簡易檢索 / 詳目顯示

回結果列表
研究生： 李佩芬
Lee, Pei-Fen
論文名稱： 探勘突變熱點以發掘慢性B型肝炎之臨床生物標記
Discovering Clinical Biomarkers of Chronic Hepatitis B by Mining Mutation Hotspots
指導教授： 曾新穆
Tseng, Vincent S.
學位類別： 碩士
Master
系所名稱： 電機資訊學院 - 醫學資訊研究所
Institute of Medical Informatics
論文出版年： 2011
畢業學年度： 99
語文別： 英文
論文頁數： 83
中文關鍵詞： 共變異網路 、單點突變 、核前/核心蛋白 、B型肝炎病毒 、e抗原 、突變熱點
外文關鍵詞： covariance network, point mutation, HBeAg, Hepatitis B virus, precore/core protein, mutation hotspot
相關次數： 點閱：89  下載：0 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • B型肝炎病毒是最常見的DNA病毒，可能會導致肝炎、肝硬化以及肝癌的發生。近幾十年來，肝癌是造成人類死亡的主要癌症之一。儘管人類仍持續感染B型肝炎病毒，但血清中的病毒量以及宿主的免疫反應會因人而異。越來越多有關B型肝炎病毒的研究宣稱由核前/核心開放閱讀框架轉譯而來的B型肝炎e抗原和核心抗原與病毒的複製有關，進而導致宿主免疫產生反應和感染。由於高頻率的突變發生在B型肝炎病毒的核前/核心蛋白質序列上可能會改變蛋白質的表現與功能，然而要如何正確地分析這些序列是一個挑戰，因此本研究將探討序列上的突變熱點以發掘慢性B型肝炎臨床特徵之生物。我們收集了23位感染慢性B型肝炎病毒長達一年且e抗原陽性的病人，依照每個月所測得血清中的ALT、DNA以及e抗原的量，這段期間至少包含4個具代表性的時間點，可將病人分為不同的群體。接著將B型肝炎病毒的核前/核心DNA序列以人為方式轉譯成胺基酸序列，並分析核前/核心蛋白質序列上的突變與臨床以及血清結果的關係。我們利用一個結合共變異網路與單點突變規則的方法找到在核前/核心蛋白質序列上具代表性的突變點。利用文獻驗證的結果顯示這些突變與病毒動力學、是否有e抗原血清轉換、病毒基因型以及胺基酸屬性的改變有高度的相關性。除此之外，我們發展了一個高覆蓋率的特徵樹，可以提供臨床醫師給予在早期受到感染的病人一個較好的療程，縱使這些病人尚未有明顯的臨床病徵。再者，當病人被分為e抗原血清轉換與否時，我們在B型肝炎病毒基因型C之核前/核心胺基酸序列中，我們發現胺基酸位置116與126存在一個顯著差異的胺基酸轉換。

    Hepatitis B virus (HBV) is the most common DNA virus that may cause hepatitis, cirrhosis and hepatocellular carcinoma (HCC). In recent decades, HCC is one of major causes of cancer death worldwide. Although many people are persistently infected with HBV, the serum viral load and host immune response varies from person to person. An increasing number of research articles on chronic hepatitis B have claimed that the activities of two proteins, hepatitis B e antigen (HBeAg) and core antigen (HBcAg), encoded by precore/core open reading frame (ORF), are associated with the DNA replication of HBV, in turn leading to the host immune response and infection. Because the high rate of mutations in HBV precore/core protein sequences during infection will alter the protein expression and/or function, how to properly analyze these sequences is a challenge. Therefore, these studies discovered clinical biomarkers of chronic hepatitis B patients by mining mutation hotspots. We collected a one year follow-up study with a total number of 23 patients with HBeAg-positive chronic hepatitis B. Serum alanine aminotransferase, HBV DNA and HBeAg levels were measured monthly and used as the criteria for clustering the patients into different subgroups. Using monthly derived precore/core ORF sequences from HBV genomic DNA, sequenced and artificially translated into amino acid sequences from each patient at least four representative time points, we analyzed the amino acid mutations within HBV precore/core proteins responsible for serologic and clinical outcome in each subgroup. Using a combination of covariance networks and point mutation rules, we identified different discriminative mutations within precore/core protein sequences. Validation with literature-curated mutation hotspots showed that these discriminative mutations were strongly associated with the patterns of viral kinetics, presence of HBeAg-seroconversion in sera, HBV genotypes and changes in amino acid properties. In addition, we developed a feature tree with high coverage rates, which is applicable for clinicians to prescribe patients a suitable treatment at early stage of HBV infection even though the patients exhibit no obvious symptoms. Furthermore, when patients were divided into two subgroups – HBeAg-seroconversion and HBeAg-nonseroconversion, we further discovered a significant alteration of amino acids at HBV genotype C precore/core position 116 and 126.

