非小细胞肺癌患者血清中EGFR、Her-2、Survivin和CyclinB1自身抗体的表位研究
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摘要
目的
自身抗体作为新的肿瘤标志物在肺癌的早期诊断和预后评价中可能发挥重要作用,本研究利用多肽阵列研究非小细胞肺癌患者血清中EGFR、Her-2、Survivin和CyclinB1自身抗体识别的抗原表位,筛选抗原表位中的高频位点,通过分析高频位点在蛋白质功能结构域的空间分布,探索EGFR、Her-2、Survivin和CyclinB1四种自身抗体在非小细胞肺癌中发挥的作用。
方法
使用intavis公司ASP SL多肽阵列合成仪合成EGFR、Her-2、Survivin和CyclinB1四种多肽阵列,分别利用EGFR、Her-2、Survivin和CyclinB1四种多肽阵列研究50例非小细胞肺癌患者血清、30例健康对照者混合血清和30例肺良性疾病患者混合血清中EGFR、Her-2、Survivin和CyclinB1自身抗体识别的抗原表位,并筛选抗原表位中的高频位点,通过比对高频位点和相应蛋白质的氨基酸序列,确定EGFR、Her-2、Survivin和CyclinB1四种自身抗体所识别的高频位点在相应蛋白质中的空间位置分布。
结果
使用intavis公司ASP SL多肽阵列合成仪合成EGFR、Her-2、Survivin和CyclinB1四种多肽阵列。多肽阵列检测结果发现在健康对照者混合血清和肺良性疾病患者混合血清中均不存在EGFR、Her-2、Survivin和CyclinB1四种自身抗体。而在50例非小细胞肺癌患者中发现有10例非小细胞肺癌患者血清中存在EGFR自身抗体,有9例非小细胞肺癌患者血清中存在Her-2自身抗体,有8例非小细胞肺癌患者血清中存在Survivin自身抗体,有8例非小细胞肺癌患者血清中存在CyclinB1自身抗体.,并且发现这四种自身抗体在某些肺癌患者血清中有共存的现象。通过表位分析发现EGFR、Her-2、Survivin和CyclinB1四种自身抗体识别多肽阵列上某些位点的频率明显高于其它位点,本研究分别发现了四种自身抗体所识别的高频位点。通过比对高频位点和相应蛋白质的氨基酸序列,确定了EGFR、Her-2、Survivin和CyclinB1四种自身抗体所识别的高频位点在相应蛋白质中的空间位置分布。高频位点和高频位点空间位置分布的发现为进一步研究EGFR、Her-2、Survivin和CyclinB四种自身抗体的功能提供了新的线索。
结论
通过表位研究,发现EGFR自身抗体识别的4个高频位点都位于EGFR蛋白保外区的L2结构域,L2结构域是EGFR蛋白的重要功能结构域,参与EGFR与其配体的相互识别,因而推测EGFR自身抗体可能会影响EGFR信号通路的功能;Her-2自身抗体识别的3个高频位点,2个位于Her-2蛋白保外区的L1结构域,1个位于Her-2蛋白保外区的L2结构域,由于Her-2没有配体,因而Her-2自身抗体的功能还需要进一步的研究;Survivin自身抗体识别的4个高频位点都位于Survivin蛋白的BIR结构域,BIR结构域是Survivin发挥凋亡抑制功能的重要功能结构域,因而推测Survivin自身抗体可能会促进肺癌细胞的凋亡;CyclinB1自身抗体识别的2个高频位点都紧邻CyclinB1蛋白的CRS结构域的N端,CRS结构域控制CyclinB1蛋白的亚细胞定位,使其发挥不同的功能,因而推测CyclinB1自身抗体可能会影响肺癌细胞的细胞周期。
Objective
Autoantibodies as new tumor markers may play an important role in the early diagnosis and evaluating the prognosis of lung cancer patients.In this study, we map the epitopes of autoantibodies against EGFR, Her-2, Survivin and CyclinB1 in sera of non-small cell lung cancer patients with peptide array and screen the epitopes with high frequency. Through matching the sequence between epitopes with high frequency and the 4 kinds of protein to discover the structure distribution of these epitopes.
