用户名: 密码: 验证码:
m1A甲基转移酶hTrm6p/hTrm61p在膀胱尿路上皮癌中的表达及意义
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
[背景和目的]
     膀胱癌为泌尿生殖系统肿瘤中最常见的恶性肿瘤,最新研究表明其发病率逐年上升。膀胱癌复发率高,5年复发率高达50%-90%,且大约35%的非肌层浸润性癌在复发时恶性程度会增加,如得不到及时治疗,约10%-20%可发展成为肌层浸润性癌而行根治性膀胱全切加尿流改道术,同时也可能会出现排尿异常、肠管闭锁及性功能障碍等并发症,给患者社会活动带来极大不便,使患者生活质量严重下降,同时给患者带来巨大的经济、心里压力。因此,对膀胱癌患者进行早期有效的诊断及治疗并预测其复发风险是临床上亟待解决的问题。
     近年来尿液修饰核苷作为一种新型的肿瘤分子标志物逐渐被人们所重视,它的分子质量比较小、分子结构比较稳定,不易与其它物质发生反应,尿液样本收集储存均较容易,留取尿样即可进行测定,且此种检测方法具有无创性,检测范围不受肿瘤病理分型甚至肿瘤种类的限制,患者容易接受等优势。研究表明,尿液中修饰核苷的水平可用于多种肿瘤的诊断、疗效评价及预后监测。我们前期研究已经证实有4中尿液修饰核苷分子在膀胱癌患者尿液中的水平显著高于正常人,他们分别是1-甲基腺苷(m1A)、N4-乙酰胞苷(ac4C)、06-甲基鸟苷(06-MeG)、1-甲基次黄苷(1-MeI),且1-甲基腺苷(m1A)和1-甲基次黄苷(1-MeI)2种尿液修饰核苷联合检测对膀胱癌的诊断及预测预后具有重要意义,可作为膀胱癌的首选肿瘤标志物。
     然而尿液修饰核苷在膀胱癌患者中明显升高的机制目前仍不清楚,研究认为恶性肿瘤细胞中存在高活性的tRNA修饰酶,可对正常结构的tRNA进行高度修饰产生异常tRNA,后者代谢.过程中即可产生大量修饰核苷。m1A是由A经tRNA甲基转移酶催化转变而形成。研究表明人体内催化m1A形成的tRNA甲基转移酶是m1A58甲基转移酶,即hTrm6p/hTrm61p。
     本研究通过检测膀胱癌患者及正常健康人尿液中m1A水平、膀胱癌患者手术切除的癌组织和癌旁组织中hTrm6p/hTrm61p的差异表达、癌组织中hTrm6p/hTrm61p的表达水平与同一患者尿液中m1A水平之间的关系及hTrm6p/hTrm61p的表达水平与临床病理特征之间的关系来探讨hTrm6p/hTrm61p在膀胱癌患者尿液中mlA高水平表达中的作用,进而为从基因表达调控水平上进一步揭示其机制打下基础,也为m1A作为膀胱癌肿瘤标志物的临床应用提供理论及实验依据。
     [方法]
     选取经病理证实的膀胱尿路上皮癌患者32例;其中男性25例,女性7例;其中初发22例,复发10例;组织学分级:Ⅰ级14例,Ⅱ级10例,Ⅲ级8例;浸润性癌18例,非侵润癌14例;手术为膀胱全切或部分切除术;患者术前留取尿液,术中留取癌组织及癌旁组织。选取16个正常健康人作为对照组。采取高效液相色谱/电喷雾-四极杆-飞行时间-质谱技术(HPLC/ESI-Q-TOF-MS)检测膀胱尿路上皮癌患者和正常健康人尿液中m1A表达水平:用western blot方法检测膀胱癌患者癌组织及癌旁组织中hTrm6p/hTrm61p的表达水平。
     [结果]
     1.膀胱癌组尿液中m1A水平(5.76±0.90)明显高于健康志愿者尿液中m1A水平(2.79±0.54),差异有统计学意义(p<0.05),且膀胱癌组每位患者尿液中m1A水平均高于对照组。
     2.32对癌组织中有31对(97%)hTrm6p/hTrm61p蛋白的表达量明显高于癌旁组织,hTrm6p/hTrm61p在膀胱癌组织中表达为(0.701±0.259),与其在癌旁组织中的表达(0.443±0.239)相比较,差异有统计学意义。
     3.初发患者hTrm6p/hTrm61p表达水平为0.679±0.250,复发患者为0.743±0.283,t=-0.641,P=0.526>0.05,差异无统计学意义;男性患者hTrm6p/hTrm61p表达水平为0.703±0.273,女性患者为0.696±0.221,t=0.057,P=0.955>0.05,差异无统计学意义;浸润性癌患者hTrm6p/hTrm61p表达水平为0.689±0.272,非浸润性癌患者为0.716±0.251,t=-0.289,P=0.775>0.05;组织学分级之间F=1.176,P=0.323>0.05,各组之间无显著性统计学差异,进一步S-N-K法两两比较中P=0.412>0.05,即两组之间无统计学显著性差异。
     4.尿液中m1A水平有随癌组织中hTrm6p/hTrm61p蛋白表达水平的升高而上升的趋势,对两变量做Pearson相关分析,r=0.799,p=0.000<0.05,认为尿液中m1A水平与癌组织中hTrm6p/hTrm61p蛋白表达水平之间有正相关关系。对两变量进一步做直线回归分析,决定系数R2=0.639,反映了尿液中m1A水平升高的原因中63.9%是癌组织中hTrm6p/hTrm61p蛋白表达水平增高所引起;检验结果F=53.018,P=0.000<0.05,即回归模型具有统计学意义,认为膀胱癌患者尿液中m1A水平的升高与癌组织中hTrm6p/hTrm61p蛋白表达水平的增高之间存在直线关系,可见常量和膀胱癌组织中hTrm6p/hTrm61p的表达水平均有统计学意义。常量a=3.816,回归系数b=2.782,回归方程为Y=3.816+2.782X。
     [结论]
     1.膀胱癌患者尿液中m1A的表达水平明显高于正常健康人尿液中m1A的表达水平,尿液m1A检测可作为对膀胱癌进行筛查和早期诊断的肿瘤标志物。
     2.同一患者癌组织中hTrm6p/hTrm61p的表达水平显著高于癌旁组织,且尿液中m1A的水平与癌组织中hTrm6p/hTrm61p的表达水平存在正相关性,提示hTrm6p/hTrm6lp的高水平表达是引起尿液中m1A水平升高的重要原因之一。
     3. hTrm6p/hTrm61p在膀胱癌组织中的表达水平与临床病理特征之间无明显相关关系。
Background and objective
     Bladder tumor is the most common malignant tumor in all the tumors of urinary system, the latest statistics show that its incidence increased year by year. The recurrence rate of bladder cancer is high, the recurrence rate as high as50%~90%in5years, about35%of the muscular layer noninvasive carcinoma will increase its grade, stage when recurrence, accordingly, if not treatment timely,10%~20%of them can be further progress to muscle invasive carcinoma, and needs radical bladder cut and urinary diersion, and the complications such as bowel atresia, dysuria and sexual dysfunction may come, this bring great difficulties to social activities of the patients, decline their life quality seriously, bring huge economic,mental stress. Therefore, early diagnosis of bladder cancer and effectively predict the risk of recurrence is the present clinical problems to be solved。
     Urinary modified nucleoside as tumor molecular markers are studied greatly in recent years, it has a stable molecular structure, it react and change shape not easily, and the molecular mass are small relatively, the collection and storage urine sample is easy, and it is noninvasive, can be directly determined after urine were clllected, and the detection range is not affected by tumor pathology classification and tumor types, patient could accept it easily. Research shows that the level of modified nucleosides in urine can be used for diagnosis of a variety of tumor, therapeutic evaluation and predicting prognosis. Our previous studies have shown that the levels of4kinds of modified nucleosides in urine of patients with bladder cancer is significantly higher than normal, they are N4interchange-acetyl cytidine (ac4C),06-methyl guanosine (06-MeG),1-MeI and1-methyl adenosine; and the joint detection of m1A and1-MeI2kinds of urinary modified nucleosides is of great significance to the diagnosis and predicting prognosis of bladder cancer, so they can be used as the first chosen tumor markers of bladder cancer.