    摘要 I Abstract II 誌謝 IV 1. Introduction 1 1.1 Background 1 1.1.1 Hepatitis B Virus 1 1.1.2 Clinical Feature and Natural Course of Hepatitis B Virus 4 1.2 Motivation 6 1.3 Contribution 7 1.4 Thesis Organization 8 2. Related Work 9 2.1 Covariance Network 9 2.2 Point mutation 10 3. Materials and Methods 12 3.1 Schematic Overview of Data Processing 12 3.2 Patients and Study Design 13 3.3 Polymerase Chain Reaction Amplification of The Precore/core ORF and Genotyping 14 3.4 Cloning Process 15 3.5 An Illustration of Computational Methods Applied on Sequence Data 16 3.6 Statistical Analysis 17 4. Experimental Results 18 4.1 A Significant Improvement to Increase The Proportion of Mutation Hotspots Within Networks 18 4.2 Informative Networks Correspond to Clinical Signatures 20 4.3 HBV Genotype C Infections Accompanied with A Cyclic Process of Point Mutation 21 4.4 Analyzing Networks Between All Patient Subgroups at Early Stage During HBV Infection 22 4.5 Development of a Feature Tree 23 4.6 Identification of Potential Biomarkers for The Prediction of HBeAg-seroconversion 24 4.7 Alteration of Amino Acids at HBV Precore/core 116 and 126 is Associated with Genotype C HBeAg-seroconversion 25 5. Conclusions and Future Work 27 5.1 Conclusions 27 5.2 Future Work 33 6. References 35 VITA 83

    1. Akarca, U.S. and Lok, A.S. Naturally occurring hepatitis B virus core gene mutations. Hepatology, 22 (1). 50-60.
    2. Akarca, U.S. and Lok, A.S.F. Naturally-Occurring Hepatitis-B Virus Core Gene-Mutations. Hepatology, 22 (1). 50-60.
    3. Alizadeh, A.H., Ranjbar, M., Ansari, S., Alavian, S.M., Shalmani, H.M., Hekmat, L. and Zali, M.R. Intra-familial prevalence of hepatitis B virologic markers in HBsAg positive family members in Nahavand, Iran. World J Gastroenterol, 11 (31). 4857-4860.
    4. Arauz-Ruiz, P., Norder, H., Robertson, B.H. and Magnius, L.O. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol, 83 (Pt 8). 2059-2073.
    5. Aurora, R., Donlin, M.J., Cannon, N.A. and Tavis, J.E. Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans. J Clin Invest, 119 (1). 225-236.
    6. Bartholomeusz, A. and Schaefer, S. Hepatitis B virus genotypes: comparison of genotyping methods. Rev Med Virol, 14 (1). 3-16.
    7. Beasley, R.P., Hwang, L.Y., Lin, C.C. and Chien, C.S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet, 2 (8256). 1129-1133.
    8. Buster, E.H. and Janssen, H.L. Antiviral treatment for chronic hepatitis B virus infection--immune modulation or viral suppression? Neth J Med, 64 (6). 175-185.
    9. Cao, T., Desombere, I., Vanlandschoot, P., Sallberg, M. and Leroux-Roels, G. Characterization of HLA DR13-restricted CD4(+) T cell epitopes of hepatitis B core antigen associated with self-limited, acute hepatitis B. J Gen Virol, 83 (Pt 12). 3023-3033.
    10. Carman, W.F., Boner, W., Fattovich, G., Colman, K., Dornan, E.S., Thursz, M. and Hadziyannis, S. Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission. Journal of Infectious Diseases, 175 (5). 1093-1100.