Method
4 kinds of peptide array which covered all the peptides in the 4 peptide libraries were synthesized by a synthesizer(ASP SL).Mapped the epitopes of autoantibodies against EGFR, Her-2, Survivin and CyclinB1 in serum of 50 NSCLC patients,. Screened the epitopes which were recognized by the 4 kinds of autoantibodies with high frequency. Through matching the sequence between epitopes with high frequency and the 4 kinds of protein to DISCOVER the structure distribution of these epitopes.
Result
4 kinds of peptide array were synthesized by a synthesizer (ASP SL). There were no the 4 kinds of autoantibodies in the mixed-serum of healthy objectives and in the mixed-serum of pulmonary tuberculosis patients. 10 of 50 NSCLC patients were found to have EGFR autoantibodies; 9 of 50 NSCLC patients were found to have Her-2 autoantibodies; 8 of 50 NSCLC patients were found to have survivin autoantibodies; 8 of 50 NSCLC patients were found to have CyclinB1 autoantibodies. Serums of A006,A022,A094,A124 had all 4 kinds of autoantibodies against EGFR Her-2 survivin and CyclinB1.Through scanning the epitopes, we found the epitopes with high frequency of the 4 kinds of autoantibodies. Discovered the structure distribution of these epitopes with high frequency.
Conclusion
Through epitope scanning , we found the epitopes with high frequency of the 4 kinds of autoantibodies. Through matching the sequence between epitopes with high frequency and the 4 kinds of protein we discover the structure distribution of these epitopes with high frequency. The discover of the epitopes with high frequency and the address of the the epitopes with high frequency will offer new clues for the further research of the 4 kinds autoantibodies.
自身抗体作为新的肿瘤标志物在肺癌的早期诊断和预后评价中可能发挥重要作用,本研究利用多肽阵列研究非小细胞肺癌患者血清中EGFR、Her-2、Survivin和CyclinB1自身抗体识别的抗原表位,筛选抗原表位中的高频位点,通过分析高频位点在蛋白质功能结构域的空间分布,探索EGFR、Her-2、Survivin和CyclinB1四种自身抗体在非小细胞肺癌中发挥的作用。
方法
使用intavis公司ASP SL多肽阵列合成仪合成EGFR、Her-2、Survivin和CyclinB1四种多肽阵列,分别利用EGFR、Her-2、Survivin和CyclinB1四种多肽阵列研究50例非小细胞肺癌患者血清、30例健康对照者混合血清和30例肺良性疾病患者混合血清中EGFR、Her-2、Survivin和CyclinB1自身抗体识别的抗原表位,并筛选抗原表位中的高频位点,通过比对高频位点和相应蛋白质的氨基酸序列,确定EGFR、Her-2、Survivin和CyclinB1四种自身抗体所识别的高频位点在相应蛋白质中的空间位置分布。
结果
使用intavis公司ASP SL多肽阵列合成仪合成EGFR、Her-2、Survivin和CyclinB1四种多肽阵列。多肽阵列检测结果发现在健康对照者混合血清和肺良性疾病患者混合血清中均不存在EGFR、Her-2、Survivin和CyclinB1四种自身抗体。而在50例非小细胞肺癌患者中发现有10例非小细胞肺癌患者血清中存在EGFR自身抗体,有9例非小细胞肺癌患者血清中存在Her-2自身抗体,有8例非小细胞肺癌患者血清中存在Survivin自身抗体,有8例非小细胞肺癌患者血清中存在CyclinB1自身抗体.,并且发现这四种自身抗体在某些肺癌患者血清中有共存的现象。通过表位分析发现EGFR、Her-2、Survivin和CyclinB1四种自身抗体识别多肽阵列上某些位点的频率明显高于其它位点,本研究分别发现了四种自身抗体所识别的高频位点。通过比对高频位点和相应蛋白质的氨基酸序列,确定了EGFR、Her-2、Survivin和CyclinB1四种自身抗体所识别的高频位点在相应蛋白质中的空间位置分布。高频位点和高频位点空间位置分布的发现为进一步研究EGFR、Her-2、Survivin和CyclinB四种自身抗体的功能提供了新的线索。
结论
通过表位研究,发现EGFR自身抗体识别的4个高频位点都位于EGFR蛋白保外区的L2结构域,L2结构域是EGFR蛋白的重要功能结构域,参与EGFR与其配体的相互识别,因而推测EGFR自身抗体可能会影响EGFR信号通路的功能;Her-2自身抗体识别的3个高频位点,2个位于Her-2蛋白保外区的L1结构域,1个位于Her-2蛋白保外区的L2结构域,由于Her-2没有配体,因而Her-2自身抗体的功能还需要进一步的研究;Survivin自身抗体识别的4个高频位点都位于Survivin蛋白的BIR结构域,BIR结构域是Survivin发挥凋亡抑制功能的重要功能结构域,因而推测Survivin自身抗体可能会促进肺癌细胞的凋亡;CyclinB1自身抗体识别的2个高频位点都紧邻CyclinB1蛋白的CRS结构域的N端,CRS结构域控制CyclinB1蛋白的亚细胞定位,使其发挥不同的功能,因而推测CyclinB1自身抗体可能会影响肺癌细胞的细胞周期。