     However it is not clear why urinary modified nucleoside increased significantly in patients with bladder cancer, research suggested that there are highly active tRNA modification enzyme in malignant cells, it can process height modification to the normal structure of tRNA, and abnormal tRNA are produced, then a large number of modified nucleosides are produced in the metabolic process. M1A are produced from A by catalytic transformation of tRNA methyltransferase. Studies have shown that the tRNA methyltransferase which catalytic the formation of m1A is m1A58methyl transferase in human body, namely hTrm6p/hTrm61p.
     This study through the detection of levels of m1A in the urine in bladder cancer patients and normal healthy people, different expression of hTrm6p/hTrm61p in carcinoma tissues and adjacent cancerous tissue removed in surgery of bladder cancer patients, the relationship of expression levels of hTrm6p/hTrm61p in cancerous tissues and the lecel of m1A in urine of the same patients, and the relationship between expression levels of hTrm6p/hTrm61p in cancerous tissues and the clinical pathologic characteristics.and to explore the role of hTrm6p/hTrm61p in the high level expression of m1A in bladder cancer patients, and then provide theoretical and experimental basis for the clinical application of m1A as the tumor markers of bladder cancer.
     Methods
     32cases bladder urothelial cell carcinoma (bladder urothelial cell carcinoma, BUCC) patients confirmed by pathology were chosen;25cases of men,7cases women;22cases of incipient, recurrence; histologic classification:14cases I level,10cases of Π level, magnitude8cases Ⅲ lecel;18cases of invasive carcinoma,14cases of noninvasive carcinoma; the surgery for bladder are full or partial resection; urine are collected before surgery, carcinoma tissues and adjacent tissues are collected intraoperative.16normal healthy people are selected as control group. High performance liquid chromatography/electrospray-quadrupole time-of-flight mass spectrometry (HPLC/ESI-Q-TOF-MS) are adopted to detect the levels of m1A in urine of bladder cancer patients and normal healthy people; Western blot method are used to detect the expression level of hTrm6p/hTrm61p in carcinoma tissues and adjacent tissues of patients with bladder.
     Results
     1. The levels of mlA in urine in the bladder cancer group (5.76±0.90) are significantly higher than those of healthy volunteers (2.79±0.54), the difference was statistically significant (P<0.05), and each patients in bladder cancer group were higher than the control group.
     2. The expression levels of hTrm6p/hTrm61p of31cancer tissue (97%) of the all32patients were obviously higher than those of tissues adjacent to carcinoma, the expression level of hTrm6p/hTrm61p in bladder cancer tissues was0.701±0.259, and its expression level in the tissue adjacent to carcinoma was0.443±0.239, the difference was statistically significant.
     3. The expression level of hTrm6p/hTrm61p in incipient patients was0.679±0.250, and recrudescent patients was0.743±0.283, t=0.641, P=0.526>0.05, the difference was not statistically significant; The expression level of hTrm6p/hTrm61p in male patients was0.703±0.273, female patients was0.696±0.221, t=0.057, P=0.955>0.05, the difference was not statistically significant; The expression level of hTrm6p/hTrm61p in invasive carcinoma was0.689±0.272, noninvasive carcinoma patients was0.716±0.251, t=0.289, P=0.775>0.05, the difference was not statistically significant; Among the histologic classification, F=1.176, P=0.323>0.05, the difference was not statistically significant, and further S-N-K method comparing between two, P=0.412>0.05, the difference was not statistically significant between two groups.
     4. m1A levels in urine has a upward trend with the high expression level of hTrm6p/hTrm61p protein in cancerous tissue, Pearson correlation analysis was used for two variables, r=0.799, p=0.000<0.05, illustrate that m1A levels in urine were correlate to the expression levels in cancerous tissue. Then linear regression analysis was used for the two variables, coefficient of determination R2=0.639, reflecting that the63.9%reasons of high expression levels of m1A in urine was the high expression level of hTrm6p/hTrm61p protein in cancerous tissue; Inspection result F=53.018, P=0.000<0.05, regression model was statistically significant, there is a linear relationship between the high expression levels of m1A in urine of bladder cancer patients and the high expression levels of hTrm6p/hTrm61p protein in cancerous tissue, constant and hTrm6p/hTrm61p expression levels in bladder cancer tissue have statistical significance. Constants a=3.816, the regression coefficient b=2.782, the regression equation Y=3.816+2.782X.
     Conclusion
     1. The expression level of m1A in urine of bladder cancer patients was obviously higher than that of normal healthy people, so the detection of m1A in urine can be used as tumor markers for the screening and early diagnosis of bladder cancer.
