用户名: 密码: 验证码:
哈萨克族食管癌与易感基因多态关系及免疫相关因素研究
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
目的:新疆是中国食管癌高发区之一,13个世居民族中哈萨克族人群(人口约200万),具有明显的地区性和家族聚集性,其在食管癌民族发病率中最高,调整死亡率达68.88/10万,为早期发现该民族食管癌患者以及降低其发病率与死亡率,本研究从食管癌发病的基因分子学角度及免疫的相关因素展开研究,探索其防治的新途径。该研究以新疆哈萨克族食管癌防治研究已有的基础为起点,从哈萨克族常用的食物受亚硝胺、多环芳烃等化学致癌物的长期污染入手,同时结合其生活习惯(吸烟、饮酒)等,探索叶酸代谢酶、致癌物代谢酶基因遗传多态性对环境致癌物的致癌效应所起的作用;利用先进的流式细胞技术(FCM)研究和探索该民族食管癌患者机体免疫状态的变化,检测血清中相应的细胞因子水平的变化,分析T淋巴细胞亚群的免疫活动,进一步了解该民族食管癌的发病机制。通过以上的研究,可为新疆哈萨克族食管癌的早期诊断、早期治疗提供科学指导依据,同时也为其在手术治疗后免疫调控方面提供科学的理论依据。
     方法:①收集经组织病理学确诊的哈萨克族食管鳞癌新发病例88例外周血液标本提取DNA;72例健康哈萨克族人群作为对照,同时调查每个研究对象的吸烟、饮酒情况。以聚合酶链反应方法进行MTHFR、CYP2C19、GSTT_1基因扩增:用PCR-限制性片段长度多态性技术检测研究对象的MTHFR 1298A→C、CYP 2C19ml、CYP
Objective: Esophageal cancer(EC) is a common disease in several areas of central Asia, including Xinjiang Uigur Autonmous Region, north of China. The incidence of Kazakh's EC has been considered as the highest among population in Xinjiang, and its aged-adjusted mortality rate up to 68.88/100, 000 reported by epidemiological study. The Kazakh population was estimated to be as 13 million around the world including 10million Kazakh distributed in Kazakhstan and 2 million in Xinjiang, north of China. The population in the current study was a Kazakh isolated community, which located at the northwest of Xinjiang. The genetic homogeneity and geography stability of the population, along with shared exposure to common environmental variables, may provide an excellent opportunity for the study on genetic influence for EC. These cancers are mostly squamous cell carcinoma (SCC). The series studies have suggested that a number of risk factors be involved in the carcinogenesis for Kazakh's ESCC, including deficiencies in vitamins and minerals, consumption of pickled foods and environmental exposure to specific nitrosamines, genetic susceptibility, etc.
    The high incidence in special areas indicated the importance of environment factors in esophageal etio-carcinogenesis. Only a small part of individuals in the high-risk area developed into EC although all the residents in that area may share very similar environment-related factors, such as the polymorphism of phase- I (CYP2C19)and phase-II enzymes (GSTT1), methylenetetrahydrofolate (MTHFR) may play an important
引文
[1] Pisani P, Parkin DM, Ferlay J. Estimates of the worldwide mortality from eighteen maj or cancers in 1985:implications for prevention and projections of future burden[J]. Int J Cancer, 1993, 55:891-903.
    [2] Coleman Mp, Esteve J, Damiecki P, et al. Esophagsus International Agency for Research on Cancer, Trends in cancer incidence and mortality. Iyon:I. A. R. C. Scientific Publications No. 121, 1993. p. 161-192.
    [3] 陈明星,龚惠芸,陈敏.新疆伊犁哈萨克自治州五种民族食管癌10年间的临床分析[J].中国内镜杂志,2002,8(11):80:81.
    [4] 李连弟.中国恶性肿瘤死亡谱及分类构成特征研究[J].中华肿瘤杂志,1997,19(5):323-328.
    [5] 张月明.新疆食管癌分布[J].新疆医学院学报,1998,11(2):139-144.
    [6] 余红平,施侣元,幺鸿雁,等.食管癌危险因素的Meta分析[J].中国公共卫生,2003.19(6):763-764.
    [7] Goldstein JA, Faletto MB, Romker GW, et al. Evidence that CYP2C19 is the major S-mephenytoin 4"-hydroxylase in hamans. Biochemistry, 1994, 33:1743-1752.
    [8] Xiao ZS, Goldstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Hunag SL, Xu ZH, zhou HH. Differences in the incidence of the CYP2c19 polymirphism affecting in the in cidence of the CYP2e19 polymirphism affecting the S-mephenytoin phenotype in Chinese Han and Bsipopulations and identification of a new rare CYP2C19 mutant allele. J Pharmacol EXP Ther, 1997, 281(1): 604-609.
    [9] Kihara M, Noda K, et al. Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorism in Japanese population. Carcinogeneis, 1999, 16:2331-2336.
    [10] Taioli E, Crofts F, et al. Racial differecesin CYP1A1 gene type and function. Toxico IL ett,.1995, 77:357-362.
    [11] Taiol E, Trachman J, then X, et al. A CYP1A1 restriction fragement length polymorism is associated with breast cancer in African-American women. Cancer Res, 1995, 55:3757-3758.
    [12] Taioli E, Ford J, Trackman J, et al. Lung cancer risk and CYP1A1 gene type African-American. Carcinogensis, 1998, 19:813-817.
    [13] 沈靖,王润田,王朝曦,等.中国南方汉族人群三种代谢基因多态性分布特征.中华医学遗传学杂志,2002,19(4):303-306。
    [14] 冷曙光,宋文佳,王雅文,等.中国汉族人中三种谷脱甘肽硫转移酶基因多态性分析[J].中华预防医学杂志,2001,35(3):159-162.
    [15] Xing D, Tan W, Lin D. Genetic polymorphisms and susceptibility to esophageal cancer among chinese population (review). Oncol Rep, 2003 sep-oct; 10(5): 1615-1623.
    [16] Wang LD, Zhang S, Liu B, et al. CYP1A1, GSTS and polymorphisms and susceptibility to carcinoma: Study of population from a high-incidence area in north china. World J Gastroneterol, 2003, 9(7): 1394-1397.
