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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 楊宏志(Hung-Chih Yang) | |
dc.contributor.author | Baptiste Thierry Romain Massart | en |
dc.contributor.author | 馬元策 | zh_TW |
dc.date.accessioned | 2021-05-19T17:45:05Z | - |
dc.date.available | 2021-08-10 | |
dc.date.available | 2021-05-19T17:45:05Z | - |
dc.date.copyright | 2018-08-10 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-09 | |
dc.identifier.citation | [1] World Health Organization, 'Global Hepatitis Report,' 2017.
[2] J. F. Perz, G. L. Armstrong, L. A. Farrington, Y. J. Hutin and B. P. Bell, 'The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide,' Journal of Hepatology, vol. 45, pp. 529-538, 2006. [3] World Health Organization, 'Monitoring and evaluation for viral hepatitis B and C: recommended indicators and framework - technical report,' 2016. [4] C. Montuclard, S. Hamza, F. Rollot, P. Evrard, J. Faivre, P. Hillon, V. D. Martino and A. Minello, 'Causes of death in people with chronic HBV infection,' Journal of Hepatology, vol. 62, pp. 1265-1271, 2015. [5] S. Nayagam, M. Thursz, E. Sicuri, L. Conteh, S. Wiktor, D. Low-Beer and T. B. Hallett, 'Requirements for global elimination of hepatitis B: a modelling study,' The Lancet Infectious Diseases, vol. 16, no. 12, pp. 1399-1408, 2016. [6] C. Lee, Y. Gong, J. Brok, E. H. Boxall and C. Gluud, 'Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers,' Cochrane Database of Systematic Reviews, no. 2, 2006. [7] M. Machaira, V. Papaevangelou, E. K. Vouloumanou, G. S. Tansarli and M. E. Falagas, 'Hepatitis B vaccine alone or with hepatitis B immunoglobulin in neonates of HBsAg+/HBeAg− mothers: a systematic review and meta-analysis,' Journal of Antimicrobial Chemotherapy, vol. 70, no. 2, p. 396–404, 2015. [8] Y.-F. Liaw and C.-M. Chu, 'Hepatitis B virus infection,' The Lancet, vol. 373, pp. 582-592, 2009. [9] T. Santantonio and M. Fasano, 'Current Concepts on Management of Chronic Hepatitis B,' in Practical Management of Chronic Viral Hepatitis, 2013. [10] C.-L. Lin, H.-C. Yang and J.-H. Kao, 'Hepatitis B virus: new therapeutic perspectives,' Liver International, vol. 36, pp. 85-92, 2016. [11] M. Nassal, 'HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B,' Gut, vol. 64, pp. 1972-1984, 2015. [12] E. C. Holmes, 'Evolutionary history and phylogeography of human viruses,' Annual Review of Microbiology, vol. 62, pp. 307-328, 2008. [13] E. Domingo, J. Sheldon and C. Perales, 'Viral Quasispecies Evolution,' Microbiology and Molecular Biology Reviews, vol. 76, no. 2, pp. 159-216, 2012. [14] F. Zoulim and S. Locarnini, 'Hepatitis B Virus Resistance to Nucleos(t)ide Analogues,' Gastroenterology, vol. 137, no. 5, pp. 1593-1608, 2009. [15] H. Thai, D. S. Campo, J. Lara, Z. Dimitrova, S. Ramachandran, G. Xia, L. Ganova-Raeva, C.