     2. The expression level of hTrm6p/hTrm61p in cancerous tissues was significantly higher than that of tissues adjacent to carcinoma of the same patients, and the levels of m1A in urine exist positive correlation to the expression level of hTrm6p/hTrm61p in cancerous tissues, this suggests that hTrm6p/hTrm61p play an important role in the occurrence of bladder cancer, the high express levels of hTrm6p/hTrm61p is an important cause of the high levels of mlA in urine of the bladder patients.
     3. The expression levels of hTrm6p/hTrm61p in bladder cancer tissues were irrelevant to clinical pathological features.
引文
[1]Rafal Turo, William Cross, Peter Whelan. Bladder cancer [J]. Medicine,2012,40:14-19.
    [2]Ashish M.Kamat, Paul K.Hegarty, Jason R. Gee. et al. ICUD-EAU International Consultation on Bladder Cancer American Cancer Society 2012:Screening, Diagnosis, and Molecular Markers. [J] EUROPEA NUROLOGY 63(2013):4-15.
    [3]吴阶平,主编.吴阶平泌尿外科学[M].济南:山东科学技术出版社,2003:919-942
    [4]Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010 [J]. CA Cancer J Clin, 2010,60(5):277-300.
    [5]Jacobs BL, Lee CT, Montie JE. Badder cancer in2010:how far have we come [J]? CA Cancer J Clin,2010,60(4):244-272
    [6]Sexton WJ, Wiegand LR, Correa JJ, et al. Bladder cancer:a review of non-muscle invasive disease [J]. Cancer Control, October 2010,17(4):256-268
    [7]Lee R, Droller MJ.The natural history of bladder cancer. Implications for therapy [J]. Urol clin North Am,2000,27(1):1-13
    [8]Dey P. Urinary markers of bladder carcinoma. [J]. Clin Chim Acta,2004,340(1-2):57-65
    [9]Van Rhijn BW, Van der Poel HG, Van der Kwast TH. Urine markers for bladder cancer surveillance:a systematic review [J]. Eur Urol.2005 Jun,47(6):736-48
    [10]Bruce L, Jacobs MD1, Cheryl T Lee, et al. Bladder Cancer in 2010 How Far Have We Come? [J].CA Cancer J Clin,2010,60(4):244-272
    [11]Hsu W Y, Chen W T, Lin W D, et al. Analysis of urinary nucleosides as potential tumor markers in human colorectal cancer by high performance liquid chromatography/electrospray ionization tandem mass speetrometry [J]. Clin Chim Acta,2009,402(1/2):31-37.
    [12]Bullinger D, Frohlich H, Klaus F, et al Bio informatical evaluation of modified nucleosides as biomedical markers in diagnosis of breast cancer [J]. Anal Chim Acta,2008,618(1):29-34.
    [13]La S, Cho JH, Kim JH, et al. Capillary electrophoretic profiling and pattern recognition analysis of urinary nucleosides from thyroid cancer patients [J]. Anal Chim Acta,2003, 486(2):171-182.
    [14]冯波,郑民华,朱正纲等.RNA修饰核苷作为肿瘤标志物的应用[J].诊断学理论与实践,2005,4(3):240-243
    [15]Wang Guang jie, Zhang XiaoLi, Chen Zhi wen, et al. Detection of Carcinoma of Urinary Bladder by Fluorescence in sit u Hybridization[J].Chin J Nosocomiol,2009, 19(5):1911-1914.
    [16]Xu G Schmid HR, Lu x, Liebich HM, et al. Excretion pattern investigation of Urinary normal and modified nucleosides of breast cancer patients by RP-HPLC and factor analysis method[J]. Biomed Chromatogr,2000,14(7):459-463
    [17]Long-Bin Jeng, Wan-Yu Lo, Wei-Yi Hsu, et al.Analysis of urinary nucleosides as helper tumor markers in hepatocellular carcinoma diagnosis[J]. Rapid Commun. Mass Spectrom, 2009,23(11):1543-1549
    [18]郑民华,冯波,陆爱国,等.尿核苷检测对结直肠癌诊断价值的临床研究[J].中华普通外科杂志,2004,19(10):595-597
    [19]吴辉,宋东奎,刘宏民,等.尿中修饰核苷水平在膀胱移行细胞癌诊断及预测预后中的意义.第三军医大学学报[J].2011,33:1714-1717.
    [20]张玉瑞,宋东奎,刘宏民,等.尿液修饰核苷检测在膀胱尿路上皮癌预后监测中的应用价值.中华泌尿外科杂志[J].2012,33:429-433.
    [21]Borek E., Transfer RNA and transfer RNA modification in differentiation and neoplasia. Introduction.Caneer. Res.1971.31(5).596
    [22]Fujioka S., Ting R.C., Gallo R.C., Transfer RNA methylases of nonnal cells, virus-transformed cells, and tumors derived from transformed cells. Cancer. Res., 1971,31(4),451
    [23]Mittelman A. Chheda G. Grace JT. Jr.Urinary pseudouridine and uric acid excretion in surgical patients.J.Surg.Res.1971.11(1).
    [24]Sharma O.K., Loeb L.A., Methylation of transfer RNA during transformation of human lymphocytes by phytohemagglutinin. Biochem. Biophys.Res. Commun.1973,50(1),172
    [25]Waalkes T.P., Adamson R.H. O, Gara R.W., Gallo R.C., Transfer RNA Methylase activity in normal monkey liver and in carcinogen-induced hepatoma. Cancer. Res.1971,31(8),1069
    [26]Bo Feng, Min-Hua Zheng, Yu-Fang Zheng, et al. Normal and modified urinary nucleosides represent novel biomarkers for colorectal cancer diagnosis and surgery monitoring. Journal of Gastroenterology and Hepatology,2005(20):1913-1919.
    [27]Lene Songe-M(?)ller, Erwin van den Born, Vibeke Leihne,et al. Mammalian ALKBH8 Possesses tRNA Methyltransferase Activity Required for the Biogenesis of Multiple Wobble Uridine Modifications Implicated in Translational Decoding. Molecular and cellular biology,2010(7):1814-1827.
    [28]SARAH OZANICK, ANNETTE KRECIC, JOSHUA ANDERSLAND. et al. The bipartite structure of the tRNA m1A58 methyltransferase from S.cerevisiae is conserved in humans. RNA [J].2005,11:1281-1290.