    [17] Soarikoski ST, Voho A, Reinikainen M, et al. Combined effect of poly- morphic GST genes on individual susceptibility to lung cancer. Int J Cancer, 1998, 77:516-522.
    [18] Liu Q, Reuing MV, et al. Simultaneous characterization of glutathione S_2 transferase M land T1 poymorphisms by polymerase chain reaction in American whites and blacks. Pharmacogenetics. 1996, 6:187-191.
    [19] Katoh T, Nagata N, Kuroda K, et al. Glutathione S_2 transferase MI(GSTM) and T1 (GSTT_1) genetic polymorphism and suscep-tibility to gastric and colorectal adenocacinogenesis. 1996, 17: 1855-1859.
    [20] 余传霖,叶天星,陆德源,等主编.现代医学免疫学.上海,上海医科大学出版社,1998,1014-1065.
    [21] Piccinni MP, Romagnaini S. Regulation of fetal allograft survival by a hormonecontrolled Th_1 and Th_2 type cytoki[J]. Immunol Res, 1996, 15:141-150.
    [22] Aniszewski JP, Valyasevi RW, Bahn RS. Relationship between duration and predominant orbital T cell subset in Graves ophthamopathy[J]. Clin Endocrinol Meta, 2000, 85:776-780.
    [23] De Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer VA, Goldstein JA. The maior genetic defect responsible for the polymorphism of S-mephemytoin metabolism in humans. J Biol Chem, 1994, 269:15419-15422.
    [24] Katoh T, Nagata N, Kuroda Y, et al. Glutathion(GSTM_1)and(GSTT_1) genetic polymorphism gastric and colorectal adnocarcinoma. Carcinogenesis.
    [25] Spitz MR, Bondy ML. Genetics susceptibility to cancer[J]. Cancer Supplement, 1993, 17(3):991.
    [26] Cassom AG, Zheng Z, Chiasson D, et al. Associations between genetic polymorphisms of Phase Ⅰ and Ⅱ metabolizing enzymes, p53 and susceptybility to esophageal adenoearcinoma[J]. Cancer Detect Prev, 2003, 27:139-146.
    [27] Tan W, Song N, Wang G Q, et al Impact of genetic polymorphisms in cytochrome p4502E1 and glutathione S-transferases M1, T1 and P1 on susceptibility to esophageal cancer among high-risk individnals in china[J]. Cancer Epidemiol Biomarkers Prev, 2000, 9:551-556. [28] Van Lieshout EM, Roelofs HM, Dekkers S, et al. Polymorphic expression of the glutathione S-transferase P1 gene and its susseptibility to Barrett's esophagus and esophageal carcinoma[J]. Cancer Res, 1999, 59:586-589.
    [29] Roth MJ, Dawsey SM, Wang G, et al. Association between GSTM1 and squamous dysplasia of the esophagus in the high risk region of Linxian, China[J]. Cancer lett, 2000, 156:73-81.
    [30] Butler WJ, Ryan P, Robers-Thomson IC. Metabolic genotypes and risk for colorectal cancer[J]. J Gastroenterol Hepatol, 2001, 16:631-635.
    [31] Goldstein JA, Faletto MB, Romker GW, et al. Evidence that CYP2C19 is the major S-mepheny to in 4'-hydroxylase in human. Biochemistry, 1994, 33:1743-1752.
    [32] Tew K, et al. Structure and function of glutathione transferses[J]. Boca Rat on Florida:CRC Press 1993:15.
    [33] Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome p4502C19: correlation between 2C19 and S-mephenytoin 4'-hydroxylation. Arch Biochem Biophys, 1993, 306:240-245.
    [34] 赵筱萍,赵鲁杭,陈枢青.100名健康人群CYP2C19基因型检测.浙江预防医学,1999,11:17-19。
    [35] 林东昕,唐永明,陆士新,等.谷胱甘肽转硫酶M1和T1基因型与食管癌危险性:病例.对照研究.中华流行病学杂志,1998,19(4):195-198.
    [36] de Morais SMF, Wickinson GR, Blaidell J, et al. Identification of a new genetic defect responsible for the polymorphism of Smephenytoin metabolism in Japanese. Mol Pharmacol, 1994, 46:594-598.
    [37] He N, Yah FX, Huang SL, Wang W, et al, CYP2c19 genotype and S-mephenytoin 4'-hydroxylation phenotype in a Chinese Dai population. Eur J Clin Pharmacol, 2002, 58:15-18.
    [38] Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Chin Phqrmacol, 2001, 5(2): 169-173.
    [39] Cai L, Yu SZ, Zhang ZF. Glutathione S-transferase M1, T1 genotypes and the risk of gastric cancer : a case-control study[J]. World J Gastroenterol, 2001, 7:506-509.
    [40]Tan W, Chen GF, Xing DY, et al. Frequency of CYP2A6 gene deletion and it relation to risk of lung and esophageal cancer in the Chinese population[J]. Int J Cancer, 2001, 95:96-101.
    [41]Shibute J, Eto T, Kataoda A, et al. Genetic polymorhism of N-ace- tyltransferase 2 in patients with esophageal cancer [J]. Am J Gastroenterol 2001, 96:3419-3424.
    [42]Lee JM, Lee YC, Yang SY, et al. Genetic polymorphisms of XRCC1 and risk of the esophageal cancer[J]. Int J Cancer, 2001, 95:240-246.
    [43]Song C, Xing D, Tan W, et al. Methylenetetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population[J]. Cancer Res, 2001, 61:3272-3275.
    
    [44] 林东昕.中国食管癌分子流行病学研究.中华流行病学杂志 2003, 24(10):939-943.
    [45]Wang AH, Sun CS, Li LS, et al. Genetic susceptibility and environmental factors of exophageal cancer in Xi'an[J]. World J Gastroenterol, 2004, 10:940-944.
    [46]Dong CH, Yu SZ, Zhao DM, et al. Association of polymorphisms of glutathiones S transferase M1 and T1 genotypes with elevated aflatoxin and increase risk of primary liver cancer [J]. Huaren Xiao Hua Zazhi, 1998, 6:463-466.