Objective
Autoantibodies as new tumor markers may play an important role in the early diagnosis and evaluating the prognosis of lung cancer patients.In this study, we map the epitopes of autoantibodies against EGFR, Her-2, Survivin and CyclinB1 in sera of non-small cell lung cancer patients with peptide array and screen the epitopes with high frequency. Through matching the sequence between epitopes with high frequency and the 4 kinds of protein to discover the structure distribution of these epitopes.
Method
4 kinds of peptide array which covered all the peptides in the 4 peptide libraries were synthesized by a synthesizer(ASP SL).Mapped the epitopes of autoantibodies against EGFR, Her-2, Survivin and CyclinB1 in serum of 50 NSCLC patients,. Screened the epitopes which were recognized by the 4 kinds of autoantibodies with high frequency. Through matching the sequence between epitopes with high frequency and the 4 kinds of protein to DISCOVER the structure distribution of these epitopes.
Result
4 kinds of peptide array were synthesized by a synthesizer (ASP SL). There were no the 4 kinds of autoantibodies in the mixed-serum of healthy objectives and in the mixed-serum of pulmonary tuberculosis patients. 10 of 50 NSCLC patients were found to have EGFR autoantibodies; 9 of 50 NSCLC patients were found to have Her-2 autoantibodies; 8 of 50 NSCLC patients were found to have survivin autoantibodies; 8 of 50 NSCLC patients were found to have CyclinB1 autoantibodies. Serums of A006,A022,A094,A124 had all 4 kinds of autoantibodies against EGFR Her-2 survivin and CyclinB1.Through scanning the epitopes, we found the epitopes with high frequency of the 4 kinds of autoantibodies. Discovered the structure distribution of these epitopes with high frequency.
Conclusion
Through epitope scanning , we found the epitopes with high frequency of the 4 kinds of autoantibodies. Through matching the sequence between epitopes with high frequency and the 4 kinds of protein we discover the structure distribution of these epitopes with high frequency. The discover of the epitopes with high frequency and the address of the the epitopes with high frequency will offer new clues for the further research of the 4 kinds autoantibodies.
引文
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2 Zhong L, Coe SP, Stromberg AJ, et al. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thorac Oncol. 2006; 1(6): 513-9.
3 Araújo A, Ribeiro R, Azevedo I, et al. Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature. Oncologist. 2007; 12(2): 201-10.
4 Garrett TP, McKern NM, Lou M, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors.Mol Cell. 2003 Feb;11(2):495-505.
5 Glushkov AN,Avosova TP,Anosov MP, et al. Detection of antibody to receptor of epidermal growth-factor in the sera of the patients with cancer. Exp. Oncology, 1996, 18(1): 81-83.
6 Pupa SM, Ménard S, Andreola S, et al. Antibody response against the c-erbB-2 oncoprotein in breast carcinoma patients. Cancer Res. 1993; 53(24): 5864-6.