    [29]Pierre Barraud, Beatrice Golinelli-Pimpaneau, C6dric Atmanene. et al. Crystal Structure of Thermus thermophilus tRNA m1A58 Methyltransferase and Biophysical Characterization of Its Interaction With tRNA. [J].Mol.Biol.2008,377:535-550.
    [30]Seidel A, Brunner S, Seidel P, et al. Modified nucleosides an accurate tumor marker for clinical diagnosis of cancer, early detection and therapy control [J]. Br J Cancer,2006, 94(11):1726-1733.
    [31]Zheng YF, Xu GW, Liu DY,et al. Study of urinary nucleosides as biological marker in cancer patients analyzed by micellar electrokinetic capillary chromatography [J]. Electrophoresis, 2002,23(24):4104-4109.
    [32]Seidel A, Brunner S, Seidel P, et,al. Modified nucleosides:an accurate tumor marker for clinical-diagnosis of cancer, early detection and therapy control. Br J Cancer, 2006,94(11):1726-1733.
    [33]Mao Y, Zhao X, Wang S, et al. Urinary nucleosides based potential biomarker selection by support vector machine for bladder cancer recognition. Anal Chim Acta,2007,598(1):34-40.
    [34]Zheng YF, Yang J, Zhao XJ, et al. Urinary nucleosides as biological markers for patients with colorectal cancer. Word J Gastroenterol,2005,11(25):3871-3876.
    [35]Xu G, Schmid HR, Lu X, et al. Excretion pattern investigation of Urinary normal and modified nucleosides of breast cancer patients by RP-HPLC and factor analysis method. Biomed Chromatogr,2000,14:459-463.
    [36]Jeng LB, Lo WY, Hsu WY, et al. Analysis of urinary nucleosides as helper tumor markers in hepatocellular carcinoma diagnosis. Rapid Commun Mass Spectrom,2009,23:1543-1549.
    [37]Kin KR, La S, Kim A, et al. Capillary electrophoretic profiling and pattern recognition analysis of urinary nucleosides from thyroid cancer patients. J Chromatoqr B Biomed Sci Appl,2001,754:97-106.
    [38]Barraud P, Golinelli P B, Atmanene C, et al. Crystal structure of Thermus thermophilus tRNA m1A58 methyltransferase and biophysical characterization of its interaction with tRNA [J]. J Mol Biol.2008,377(2):535-550.
    [1]陈万青,张思维,郑荣寿,曾红梅,邹小农,赵平,吴良有,李光琳,赫捷,中国2009年恶性肿瘤发病和死亡分析.中国肿瘤,2013,22(1),2-12.
    [2]Suresh M.R., Classification of tumor markers. Anticancer. Res.,1996,16(4B),2273
    [3]施先艳,周燕,夏琳,肖建群,邓长生,若干肿瘤标志物对原发性肝癌诊断的临床评价.中华肿瘤杂志,1998,20(6),437
    [4]Ychou M., Duffour J., Kramar A., Gourgou S., Grenier J., Clinical significance and prognostic value of CA72-4 compared with CEA and CA19-9 in patients with gastric cancer. Dis. Markers.,2000,16(3-4),105
    [5]Filella X., Alcover J., Molina R., Rodriguez A., Carretero P., Ballesta A.M., Free and total PSA in the diagnosis of prostate cancer. Tumor. Biol.,1997,18(6),332
    [6]Evans J.R., Berchuck A., Tumor marker. Inn:Hosbins W.J., Perez C.A., Young R.C, eds. Principles and practice of gynecologic oncology.2nd. Philadelphia:Lippi-cott-raven Riblisher,1997, pp.177
    [7]Safi F., Schlosser W., Falkenreck S., Beger H.G., CA19-9 serum course and prognosis of pancreatic cancer. Int.J. Pancreatol.,1996,20(3),155
    [8]Stieber P., Hasholzner U., Bodenmuller H., Nagel D., Sunder-Plassmann L., Dienemann H., Meier W., Fateh-Moghadam A., CYFRA 21-1. A new marker in lung cancer. Cancer,1993, 72(3),707
    [9]金炳文,赵兰,周彩存,李德仁,徐建芳,神经元特异性烯醇化酶检测在小细胞肺癌预后中的价值.中华结合和呼吸杂志,2001,24(12),722
    [10]Ebeling F.G., Stieber P., Untch M., Nagel D., Konecny GE., Schmitt U.M., Fatch-Moghadam A., Seidel D., Serum CEA and CA 15-3 as prognostic factors in primary breast cancer. Br.J.Cancer.,2002,22,86(8),1217
    [11]Mulcahy H.E., Lyautey J., Lederrey C., Chen X.Q., Anker P., Alstead E.M., Ballinger A., Farthing M.J., Stroun M., A prospective study of K-ras mutations in the plasma of pancreatic cancer patients. Clin. Cancer. Res.,1998,4(2),271.
    [12]Sindransky D., Von Eschenbach A., Tsai Y.C., Jones P., Summerhayes I., Marshall F., Paul M., Green P., Hamilton S.R., Frost P., Identification of p53 gene mutations in bladder cancers and urine samples. Science,1991,252,706
    [13]Wood DP. Jr., Anderson A.E., Fair R., Chaganti R.S., Ras oncogene point mutations in bladder cancer resistant to cisplatin. Urol. Res.,1992,20(4),313
    [14]Fitzgerald J.M., Ramchurren N., Rieger K., Levesque P., Silverman M., Libertino J.A., Summerhayes I.C., Identification of H-ras mutations in urine sediments complements cytology in the detection of bladder tumors. J. Nat. Cancer Inst.,1995,87(2),129
    [15]Sidransky D., Tokino T., Hamilton S.R., Kinzler K.W., Levin B., Frost P., Vogelstein B., Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science,1992,256,102
    [16]Fearon E.R., Vogelstein B., A genetic model for colorectal tumorigenesis. Cell,1990,61(5), 759
    [17]Tada M., Omata M., Ohto M., Clinical application of ras gene mutation for diagnosis of pancreatic adenocarcinoma. Gastroenterology,1991,100(1),233
    [18]Caldas C., Hahn S.A., Hruban R.H., Redston M.S., Yeo C.J., Kern S.E., Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer. Res.,1994,54(13),3568
    [19]Mao L., Sidransky D., Cancer screening based on genetic alterations in human tumors. Cancer. Res.,1994,54(7 Suppl),1939s
    [20]Kerns B.J., Jordan P.A., Huper G., Marks J.R.,Iglehart J.D., Layfied L.J., Assessment of c-erbB-2 amplification by immunohistochemistry in paraffin-embedded breast cancer. Mod.Pathol.,1993,6(6),673
    [21]Inaji H., Koyama H., Motomura K., Noguchi S., Mori Y., Kimura Y., Sugano K., Ohkura H., ErbB-2 protein levels in nipple discharge:role in diagnosis of early breast cancer. Tumor. Biol.,1993,14(5),271
    [22]Takei Y, Kurobe M., Uchida A., Hayashi K., Serum concentrations of basic fibroblast growth factor in breast cancer. Clin. Chem.,1994,40(10),1980
    [23]Zhou G, Yu Q., Ma Y, Xue J., Zhang Y, Lin B., Determination of polyamines in serum by high-performance capillary zone electrophoresis with indirect ultraviolet detection. J. Chromatogr. A.,1995,717,345.