    
    [47]Gao J, Ren CL, Zhang Q. CYP2D6 and GSTM1 genetic polymorphism and lung cancer susceptibility [J]. Zhonghua Zhongliu Zazhi, 1998,20:185-186.
    [48]Cai L, Yu SZ. A molecular epidemiologic study on gastric cancer in changle, Fujian province[J]. Shijie Huaren Xiaohua Zazhi, 1999, 7(8):652-655.
    [49]Cai L, Yu SL. Preliminary studies on cytochrome P4502E1 and Glutathione S-transferaseT1 polymorphisms and susceptibility to gastric cancer [J]. Zhongguo Gonggong Weisheng, 1979. 15:895-897.
    [50]Matsuo K, Suzuki R, Hamajima N, et al. Association between polymorphisms of folate-and methionine methionine metabolizing enzymes and susceptibility to malignant lymphoma. Blood, 2001, 97:3205-3209.
    [51]Keku T, Millikan R, Worley K, et al. 5, 10-Methylenetetrahydrofolate Rductase codon 677and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epoidemiol Biomark Prev, 2002, 11:1611-1621.
    [52] 缪小平,刑德印,谭文,等. MTHFR 基因 677T 和A1298C 多态与贲门癌的易感性.中华医学杂志, 2002, 82:669-672.
    [53]Song C, Xing D, Tan W, et al. Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res, 2001, 61:3272-3275.
    [54]Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism dietary interactions and risk of colorectal cancer. Cancer Res, 1997, 57:1098-1102.
    [55]Ulrich CM, Kampman E, Bigler J, et al. Colorectal adnomas and the c677T MTHFR polymorhism evidence for gene-environm ent interaction? Cancer Epidemiol Biomark Prev, 1999, 8:659-668.
    [56]Lathrop Stern L, Mason IB, Selhub J, et al. Gemomic DNA hypomethylation, a characteristic of most cancer is present in peripheral leukocytes of individuals who are homozygous for the c677 T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomark Prev, 2000, 9:849-853.
    [57]Halsted CH, Villanueva JA, Devlin AM, et al. Metabolic interactions of alcohol and folate. J Nutr, 2002, 132:s2367-s2372.
    [58]Kenyon SH, Nicolaon A, Gibbons WA. The effect of ethanol and its metabolites upon methionine synthase activity in vitro alcohol. 1998, 15:305-309.
    [59]Piyathilake C J, Macaluso M, Hine RJ, et al. Local and systemic effects of cigarette smoking on folate and vitamin B12. Am J Clin Nutr, 1994, 60:559-566.
    [60]Van der Put NMJ, Gabreels F, Stevens EMB, et al. A second common mutation in the metylenetrahydrofolate reductase gene: a additional risk factor for neurualtube defects. Am J Hum Genet, 1998, 62:1044-1051.
    [61]Skibola CF, Smith MJ, kane E, et al. Polymorphisms in the methylenetetrahydrofolate leductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA, 1999, 96:12810-12815.
    [62]Yamamura M, Modlin Rl, Ohmen JD, et al. Local expression of anti-in-flammatory cytokines in cancer[J]. Clin Invest, 1993;91:1005.
    [63]Kharkevitch DD, Seito D, Balch GC, et al. Characterization of antologous tumor-specific T-helper 2 cells in tumor-infiltrating lymphocytes from a patient with metastatic melanoma [J]. Int J Cancer, 1994,58:317.
    [64]Tabata T, Hazama S, Yoshino S, et al. TH2 subset dominance among peripheral blood T lymphocytes in patients with digestive cancers[J]. Am J Surg, 1999, 177:203.
    [65]Seiter S, Marinola FM. The multiple ways to tumor torlerance [J]. Mod Asp Immunobiol, 2000;l(3):121.
    [66]Matsui S, Ahlers JD, Vortmeyer AO, et al. A model for CD8+CTL tumor IMMunosurveillance and regulation of tumor escape by CD4+T cell through an effect on quality of CTL[J]. J Immunol, 1999, 165:184.
    [67]Satto T, Shimoda K, Kinoshtta T, et al. Prediction of ope-ractive mortality based on impairment of host defense system in patient with esophageal cancer. J Surg Oncol, 1993, 52:1-2.
    [68]Tsutsui SH, Mortta M, Kuwano H, et al. Innfluence of preoperative treatment and surgical operation on immune function of patient with esophageal carcinoma. J Surg Oncol, 1992, 49:176-177.
    [69] Jablonska E, Kozlowski M, Pietruska Z, et al. Soluble interleukin-2 receptor in serum of patients with esophageal carcinoma. Neoplasma, 1994, 41: 315-316.
    [70] 陈强,陈荫椿,钱镜秋,等.肺癌食管癌病人手术前后T淋巴细胞亚群的动态研究.中华胸心血管外科杂志,1992,8:166-167.
    [71] 程邦昌,陈克能,梅强,等.食管癌患者外周血T淋巴细胞亚群,肿瘤坏死因子的改变及其相关因素研究.中华实验外科杂志,1998,15:226-228.
    [1] D.M, Parkin, F, Bray J, Ferlay, et al. Estimatiny the world cancer burden: Go.dbocan 2000[J]. Int. J. Cancer, 2001, 94:153-156.
    [2] Munoz N. Epidemiologieal aspects of esophageal cancer[J]. Endoscopies. 1993, 23:609-612.
    [3] 王瑞林.食管癌研究进展[M].第一版,郑州:河南医科大学出版社,1993,15.
    [4] 李连弟.中国恶性肿瘤死亡谱及分类构成特征研究[J].中华肿瘤杂志,1997,19(5):323-328.
    [5] Murphy LO, Cluch MW, Lovas S, Otvos F, Murphy RF, et al. Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions[J]. Br J cancer. 2001, 84(7):926-935.
    [6] 兰春慧,吴小翎.胃癌及胃癌前病变中表皮生长因子和受体表达研究[J].重庆医学,2000,29(3):196-197.