    11. Chan, H.L., Wong, G.L., Tse, C.H., Chim, A.M., Yiu, K.K., Chan, H.Y., Sung, J.J. and Wong, V.W. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B. Clin Gastroenterol Hepatol, 7 (12). 1361-1366.
    12. Chan, H.L., Wong, M.L., Hui, A.Y., Hung, L.C., Chan, F.K. and Sung, J.J. Hepatitis B virus genotype C takes a more aggressive disease course than hepatitis B virus genotype B in hepatitis B e antigen-positive patients. J Clin Microbiol, 41 (3). 1277-1279.
    13. Chan, H.L.Y., Hui, A.Y., Wong, M.L., Tse, A.M.L., Hung, L.C.T., Wong, V.W.S. and Sung, J.J.Y. Genotype C hepatitis B virus infection is associated with increased risk of hepatocellular carcinoma. A prospective cohort study. Journal of Hepatology, 40. 75-75.
    14. Chan, H.L.Y., Wong, M.L., Hui, A.Y., Hung, L.C.T., Chan, F.K.L. and Sung, J.J.Y. Use of hepatitis B virus DNA quantitation to predict hepatitis B e antigen reversion in cases of chronic hepatitis B. Journal of Clinical Microbiology, 41 (10). 4793-4795.
    15. Chen, C.H., Hung, C.H., Lee, C.M., Hu, T.H., Wang, J.H., Wang, J.C., Lu, S.N. and Changchien, C.S. Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients. Gastroenterology, 133 (5). 1466-1474.
    16. Chen, C.J., Yang, H.I., Su, J., Jen, C.L., You, S.L., Lu, S.N., Huang, G.T., Iloeje, U.H. and Grp, R.-H.S. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. Jama-Journal of the American Medical Association, 295 (1). 65-73.
    17. Chu, C.J., Hussain, M. and Lok, A.S. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology, 122 (7). 1756-1762.
    18. Chu, C.M., Yeh, C.T., Lee, C.S., Sheen, I.S. and Liaw, Y.F. Precore stop mutant in HBeAg-positive patients with chronic hepatitis B: clinical characteristics and correlation with the course of HBeAg-to-anti-HBe seroconversion. J Clin Microbiol, 40 (1). 16-21.
    19. Chuang, W.L., Omata, M., Ehata, T., Yokosuka, O., Ito, Y., Imazeki, F., Lu, S.N., Chang, W.Y. and Ohto, M. Precore mutations and core clustering mutations in chronic hepatitis B virus infection. Gastroenterology, 104 (1). 263-271.
    20. Colucci, G., Beazer, Y., Cantaluppi, C. and Tackney, C. Identification of a major hepatitis B core antigen (HBcAg) determinant by using synthetic peptides and monoclonal antibodies. J Immunol, 141 (12). 4376-4380.
    21. Dahari, H., Layden-Almer, J.E., Kallwitz, E., Ribeiro, R.M., Cotler, S.J., Layden, T.J. and Perelson, A.S. A mathematical model of hepatitis C virus dynamics in patients with high baseline viral loads or advanced liver disease. Gastroenterology, 136 (4). 1402-1409.
    22. de Franchis, R., Hadengue, A., Lau, G., Lavanchy, D., Lok, A., McIntyre, N., Mele, A., Paumgartner, G., Pietrangelo, A., Rodes, J., Rosenberg, W. and Valla, D. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol, 39 Suppl 1. S3-25.
    23. Devesa, M., Loureiro, C.L., Rivas, Y., Monsalve, F., Cardona, N., Duarte, M.C., Poblete, F., Gutierrez, M.F., Botto, C. and Pujol, F.H. Subgenotype diversity of hepatitis B virus American genotype F in Amerindians from Venezuela and the general population of Colombia. J Med Virol, 80 (1). 20-26.
    24. Ding, X., Mizokami, M., Yao, G.B., Xu, B., Orito, E., Ueda, R. and Nakanishi, M. Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. Intervirology, 44 (1). 43-47.
    25. Edmunds, W.J., Medley, G.F., Nokes, D.J., Hall, A.J. and Whittle, H.C. The influence of age on the development of the hepatitis B carrier state. Proc Biol Sci, 253 (1337). 197-201.
    26. Ehata, T., Omata, M., Yokosuka, O., Hosoda, K. and Ohto, M. Variations in codons 84-101 in the core nucleotide sequence correlate with hepatocellular injury in chronic hepatitis B virus infection. J Clin Invest, 89 (1). 332-338.
