B/核因子κB通路探讨高原缺氧对大鼠蛛网膜下腔出血后血脑屏障的作用

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解剖学报 2023年第2期54卷 156-164页

作者：魏艳娜王锋存马香莲索田莎陈胜王兰桂孙娟赵秀丽青海大学附属医院神经内科西宁810001

目的探讨高原缺氧对大鼠蛛网膜下腔出血(SAh)后血脑屏障的作用及其机制。方法SPF级健康成年雄性SD大鼠(n=78),随机分为4组:假手术组(sham)、蛛网膜下腔出血模型组(SAh)、高原缺氧假手术组(hp sham)和高原缺氧蛛网膜下腔出血模型组(hp S... 详细信息

目的探讨高原缺氧对大鼠蛛网膜下腔出血(SAh)后血脑屏障的作用及其机制。方法SPF级健康成年雄性SD大鼠(n=78),随机分为4组:假手术组(sham)、蛛网膜下腔出血模型组(SAh)、高原缺氧假手术组(hp sham)和高原缺氧蛛网膜下腔出血模型组(hp SAh)。通过低压模拟舱(海拔5000 m)饲养4 d建立高原缺氧大鼠动物模型,采用颈内动脉刺破法建立SAh大鼠动物模型。SAh后24 h,各组大鼠进行神经功能学评分和出血严重程度评估,Nissl染色和TUNEL染色分别观察大鼠海马组织CA1区神经元形态变化和神经细胞凋亡,Western blotting检测大鼠海马组织磷酸化PI3K(p-PI3K)、PI3K、磷酸化Akt(p-Akt)、Akt、磷酸化核因子κB(p-NF-κB)、NF-κB及基质金属蛋白酶9(MMP-9)、闭锁蛋白(occludin)、紧密连接蛋白-5(claudin-5)的表达,免疫荧光染色观察大鼠海马组织CA1区occludin、claudin-5蛋白表达。结果SAh后24 h,SAh组与sham组、hp SAh组与hp sham组比较,大鼠神经功能评分明显下降,颅底出血量明显增加(Php SAh组与SAh组比较,神经功能评分明显下降(Ph组与sham组比较,大鼠海马组织CA1区神经元形态萎缩变形,神经元细胞排列紊乱,神经元数量明显下降,神经细胞凋亡明显增加(Ph组与sham组、hp SAh组与hp sham组比较,p-PI3K/PI3K、p-Akt/Akt、occludin及claudin-5蛋白的表达明显下降,p-NF-κB/NF-κB和MMP-9蛋白表达明显升高(Php SAh组与SAh组比较,p-PI3K/PI3K和MMP-9蛋白表达明显升高,hp sham组与sham组比较,claudin-5蛋白表达明显升高,差异均具有统计学意义(Ph组大鼠海马组织CA1区occludin、claudin-5蛋白的表达下降,高原缺氧后occludin、claudin-5蛋白的表达进一步降低。结论高原缺氧通过抑制PI3K/Akt/NF-κB通路加重蛛网膜下腔出血大鼠模型后血脑屏障破坏。

关键词：高原缺氧蛛网膜下腔出血血脑屏障磷脂酰肌醇-3激酶/蛋白激酶B/核因子κB通路免疫印迹法免疫荧光大鼠

美仁牦牛MYL 9基因克隆、生物信息学分析及组织表达研究

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中国畜牧兽医 2024年第4期51卷 1410-1419页

作者：马荣喇永福包鹏甲郭宪路建卫扎老赵雪梁春年成述儒甘肃农业大学兰州730070 中国农业科学院兰州畜牧与兽药研究所甘肃省牦牛繁育工程重点实验室农业农村部青藏高原畜禽遗传资源育种重点实验室兰州730050 合作市佐盖多玛乡畜牧站合作747000 合作市农畜产品质量安全检测检验中心合作747000

【目的】克隆美仁牦牛肌球蛋白轻链9(myosin light chain 9,MYL9)基因CDS区并对其进行生物信息学分析,检测MYL 9基因的组织表达特征,为探究该基因功能提供一定理论依据。【方法】以美仁牦牛肌肉组织cDna为模板,利用PCR扩增并克隆美仁牦... 详细信息