    [7] Pfeiffer A, Rothbauer E, Wiebecke B, et al. Increased epidermal growth factor receptor in gasti carcinomas[J]. Gastroenterdogy, 1990, 98(4):961-967.
    [8] Leu CM, Chang C, Hu C. Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway[J]. Ocogene, 2000, 19(13):1665-1675.
    [9] 辜鸣,周南进.胃癌及食管癌患者癌组织中表皮生长因子和生长抑素含量变化[J].江西医药,1999,6:352-354.
    [10] 许翠萍,耿引风,徐大毅.转化生长因子-A与肝脏[J].中华消化杂志,1998,18(3):174-176.
    [11] Berynck R. Transforming growth factor alpha[J]. Cell, 1988, 54:593-594.
    [12] Jones MK, Tonikawa M, Mohajer B, et al. Gastrointestinal mucosal regeneration: role of growth factors[J]. Front Biosci, 1999, 15:D303-309.
    [13] 高文宽,武金有,浦佩玉.人脑胶质癌转化生长因子-A基因表达的研究[J].中华神经外科杂志.1998,13(2):68-69.
    [14] 章有翠.食管癌患者手术前后SP-selection及TGF-α含量测定的临床意义[J].放射免疫学杂志,2002.15(2):100-101.
    [15] 何浩明,李国仁,田小平,等.食管癌患者手术前后血清IL-2与slL-2R水平的检测[J].标记免疫分析与临床,1999,6(3):141.
    [16] Wang Y, Minoshima S, Shimizu N. Precise mapping of the EGF receptor gene on the human chromosome 7p12 using an improve FISH technique. Jpn J Hum Gene, 1993, 38:399-406.
    [17] Fabricant RN, Delarco JE, Toduro J. Ner regrowth factor receptor on human melanoma cells in Culture[J]. Proc Natl Acad Sci USA. 1997, 74:565-569.
    [18] Ozawa S, Ueda M, Ando N, et al. Epidermal growth factor receptors in cancer tissues of esophagus, lung, pancreas, colorectum, breast and stomach[J]. Jpn J Cancer, 1988, 79:1201-1207.
    [19] 赵金满,李福才,傅宝玉,等.食管癌中表皮生长因子受体基因扩增的研究[J].中华消化杂志.2001,21(11):694-695.
    [20] Gibson MK, Abraham SC, Wu TT, et al. Epidermal growth factor receptor, p53 mutation and pathological response predict survival in patients with locally advanced esophageal cancer treated with preoperative chemoradiotherapy[J]. Clin Cancer Res, 2003, 159(17):6461-6468.
    [21] Iihara k, Shiozaki H, Tahara H, et al. Prognostic significance of trans-forming growth factor-alpha in human esophageal carcinoma. Implication for the autoerine proliferation[J]. Cancer, 1993, 71(10):2902-2909.
    [22] Bargmann CL, Hung MC, Wenberg RA. The nen oncogene encodes an epidermal growth factor receptor-realted protein[J]. Nature, 1986. 39(6050):226.
    [23] Stemmermann G, et al. Hum Pathol, 1994, 25:968.
    [24] Lain KY, Tin L, Ma L. C-erbB-2 protein expression in esophageal squamous epithelium from oesophageal squamous cell carcinoma, with special reference to histological grade of carcinoma and pre-invasive lesions[J]. Eur J Surg Oncol, 1998, 24(5):431-435.
    [25] Felip E, Campo JM, Rubio D, et al. Overexpression of cerbB-2 in epithelial ovarian cancer[J]. Cancer, 1995, 75(1)2147.
    [26] 刘国龙,张万岱,宋子刚,等.食管癌与正常食管组织EGF、EGFR和Cerb-B2蛋白的表达[J],新消化病学杂志,1996,4(2):86-87.
    [27] 石勇,袁尔思,王树成.nm23-H1、Cerb-B2的表达与食管癌的预后关系[J].山东医药,2001,41(4):17.
    [28] 仲崇俊,陆松华,钱东生,等.食管癌nm-23-H1、cerb-B2基因mRNA表达及临床意义.南通医学院学报,2003,23(3):249-252.
    [29] 胡晓明,曹晴,刘玉龙,等.多项癌基因表达在食管癌术后随访病人中的临床意义.中华临床医药,2003.4(4):18.
    [30] Holstein MC, Peri L, Mandard AM, et al. Genetic analysis of human esophageal tumors from two high incidence geographic area. Cancer Res, 1991, 51(8):4102.
    [31] Sorsdah, K, Gasson AG, Troste M, et al. P53 and ras gene expression in human esophageal cancer and Barrett's epithelium. Cancer Dete and Prey, 1994, 18(3): 179.
    [32] 仇容,聂晓敏,何新康.K-ras基因的临床研究进展[J].杭州医学高等专科学校学报,2003,24(3):117-120.
    [33] 王小闯,李秀霞,孙润芹,等.细胞周期素D_1和P_(21)WAFi/CIP_1蛋白在肺癌组织中的表达[J].西安医科大学学报,2002.23:220-222.
    [34] 周俊,杨文铎,袁建华.周围型肺腺鳞癌CT表现与ras-P21蛋白异常表达的关系[J].实用医学影像杂志,2002,3:1-3.
    [35] 丁续红,杨炯,张旗,等.P21 wafl P53和PCNA在肺癌组织中的 表达肿瘤,2001,21:363-366.
    [36] 丁续红,田素梅,李清泉,等.肺癌组织P21waft蛋白表达与细胞增生的关系[J].武汉大学学报,2001,22:14-17.
    [37] 丁续红,杨炯,胡苏萍,等.P53,P21wafl和增生细胞核抗原诊断肺癌的评估.中华流行病学杂志,2001,22:54-57.
    [38] 杨力军,邵国兴,刘荣福,等.人前列腺癌中P_(21)CIP_1/WAF_1Rb表达意义[J].第四军区大学学报,2001,22:1108-1110.
    [39] 杜少陵,黄文斌,李树仁,等.P27KIP和P53及P_(21)WF_1/CIP,表达与胃癌临床病理及预后的关系[J].中华胃肠外科杂志,2002,5:41-44.