7 Chapman CJ, Murray A, McElveen JE, et al. Autoantibodies in lung cancer: possibilities for early detection and subsequent cure. Thorax. 2008; 63(3):228-33.
8 Bei R, Masuelli L, Moriconi E, et al. Immune responses to all ErbB family receptors detectable in serum of cancer patients. Oncogene. 1999; 18(6): 1267-75.
9 Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997 Aug;3(8):917-21
10 Caldas H, Honsey LE, Altura RA. Survivin 2alpha: a novel Survivin splice variant expressed in human malignancies. Mol Cancer. 2005 Mar 2;4(1):11
11 Akyürek N, Memis L, Ekinci O, et al. Survivin expression in pre-invasive lesions and non-small cell lung carcinoma. Virchows Arch. 2006 Aug;449(2):164-70. Epub 2006 Jun 30.
12 Rohayem J, Diestelkoetter P, Weigle B, et al. Antibody response to thetumor-associated inhibitor of apoptosis protein survivin in cancer patients..Cancer Res. 2000 Apr 1;60(7):1815-7.
13 Zhang JY, Casiano CA, Peng XX, et al.Enhancement of antibody detection in cancer using panel of recombinant tumor-associated antigens. Cancer Epidemiol Biomarkers Prev. 2003 Feb;12(2):136-43.
14 Porter LA, Donoghue DJ. Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog Cell Cycle Res. 2003;5:335-47.
15 Kao H, Marto JA, Hoffmann TK, et al.Identification of cyclin B1 as a shared human epithelial tumor-associated antigen recognized by T cells. J Exp Med. 2001 Nov 5;194(9):1313-23.
16 Singhal S, Vachani A, Antin-Ozerkis D, et al Prognostic implications of cell cycle, apoptosis, and angiogenesis biomarkers in non-small cell lung cancer: a review. Clin Cancer Res. 2005 Jun 1;11(11):3974-86.
17 Covini G, Chan EK, Nishioka M, et al. Immune response to cyclin B1 in hepatocellular carcinoma. Hepatology. 1997 Jan;25(1):75-80.
18 Koziol JA, Zhang JY, Casiano CA, et al. Recursive partitioning as an approach to selection of immune markers for tumor diagnosis.. Clin Cancer Res. 2003 Nov 1;9(14):5120-6
19 Saleh J, Brunner C, G?lzer R, et al. p53 autoantibodies from patients with head and neck cancer recognise common epitopes on the polypeptide chain of p53. Cancer Lett. 2006 Feb 20;233(1):48-56
20 Reineke U, Sabat R, Misselwitz R, et al. A synthetic mimic of a discontinuous binding site on interleukin-10. Nat Biotechnol. 1999 Mar;17(3):271-5.
21 Reineke U, Sabat R. Antibody epitope mapping using SPOT peptide arrays. . Methods Mol Biol. 2009;524:145-67.
22 Lubin R,Zalcman G,Bouchet L,et al.Serum p53 antibodies as early markers of lung cancer. Nat Med. 1995 Jul;1(7):701-2
23 Lechpammer M, Lukac J, Lechpammer S, et al. Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvantchemotherapy. Int J Colorectal Dis. 2004; 19(2): 114-20.
24 Disis ML, Pupa SM, Gralow JR, et al. High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J Clin Oncol. 1997; 15(11): 3363-7.
25 Zhong L, Ge K, Zu JC, et al. Autoantibodies as potential biomarkers for breast cancer. Breast Cancer Res. 2008; 10(3): R40.
26 Garrett TP, McKern NM, Lou M, et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell. 2002 Sep 20;110(6):763-73.
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29 Sharma SV, Settleman J. ErbBs in lung cancer. Exp Cell Res. 2009; 315(4): 557-71.
30 Duneau JP, Garnier N, Genest M. Insight into signal transduction: structural alterations in transmembrane helices probed by multi-1 ns molecular dynamics simulations. J Biomol Struct Dyn. 1997 Dec;15(3):555-72.
31 Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 2008 Jan;8(1):61-70.
