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系統識別號 U0026-2008201514363700
論文名稱(中文) 篩選新型治療惡性卵巢癌的藥物
論文名稱(英文) A screening-based approach to select drugs for ovarian cancer treatment
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 高翊瑋
研究生(英文) Yi-Wei Kao
學號 T46024049
學位類別 碩士
語文別 中文
論文頁數 100頁
口試委員 指導教授-陳玉玲
指導教授-洪澤民
口試委員-洪良宜
召集委員-許耿福
中文關鍵字 卵巢癌  篩選藥物  抗藥性 
英文關鍵字 ovarian cancer  drug screening  drug resistance 
學科別分類
中文摘要 卵巢癌為婦女癌症死亡率的第一名。大部分的卵巢癌患者無法被早期診斷,整體病人的五年存活率低於50%。儘管化療一開始幾乎都可使疾病得到控制,但最後常因抗藥性的產生而死亡。因此,尋找潛在的治療藥物對於惡性卵巢癌的治療是迫切需要的。我們選擇兩個對順鉑(cisplatin)有不同耐受性的卵巢癌細胞株A2780和A2780CP70做為篩選新的治療藥物模組,希望找到有效毒殺抗藥性細胞的藥物。這裡我們利用Cmap資料庫預測以及即時、高通量的篩選系統RTCA,使用一個包含640個經過生物活性且經過美國食品藥物管理局認證的藥物庫來篩選出治療惡性卵巢癌的藥物。我們藉由兩株細胞總共分析篩選了100個藥物,經過實驗分析後最後挑選了MPA和DS候選藥物,此二藥物同時具有抑制抗藥性細胞A2780CP70以及A2780癌細胞的效果。因此我們更進一步透過西方墨點法分析處理藥物後細胞凋亡標記cleaved PARP以及caspase-3活化的表現量。實驗結果得知MPA、DS藥物可以誘導cleaved PARP蛋白表現量上升。此外,我們也觀察了候選藥物對於細胞週期的影響。實驗結果發現MPA藥物造成細胞停滯G1/S phase,而且Sub/G1的細胞比例也有增加。在DS藥物處理下,使A2780及A2780CP70細胞停滯於G2/M。Sub/G1細胞比例些微上升。從實驗結果知道,MPA、DS能抑制細胞的增殖,並會誘導細胞死亡。因此,可以知道MPA與DS是潛在的卵巢癌治療藥物。而這些FDA認證藥物將可以提供惡性卵巢癌患者新的治療策略。
英文摘要 Ovarian cancer is the most lethal gynecologic malignancy. Most patients with ovarian cancer are diagnosed in advanced stages and the overall five-year survival rate for all stages of ovarian cancer is less than 50%. In spite of the high response rate of initial treatment, the majority will relapse and eventually die due to the development of chemoresistance. Therefore, to screen new therapeutic drugs for patients with malignant ovarian cancer is urgently needed. For screening new therapeutic drugs, we used a chemoresistant ovarian cancer cell line pair, A2780 and A2780CP70. We used connectivity map (Cmap) database prediction and a FDA approved drug library, in which 640 diverse compounds have well-characterized bioactivities, to screen therapeutic drugs by a real time and high-throughput screening RTCA system. 100 FDA approved drugs have been screened and we selected the 2 candidate compounds, MPA and DS, which had a good cytotoxicity on A2780CP70 and parental cells. Furthermore, we treated A2780CP70 and A2780 with MPA and DS and analyzed the protein level of cleaved PARP and active form caspase-3, which plays a significant role in apoptosis, by western blot analyses. The result showed that MPA induced the protein level upregulation of cleaved PARP. But, DS didn’t significantly cause apoptotic processes. In addition, we assessed the effect of MPA and DS on cell cycle perturbations. Cell cycle analysis showed that MPA caused A2780CP70 and A2780 cell cycle arrest at G1/S phase, and the amount of cells at Sub-G1 increased. Treatment of DS in A2780CP70 and A2780 cells showed that the cell cycle was arrested at G2/M phase. Our data suggest that MPA and DS inhibited cell growth, and also induced cell death. Thus, MPA and DS are potential therapeutic drugs for ovarian cancer. In the future, these FDA approved drugs could provide a new treatment strategy for patients with advanced ovarian cancer.