【目的】克隆美仁牦牛肌球蛋白轻链9(myosin light chain 9,MYL9)基因CDS区并对其进行生物信息学分析,检测MYL 9基因的组织表达特征,为探究该基因功能提供一定理论依据。【方法】以美仁牦牛肌肉组织cDna为模板,利用PCR扩增并克隆美仁牦牛CDS区序列,与其他物种进行相似性比对及系统进化树构建;通过在线软件对MYL9蛋白进行生物信息学分析,利用实时荧光定量PCR检测MYL 9基因在美仁牦牛心脏、肝脏、脾脏、肺脏、肾脏、肌肉、脂肪和睾丸组织中表达情况。【结果】美仁牦牛MYL 9基因CDS区长516 bp,共编码171个氨基酸。系统进化树结果显示,美仁牦牛与野牦牛、普通牛亲缘关系最近,与高山倭蛙亲缘关系最远。MYL9蛋白分子式为C 858 h 1324 N 234 O 274 S 12,原子数为2702,理论等电点为4.85,不稳定系数和总平均亲水性分别为37.22和―0.772,属于稳定亲水性蛋白。MYL9蛋白无信号肽和跨膜螺旋结构,属于非分泌性蛋白;主要定位于线粒体、细胞核、细胞质中,具有17个特异性磷酸化位点。MYL9蛋白二级结构主要由α-螺旋、无规则卷曲、β-折叠和延伸链构成,三级结构预测结果与二级结构一致。实时荧光定量PCR结果显示,MYL 9基因在美仁牦牛心脏、肝脏、脾脏、肺脏、肾脏、肌肉、脂肪和睾丸组织中均表达,且肝脏和肌肉组织中表达量显著高于其他组织(P<0.05)。【结论】本研究成功克隆美仁牦牛MYL 9基因CDS区,探究了MYL 9基因的生物学功能及组织表达特征,研究结果为进一步探究牦牛MYL 9基因功能特征提供了参考。

关键词：美仁牦牛 MYL 9基因克隆生物信息学组织表达

shRna抑制survivin基因表达对脐静脉血管内皮细胞增殖与凋亡的影响

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重庆医学 2015年第35期44卷 4922-4924,4928页

作者：马莎林俊晋松李芹张虹王静云南省第一人民医院风湿免疫科昆明650032

目的研究靶向存活素(survivin)的短发夹Rna真核表达质粒(shRna)对脐静脉血管内皮细胞增殖与凋亡的影响。方法合成靶向survivin的shRna真核表达质粒及阴性对照质粒,用脂质体法将质粒转染至经VEGF(50ng/mL)处理的hUVEC细胞;转染48h后,采... 详细信息

目的研究靶向存活素(survivin)的短发夹Rna真核表达质粒(shRna)对脐静脉血管内皮细胞增殖与凋亡的影响。方法合成靶向survivin的shRna真核表达质粒及阴性对照质粒,用脂质体法将质粒转染至经VEGF(50ng/mL)处理的hUVEC细胞;转染48h后,采用实时定量聚合酶链反应(PCR)和蛋白印迹法检测hUVEC中survivin的mRna表达及蛋白水平。四甲基偶氮唑蓝(MTT)法检测细胞增殖;TUNEL法检测细胞凋亡。结果(1)survivin-shRna质粒试验组与阴性对照shRna质粒组及空白对照组比较,转染48h后人脐静脉血管内皮细胞survivin的mRna及蛋白表达水平明显下降(PhRna组及空白对照组比较,转染后的人脐静脉血管内皮细胞增殖能力明显下降。转染后24、48、72h生长抑制率分别为(13.53±3.91)%、(38.97±1.82)%、(65.75±1.83)%,于转染后72h最为显著。(3)试验组凋亡率为(28.07±1.71)%,较阴性对照组(11.45±1.52)%和空白对照组(10.04±1.46)%显著增高(PhRna质粒能通过下调survivin表达,进而抑制人脐静脉血管内皮细胞增殖并促进其凋亡。

关键词：血管内皮生长因子存活素 shRna 增殖细胞凋亡

CEPC Technical Design Report

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Radiation Detection Technology and Methods 2024年第1期8卷 I0003-I0016,1-1091页