32 Ceballos-Cancino G, Espinosa M, Maldonado V, et al. Regulation of mitochondrial Smac/DIABLO-selective release by survivin. Oncogene. 2007 Nov 29;26(54):7569-75..
33 Brown NR, Lowe ED, Petri E, et al. Cyclin B and cyclin A confer different substrate recognition properties on CDK2. Cell Cycle. 2007 Jun 1;6(11):1350-9.
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2 Araújo A, Ribeiro R, Azevedo I, et al. Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature. Oncologist. 2007; 12(2): 201-10.
3 Ohsaki Y, Tanno S, Fujita Y, et al. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep. 2000; 7(3): 603-7.
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7 Calikusu Z, Yildirim Y, Akcali Z, et al. The effect of HER2 expression on cisplatin-based chemotherapy in advanced non-small cell lung cancer patients. J Exp Clin Cancer Res. 2009 3; 28: 97
8 Korrapati V, Gaffney M, Larsson LG, et al. Effect of HER2/neu expression on survival in non-small-cell lung cancer. Clin Lung Cancer. 2001; 2(3): 216-9
9 Sharma SV, Settleman J. ErbBs in lung cancer. Exp Cell Res. 2009; 315(4): 557-71.
10 Ugocsai K, Mándoky L, Tiszlavicz L, et al. Investigation of HER2 overexpression in non-small cell lung cancer. Anticancer Res. 2005; 25(4): 3061-6.
11 Koutsopoulos AV, Mavroudis D, Dambaki KI, et al. Simultaneous expression of c-erbB-1, c-erbB-2, c-erbB-3 and c-erbB-4 receptors in non-small-cell lung carcinomas: correlation with clinical outcome. Lung Cancer. 2007; 57(2): 193-200.
12 Glushkov AN,Avosova TP,Anosov MP, et al. Detection of antibody to receptor of epidermal growth-factor in the sera of the patients with cancer. Exp. Oncology, 1996, 18(1): 81-83.
13 Pupa SM, Ménard S, Andreola S, et al. Antibody response against the c-erbB-2 oncoprotein in breast carcinoma patients. Cancer Res. 1993; 53(24): 5864-6.
14 Chapman CJ, Murray A, McElveen JE, et al. Autoantibodies in lung cancer: possibilities for early detection and subsequent cure. Thorax. 2008; 63(3):228-33.
15 Bei R, Masuelli L, Moriconi E, et al. Immune responses to all ErbB family receptors detectable in serum of cancer patients. Oncogene. 1999; 18(6): 1267-75.
16 Disis ML, Knutson KL, Schiffman K, et al. Pre-existent immunity to the HER-2/neu oncogenic protein in patients with HER-2/neu overexpressing breast and ovarian cancer. Breast Cancer Res Treat. 2000; 62(3): 245-52.
17 Zhong L, Coe SP, Stromberg AJ, et al. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thorac Oncol. 2006; 1(6): 513-9.
18 Lechpammer M, Lukac J, Lechpammer S, et al. Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy. Int J Colorectal Dis. 2004; 19(2): 114-20.
19 Disis ML, Pupa SM, Gralow JR, et al. High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J Clin Oncol. 1997; 15(11): 3363-7.
20 Zhong L, Ge K, Zu JC, et al. Autoantibodies as potential biomarkers for breast cancer. Breast Cancer Res. 2008; 10(3): R40.
21 Planque S, Zhou YX, Nishiyama Y, et al. Autoantibodies to the epidermal growth factor receptor in systemic sclerosis, lupus, and autoimmune mice.FASEB J. 2003; 17(2): 136-43
22 Lai MD, Yen MC, Lin CM, et al. The effects of DNA formulation and administration route on cancer therapeutic efficacy with xenogenic EGFR DNA vaccine in a lung cancer animal model. Genet Vaccines Ther. 2009; 7: 2.
23 Disis ML, Smith JW, Murphy AE, et al. In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein. Cancer Res. 1994; 54(4): 1071-6.