論文目次 中文摘要 I
英文摘要 II
致謝 VII
目錄 VIII
英文縮寫檢索表 XIII
第一章 緒論 1
第一節 、卵巢癌(ovarian cancer) 1
第二節 、卵巢癌與癌幹細胞 4
第三節 、老藥新用(Drug repurposing) 6
第四節 、細胞凋亡(Cell Apoptosis) 7
第五節 、細胞週期(Cell cycle) 10
第六節 、Connectivity map(Cmap) 11
第二章 研究動機及架構 13
第一節 、研究動機 13
第二節 、研究架構 14
第三章 實驗材料與方法 15
第四章 實驗結果 36
第五章 討論 51
第六章 結論 58
參考文獻 60
實驗結果圖表 67
附錄 91
參考文獻 [1] V. R. Martin, "Ovarian cancer: an overview of treatment options," Clin J Oncol Nurs, vol. 11, pp. 201-7, Apr 2007.
[2] M. A. Bookman, "First-line chemotherapy in epithelial ovarian cancer," Clin Obstet Gynecol, vol. 55, pp. 96-113, Mar 2012.
[3] C. Wikborn, F. Pettersson, C. Silfversward, and P. J. Moberg, "Symptoms and diagnostic difficulties in ovarian epithelial cancer," Int J Gynaecol Obstet, vol. 42, pp. 261-4, Sep 1993.
[4] W. J. Hoskins, "Prospective on ovarian cancer: why prevent?," J Cell Biochem Suppl, vol. 23, pp. 189-99, 1995.
[5] S. A. Cannistra, "Cancer of the ovary," N Engl J Med, vol. 351, pp. 2519-29, Dec 9 2004.
[6] G. D. Aletti, M. M. Gallenberg, W. A. Cliby, A. Jatoi, and L. C. Hartmann, "Current management strategies for ovarian cancer," Mayo Clin Proc, vol. 82, pp. 751-70, Jun 2007.
[7] H. Naora and D. J. Montell, "Ovarian cancer metastasis: integrating insights from disparate model organisms," Nat Rev Cancer, vol. 5, pp. 355-66, May 2005.
[8] L. E. Puls, T. Duniho, J. E. Hunter, R. Kryscio, D. Blackhurst, and H. Gallion, "The prognostic implication of ascites in advanced-stage ovarian cancer," Gynecol Oncol, vol. 61, pp. 109-12, Apr 1996.
[9] E. Kipps, D. S. Tan, and S. B. Kaye, "Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research," Nat Rev Cancer, vol. 13, pp. 273-82, Apr 2013.
[10] A. A. Ayantunde and S. L. Parsons, "Pattern and prognostic factors in patients with malignant ascites: a retrospective study," Ann Oncol, vol. 18, pp. 945-9, May 2007.
[11] K. L. Sodek, M. J. Ringuette, and T. J. Brown, "Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype," Int J Cancer, vol. 124, pp. 2060-70, May 1 2009.
[12] S. Condello, C. A. Morgan, S. Nagdas, L. Cao, J. Turek, T. D. Hurley, et al., "beta-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids," Oncogene, vol. 34, pp. 2297-308, Apr 30 2015.
[13] T. Reya, S. J. Morrison, M. F. Clarke, and I. L. Weissman, "Stem cells, cancer, and cancer stem cells," Nature, vol. 414, pp. 105-11, Nov 1 2001.
[14] S. K. Singh, I. D. Clarke, M. Terasaki, V. E. Bonn, C. Hawkins, J. Squire, et al., "Identification of a cancer stem cell in human brain tumors," Cancer Res, vol. 63, pp. 5821-8, Sep 15 2003.
[15] T. Chiba, K. Kita, Y. W. Zheng, O. Yokosuka, H. Saisho, A. Iwama, et al., "Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties," Hepatology, vol. 44, pp. 240-51, Jul 2006.
[16] L. Ricci-Vitiani, D. G. Lombardi, E. Pilozzi, M. Biffoni, M. Todaro, C. Peschle, et al., "Identification and expansion of human colon-cancer-initiating cells," Nature, vol. 445, pp. 111-5, Jan 4 2007.
[17] P. P. Szotek, R. Pieretti-Vanmarcke, P. T. Masiakos, D. M. Dinulescu, D. Connolly, R. Foster, et al., "Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness," Proc Natl Acad Sci U S A, vol. 103, pp. 11154-9, Jul 25 2006.
[18] S. A. Bapat, "Human ovarian cancer stem cells," Reproduction, vol. 140, pp. 33-41, Jul 2010.