作者： waleed Abdallah Tiago Carlos Adorno de Freitas Konstantin Afanaciev shakeel Ahmad Ijaz Ahmed Xiaocong Ai Abid Aleem Wolfgang Altmannshofer Fabio Alves Weiming An Rui An Daniele Paolo Anderle Stefan Antusch Yasuo Arai Andrej Arbuzov Abdesslam Arhrib Mustafa Ashry sha Bai Yu Bai Yang Bai Vipul Bairathi Csaba Balazs Philip Bambade Yong Ban Tripamo Bandyopadhyay Shou-shan Bao Desmond P.Barber Ayse Bat Varvara Batozskaya Subash Chandra Behera Alexander Belyaev Michele Bertucci Xiao-Jun Bi Yuanjie Bi Tianjian Bian Fabrizio Bianchi Thomas Biekotter Michela Biglietti shalva Bilanishvili Deng Binglin Denis Bodrov Anton Bogomyagkov Serge Bondarenko Stewart Boogert maarten Boonekamp marcello Borri Angelo Bosotti Vincent Boudry Mohammed Boukidi Igor Boyko Ivanka Bozovic Giuseppe Bozzi Jean-Claude Brient Anastasiia Budzinskaya masroor Bukhari Vladimir Bytev Giacomo Cacciapaglia hua Cai Wenyong Cai Wujun Cai Yijian Cai Yizhou Cai Yuchen Cai haiying Cai huacheng Cai Lorenzo Calibbi Junsong Cang Guofu Cao Jianshe Cao Antoine Chance Xuejun Chang Yue Chang Zhe Chang Xinyuan Chang Wei Chao Auttakit Chatrabhuti Yimin Che Yuzhi Che Bin Chen Danping Chen Fuqing Chen Fusan Chen Gang Chen Guoming Chen hua-Xing Chen huirun Chen Jinhui Chen Ji-Yuan Chen Kai Chen mali Chen Mingjun Chen Mingshui Chen Ning Chen shanhong Chen shanzhen Chen shao-Long Chen shaomin Chen Shiqiang Chen Tianlu Chen Wei Chen Xiang Chen Xiaoyu Chen Xin Chen Xun Chen Xurong Chen Ye Chen Ying Chen Yukai Chen Zelin Chen Zilin Chen Gang Chen Boping Chen Chunhui Chen hok Chuen Cheng huajie Cheng shan Cheng Tongguang Cheng Yunlong Chi Pietro Chimenti Wen han Chiu Guk Cho Ming-Chung Chu Xiaotong Chu Ziliang Chu Guglielmo Coloretti Andreas Crivellin hanhua Cui Xiaohao Cui Zhaoyuan Cui Brunella D'Anzi Ling-Yun Dai Xinchen Dai Xuwen Dai Antonio De maria Nicola De Filippis Christophe De La Taille Francesca De Mori Chiara De Sio Elisa Del Core Shuangxue Deng Wei-Tian Deng Zhi Deng Ziyan Deng Bhupal Dev Tang Dewen Biagio Di Micco Ran Ding Siqin Dingl Yadong Ding haiyi Dong Jianin AGh University of Science and Technology Faculty of Physics and Applied Computer ScienceKrakow Anhui University HefeiAnhui Applied Physics Department Federal Urdu University of ArtsScience and TechnologyIslamabad Bana.a. hindu University Institute of ScienceVaranasi Bandirma Onyedi Eylul University Bandirma Beihang University Beijing Beijing Computational Science Research Center Beijing Beijing Conveyi LTD Beijing Beijing Glass Research Institute Co. LtdBeijing Beijing Institute of Technology Beijing Beijing Normal University Beijing Brown University ProvidenceRI Budker Institute of Nuclear Physics Novosibirsk Cadi Ayyad University Laboratory of Fundamental and Applied PhysicsPolydisciplinary FacultyMarrakech Cairo University Giza Center for Theory and Computation National Tsing Hua UniversityHsinchu Central China Normal University WuhanHubei Central South University ChangshaHunan Centro de Fisica Teorica de Particulas Universidade Tecnica de LisboaLisboa Chengdu KaitengSifang Digital Radio&TV Equipment Co. LtdChengduSichuan China.a.ademy of engineering physics MianyangSichuan China building materials academy Beijing China Center of Advanced Science and Technology Beijing China Institute of Atomic Energy Beijing China Jiliang University HangzhouZhejiang China Nuclear Instrument CO. LTDBeijing China University of Geosciences Beijing China University of Geosciences WuhanHubei China University of Mining and Technology XuzhouJiangsu China West Normal University NanchongSichuan Chongqing University Department of PhysicsChongqing Chulalongkorn University Bangkok City University of hong Kong Department of PhysicsHong Kong Cockcroft Institute Daresbury Cornell University IthacaNY CPPM(AMU/IPhU&CNRS/INP) Marseille Dalian Minzu University DalianLiaoning Dalian University of Technology Department of PhysicsDalian Deutsches Elektronen-Synchrotron DESY Hamburg Dzhelepov Laboratory of Nuclear Problems of Joint Institute for Nuclear Research(DLNP JINR) Dubna East China University Of Science And Technol