24 Wang X, Wang JP, Rao XM, et al. Prime-boost vaccination with plasmid and adenovirus gene vaccines control HER2/neu+ metastatic breast cancer in mice. Breast Cancer Res. 2005; 7(5): R580-8.
25 Roth A, Rohrbach F, Weth R, et al. Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct. Br J Cancer. 2005 ; 92(8): 1421-9.
2 Zhong L, Coe SP, Stromberg AJ, et al. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thorac Oncol. 2006; 1(6): 513-9.
3 Araújo A, Ribeiro R, Azevedo I, et al. Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature. Oncologist. 2007; 12(2): 201-10.
4 Garrett TP, McKern NM, Lou M, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors.Mol Cell. 2003 Feb;11(2):495-505.
5 Glushkov AN,Avosova TP,Anosov MP, et al. Detection of antibody to receptor of epidermal growth-factor in the sera of the patients with cancer. Exp. Oncology, 1996, 18(1): 81-83.
6 Pupa SM, Ménard S, Andreola S, et al. Antibody response against the c-erbB-2 oncoprotein in breast carcinoma patients. Cancer Res. 1993; 53(24): 5864-6.
7 Chapman CJ, Murray A, McElveen JE, et al. Autoantibodies in lung cancer: possibilities for early detection and subsequent cure. Thorax. 2008; 63(3):228-33.
8 Bei R, Masuelli L, Moriconi E, et al. Immune responses to all ErbB family receptors detectable in serum of cancer patients. Oncogene. 1999; 18(6): 1267-75.
9 Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997 Aug;3(8):917-21
10 Caldas H, Honsey LE, Altura RA. Survivin 2alpha: a novel Survivin splice variant expressed in human malignancies. Mol Cancer. 2005 Mar 2;4(1):11
11 Akyürek N, Memis L, Ekinci O, et al. Survivin expression in pre-invasive lesions and non-small cell lung carcinoma. Virchows Arch. 2006 Aug;449(2):164-70. Epub 2006 Jun 30.
12 Rohayem J, Diestelkoetter P, Weigle B, et al. Antibody response to thetumor-associated inhibitor of apoptosis protein survivin in cancer patients..Cancer Res. 2000 Apr 1;60(7):1815-7.
13 Zhang JY, Casiano CA, Peng XX, et al.Enhancement of antibody detection in cancer using panel of recombinant tumor-associated antigens. Cancer Epidemiol Biomarkers Prev. 2003 Feb;12(2):136-43.
14 Porter LA, Donoghue DJ. Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog Cell Cycle Res. 2003;5:335-47.
15 Kao H, Marto JA, Hoffmann TK, et al.Identification of cyclin B1 as a shared human epithelial tumor-associated antigen recognized by T cells. J Exp Med. 2001 Nov 5;194(9):1313-23.
16 Singhal S, Vachani A, Antin-Ozerkis D, et al Prognostic implications of cell cycle, apoptosis, and angiogenesis biomarkers in non-small cell lung cancer: a review. Clin Cancer Res. 2005 Jun 1;11(11):3974-86.
17 Covini G, Chan EK, Nishioka M, et al. Immune response to cyclin B1 in hepatocellular carcinoma. Hepatology. 1997 Jan;25(1):75-80.
18 Koziol JA, Zhang JY, Casiano CA, et al. Recursive partitioning as an approach to selection of immune markers for tumor diagnosis.. Clin Cancer Res. 2003 Nov 1;9(14):5120-6
19 Saleh J, Brunner C, G?lzer R, et al. p53 autoantibodies from patients with head and neck cancer recognise common epitopes on the polypeptide chain of p53. Cancer Lett. 2006 Feb 20;233(1):48-56
20 Reineke U, Sabat R, Misselwitz R, et al. A synthetic mimic of a discontinuous binding site on interleukin-10. Nat Biotechnol. 1999 Mar;17(3):271-5.
21 Reineke U, Sabat R. Antibody epitope mapping using SPOT peptide arrays. . Methods Mol Biol. 2009;524:145-67.
22 Lubin R,Zalcman G,Bouchet L,et al.Serum p53 antibodies as early markers of lung cancer. Nat Med. 1995 Jul;1(7):701-2
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