    27. Fariselli, P., Olmea, O., Valencia, A. and Casadio, R. Progress in predicting inter-residue contacts of proteins with neural networks and correlated mutations. Proteins-Structure Function and Genetics. 157-162.
    28. Fattovich, G., Bortolotti, F. and Donato, F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol, 48 (2). 335-352.
    29. Ferrari, C., Bertoletti, A., Penna, A., Cavalli, A., Valli, A., Missale, G., Pilli, M., Fowler, P., Giuberti, T., Chisari, F.V. and et al. Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen. J Clin Invest, 88 (1). 214-222.
    30. Frenkel-Morgenstern, M., Magid, R., Eyal, E. and Pietrokovski, S. Refining intra-protein contact prediction by graph analysis. BMC Bioinformatics, 8 Suppl 5. S6.
    31. Gobel, U., Sander, C., Schneider, R. and Valencia, A. Correlated Mutations and Residue Contacts in Proteins. Proteins-Structure Function and Genetics, 18 (4). 309-317.
    32. Guarnieri, M., Kim, K.H., Bang, G., Li, J., Zhou, Y.H., Tang, X.L., Wands, J. and Tong, S.P. Point mutations upstream of hepatitis B virus core gene affect DNA replication at the step of core protein expression. Journal of Virology, 80 (2). 587-595.
    33. Gust, I.D. Epidemiology of hepatitis B infection in the Western Pacific and South East Asia. Gut, 38 Suppl 2. S18-23.
    34. Harrison, T.J. Hepatitis B virus: molecular virology and common mutants. Semin Liver Dis, 26 (2). 87-96.
    35. Hosono, S., Tai, P.C., Wang, W., Ambrose, M., Hwang, D.G., Yuan, T.T., Peng, B.H., Yang, C.S., Lee, C.S. and Shih, C. Core antigen mutations of human hepatitis B virus in hepatomas accumulate in MHC class II-restricted T cell epitopes. Virology, 212 (1). 151-162.
    36. Hsu, Y.S., Chien, R.N., Yeh, C.T., Sheen, I.S., Chiou, H.Y., Chu, C.M. and Liaw, Y.F. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology, 35 (6). 1522-1527.
    37. Hunt, C.M., McGill, J.M., Allen, M.I. and Condreay, L.D. Clinical relevance of hepatitis B viral mutations. Hepatology, 31 (5). 1037-1044.
    38. Hyams, K.C. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis, 20 (4). 992-1000.
    39. Iloeje, U.H., Yang, H.I., Su, J., Jen, C.L., You, S.L., Chen, C.J. and Load, R.E.V. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology, 130 (3). 678-686.
    40. Jung, M.C., Diepolder, H.M., Spengler, U., Wierenga, E.A., Zachoval, R., Hoffmann, R.M., Eichenlaub, D., Frosner, G., Will, H. and Pape, G.R. Activation of a heterogeneous hepatitis B (HB) core and e antigen-specific CD4+ T-cell population during seroconversion to anti-HBe and anti-HBs in hepatitis B virus infection. J Virol, 69 (6). 3358-3368.
    41. Kao, J.H. Role of viral factors in the natural course and therapy of chronic hepatitis B. Hepatol Int, 1 (4). 415-430.
    42. Kashyap, A.K., Steel, J., Oner, A.F., Dillon, M.A., Swale, R.E., Wall, K.M., Perry, K.J., Faynboym, A., Ilhan, M., Horowitz, M., Horowitz, L., Palese, P., Bhatt, R.R. and Lerner, R.A. Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci U S A, 105 (16). 5986-5991.
    43. Kim, H., Jee, Y., Mun, H.S., Song, B.C., Park, J.H., Hyun, J.W., Hwang, E.S., Cha, C.Y., Kook, Y.H. and Kim, B.J. Comparison of full genome sequences between two hepatitis B virus strains with or without preC mutation (A1896) from a single Korean hepatocellular carcinoma patient. J Microbiol Biotechnol, 17 (4). 701-704.
    44. Kim, H.J., Lee, D.H., Gwak, G.Y., Choi, M.S., Lee, J.H., Koh, K.C., Paik, S.W. and Yoo, B.C. Analysis of the core gene of hepatitis B virus in Korean patients. Liver Int, 27 (5). 633-638.