-G. Teo, A. Lok and Y. Khudyakov, 'Convergence and coevolution of Hepatitis B virus drug resistance,' Nature Communications, vol. 3:789, 2012. [16] J. M. Carlson, A. Q. Le, A. Shahid and Z. L. Brumme, 'HIV-1 adaptation to HLA: a window into virus–host immune interactions,' Trends in Microbiology, vol. 23, no. 4, pp. 212-224, 2015. [17] M. A. Ansari, V. Pedergnana, C. Ip, A. Magri, A. V. Delft, D. Bonsall, N. Chaturvedi, I. Bartha, D. Smith, G. Nicholson, G. McVean, A. Trebes, P. Piazza, J. Fellay, G. Cooke, G. R. Foster, STOP-HCV consortium, E. Hudson, J. McLauchlan, P. Simmonds, R. Bowden, P. Klenerman, E. Barnes and C. C. A. Spencer, 'Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus,' Nature Genetics, vol. 49, p. 666–673, 2017. [18] M. B. Zeisel, J. Lucifora, W. S. Mason, C. Sureau, J. Beck, M. Levrero, M. Kann, P. A. Knolle, M. Benkirane, D. Durantel, M.-L. Michel, B. Autran, F.-L. Cosset, H. Strick-Marchand, C. Trépo, J.-H. Kao, F. Carrat, K. Lacombe, R. F. Schinazi, F. Barré-Sinoussi, J.-F. Delfraissy and F. Zoulim, 'Towards an HBV cure: state-of-the-art and unresolved questions — report of the ANRS workshop on HBV cure,' Gut, vol. 64, pp. 1314-1326, 2015. [19] T.-H. Chu, A.-T. Liou, P.-Y. Su, H.-N. Wu and C. Shih, 'Nucleic Acid Chaperone Activity Associated with the Arginine-Rich Domain of Human Hepatitis B Virus Core Protein,' Journal of Virology, vol. 88, p. 2530–2543, 2014. [20] Y.-J. Lin, L.-R. Huang, H.-C. Yang, H.-T. Tzeng, P.-N. Hsu, H.-L. Wu, P.-J. Chen and D.-S. Chen, 'Hepatitis B virus core antigen determines viral persistence in a C57BL/6 mouse model,' Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 20, p. 9340–9345, 2010. [21] N.-F. Ma, S. H. Lau, L. Hu, D. Xie, J. Wu, J. Yang, Y. Wang, M.-C. Wu, J. Fung, X. Bai, C.-H. Tzang, L. Fu, M. Yang, Y. A. Su and X.-Y. Guan, 'COOH-terminal truncated HBV X protein plays key role in hepatocarcinogenesis,' Clinical Cancer Research, vol. 14, pp. 5061-5068, 2008. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7503 | - |
dc.description.abstract | B型次肝炎病毒很適合當作模式來觀察宿主的免疫反應。HBV的演化速度跟RNA病毒一樣快, 因此HBV會因爲宿主的因素(包含免疫反應)而改變。再加上,HBV經常造成慢性的感染,所以該病毒有足夠的時間因爲免疫反應而演化。我們的目標是利用這兩個特色來研究HBV演化的衡量方式如何能提供病人免疫反應的更多資訊。
我們主要的假設是不同的免疫反應帶來不同的演化壓力。本論文的研究目的是找到一個方法利用HBV演變的分析來評估病人免疫反應的品質。最後的目標是探討從這個分析得到的資訊是否跟臨床病情有關係,且是否可以利用這些資訊來協助病人的治療。 23位慢性B型肝炎病人(基因型B)經過24周的干擾素治療。治療前,所有病人屬於HBeAg陽性的狀態。在四個時間點,我們利用次世代定序技術來分析病人的樣本:治療前,治療中點(第12周),治療結束,以及治療後第24周。 我們研究HBV的演變與兩個臨床結果的關係:HBeAg seroconversion和病毒量達到90%以上的減少。這兩個臨床結果在HBV的自然歷史成爲跟免疫系統有關的最重要的結果,而且對病人死亡率的減少和對母親傳染嬰兒機率的減少都有重要的貢獻。目前嬰兒HBV疫苗接種越來越普遍,因此,這兩個臨床結果逐漸成爲預防母親傳染嬰兒的重要工具,利於協助解決HBV大流行。 本研究介紹不同計量衡量方式來分析病毒定序檢測對等位基因不利的演化壓力 (多樣化壓力)。這個工具可以辨認多樣化壓力是針對基因裏頭的哪一個位子,以及衡量其多樣化壓力的强度。 這個分析方法可以在不同的病患組顯示多數的趨勢以及建立病患個人的資料. 我們希望未來更多的進步能讓本論文介紹的計量方法提供醫師更多的資訊,協助預後判斷與治療客製化,改善B型肝炎病患的治療績效。 | zh_TW |
dc.description.abstract | The Hepatitis B Virus is a promising candidate to observe the immune response of its host. Because the evolutionary rate of HBV is as high as that of RNA viruses, the virus has the opportunity to change in response to host factors, including the immune pressure. In addition, HBV causes a chronic infection that lasts long enough for the virus to change in response to the immune pressure. We aim to use this opportunity to investigate how measurements of HBV evolution may provide information about the immune response of patients.