    [24]Nakano K., Nakal T., Schram K.H., Hammargren W.M., McClure T.D., Katz M., Petersen E., Urinary excretion of modified nucleosides as biological marker of RNA turnover in patients with cancer and AIDS. Clin. Chim. Acta.,1993,218(2),169
    [25]Marshall C.J., Vousden K.H., Phillips D.H., Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo(a)pyrene diol-epoxide. Nature,1984, 310(5978),586
    [26]Tagesson C., Kallberg M., Kintenberg, Starkhammer H., Determination of urinary 8-hydroxydeoxyguanosine by automated coupled-column high performance liquid chromatography:a powerful technique for assaying in vivo oxidative DNA damage in cancer patients. Eur.J. Cancer.,1995,31(6),934
    [27]Dong X., Xu X., Han F., Ping X., Lin B., Determination of sialic acids in the serum of cancer patients by capillary electrophoresis Electrophoresis,2001,22,2231
    [28]Han F., Bryan H., Honglan S., Lin B., Ma Y, Pteridine Analysis in Urine by Capillary Electrophoresis Using Laser-Induced Fluorescence Detection., Anal. Chem.,1999,71,1265
    [29]Bond A, Dudley E, Lemiere F, Tuytten R, El-sharkawi R, Brenton A G, Esmans E L, Newton R P. Analysis of urinary nucleosides. V. Identification of urinary pyrimidine nucleosides by liquid chromatography/electrospray mass spectrometry. [J]. Rapid commun. Mass Spectrom. 2006,20:137-150
    [30]Limbach P A, Crain P F; McCloskey J A. Summary:the modified nucleosides of RNA [J]. Nucleic. Acids Res.1994,22:2183-2196.
    [31]BjorkG.R.,EriesonJ.U., GustafssonC.E.D., HagervallT.G, JonssonYH., WikstromP.M., Transfer RNA Modifieation. Annu. Rev. Bioehem.,1987,56,263
    [32]Gehrke.C.W., KuoK.C.T., J.Chromatog.Elsevier, Alnsterdam.l990b
    [33]Prankel B.H., Clemens P.C, Bunnester J.G, Urinary exeretion of nueleosides varies with age and Protein metabolism. Clin. Chim.Aeta.,1995,234(1-2),181
    [34]Sehoeh G, Sander G, Topp H., Heller-Schoeh G. in Chromatography and Modifieation of Nueleosides Part C:Modified Nucleosides in Cancer and Normal Metabolism. Mcthods and Applications., Amsterdam, Elsevier,1990,PP.389
    [35]Waalkes P.T, Gehrke C.W., Zumwalt R.W., Chang S.Y., Lakings D.B., Tormey D.C., Alllliann D.L., Moertel C.G, The urinary exeretion of nucleosides of ribonucleic acid by patienis with advanced cancer. Cancer,1975,36,390
    [36]Itoh K., Konno T., Sasaki T., Ishiwata S., Ishida N., Misugaki M., Relationship of urinary pseudouridine andl-methyladenosine to activity of Leukemia and lymphoma. Clin. Chim. Aeta.1992,206,181
    [37]RasmusonT, Bjork GR., Hietala S.O., Stenling R., Ljungberg B., Exeretion of pseudouridine as an independent prognostic factor in renal cell carcinoma. Acta. Oncol.,1991,30,11
    [38]Clarkl., MaeKenzieJ.W., MeCoyJ.R., LinW., inRecentResultsin CaneerResearch.SPringer-Verlag, Berlin,1983, pp.388
    [39]Clark I., Lin W., Mackenzie J.W., in Chromatography and Modification of Nucleosides PartC: Modified Nucleosides in Cancer and Normal Metabolism Methods and APPlieations., Amsterdam, Elsevier,1990, PP.341
    [40]Randerath E., Gopalakrishnan A.S., Randerath K, in Motris Hepatomas, Mechanisms of Regulation., Plenum, NewYork,1978, pp.517
    [41]Borek E., Transfer RNA and transfer RNA modification in differentiation and neoplasia. Introduction.Caneer. Res.,1971,31(5),596
    [42]Fujioka S., Ting R.C., Gallo R.C., Transfer RNA methylases of nonnal cells, virus-transformed cells, and tumors derived from transformed cells. Cancer. Res.,1971,31(4), 451
    [43]Mittelman A., Chheda G., Grace JT. Jr., Urinary pseudouridine and uric acid excretion in surgical patients. J.Surg.Res.,1971,11(1)
    [44]Sharma O.K., Loeb L.A., Methylation of transfer RNA during transformation of human lymphocytes by phytohemagglutinin. Biochem. Biophys.Res. Commun.,1973,50(1),172
    [45]Waalkes T.P., Adamson R.H., O, Gara R.W., Gallo R.C., Transfer RNA Methylase activity in normal monkey liver and in carcinogen-induced hepatoma. Cancer. Res.,1971,31(8),1069
    [46]Randerath K., Tseng W.C., Harris J.S., Lu L.J.W, in Recent Results in Cancer Research Modified ucleosides and Caneer. Springer-Verlarg, Berlin,1983, PP.283
    [47]Hua-Yu Li, Shao-Min Wang, Hong-Min Liu, Shan-Shan Bu, Juan Li, Dong Han, Ming-zhi Zhang and Guang-Yin Wu,Separation and identification of purine nucleosides in the urine of patients with malignant cancer by reverse phase liquid chromatography/electrospray tandem mass spectrometry [J]. Mass. Spectrom. Published online:13, Jan.2009.