The Circular Electron Positron Collider(CEPC)is a large scientific project initiated and hosted by China,fostered through extensive collaboration with international *** complex comprises four accelerators:a 30 GeV Linac,a 1.1 GeV Damping Ring,a Booster capable of achieving energies up to 180 GeV,and a Collider operating at varying energy modes(Z,W,h,and tt).The Linac and Damping Ring are situated on the surface,while the subterranean Booster and Collider are housed in a 100 km circumference underground tunnel,strategically accommodating future expansion with provisions for a potential Super Proton Proton Collider(SPPC).The CEPC primarily serves as a higgs *** its baseline design with synchrotron radiation(SR)power of 30 MW per beam,it can achieve a luminosity of 5×10^(34)cm^(-2)s^(-1)per interaction point(IP),resulting in an integrated luminosity of 13 ab^(-1)for two IPs over a decade,producing 2.6 million higgs *** the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million higgs bosons,facilitating precise measurements of higgs coupling at sub-percent levels,exceeding the precision expected from the hL-LhC by an order of *** Technical Design Report(TDR)follows the Preliminary Conceptual Design Report(Pre-CDR,2015)and the Conceptual Design Report(CDR,2018),comprehensively detailing the machine's layout,performance metrics,physical design and analysis,technical systems design,R&D and prototyping efforts,and associated civil engineering ***,it includes a cost estimate and a preliminary construction timeline,establishing a framework for forthcoming engineering design phase and site selection *** is anticipated to begin around 2027-2028,pending government approval,with an estimated duration of 8 *** commencement of experiments and data collection could potentially be initiated in the mid-2030s.

关键词： initiated exceeding precise

复合金属板用高强度耐腐蚀聚酯型热熔胶的研制

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中国胶粘剂 2011年第1期20卷 44-48页

作者：李雅莎江静华何辉马爱斌河海大学力学与材料学院江苏南京210098

按照m[氯乙烯醋酸乙烯酯(VC-VAc)]∶m[二月桂酸二丁基锡(DBTDL)]∶m[邻苯二甲酸二丁酯(DBP)]∶m(硬脂酸钙)=50∶3∶4∶1比例配制复合氯醋树脂,然后以此作为聚酯热熔胶的改性剂。结果表明:当w(复合氯醋树脂)=30%(相对于热熔胶而言)时,改... 详细信息

按照m[氯乙烯醋酸乙烯酯(VC-VAc)]∶m[二月桂酸二丁基锡(DBTDL)]∶m[邻苯二甲酸二丁酯(DBP)]∶m(硬脂酸钙)=50∶3∶4∶1比例配制复合氯醋树脂,然后以此作为聚酯热熔胶的改性剂。结果表明:当w(复合氯醋树脂)=30%(相对于热熔胶而言)时,改性热熔胶的粘接强度为7.6 MPa,Tg提高到91.2℃;改性热熔胶在10%醋酸或40%naOh溶液中浸泡48 h后未发生剥离现象,其最大粘接强度分别为6.68 MPa和6.39 MPa;经5%naCl喷雾24 h或10%na2CO3溶液浸泡48 h后,其性能最接近未浸泡试样;该高性能热熔胶适用于双金属板的热复合。

关键词：聚酯热熔胶氯醋树脂耐介质性耐腐蚀

2010—2020年菏泽市麻疹监测病例实验室检测结果与流行病学特征

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医学动物防制 2022年第10期38卷 951-954页

作者：袁辉马敬仓沙娜刘景顺徐凌忠菏泽市疾病预防控制中心山东274010 济宁市第一人民医院山东大学公共卫生学院

目的分析2010—2020年菏泽市麻疹监测病例(measles surveillance cases, MSC)流行病学特征及病原学基因类型,为麻疹控制提供参考依据。方法对MSC进行调查并采集其急性期血清标本和咽拭子标本,使用酶联免疫吸附试验(enzyme-linked immu... 详细信息