    [40] 苏琦,谢海龙,凌晖,等.P21WAF1基因在胃癌及癌前病变中表达的临床病理意义[J].肿瘤防治研究,2002,29:43-45.
    [41] 张远费,张钢锋,王桂荣,等.rasP21GST在胃癌及癌前病变组织表达的研究.临床消化病杂志,2001,13:264-266.
    [42] 孙哲,高鹤立.P2l rasP16在大肠癌中的表达及临床意义[J].世界华人消化杂志,2001,9:1399-1403.
    [43] 王锡山,薛英威,董薪舒,等.结肠癌P21 nm23基因表达联合检测的意义[J].实用肿瘤学杂志,2001,15:264-265.
    [44] 叶龙珍,董淑兰,杨玲芳,等.胃癌中生长抑素P21基因蛋白表达及意义[J].青海医药杂志,2001,31:3-6.
    [45] 戴文斌,任占平,阮伶,等.胃癌及癌前病变中P16、P21WAF1、CDK4、CyclinD1蛋白的表达及其意义[J].癌症,2001,20:1074-1077.
    [46] 张允清,谢立.P53P2l在食管癌和鼻咽癌中的表达及意义[J].河南肿瘤学杂志,2002,15:287-288.
    [47] 牛韵韵,高巍,张云汉,等.P53 P21与细胞周期调节蛋白在食管癌中的表达及意义[J].中国民政医学杂志,2000,12:339-341.
    [48] Shirakawa Y, Naomoto Y, Kimura M, et al. Topological analysis of P21 WAF1/CIP1 expression in esophageal squamous dysplasis[J]. Clin Cancer Res, 2000, 6:541-550.
    [49] Hanax JS, Lerner MR, Lightfoot SA, et al. Expression of the cyclin-dependentkinase inhibitor P21 (WAF 1/CIP 1) and P53 tumor suppressio.n dysplastic progression and adenocarcinoma in Barrett esophagus[J]. Cancer, 1999, 86:756-763.
    [50] 赵振林,李家成,唐进,等.P21蛋白在食管癌及食管良性增生性病变中的表达[J].山西临床医药,2002,11:329-331.
    [51] Neel BG. Two human concgens are located on the long arm of chromosome[J]. Proc Nal Aca Sci USA, 1982, 79(24):7842-7844.
    [52] Fan X, Yu CY, Zhao YL. Clinial significance and expression of c-myc gene protein in genitalial leukoplakia and squmous cen carcinoma of vulva[J]. J Fourth Mil Meal Univ, 2001, 22(24): 2262-2265.
    [53] 王成裕,付保进,张云汉,等.食管癌发生发展过程中C-myc蛋白与GST的表达[J].郑州大学学报(医学版),2002,37:341-343.
    [54] 李娟,王泌,严祥,等.食管癌组织hTERT和c-myc的表达[J].第四军医大学学报,2003,24(18):1662-1664.
    [55] 杨立峰,王跃江,佟倜,等.Myc族癌基因与食管癌相关性的研究[J].中国肿瘤临床与康复,2000,7(5):16-17.
    [56] Kamb A, Gruis NA, Felduaus JW, et al. A cell cycle regulator potentially involved in genesis of many tumor gypes[J]. Science, 1994, 264(15):436-460.
    [57] Eads CA, Danenberg KD, kawakamiK, et al. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyl- transferase[J]. Cancer Res, 1999, 59(19):2302-2306.
    [58] Takeuehi H, Ozawa S, Ando N, et al. Altered P16/MTS1/CDKN2 and cyclin D 1/PRAD-1 gene expression is associated with the prognosis of squarnous cell carcinoma of the esophagus[J]. Clin Cancer Res, 1997, 3(12pt1):2229-2236.
    [59] 郑杰,侯萍,周传龙,等.CDKN2(P~(16INK4)/MTS_1)基因丢失和CyclinD1扩增在食管癌发生中的意义[J].中华肿瘤杂志,1996, 18(6):408-411.
    [60] Barnett MT, Sanchez CA, Galipeau PC, et al. Allelic loss of 9p21 and mutation of the CDKN2/pt6 gene develop as early lesions during neoplastic progression in Barrett's esophagus[J]. Oncogene, 1996, 13(9):1867-1873.
    [61] Xing EP, Nie Y, Wang LD, et al. Aberrant methylation of P16 Ink4a and deletion of p15 INK4b are frequent events in human esophageal concer in Linxian, China[J]. Carcinogenesis, 1999, 20(1):77-84.
    [62] 李小飞,刘锟,程庆书,等.P53和P16在食管癌中的表达[J].世界华人消化杂志,2004,12(6):1476-1478.
    [63] 张红,牛韵韵,胡曼平。食管癌中P53、P21、P16、cyciinD1、CDK4免疫组化检测.免疫学杂志,2003,19(4):312-321.
    [64] Ewen ME, Sluss HK, sherr CJ, et al. Functional interactions of the retinoblastoma protein with mammalian D-type cyclines[J]. Cell, 1993, 73:487-497.
    [65] Motokura T, Bloom J, Kim HG, et al. A novel cyclin encodea by abcll linked candidate oncogene[J]. Nature, 1991, 350(6318):512-515.
    [66] Roncalli M, Bosari S, Marehetti A, et al. Cell cycle-related gene abnormalities and product expression in esophageal carcinoma[J]. Lab Invest. 1998, 78(9): 1049-1057.
    [67] 李吉学,向欣,王立东,等.河南食管癌高发区居民食管癌和癌变组织细胞周其素D1蛋白和mRNA表达[J].河南医学研究,2003,12(3):197-200.
    [68] 范祖森,敖世洲.肿瘤抑制基因Rb与细胞周期调控研究新进展[J].生物化学与生物物理进展,1999,26(5):429-433.
    [69] Good rich DW, Wang NP, Qian YW, et al. The retinoblastoma gene product regulates progressing through the GI phase of cell cycle[J]. cell, 1991, 67:293-302.
    [70] Pogi MG, Baldi A, Bonetto F, et al. Retinoblastona protein family in cell cycle and cancer[J]. J Cell Biochem, 1996, 62:418-438.