    45. Kramvis, A., Kew, M. and Francois, G. Hepatitis B virus genotypes. Vaccine, 23 (19). 2409-2423.
    46. Krishnan, S.M. and Dixit, N.M. Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy. PLoS Comput Biol, 7 (2). e1001072.
    47. Larson, S.M., Di Nardo, A.A. and Davidson, A.R. Analysis of covariation in an SH3 domain sequence alignment: Applications in tertiary contact prediction and the design of compensating hydrophobic core substitutions. Journal of Molecular Biology, 303 (3). 433-446.
    48. Lavanchy, D. Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol, 34 Suppl 1. S1-3.
    49. Le Pogam, S., Yuan, T.T., Sahu, G.K., Chatterjee, S. and Shih, C. Low-level secretion of human hepatitis B virus virions caused by two independent, naturally occurring mutations (P5T and L60V) in the capsid protein. J Virol, 74 (19). 9099-9105.
    50. Leung, N. Treatment of HBeAg-positive chronic hepatitis B with nucleos(t)ide analogues. Liver Int, 31 Suppl 1. 85-89.
    51. Liaw, Y.F., Leung, N., Kao, J.H., Piratvisuth, T., Gane, E., Han, K.H., Guan, R., Lau, G.K. and Locarnini, S. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int, 2 (3). 263-283.
    52. Liu, W.C., Mizokami, M., Buti, M., Lindh, M., Young, K.C., Sun, K.T., Chi, Y.C., Li, H.H. and Chang, T.T. Simultaneous quantification and genotyping of hepatitis B virus for genotypes A to G by real-time PCR and two-step melting curve analysis. J Clin Microbiol, 44 (12). 4491-4497.
    53. Liu, Z., Luo, K., He, H. and Hou, J. Hot-spot mutations in hepatitis B virus core gene: eliciting or evading immune clearance? J Viral Hepat, 12 (2). 146-153.
    54. Livingston, S.E., Simonetti, J.P., McMahon, B.J., Bulkow, L.R., Hurlburt, K.J., Homan, C.E., Snowball, M.M., Cagle, H.H., Williams, J.L. and Chulanov, V.P. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis, 195 (1). 5-11.
    55. Locarnini, S., McMillan, J. and Bartholomeusz, A. The hepatitis B virus and common mutants. Semin Liver Dis, 23 (1). 5-20.
    56. Locarnini, S., McMillan, J. and Bartholomeusz, A. The hepatitis B virus and common mutants. Seminars in Liver Disease, 23 (1). 5-20.
    57. Luciani, F. and Alizon, S. The evolutionary dynamics of a rapidly mutating virus within and between hosts: the case of hepatitis C virus. PLoS Comput Biol, 5 (11). e1000565.
    58. Luo, K.X., Yang, J. and Liang, Z.S. [Correlation between HBV pre-C/C gene mutations and advanced pathologic activity in chronic hepatitis B]. Zhonghua Nei Ke Za Zhi, 33 (11). 763-766.
    59. Magnius, L.O. and Norder, H. Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene. Intervirology, 38 (1-2). 24-34.
    60. McMahon, B.J. The natural history of chronic hepatitis B virus infection. Hepatology, 49 (5 Suppl). S45-55.
    61. McMahon, B.J., Alward, W.L., Hall, D.B., Heyward, W.L., Bender, T.R., Francis, D.P. and Maynard, J.E. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis, 151 (4). 599-603.
    62. Menne, S., Maschke, J., Tolle, T.K., Lu, M. and Roggendorf, M. Characterization of T-cell response to woodchuck hepatitis virus core protein and protection of woodchucks from infection by immunization with peptides containing a T-cell epitope. J Virol, 71 (1). 65-74.
    63. Missale, G., Redeker, A., Person, J., Fowler, P., Guilhot, S., Schlicht, H.J., Ferrari, C. and Chisari, F.V. HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis. J Exp Med, 177 (3). 751-762.
    64. Mohamadkhani, A., Jazii, F.R., Poustchi, H., Nouraein, O., Abbasi, S., Sotoudeh, M. and Montazeri, G. The role of mutations in core protein of hepatitis B virus in liver fibrosis. Virol J, 6. 209.