Our main hypothesis is that different immune responses cause different evolutionary pressures. As a result, the goal of this research project is to develop a method to monitor the quality of the patient’s immune response through analysis of its impact on the evolution of the HBV virus. The final objective is to correlate this information with clinical outcomes to evaluate the potential of this analytical method as a tool that might provide additional indications to help guide HBV treatment. To conduct this study, we used samples from 23 patients with chronic HBV genotype B infection that underwent 24 weeks of interferon therapy. We analyzed NGS sequences of the virus before treatment, at the halfway point of treatment, at the end of treatment, and 24 weeks after termination of treatment. All patients were HBeAg-positive at the beginning of the treatment. We studied the differences in HBV evolution that correlated with two clinical outcomes: HBeAg seroconversion and viral load reduction by at least 90%. These two outcomes are the most important immune-related events in the natural course of HBV infection. These two outcomes are particularly important because of their association with a decreased probability of mother-to-child transmission. With the now widespread use of vaccination at birth for children born of HBV carriers, these clinical endpoints are likely to become of increased public health relevance as the next best actionable levers to control the HBV pandemic. We developed quantitative measurements to detect signs of selection against a particular allele (diversifying selection) in the evolution of the virus sequences. This allows for the evaluation of the intensity of the diversifying selection as well as the identification of the precise location of the amino acids that cause the allele to be selected against. This method can be used to derive general trends in groups of patients as well as to build personal profiles of individual patients. We hope that further advances in the development of applications from the methods described in this document will provide clinicians with additional information for their prognosis and for guiding targeted treatment to improve the clinical outcomes of patients suffering from chronic Hepatitis B. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:45:05Z (GMT). No. of bitstreams: 1 ntu-107-R05445135-1.pdf: 3058722 bytes, checksum: 8a3517c2e6d7ba19290f04d7f9862f07 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | Dedication i
Acknowledgements i Abstract ii 中文摘要 iv List of figures and tables viii 1. Introduction 1 1.1 The public health burden of HBV 1 1.2 The long-term control of the HBV pandemic 2 1.3 Important milestones toward recovery from chronic HBV infection 3 1.4 Natural history of chronic HBV infection 4 1.5 Treatment options for Chronic Hepatitis B 5 1.6 HBV specificities making it suitable to observe the host immune response 6 1.7 Current knowledge on virus host interaction 7 2. Study aims 8 3. Materials and methods 9 3.1 Patients 9 3.2 Treatment 9 3.3 Sample collection and analysis 10 3.4 Next-generation sequencing 10 3.5 Software analysis 11 4. Clinical outcomes and classification of patients 12 5. Identification of factors in the HBV genome that might influence clinical outcomes in chronic HBV patients 14 5.1 Identification of point mutations that could be associated with important adaptation mechanisms 15 5.1.1 Points with extensive change in amino acid frequencies 15 5.1.2 Abnormal stop codons 16 5.1.3 Stop codon at position 28 of gene C: pre-core stop mutation 16 5.1.4 Stop codon at position 211 of gene C 17 5.1.5 Stop codon at position 141 of gene X 18 5.1.6 Multiple stop codons on the S gene 18 5.2 Analysis of the pair-wise distances between viral genomes that lead to similar clinical outcomes 21 5.2.1 Estimation of amino acid frequencies from nucleotide frequencies 21 5.2.2 Measurement of genetic distance 23 5.2.3 Pair-wise distances within patient groups for each HBV gene 24 5.2.4 Regions in HBV genes that vary in pair-wise distances within patient groups 24 6. Developing a method to evaluate the quality of the host immune response through analysis of its influence on the evolution of the HBV virus 28 6.1 Influence of clinical outcomes on HBV evolution 29 6.2 Flexibility index 31 6.2.1 Purpose 31 6.2.2 Mechanism 31 6.2.3 Computation 32 6.2.4 Interpretation 32 6.3 Selection index 33 6.3.1 Purpose 33 6.3.2 Mechanism 33 6.3.3 Computation 35 6.3.4 Interpretation 35 6.4 Susceptibility index 36 6.4.1 Purpose 36 6.4.2 Mechanism 36 6.4.3 Computation 36 6.4.4 Interpretation 36 6.5 Establishing patient profiles 37 7. Discussion 38 8. References 40 Annex: Patient profiles 44 | |
dc.language.iso | en | |
dc.title | 利用次世代定序分析B型肝炎病毒在干擾素治療中的演變 | zh_TW |
dc.title | Analysis of HBV adaptations to interferon treatment – NGS approach | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王弘毅(Hurng-Yi Wang),陳沛隆(Pay-Long Chen) | |
dc.subject.keyword | B型肝炎,次世代定序,演化,免疫, | zh_TW |
dc.subject.keyword | Hepatitis B,NGS,evolution,seroconversion,immunogenetics,virus host interaction,HBeAg, | en |
dc.relation.page | 55 | |
dc.identifier.doi | 10.6342/NTU201802768 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2018-08-09 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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