    [71] 王立东,陈虹,郭丽梅.肿瘤抑制基因P53-Rb系统变化与食管癌变关系研究及展望[J].世界华人消化杂志,2001,9(4):367.
    [72] Xing EP, Yang GY, Wang LD, et al. Loss of heterozygosity of the Rb gene correlates with pRb protein expression and associates with p53 alteration in human esophageal cancer[J]. Clin Cancer Res, 1999, 5(5):1231-1240.
    [73] Kawaguchi H, Ohno S, Araki k, et al. p53 polymorphism in human papillomavirus-associated esophageal cancer[J]. Cancer Res, 2000, 60(11):2753-2755.
    [74] Hamada M, Naomoto Y, Shirakawa Y, et al. P53 expression and P21 expression are mutually exclusive in esophageal squamons cell carcinoma[J]. Oncol Rep, 2004, 11:57-63.
    [75] Hattori K, Kajiyama Y, Tsurumaru M. Mutation of the P53 gene predicts lymph node metastases in Japanese patients with esophageal carcinoma: DNA and immunohistochemical analyses[J]. Dis Esophagus, 2003, 16:301-306.
    [76] 靳玉兰,张伟,刘伯齐,等.食管癌前病变及原位癌组织中Ki67P53iNos的异常表达[J].中华肿瘤杂志,2001,23:129-131.
    [77] 张允清,谢立.P53、P21在食管癌和鼻咽癌中的表达及意义[J].河南肿瘤学杂志,2002,15:287-288.
    [78] 李小飞,刘辊,程庆书,等.P53和P16在食管癌中的表达[J].世界华人消化杂志,2004,12(6):1476-1478.
    [79] 陶仪声,宗永生.食管癌旁上皮及原位癌中P53蛋白的表达及意义[J].临床肿瘤学杂志,2002,17:168-169.
    [80] 廖琼,杨霞,孙维纲,等.食管鳞癌P53、c-erebB2蛋白的表达研究[J].中国组织化学与细胞化学杂志,2000,9:175-177.
    [81] Chatelain D, Flejou JF. High-grade dysplasia and superficial adenocarcinoma in Barrett's esophahus: histologieal mapping and expression of p53,P21and Bcl-2 oncoproteins[J]. Virehows Arch, 2003, 442:18-24.
    [82] Doak SH, Jenkins GJ, Parry EM, et al. Characterisation of P53 status at the gene, chromosomal and protein levels in esophageal adenocarcinoma[J]. Br J Cancer, 2003, 89:1729-1735.
    [83] Matsumoto M, Furihata M, Kurabayashi A, et al. Association between inclucible nitric oxide synthase expression and P53 status in human esophageal squamous cell carcinoma[J]. Oncology, 2003, 64:90-96.
    [84] Chen H, Wang LD, Guo M, et al. Alternations of P53 and PCNA in cancer and adjacent tissues concurrent carcinomas of the esophagus and gastric cardia in the same patient in Linzhou, a high incidence area for esophageal cancer in northern china. World J Gastroenterol, 2003, 9:16-21.
    [85] 毛友生,赵晓航,张德超,等.食管癌肿瘤标志物研究进展[J].世界华人消化杂志,2002,10:1321-1323.
    [86] Shimada H,, Okazumi S, Takeda A, et al. Presence of serum p53 antibodies is associated with decreased in vitro hemosensitivity in patients with esopheal cancer[J]. Surg Today, 2001, 31:591-596.
    [87] Shimada H, Takeda A, Arima M, et al. Serum P53 antibody is a useful tumormarker in superficial esophageal squamous cell carcinma[J]. Cancer, 2000, 89:1677-1683.
    [88] Fujiki T, Haraoka S, Yoshioka S, et al. P53 Gene mutation and genetic instability in superficial multifocal esophageal squamous cell carcinoma[J]. Int J Oncol, 2002, 20:669-679.
    [89] Thomas M, Kalita A, Labrecques, et al. Two polymorphic Variants of wild-type P53 differ biochemically and biologically. Mol Cell Biol, 1999, 19:1092-1100.
    [90] 林东昕.中国食管癌分子流行病学研究.中华流行病学杂志,2003,24(10):939-943.
    [91] Lee JM, Lee YC, Yang SY, et al. Genetic polymorphisms of P53 and GSTP1 but not NAT2, are associated with susceptibility to squamous cell carcinoma of the esophagns. Int J Cancer, 2000, 89:458-464.
    [92] Kawaguchi H, Ohno S, Araki K, et al. P53 polymorphism in human papillomavirus associated esophageal cancer. Cancer Res, 2000, 60:2753-2755.
    [93] Peixoto GD, Lu SH, Snijders P, et al. Absence of association between Hpv DNA, T P53 codon 72 polymorphism and risk of oesophageal cancer in a high-risk area of china. Cancer Lett, 2001, 162:231-235.
    [94] Li T, Lu ZM, Gno M, et al. P53 codon 72 polymorphism (C/G)and the risk of human papillomavirus-associated carcinoma in china. Cancer, 2002, 95:2571-2576.
    [95] Gleeson CM, Sloan JM, Mcguigan JZ, et al. Base transitions at CpG dinucleotides in the P53 gene are common in esophageal adenocarcinoma[J]. Cancer Res, 1995, 55(15):3406-3411.
    [96] Lung ML, Chan WC, Zong YS, et al. P53 mutational spectrum of esophageal carcinoma from five different geographical locales in china[J]. Cancer Epidemiol Biomarkers Prev, 1996, 5(4):277-284.
    [97] Montesano R, Hollstein M, Hainant P. Genetic alternations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer, 1996, 69(3):225-235.
    [98] Baron PL, Gates CE, Reed CE, et al. P53 over expression in squamous cell carcinoma of the esophagns[J]. Ann surg oncol, 1997, 4(1):37-45.
    [99] An-Hui Wang, chang-sheng Sun, Liang shou Li, et al. Genetic susceptibility and environmental factors of esophageal factors of esophageal cancer in xi'an[J]. world J Gastroenterol, 2004, 10(7):940-644.
    [100]Lin DX, Tang YM, Deng Q, et al. Suspectibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2El. Cancer Epidemiol Biomarkers Prev, 1998, 7:1013-1018.