    65. Nattermann, J. and Tacke, F. The structure behind diversity: covariance networks in hepatitis C virus sequences are associated with treatment response. Hepatology, 49 (5). 1767-1769.
    66. Nguyen, V.T., Law, M.G. and Dore, G.J. Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat, 16 (7). 453-463.
    67. Ni, Y.H., Chang, M.H., Hsu, H.Y. and Tsuei, D.J. Different hepatitis B virus core gene mutations in children with chronic infection and hepatocellular carcinoma. Gut, 52 (1). 122-125.
    68. Ogura, Y., Kurosaki, M., Asahina, Y., Enomoto, N., Marumo, F. and Sato, C. Prevalence and significance of naturally occurring mutations in the surface and polymerase genes of hepatitis B virus. Journal of Infectious Diseases, 180 (5). 1444-1451.
    69. Okuda, K. Primary liver cancer. Quadrennial review lecture. Dig Dis Sci, 31 (9 Suppl). 133S-146S.
    70. Penna, A., Bertoletti, A., Cavalli, A., Valli, A., Missale, G., Pilli, M., Marchelli, S., Giuberti, T., Fowler, P., Chisari, F.V. and et al. Fine specificity of the human T cell response to hepatitis B virus core antigen. Arch Virol Suppl, 4. 23-28.
    71. Pumpens, P. and Grens, E. HBV core particles as a carrier for B cell/T cell epitopes. Intervirology, 44 (2-3). 98-114.
    72. Pumpens, P., Grens, E. and Nassal, M. Molecular epidemiology and immunology of hepatitis B virus infection - an update. Intervirology, 45 (4-6). 218-232.
    73. Rabbi, F.J., Rezwan, M.K. and Shirin, T. HBeAg/anti-HBe, alanine aminotransferase and HBV DNA levels in HBsAg positive chronic carriers. Bangladesh Med Res Counc Bull, 34 (2). 39-43.
    74. Ruiz-Moreno, M., Otero, M., Millan, A., Castillo, I., Cabrerizo, M., Jimenez, F.J., Oliva, H., Ramon y Cajal, S. and Carreno, V. Clinical and histological outcome after hepatitis B e antigen to antibody seroconversion in children with chronic hepatitis B. Hepatology, 29 (2). 572-575.
    75. Salfeld, J., Pfaff, E., Noah, M. and Schaller, H. Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus. J Virol, 63 (2). 798-808.
    76. Seeff, L.B., Beebe, G.W., Hoofnagle, J.H., Norman, J.E., Buskell-Bales, Z., Waggoner, J.G., Kaplowitz, N., Koff, R.S., Petrini, J.L., Jr., Schiff, E.R. and et al. A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army. N Engl J Med, 316 (16). 965-970.
    77. Sheldon, J., Rodes, B., Zoulim, F., Bartholomeusz, A. and Soriano, V. Mutations affecting the replication capacity of the hepatitis B virus. J Viral Hepat, 13 (7). 427-434.
    78. Sheng, C., Hsu, W., Lee, M.L., Tong, J.C. and Ng, S.K. Mining mutation chains in biological sequences 2010 IEEE 26th International Conference on Data Engineering(ICDE 2010), Long Beach, CA, USA 2010, 473-484.
    79. Shinkai, N., Tanaka, Y., Ito, K., Mukaide, M., Hasegawa, I., Asahina, Y., Izumi, N., Yatsuhashi, H., Orito, E., Joh, T. and Mizokami, M. Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C2. J Clin Microbiol, 45 (10). 3191-3197.
    80. Shneider, B.L., Gonzalez-Peralta, R. and Roberts, E.A. Controversies in the management of pediatric liver disease: Hepatitis B, C and NAFLD: Summary of a single topic conference. Hepatology, 44 (5). 1344-1354.
    81. Sitnik, R., Pinho, J.R.R., Bertolini, D.A., Bernardini, A.P., da Silva, L.C. and Carrilho, F.J. Hepatitis B virus genotypes and precore and core mutants in Brazilian patients. Journal of Clinical Microbiology, 42 (6). 2455-2460.
    82. Stuyver, L., De Gendt, S., Van Geyt, C., Zoulim, F., Fried, M., Schinazi, R.F. and Rossau, R. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol, 81 (Pt 1). 67-74.