[19] K. D. Bunting, "ABC transporters as phenotypic markers and functional regulators of stem cells," Stem Cells, vol. 20, pp. 11-20, 2002.
[20] N. S. Wolf, A. Kone, G. V. Priestley, and S. H. Bartelmez, "In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection," Exp Hematol, vol. 21, pp. 614-22, May 1993.
[21] T. Leemhuis, M. C. Yoder, S. Grigsby, B. Aguero, P. Eder, and E. F. Srour, "Isolation of primitive human bone marrow hematopoietic progenitor cells using Hoechst 33342 and Rhodamine 123," Exp Hematol, vol. 24, pp. 1215-24, Aug 1996.
[22] D. Ponti, A. Costa, N. Zaffaroni, G. Pratesi, G. Petrangolini, D. Coradini, et al., "Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties," Cancer Res, vol. 65, pp. 5506-11, Jul 1 2005.
[23] S. J. Kim, S. Cheung, and M. K. Hellerstein, "Isolation of nuclei from label-retaining cells and measurement of their turnover rates in rat colon," Am J Physiol Cell Physiol, vol. 286, pp. C1464-73, Jun 2004.
[24] Q. Z. He, X. Z. Luo, K. Wang, Q. Zhou, H. Ao, Y. Yang, et al., "Isolation and characterization of cancer stem cells from high-grade serous ovarian carcinomas," Cell Physiol Biochem, vol. 33, pp. 173-84, 2014.
[25] A. T. Collins, P. A. Berry, C. Hyde, M. J. Stower, and N. J. Maitland, "Prospective identification of tumorigenic prostate cancer stem cells," Cancer Res, vol. 65, pp. 10946-51, Dec 1 2005.
[26] P. Grosse-Gehling, C. A. Fargeas, C. Dittfeld, Y. Garbe, M. R. Alison, D. Corbeil, et al., "CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges," J Pathol, vol. 229, pp. 355-78, Feb 2013.
[27] I. A. Silva, S. Bai, K. McLean, K. Yang, K. Griffith, D. Thomas, et al., "Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival," Cancer Res, vol. 71, pp. 3991-4001, Jun 1 2011.
[28] V. Vathipadiekal, D. Saxena, S. C. Mok, P. V. Hauschka, L. Ozbun, and M. J. Birrer, "Identification of a potential ovarian cancer stem cell gene expression profile from advanced stage papillary serous ovarian cancer," PLoS One, vol. 7, p. e29079, 2012.
[29] T. Xiang, H. Long, L. He, X. Han, K. Lin, Z. Liang, et al., "Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer," Oncogene, vol. 34, pp. 165-76, Jan 8 2015.
[30] I. Ma and A. L. Allan, "The role of human aldehyde dehydrogenase in normal and cancer stem cells," Stem Cell Rev, vol. 7, pp. 292-306, Jun 2011.
[31] T. Morris, M. Stables, A. Hobbs, P. de Souza, P. Colville-Nash, T. Warner, et al., "Effects of low-dose aspirin on acute inflammatory responses in humans," J Immunol, vol. 183, pp. 2089-96, Aug 1 2009.
[32] J. R. Vane and R. M. Botting, "The mechanism of action of aspirin," Thromb Res, vol. 110, pp. 255-8, Jun 15 2003.
[33] J. S. Berger, A. Lala, M. J. Krantz, G. S. Baker, and W. R. Hiatt, "Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials," Am Heart J, vol. 162, pp. 115-24 e2, Jul 2011.
[34] T. Wolff, T. Miller, and S. Ko, "Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force," Ann Intern Med, vol. 150, pp. 405-10, Mar 17 2009.
[35] H. A. Ghofrani, I. H. Osterloh, and F. Grimminger, "Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond," Nat Rev Drug Discov, vol. 5, pp. 689-702, Aug 2006.
[36] S. Uthayathas, S. S. Karuppagounder, B. M. Thrash, K. Parameshwaran, V. Suppiramaniam, and M. Dhanasekaran, "Versatile effects of sildenafil: recent pharmacological applications," Pharmacol Rep, vol. 59, pp. 150-63, Mar-Apr 2007.
[37] S. M. Baidas, E. P. Winer, G. F. Fleming, L. Harris, J. M. Pluda, J. G. Crawford, et al., "Phase II evaluation of thalidomide in patients with metastatic breast cancer," J Clin Oncol, vol. 18, pp. 2710-7, Jul 2000.