    [48]Sylvester RJ, van derMeijden AP,Ooster linckW, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables:a combined analysis of 2596 patients from seven EORTC trials [J]. Eur Urol,2006,49 (3):466-477.
    [49]Masuda M., Nishihira T, Itoh K., Mizugaki M., Ishida N., Mori S., An immunohistochemical anaiysis for cancer of the esophagus using Monoclonal antibodies specific for modified nueleosides.Caneer,1993,72,3571
    [50]Liebich H.M., Di Stefano C., Wixforth A., Schmid H.R., Quantitation of urinary nucleosides by high-performance liquid chromatographv.1997,763,193
    [51]Liebich H.M., Xu G, Di Stefano C., Lehmann R., Capillary electrophoresis of urinary normal and modified nucleosides of cancer patient.J. Chromatogr.A.,1998,793,341
    [52]Xu G, Di Stefano C., Liebieh H.M., Zhang Y, Lu P., Reversed-phase high-performance liquid chromatographic investigation of urinary normal and modified nucleosides of cancer patients.J.Chromatogr.B.,1999,732,307
    [53]许国旺,路鑫,张玉奎,Di Stefano C., Lehmann R., Liebich H.M., Two approaches to determining the urinary excretion patterns of nucleosides-HPLC and CE.色谱,1999,17(2), 97
    [54]Xu G, Liebich H.M., Normal and modified nucleosides in urine as potential tumor markers determined by MEKC and HPLC. American.Clin.Lab.,2001,20,22
    [55]Ishiwata S., Itoh K., Yarnguchi T., Ishida N., Mizugaki M., Comparison of serum and urinary levels of modified nucleoside,1-methyladenosine, in cancer patients using a monoclonal antibody-based inhibition ELISA. Tohoku.J.ExP. Med.,1995,176,61
    [56]Reynaud C., Bruno C., Boullanger P., Grange J., Barbesti S., Niveleau A., Monitoring of urinary excretion of modified nucleosides in cancer patients using a set of six monoelonal antibodies.Cancer.lett.,1991,61,255
    [57]Speer.J., Gehrke C.W., Kuo K.C., WaaIkes T.P., Borek E., tRNA breakdown products as markers for cancer. Cancer,1979,44:2120
    [58]Liebieh H.M., Lehmann R., Xu G, Wahl H.G, Haring H.U., Application of capillary electrophoresis in clinical chemistry:clinical value of urinary modified nucleosides.J. Chromatogr.B.,2000,745,189
    [59]Mitchell E.P., Evans L., Schultz P., Madsen R., Yarbro J.W., Modified nucleosides in human serum.J.Chromatogr. A.,1992,581,31
    [60]Zhao R., Xu G, Yue B., Liebich H.M., Zhang Y, Artificial neural network classification based on capillary electrophoresis of urinary nucleosides for the clinical diagnosis of tumors.J.Chromatogr.A.,1998,828,489
    [61]江丽,梁统,凌光鑫,恶性肿瘤患者血清和尿中假尿苷检测的意义。中国实验诊断学,1997,1(3),19
    [62]Koshida K., Harmenberg J., Stendahl U., Wahren B., Borgstrom E., Helstrom L., Urinary modified nuclesides as tumor markers in cancer of the urinary organs or female genital tract. Urol. Res.,1985,13,213
    [63]Nakano K., Shindo K., Yasaka T., Reversed-Phase high-performance liquid chromatographic investigation of mucosal nucleosides and bases and urinary modified nucleosides of gastrointestinal cancer patients.J.Chromatogr.A.,1985,343,21
    [64]Nakano K.,Yasaka T., Schrarn K.H., Isolation and identification of urinary nucleosides Application of high-performance liquid chromatographic methods to the synthesis of 5-deoxyxanthosine and the simultaneous determination of 5,6-dihydrouridine and pseudouridine.J.Chromatogr.A.,1990,515,537
    [65]Rasmuson T., Bjork G.R., Urinary excretion of pseudouridine and prognosis of patients with malignant lymphoma. Acta.Oncol.,1995,34,61
    [66]Trewyn R.W., Glaser R., Kelly D.R., Jackson D.G., Graham W.P., Elevated nucleoside excretion by patients with nasopharyngeal carcinoma.Caneer,1982,49,2513
    [67]陈英杰,郑育芳,陶雅军,吕申,杨青,许国旺,等,恶性肿瘤患者尿中修饰核苷的检测[J],肿瘤学杂志2003,9,(1),57-58
    [68]符雪松,白文元,姚希贤,孙泽明,宋光辉,胃癌患者假尿嘧啶核苷测定的临床意义,中国肿瘤临床2002,29(10),706-709.
    [69]Itoh, K; Konno, T; Sasaki, T; Ishiwata, S; Ishida, N; Misugaki, M. Relationship of urinary pseudouridine and 1-methyladenosine to activity of leukemia and lymphoma. Clin.Clim. Acta 1992,206(3),181-189.
    [70]Dino Bullingera,, Holger Frohlich, Fabian Klausc, Hans Neubauerd, Bernd Kammerera, Bioinformatical evaluation of modified nucleosides as biomedical markers in diagnosis of breast cancer[J], analytica Chimica acta 618(2008) 29-34.
    [71]Zheng YF, Kong HW, Xiong JH, et al.Clinical significance and prognostic value of urinary nucleosides in breast cancer patien ts[J].Clin Biochem,2005,38(1):24-30.
    [72]王文昭,赵欣捷,李响,陈静,李方楼,许国旺,尿中修饰核苷代谢轮廓分析在肺癌诊断中的作用,中国医学科学学报,2007,29(6),738-741.
    [73]Solomon, S, J.; Fischbein, A.; Sharma,0. K.; Borek, E. Modified nucleosides in asbestos workers at high risk of malignant disease:results of a preliminary study applying discriminant analysis. Br.J.Ind.Med.1985,42(8),560-562.
    [74]Chen ying-jie, Zheng yu-fang, Xu Guo-wang, Significance urinary nucleosides diagnosis of Gastric Carcinoma, Chinese journal of cancer.2003,22(5),537-540.
    [75]郑育芳,陈英杰,逢涛,石先哲,孔宏伟,吕中,杨青,许国旺,肠癌患者尿中核苷排放的高效液相色谱法研究,色谱,2006,20(6),498-501.