    [101] Tan W, Song N, Wang GQ, et al. Impact of genetic polymorphisms in cyto -chrome P450 2El and glutathione S-transferases M1, T1, and P1 on susceptibility to esophageal cancer among high risk individuals in china. Cancer Epidemiol Biomarkers Prev, 2000, 9:551-556.
    [102] Andrew FO, Mark CW, Mary AW, et al. GSTM1 GSTT1, GSTP1, CYP 1A1 and NAT1 polymorphisms, tabaccouse and the risk of head and neck cancer[J]. Cancer Epidemio Biomarkers Prve, 2000, 9:185-191.
    [103] Hayashi S, Watanabe J, Nakachi K, et al. Genetic linkage of lungcancerassociated Msp I polymorphism switaminoacid replacement in the hemebinding region of the humanly tochrome P4501A1 gene[J]. J Biochem. 1991, 110(3):40-47.
    [104] Wang AH, Sun CS, Li LS, et al. World J Gastroenterol, 2002, 8(1):49-53.
    [105] Nimura Y, Yokogamas, Fujimori M, et al. Cancer, 1997, 80(5): 852-857.
    [106] Hori H, kawamo T, Endo M, et al. J Clin gastroenterol, 1997, 25(4):568-575.
    [107] Mannervirk B, Awasthi YC, Board PG, et al. Nomeuclature for human glutathione transferase[J]. Biochem J, 1992, 282:305-306.
    [108] 黄志刚.谷胱苷肽硫转移酶GSTMl基因多态性与食管癌Meta分析[J].中国肿瘤,2003,12(11):462-464.
    [109] Roth MJ. Dawsey SM, Wang G, et al. Association between GSTM1 (-) and squamous dysplasia of the esophagus in the high risk region of Linxian, china, cancer Lett, 2000, 156:73-81.
    [110] 邵根泽,苏艳蓉,黄革,等.CYP1A1、GSTM1基因多态性与食管癌遗传易感性的关系.中华流行病学杂志,2000,21:420-423.
    [111] Nimura Y, Yokoyama S, Fujimori M, et al. Genotyping of the CYP1A1 and GSTM1 genes in esophageal carcinoma patients with special reference to smoking. Cancer, 1997, 80:852-857.
    [112] Wang AH, Sun CS, Li LS, et al. Relationship of tobacco smoking CYP1A1, GSTM1 genes polymorphism and esophageal cancer in xi'an World J Gastroenterol, 2002, 8:49-53.
    [113] Van Lieshout E M, Reelers HM, Dekker S, et al. Polymorphic expression of the glutathione S- transferase P1 gene and its susceptibility to Barrett's esophagus and esophageal carcinoma[J]. Cancer Res, 1999, 59(3):586-589.
    [114] Morita S, Yano M, Tsujinaka T, et al. Association between gentic polymorphism of glutathione S-tramsferases p1 and N-acetyl-transferase 2 and susceptibility to squamous-cell carcinoma of the esophagus[J]. Int J Cancer, 1998, 79(5):517-520.
    [116] Keitoro M, Nouyuki H, Mosayuki S, et al. Carcinogesis, 2001, 22(6):913-916.
    [116] 杨怀瑾,刘杰,黄洪林.细胞色素P450lAl基因多态与我国某些肿瘤遗传易感性[J].生命化学,2003,23(6):460-462.
    [117] Song CY, Xing DX, Tan W, et al. Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a chinese population. Cancer Res, 2001, 61:3272-3275.
    [118] 林东昕.中国食管癌分子流行病学研究.中华流行病学杂志,2003,24(10):939-943.
    [119] Thompson LH, Brookman KW, Jone NJ, et al. Molecular cloning of the human XRCC 1 gene, which corrects defective DNA strand break repair and sister chromatid exchang. Mol Cell Biol, 1990, 10:6160-6171.
    [120] Tebbs RS, Flannery ML, Meneses JJ. et al. Requirement for the XRCC1 DNA base excision repair gene during early mouse development. Dev Biol, 1999, 208:513-529.
    [121] Abdel-Rahman SZ, EL-Zein RA. The 399 GLn polymorphism in the DNA repair gene XRCC1 modulates the genotoxis response induced in human lymphocytes by tobacco-specific nitrosamine NNK. Cancer Lett, 2000, 159:63-71.
    [122]Lee JM, Lee YC, Yang SY, et al. Genetic polymorphisms of XRCC1 and risk of the esophageal cancer. Int J Cancer, 2001, 95:240-246.
    [123]Kohno T, Shinmura K, Tosaka M, et al. Genetic Polymorphisms and alternative splicing of the hoGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogen, 1998, 16:3219-3226.
    [124]Xing D, Tan W, Lin D. Genetic polymorphisms and susceptibility to esophageal cancer among Chinese population (review). Oncol Rep, 2003 sep-oct;10(5):1615-1623.
    [125]Tanaka S, Akiyoshi T, Mori M, et al. A novel frizzled gene identified in human esophageal carcinoma mediates Apc/beta- catenin signals[J]. Proc Nail Acad Sci USA. 1998, 95(17):10164- 10169.
    [126]Ohta M, Inoue H, Cotticelli MG, et al. The FHIT gene, spanning the chromosome 3 P14. 2 fragile site and renal carcinoma associated (3;8) breakpoint, is abnormal in digestive tract cancers [J]. Cell, 1996, 84(4):587-597.
    [127]Michael D, Beer DG, Wilkes CW, et al. Frequent deletions of FHIT and FRA3B in Barrett's metaplasia and esophageal adenocarcinomas [J]. Oncogene, 1997, 15(14):1653-1659.
    [128]Zou TT, Lei J, Shi YQ, et al. FHIT gene alterations in esophageal cancer and ulcerative colitis(UC)[J]. Oncogene, 1997, 15(1): 101- 105.
    [129]Mollenhauer J, Wie mann S, Scheurlen W, et al. DMBT1, a new memberof the SRCR superfamily on chormosome 10925. 3-26. 1 is deleted in malignant brain tumors[J]. Nature Gentt, 1997, 17:32-39.