目的分析2010—2020年菏泽市麻疹监测病例(measles surveillance cases, MSC)流行病学特征及病原学基因类型,为麻疹控制提供参考依据。方法对MSC进行调查并采集其急性期血清标本和咽拭子标本,使用酶联免疫吸附试验(enzyme-linked immunosorbent assay, ELISA)对血清标本进行IgM抗体检测,使用荧光定量反转录-聚合酶链反应(reverse transcription PCR,RT-PCR)对病原学标本进行核酸检测。采用统计软件对数据资料进行统计分析。结果 2010—2020年菏泽市共报告MSC 2 288例,检测1 979例麻疹病例IgM,阳性830例,阳性率为41.94%(830/1 979);检测1 760例风疹病例IgM,阳性88例,阳性率为5.00%(88/1 760)。麻疹发病年龄主要集中在14岁以下,占79.47%,男性多于女性(χ^(2)=8.46,Ph1a型。结论 2010—2020年菏泽市麻疹发病较低,MSC中存在麻疹、风疹病例,以麻疹病例居多,麻疹病毒类型为h1a基因型;要继续加强MSC报告,提高含麻疹成分疫苗(Measles-containing Vaccine, MCV)及时接种率。

关键词：麻疹监测病例流行病学特征病毒疫苗监测儿童试验

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

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Frontiers of Medicine 2021年第2期15卷 275-291页

作者： na Qin Yuancheng Li Cheng wang Meng Zhu Juncheng Dai Tongtong hong Demetrius Albanes Stephen Lam Adonina Tardon Chu Chen Gary Goodman Stig EBojesen maria Teresa Landi mattias Johansson Angela Risch h-Erich Wichmann heike Bickeboller Gadi Rennert Susanne Arnold Paul Brennan John KField Sanjay Shete Loic Le marchand Olle Melander hans Brunnstrom Geoffrey Liu Rayjean Jhung Angeline Andrew Lambertus AKiemeney shan Zienolddiny Kjell Grankvist Mikael Johansson Neil Caporaso Penella Woll Philip Lazarus matthew BSchabath Melinda CAldrich Victoria LStevens Guangfu Jin David CChristiani Zhibin hu Christopher IAmos hongxia ma hongbing Shen Department of Epidemiology Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing 211166China State Key Laboratory of Reproductive Medicine Center for Global HealthNanjing Medical UniversityNanjing 211166China Department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing 211166China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjing 211166China China International Cooperation Center for Environment and human health School of Public HealthNanjing Medical UniversityNanjing 211166China Division of Cancer Epidemiology and Genetics National Cancer InstituteBethesdaMD 20892-9304USA Department of Integrative Oncology British Columbia Cancer AgencyVancouverBC V5Z 1L3Canada Faculty of Medicine University of Oviedo and CIBERESPOviedo 33006Spain Program in Epidemiology Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleWA 98109-1024USA Public health Sciences Division Swedish Cancer InstituteSeattleWA 98026USA Department of Clinical Biochemistry Copenhagen University HospitalCopenhagen DK-1017Denmark national Cancer Institute BethesdaMD 20892-9304USA Genetic Epidemiology Group International Agency for Research on CancerLyon 69372France Cancer Center Cluster Salzburg at PLUS Department of Molecular BiologyUniversity of SalzburgHeidelberg 5020Austria Institute of Medical Informatics Biometry and EpidemiologyChair of EpidemiologyLudwig Maximilians UniversityMunichBavaria 80539Germany Department of Genetic Epidemiology University Medical Center GoettingenGoettingen 37075Germany Technion Faculty of Medicine Carmel Medical CenterHaifa 3448516Israel markey Cancer Center University of KentuckyLexingtonKY 40506-0054USA Department of Molecular and Clinical Cancer Medicine Roy Castle Lung Cancer Research ProgrammeThe University of Liverpool Institute of Translational MedicineLiverpool L697Z

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely *** integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility *** identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as Dnase I hypersensitive *** factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was *** annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency *** results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GwaS functional experiments.

关键词： lung cancer genome-wide association study function annotation immune homologous recombination repair deficiency genetic heterogeneity