    83. Sudarsan, D., Mahalingam, P.R. and Jisha, G., A Novel Approach to Represent Detected Point Mutation in Advances in Computing and Communications(ACC-2011), (India, 2011), 137-144.
    84. Tsai, S.L., Chen, P.J., Yang, P.M., Liao, T.H., Sung, J.L., Lai, M.Y., Huang, J.H., Chang, T.H. and Chen, D.S. Characterization of T Cell Clones Specific to a Determinant of Hepatitis B Virus Core and e Antigens in Chronic Type B Hepatitis: Implication for a T Cell Mechanism of HBV Immunopathogenesis. J Biomed Sci, 1 (2). 105-118.
    85. Venegas, M., Munoz, G., Hurtado, C., Alvarez, L., Velasco, M., Villanueva, R.A. and Brahm, J. Prevalence of hepatitis B virus genotypes in chronic carriers in Santiago, Chile. Arch Virol, 153 (11). 2129-2132.
    86. Vieth, S., Manegold, C., Drosten, C., Nippraschk, T. and Gunther, S. Sequence and phylogenetic analysis of hepatitis B virus genotype G isolated in Germany. Virus Genes, 24 (2). 153-156.
    87. Wasley, A., Grytdal, S. and Gallagher, K. Surveillance for acute viral hepatitis--United States, 2006. MMWR Surveill Summ, 57 (2). 1-24.
    88. Weinbaum, C.M., Mast, E.E. and Ward, J.W. Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection. Hepatology, 49 (5). S35-S44.
    89. Wintermeyer, P., Gerner, P., Gehring, S., Karimi, A. and Wirth, S. Prevalence of hepatitis B virus precore stop codon mutations in chronically infected children. World J Gastroenterol, 12 (14). 2235-2238.
    90. Wu, I.C., Chow, N.H., Cheng, P.N., Liu, W.C., Young, K.C., Chang, W.L., Chen, C.Y., Tseng, K.C. and Chang, T.T. Characterization of viral kinetics in patients with hepatitis B e antigen-positive chronic hepatitis B. J Med Virol, 79 (6). 663-669.
    91. Wu, J.F., Ni, Y.H., Lin, Y.T., Lee, T.J., Hsu, S.H.J., Chen, H.L., Tsuei, D.J., Hsu, H.Y. and Chang, M.H. Human Interleukin-10 Genotypes Are Associated with Different Precore/Core Gene Mutation Patterns in Children with Chronic Hepatitis B Virus Infection. Journal of Pediatrics, 158 (5). 808-813.
    92. Yang, H.I., Lu, S.N., Liaw, Y.F., You, S.L., Sun, C.A., Wang, L.Y., Hsiao, C.K., Chen, P.J., Chen, D.S. and Chen, C.J. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med, 347 (3). 168-174.
    93. Yap, S.F., Wong, P.W., Chen, Y.C. and Rosmawati, M. The frequency of pre-core gene mutations in chronic hepatitis B infection: a study of Malaysian subjects. Southeast Asian J Trop Med Public Health, 33 (1). 102-109.
    94. Yin, J., Xie, J., Liu, S., Zhang, H., Han, L., Lu, W., Shen, Q., Xu, G., Dong, H., Shen, J., Zhang, J., Han, J., Wang, L., Liu, Y., Wang, F., Zhao, J., Zhang, Q., Ni, W., Wang, H. and Cao, G. Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. Am J Gastroenterol, 106 (1). 81-92.
    95. Yuen, M.F., Wong, D.K., Zheng, B.J., Chan, C.C., Yuen, J.C., Wong, B.C. and Lai, C.L. Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion. J Viral Hepat, 14 (4). 269-275.
    96. Zhijian, Y., Zhen, H., Fan, Z., Jin, Y., Qiwen, D. and Zhongming, Z. Hepatitis B virus core protein with hot-spot mutations inhibit MxA gene transcription but has no effect on inhibition of virus replication by interferon alpha. Virol J, 7. 278.
    97. Zhou, F., Sui, L., Luo, K. and Hou, J. Cloning and expression and purification of hepatitis B e-antigen precursor in Escherichia coli. Chin Med J (Engl), 115 (5). 722-725.

    無法下載圖示 校內：2015-09-09公開
    校外：不公開
    電子論文尚未授權公開，紙本請查館藏目錄
    QR CODE