    [130] Mori, shiraishi T, Janaks S, et al. Lack of DMBT1 expression inesophage.al, gastric and colon cancer[J]. Br J Cancer, 1999, 79(2):211-213.
    [131] Ishii H, Baffa R, Numata SI, et al. The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein and its expression is altered in multiple human tumors[J]. Proc Natl Acad Sci USA, 1999, 96(7):3828-3933.
    [132] Frecleok J. Bhaha S, Subbiah M, etal. Multifunctional roke for fetuin in tipid transport[J], Faseb J, 1999, 5(7):2145.
    [133] Jumper C, Cobos E, Lox C, Determination of the serum matrix metallo- proteinase-9(MMP-9)and tissue in tabitor of matrix metalloproteinase-1(TIMP-1) in patients with either aclvanced small-cell lung cancer or non-small cell lung cancer prior to treatment[J] Respir Med, 2004, 98(2):173-177.
    [134] 林秋雄,曾仁海、蔡秀玲,等.基质金属蛋白酶MMP-2和MMP-9在食管癌组织中的表达意义[J].肿瘤防治杂志,2002,9(3):271-272.
    [135] Edwards JG, Mclaren J, Jones JL, et al. Matrix metalloproteinase 2 and9 expression in malignant mesothelioma and benign pleura[J]. Br J Cancer, 2003, 88(18):1553.
    [136] 陈美芳,季峰,厉有名.食管癌基质金属蛋白酶及其组织抑制剂表达的研究[J].中华消化杂志,2002,22(3):181。
    [137] 温洪涛,张蕾,高冬玲等基质金属蛋白酶-9 mRNA在食管癌中的表达[J].中华消化杂志,2002,22(1):52
    [138] Sato F, Shimoda y, Watanabe C, et al. Expression of Vascular endothelial growth factor, matrix metalloproteinase 9 and Ecadherin in the process of lymphnode metastasis in esophageal cancer[J] Br J Cancer, 1999, 80(90):1366,
    [139] 李海、吴名耀、吴贤英.食管癌MMP2、MMP9及其组织抑制剂 TIMP-1,TIMP-2的表达及临床意义.实用癌症杂志[J],2004,19(2):8139-141。
    [140] Nakanishi Y, Ochiai A, Akimoto S, et al. Expression of E-cadherin, alpha-catenin, beta-catenin and plakoglobin in esophageal carcinoma and its prognostic significance:immunohistochemical analysis of 96 lesions[J] Ontology, 1997, 54(2): 158-165.
    [141] 王旭东,消化道肿瘤治疗进展[M].成都,四川科技出版社,2000,100.
    [142] Christopher J, Anil K.. CD44 isoform expression in primary and metastatic pancreatic adnocarcinoma[J]. Cancer Res, 1995, 55(3):1831-1835.
    [143] Karfmann M, Heider KH, Sinn HP, CD44 variant exon epitopes in primary breast cancer and length of surviva[J]. Lanet, 1995, 34(5):615-619
    [144] 龚非力,沈关心,李卓娅,等.医学免疫学[M].上海科学技术出版社,2006.6。
    [145] Guner D, Sturm I, Hemmati P, et al. Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis[J]. Int J Cancer, 2003, 103:445-454.
    [146] Cheng EH, Kirsch DG, Clath RJ, et al. Conversion of BCL-2 to a Bax like death effector by caspases[J]. science, 1997, 278:1966-1968.
    [147] Reed JC. BcL-2 and regulation of programmed cell death[J]. J Cell Biol, 1994, 124(1-2):1-6.
    [148] 刘丽萍,涂响安,赵志毅,等.食管癌bax和bcl-2蛋白的定性和定量研究[J].中国基层医药,2002,9:198-199.
    [149] 赵志毅,张明,涂响安,等.细胞凋亡增生DNA倍体和相关基因Fas、bax和Bc1-2在食管癌中的表达和临床意义[J].中国肿瘤临床与康复,2001,8:6-9。
    [150] Lo Muzio L, Pannine G, Staibano S, et al. Survivin expression in oral squamous cell carcinoma[J].Br J Cancer, 2003, 89:2244-2248.
    [151] Yang LQ, F.ang DC, Wang RQ, et al. Effect of NF-kappa B, survivin, Bcl-2 and capase 3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand[J]. World J Gastroenterol, 2004, 10:22-25.
    [152] Kania J, Konturek SJ, Marlicz K, et al. Expression of Survivin and Caspase 3 in gastric cancer[J]. Dig Dis Sci, 2003, 48:266-271.
    [153] Kawasaki H, Toyoda M, Shinohara H, et al. Expression of survivin correlates with apoptosis, proliferation and angiogenesis during human colorectal tumorigenesis[J]. Cancer, 2001, 91:2006-2032.
    [154] 王颖,王家,马龙,等.Survivn在原发性肝细胞癌中的表达及意义[J].中华消化杂志,2002,22:463-466.
    [155] Kappler M, Kotzsch M, Barte LF, et al. Elevated expression Level of survivng protein in soft-tissue sarcomas is a strong independent predictor of survival[J]. Clin Cancer Res, 2003, 9:1098-1104.
    [156] 候萍,王志华,徐昕,等.人食管癌中缺失基因片段的分离和鉴定[J].中华医学杂志,1997,77(10):737-741。
    [157] 候萍,郑杰,王志华,等.人食管癌细胞素中缺失的新基因片段在食管癌发生中的可能意义[J].中华肿瘤杂志,1997,19(5):336-338.
    [158] 周津,刘芝华,王秀琴,等.食管鳞癌组织中差异表达基因的初步研究云南大学学报(自然科学版),1999,21:313-314。
    [159] Grabcr MW, Schweinfest CW, Reed CE, et al. Isolation of differentially experssed genes in carcinoma of esophagus[J]. Ann Surg Oncol, 1996, 3(2):192-197.
    [160] Shiraishi T, Mori M, Tanaka S, et al. Identification of cystatin B in human esophageal carcinoma, using differential displays in which the gene expression is related to lymphnode metastasis[J]. Int J Cancer, 1998, 79(2): 175-178.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700