    [76]陈坛辀,黄智铭,尿中修饰核苷检测在肝细胞性肝癌诊断中的意义,温州医学院学报,2008,38(5),456-458.
    [77]冯波,郑民华,郑育芳,尿核苷检测在结直肠癌诊断与手术治疗监测中的应用,中华外科杂志,2005,43(9),564-568.
    [78]郑民华,冯波,陆爱国,郑育芳,毛志海,马君俊,许国旺,尿核苷检测对结直肠癌诊断价值的临床研究,中华普通外科杂志,2004,19(10),595-97.
    [79]Kim, K. R.; la, S.; Kim, A.; Kim, J. H.; Liebich, H.M. Capillary electrophoretic profiling and pattern recognition analysis of urinary nucleosides from uterine myoma and cervical cancer patients. J. Chromatogr. B 2001,754(1),97-106.
    [80]吴辉,宋东奎,刘宏民等.尿中修饰核苷水平在膀胱移行细胞癌诊断及预测预后中的意义.第三军医大学学报[J].2011,33:1714-1717.
    [81]张玉瑞,宋东奎,刘宏民等.尿液修饰核苷检测在膀胱尿路上皮癌预后监测中的应用价值.中华泌尿外科杂志[J].2012,33:429-433.
    [82]Manjula S., Aroor A.R., Raja A., Rao S., Rao A., Urinary excretion of pseudouridine in patients with brain tumours. Acta. Oncol.,1993,32(3),311
    [83]Trewyn R.W., Glaser R., Kelly D.R., Jackson D.G, Graham W.P., Elevated nucleoside excretion by patients with nasoparyngeal carcinoma.Caneer,1982,49,2513
    [84]La, S.; Cho, J. H.; Kim, K. R. Capillary electrophoretic profiling and pattern recognition analysis of urinary nucleosides from thyroi d cancer patients. Anal. Chim.Acta 2003,486, 171-182
    [85]Harmenberg J., Larsson A., Hagberg C-E., Reversed-phase high performance liquid chromatograph(HPLC) of nucleosides in eell extracts with special reference to deoxythymidine.J. Liq. Chromatogr.,1983,6(4),655
    [86]Klabunde R.E., Winser C.L., Ito C.S., Mayer S.E., Measurement of adenosine and inosine in heart samples by high pressure liquid chromatography.J.Mol.Cell.Cardlol.,1979,11(7),707
    [87]Musto, p; Cascavilla, N; Ladogana, S; Modoni, S; Carotenuto, M. Determination of thymidie kinase in the cerebrospinal fluid as a marker of leukemic meningosis. Medicina 1989,91(1),49-51.
    [88]李方楼,赵欣捷,许国旺,硅胶基苯硼酸亲和色谱填料的合成和应用,分析化学研究报告2006,34(10),1366-1370.
    [89]Pfadenhauer E.H., Tong S-D., J. Chromatogr.,1979,162,585
    [90]Koller C.A., Stetson P.L., Nichamin L.D., Mitchell B.S., An assay of deoxyadenosine and adenosine in human plasma by HPLC. Bioehem. Med.,1980,24(2),179
    [91]Karle J.M., Anderson L.W., Dietrick D.D., Cysyk R.L., Determination of serum and plasma uridine levels in mice, rats, and humans by hig-pressure liquid chromatography. Anal..Bioehem.,1980,109(1),41
    [92]Gehrke C.W., Kuo K C, Davis G E, Suits R D, Waakes T P, Borek E. Quantitative high-performance liquid chromatography of nucleosides in biologieal material [J].J. Chromatogr.A.1978,150(2):455-476.
    [93]Schoch G, Thomale J, Lorenz H, Suberg H, Karsten U.A new method for the simultaneous Analysis of unmodified and modified urinary nucleosides and nucleobases by high-performance liquid chromatography [J].Clin.Chim.Acta.1980,108(2):247-257.
    [94]Putterman GJ, Shaikh B, Hallmark M R, Sawyer C G, Hixson C V, Perini F. Simultaneous analysis of substrates, produets, and inhibitors of xanthine oxidase by high-pressure liquid chromatography and gas chromatography[J].Anal.Bioehem.1979,98(1):18-26.
    [95]胡永狮,汤秋华,刘标生.高效液相色谱法测定人血清中假尿嘧啶核苷的浓度[J].色谱1997,15(4):349-472.
    [96]屠振兴,许盛献.血清假尿喀陡核普的高效液相色谱测定[J].第二军医大学学报,1994,15(5):470-472.
    [97]高建,沈鼎明.反相高效液相色谱法直接测定尿液中假尿嘧啶核苷[J],中华肝病学会肝脏病杂志,1994,2(1).49-51
    [98]Zakaria M, Brown P R, Farnes M P, Barker B E.HPLC analysis of aromatic amino acids, nueleosides, and bases in plasma of acute lymphocytic leukemia on chemotherapy [J].Clin.Chim.Acta.1982,126(1):69-80.
    [99]Xu G, Enderle H, Liebich H M, Lu P. Study of normal and modified nucleosides in serum by RP-HPL [J]C.Chromatogr.2000,52(3/4):152-158.
    [100]Hartwick R A, Assenza S P, Brown P R. Identification and quantitation of nueleosides, bases and other UV-absorbing compounds in serum, using reversed-phase high-performance liquid chromatography.l.Chromatographic methodology[J].J.Chromatogr A.1979, 186:647-658.
    [101]Gehrke C W, Kuo K C, Zumwalt R W. Chromatography of Nucleosides. [J].J. Chromatogr. A.1980,188:129-147.
    [102]Gehrke C W, Kuo K C. Ribonucleoside analysis by reversed-phase high-performance liquid Chromatography [J] J. Chromatogr A.1989,471:3-36.
    [103]Werner A. Reversed-Phase and ion-pair separation of nucleosides, nucleosides and nueleosides:analysis of biological samples in health and diseas [J].J.Chromatogr.A.1993, 618(1-2):3-14.
    [104]Liebieh H M, Muller-Hagedorn S, Bacher M, Seheel-Walterc H J, Lu X, Frickenschmidt A, Kammerer B, Kim K R, Gerard H.Age-dependence of urinary normal and modified nucleosides in childhood as determined by reversed-phase high-Performance liquid chromatography [J].J. Chromatogr.B.2005,814:275-283.