[38] A. J. Hanje, J. L. Shamp, F. B. Thomas, and G. M. Meis, "Thalidomide-induced severe hepatotoxicity," Pharmacotherapy, vol. 26, pp. 1018-22, Jul 2006.
[39] C. E. Milligan and L. M. Schwartz, "Programmed cell death during animal development," Br Med Bull, vol. 53, pp. 570-90, 1997.
[40] M. J. Arends and A. H. Wyllie, "Apoptosis: mechanisms and roles in pathology," Int Rev Exp Pathol, vol. 32, pp. 223-54, 1991.
[41] A. H. Wyllie, J. F. Kerr, and A. R. Currie, "Cell death: the significance of apoptosis," Int Rev Cytol, vol. 68, pp. 251-306, 1980.
[42] J. F. Kerr, C. M. Winterford, and B. V. Harmon, "Apoptosis. Its significance in cancer and cancer therapy," Cancer, vol. 73, pp. 2013-26, Apr 15 1994.
[43] R. A. Lockshin and J. Beaulaton, "Cell death: questions for histochemists concerning the causes of the various cytological changes," Histochem J, vol. 13, pp. 659-66, Jul 1981.
[44] S. C. Cosulich, P. J. Savory, and P. R. Clarke, "Bcl-2 regulates amplification of caspase activation by cytochrome c," Curr Biol, vol. 9, pp. 147-50, Feb 11 1999.
[45] L. Ou, C. Ip, B. Lisafeld, and M. M. Ip, "Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss," Biochem Biophys Res Commun, vol. 356, pp. 1044-9, May 18 2007.
[46] G. S. Salvesen and M. Renatus, "Apoptosome: the seven-spoked death machine," Dev Cell, vol. 2, pp. 256-7, Mar 2002.
[47] W. C. Earnshaw, L. M. Martins, and S. H. Kaufmann, "Mammalian caspases: structure, activation, substrates, and functions during apoptosis," Annu Rev Biochem, vol. 68, pp. 383-424, 1999.
[48] D. Green and G. Kroemer, "The central executioners of apoptosis: caspases or mitochondria?," Trends Cell Biol, vol. 8, pp. 267-71, Jul 1998.
[49] M. O. Hengartner, "The biochemistry of apoptosis," Nature, vol. 407, pp. 770-6, Oct 12 2000.
[50] J. Lamb, E. D. Crawford, D. Peck, J. W. Modell, I. C. Blat, M. J. Wrobel, et al., "The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease," Science, vol. 313, pp. 1929-35, Sep 29 2006.
[51] J. Lamb, "The Connectivity Map: a new tool for biomedical research," Nat Rev Cancer, vol. 7, pp. 54-60, Jan 2007.
[52] H. W. Cheng, Y. H. Liang, Y. L. Kuo, C. P. Chuu, C. Y. Lin, M. H. Lee, et al., "Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data," Cell Death Dis, vol. 6, p. e1753, 2015.
[53] S. Claerhout, J. Y. Lim, W. Choi, Y. Y. Park, K. Kim, S. B. Kim, et al., "Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer," PLoS One, vol. 6, p. e24662, 2011.
[54] R. J. Parker, A. Eastman, F. Bostick-Bruton, and E. Reed, "Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation," J Clin Invest, vol. 87, pp. 772-7, Mar 1991.
[55] L. Rosano, R. Cianfrocca, F. Spinella, V. Di Castro, M. R. Nicotra, A. Lucidi, et al., "Acquisition of chemoresistance and EMT phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells," Clin Cancer Res, vol. 17, pp. 2350-60, Apr 15 2011.
[56] B. J. Chiasson, V. Tropepe, C. M. Morshead, and D. van der Kooy, "Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics," J Neurosci, vol. 19, pp. 4462-71, Jun 1 1999.
[57] K. Yu, L. Toral-Barza, C. Shi, W. G. Zhang, J. Lucas, B. Shor, et al., "Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin," Cancer Res, vol. 69, pp. 6232-40, Aug 1 2009.
[58] P. W. Schlosshauer, W. Li, K. T. Lin, J. L. Chan, and L. H. Wang, "Rapamycin by itself and additively in combination with carboplatin inhibits the growth of ovarian cancer cells," Gynecol Oncol, vol. 114, pp. 516-22, Sep 2009.
[59] R. C. Jackson, G. Weber, and H. P. Morris, "IMP dehydrogenase, an enzyme linked with proliferation and malignancy," Nature, vol. 256, pp. 331-3, Jul 24 1975.