    [105]VanGennip A H, Grift J, Wadman S K, DeBree P K. Biological/Biomedical Applications of Liquid Chromatograph Ⅱ [J], Marcel Dekker, New York.1979,337.
    [106]Li F, Zhao X, Wang W, Xu G. Synthesis of silica-bases benzeneboronic acid affinity materials and application as pre-column in coupled-column high-performance liquid chromatography [J].Anal.Chim.Acta.2006,580:181-187.
    [107]Yang J, Xu G, Kong H, Zheng Y, Pang T, Yang Q. Artificial neural networke classification based on high-performance liquid chromatography of urinary and serum nueleosides for the clinical diagnosis of cancer[J] J. Chromatogr. B.2002,78:23-27
    [108]Zhao R, Xu G, Yue B, Liebieh H M, Zhang Y Artificial neural network classification based on capillary electrophoresis of urinary nueleosides for the clinical diagnosis of tumors [J], J Chromatogr. A.1998,828(1-2):489-496.
    [109]Seidel A, Brunner S, Seidel P, Fritz G, Herbarth O.Modified nucleosides:an accurate tumor marker for clinical diagnosis of cancer, early detection and therapy control [J].Br.J. Cancer2006,94:17261733.
    [110]张益彬,王科太,谢家理,程贵钧,胡子文.间接标记甲尿嘧啶核苷方法的研究[J].化学研究与应用.2001,13(3):261-264.
    [11]Chiou CC,Chang PY,Chan EC,et al.Urinary 8-hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress:developmen t of an ELISA and measurement in both bladder and prostate cancers[J].Cli n Chim Acta,2003,334(1-2):87-94.
    [112]Schram, K.H.; Methods in Enzymology, Vol.193, Academic, San Diego,1990, pp.791.
    [113]Liebieh H M, Xu G, Di Stefano. Capillary electrophoresis of urinary normal and modified nueleosides of caneer patients [J].J. Chromatogr.A.1998,793(2):341-347
    [114]Kim K R, La S, Kim A, Kim J H, Liebich H M. Capillary eleetrophoretic profiling and pattern recognition analysis of urinary nueleosides from uterine myoma and cervical caneer patients [J].J. Chromatogr. B.2001,754(1):97-106.
    [115]程明刚,梁统,周克元,凌光鑫.高效毛细管电泳法检测尿液中的假尿啼咙核普[J].色谱1997,15,(5):417-419.
    [116]Lee M S, Kems E H.LC/MS applications in drug development [J] Mss spectrum. Res.1999,18:187-279
    [117]Esmans E L, Broes D, Hoes I., Lemiere F, Vanhoutte K. Liquid chromatography-mass speetrometry in nueleoside, nucleotide and modified nucleotide characterization [J].J. Chromatogr.A.1998,794:109-127.
    [118]Zambonin C G, Palmisano F. Gas chromatography-mass spectrometry identification of a novel N3-methylated metabolite of 5'-deoxy-5-fluorouridine in plasma of cancer patients undergoing chemotherapy [J].J. Pharm.Biome.Anal.1996,14:1521-1528.
    [119]Dudley E, Leniere F, Van Dongen W, Langridge J I, El-Sharkawi S, Games D E, Esmans E L, Newton R P. Analysis of urinary nucleosides. Ⅱ.Comparison of mass speetrometric methods for the analysis of urinary nucleosides [J]. RaPid Commun. Mass Spectrom.2001,15: 1701-1707.
    [120]Dudley E, Leniere F, Van Dongen W, TuyttenR, EI-Sharkawi S, Brentonl A G, Esmans E L, Newton R P. Analisis of urinary nucleosides. Ⅳ.Indentification of urinary purine nucleosides by liquid chromatography/eleetrosray mass speetrometry [J].Rapid Commun. Mass spectrum.2004,18:2730-2738.
    [121]Bond A, Dudley E, Lemiere F, Tuytten R, El-Sharkawi R, Brenton A G, Esmans E L, Newton R P.Analysis of urinary nucleosides. V. Identification of urinary pyrimidine nueleosides by liquid chromatography/eleetrospray mass speetrometry[J].Rapid Commun. Mass spectrum. 2006,20:137-150.
    [122]Zambonin C G, Palmisano F. Electrospray Ionization Mass Spectrometry of 5-methyl-2'-deoxycytidine and Its Determination in Urine by Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometry [J]. Rapid Commun.Mass Spectrom.1999,13: 2160-2165.
    [123]Zambonin C G, Aresta A, Palmisano F, Specchia G, Liso V. Liauid chromatographic Determination of urinary 5-methyl-2'-deoxycytidine and pseudouridine as potential biological markers for leukemia [J]. J.Pharm. Biomed.Anal.1999,21(5):1045-1051.
    [124]Kammerer B, Frickenschmidt A, Muller C E, Laufer S, Gleiter C H, Liebich H M. Mass spectrometric identification of modified urinary nucleosides used as potential biomedical markers by LC-ITMS coupling [J].Anal.Bioanal.Chem.2005,382:1017-1026
    [125]Liebich H M, Muller-Hagedom S, Klaus F, Meziane K, Kim K R. Frickenschmidt A, Kammerer B. Chromatographic, capillary electrophoretic and matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis of urinary modified nucleosides as tumor markers [J].J.Chromatogr.A.2005,1071:271-275.
    [126]Tuytte R, Lemiere F, Van Dongen W, Witters E, Esmans E L, Newton R P, Dudley E. Development of an on-line SPE-LC-ESI-MS method for urinary nucleosides:Hyphenation of aprotic Boronic acid chromatography with hydrophilic interaction LC-ESI-MS[J].AnaL Chem.2008,80(4):1263-1271.
    [127]Thytten B, Lemiere F, Eamans E L, Herrebout W A, Vander V B J, Dudley E, Newton R P,Witters E. In-Source CID of guanosine:Gas phase ion-molecule reactions[J].J.Am. Soc.Mass Spectrom.2006,17:1050-1062.
    [128]Dudley E, Tuytten R, Bond A, Lemiere F, Brenton A G, Esmans E L, Newton R P. Study of the mass spectrometric franmentation of pseudouridine Comparison of fragmentation data obtained by matrix-assisted laser desorption/ionization post-source decay, eleetrospray ion trap multistage mass spectrometry, and by a method utilizing electrospray quadrupole time-of-flight tandem mass spectrometry and insource fragmentation [Jl..Rapid Commun.Mass Spectrom.2005,19:3075-3085.

© 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