[60] R. J. Tressler, L. J. Garvin, and D. L. Slate, "Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo," Int J Cancer, vol. 57, pp. 568-73, May 15 1994.
[61] E. M. Freeburg, A. A. Goyeneche, E. E. Seidel, and C. M. Telleria, "Resistance to cisplatin does not affect sensitivity of human ovarian cancer cell lines to mifepristone cytotoxicity," Cancer Cell Int, vol. 9, p. 4, 2009.
[62] E. Meng, A. Mitra, K. Tripathi, M. A. Finan, J. Scalici, S. McClellan, et al., "ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling," PLoS One, vol. 9, p. e107142, 2014.
[63] A. Singh and J. Settleman, "EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer," Oncogene, vol. 29, pp. 4741-51, Aug 26 2010.
[64] A. M. Haslehurst, M. Koti, M. Dharsee, P. Nuin, K. Evans, J. Geraci, et al., "EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer," BMC Cancer, vol. 12, p. 91, 2012.
[65] Y. Kwon, E. Cukierman, and A. K. Godwin, "Differential expressions of adhesive molecules and proteases define mechanisms of ovarian tumor cell matrix penetration/invasion," PLoS One, vol. 6, p. e18872, 2011.
[66] M. Y. Fong, S. Jin, M. Rane, R. K. Singh, R. Gupta, and S. S. Kakar, "Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer," PLoS One, vol. 7, p. e42265, 2012.
[67] U. D. Renner, C. Thiede, M. Bornhauser, G. Ehninger, and H. M. Thiede, "Determination of mycophenolic acid and mycophenolate mofetil by high-performance liquid chromatography using postcolumn derivatization," Anal Chem, vol. 73, pp. 41-6, Jan 1 2001.
[68] X. Yang, F. Zheng, H. Xing, Q. Gao, W. Wei, Y. Lu, et al., "Resistance to chemotherapy-induced apoptosis via decreased caspase-3 activity and overexpression of antiapoptotic proteins in ovarian cancer," J Cancer Res Clin Oncol, vol. 130, pp. 423-8, Jul 2004.
[69] Y. F. Lin, T. C. Lai, C. K. Chang, C. L. Chen, M. S. Huang, C. J. Yang, et al., "Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies," J Clin Invest, vol. 123, pp. 3861-75, Sep 2013.
[70] G. Guidicelli, B. Chaigne-Delalande, M. S. Dilhuydy, B. Pinson, W. Mahfouf, J. M. Pasquet, et al., "The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells," PLoS One, vol. 4, p. e5493, 2009.
[71] M. F. Neerman and D. M. Boothe, "A possible mechanism of gastrointestinal toxicity posed by mycophenolic acid," Pharmacol Res, vol. 47, pp. 523-6, Jun 2003.
[72] N. Nagai, Y. Ito, and N. Takeuchi, "Pharmacokinetic and pharmacodynamic evaluation of the anti-cataract effect of eye drops containing disulfiram and low-substituted methylcellulose using ICR/f rats as a hereditary cataract model," Biol Pharm Bull, vol. 35, pp. 239-45, 2012.
[73] H. Zhang, D. Chen, J. Ringler, W. Chen, Q. C. Cui, S. P. Ethier, et al., "Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo," Cancer Res, vol. 70, pp. 3996-4004, May 15 2010.
[74] B. W. Morrison, N. A. Doudican, K. R. Patel, and S. J. Orlow, "Disulfiram induces copper-dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic pathway in melanoma," Melanoma Res, vol. 20, pp. 11-20, Feb 2010.
[75] W. Wang, H. L. McLeod, and J. Cassidy, "Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines," Int J Cancer, vol. 104, pp. 504-11, Apr 20 2003.
[76] N. C. Yip, I. S. Fombon, P. Liu, S. Brown, V. Kannappan, A. L. Armesilla, et al., "Disulfiram modulated ROS-MAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties," Br J Cancer, vol. 104, pp. 1564-74, May 10 2011.
[77] P. Liu, I. S. Kumar, S. Brown, V. Kannappan, P. E. Tawari, J. Z. Tang, et al., "Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells," Br J Cancer, vol. 109, pp. 1876-85, Oct 1 2013.
[78] P. Liu, S. Brown, T. Goktug, P. Channathodiyil, V. Kannappan, J. P. Hugnot, et al., "Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells," Br J Cancer, vol. 107, pp. 1488-97, Oct 23 2012.
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