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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 | 楊偉勳 | |
dc.contributor.author | Yu-Tzu Chen | en |
dc.contributor.author | 陳玉慈 | zh_TW |
dc.date.accessioned | 2021-06-15T16:29:05Z | - |
dc.date.available | 2020-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-14 | |
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Lie, J., R. Miller, and D. Williams. Cystic disease of the lungs in tuberous sclerosis: clinicopathologic correlation, including body plethysmographic lung function tests. in Mayo Clinic proceedings. 1980. 57. Tee, A.R., et al., Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current Biology, 2003. 13(15): p. 1259-1268. 58. Franz, D.N., et al., Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Annals of neurology, 2006. 59(3): p. 490-498. 59. Inoki, K., M.N. Corradetti, and K.-L. Guan, Dysregulation of the TSC-mTOR pathway in human disease. Nature genetics, 2005. 37(1): p. 19-24. 60. Vezina, C., A. Kudelski, and S. Sehgal, Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. The Journal of antibiotics, 1975. 28(10): p. 721-726. 61. Sehgal, S.N., Rapamune®(RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clinical biochemistry, 1998. 31(5): p. 335-340. 62. Tay, Y.-K., Topical calcipotriol ointment in the treatment of morphea. Journal of dermatological treatment, 2003. 14(4): p. 219-221. 63. Fraser, F.C., Genetic counseling. American Journal of Human Genetics, 1974. 26(5): p. 636. 64. Resta, R., et al., A new definition of genetic counseling: National Society of Genetic Counselors’ task force report. Journal of genetic counseling, 2006. 15(2): p. 77-83. 65. Li, H. and R. Durbin, Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics, 2009. 25(14): p. 1754-1760. 66. McKenna, A., et al., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research, 2010. 20(9): p. 1297-1303. 67. DePristo, M.A., et al., A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature genetics, 2011. 43(5): p. 491-498. 68. Tanaka, M., et al., First left–right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex. British Journal of Dermatology, 2013. 169(6): p. 1314-1318. 69. Foster, R.S., L.J. Bint, and A.R. Halbert, Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australasian Journal of Dermatology, 2012. 53(1): p. 52-56. 70. Salido, R., et al., Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis–associated facial angiofibroma. Journal of the European Academy of Dermatology and Venereology, 2012. 26(10): p. 1315-1318. 71. Haemel, A.K., A.L. O’Brian, and J.M. Teng, Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Archives of dermatology, 2010. 146(7): p. 715-718. 72. Wataya‐Kaneda, M., et al., A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. British Journal of Dermatology, 2011. 165(4): p. 912-916. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52819 | - |
dc.description.abstract | 結節硬化症(Tuberous Sclerosis Complex)是一種自體顯性遺傳疾病。其臨床表現涉及人體多種器官,如皮膚、腦部、腎臟、肺臟、心臟及其他器官會形成缺陷瘤(hamartomas)。結節硬化症患者有三分之一是遺傳而來,另外三分之二的病人則為新發生(de novo)的突變所致。皮膚表徵是結節硬化症患者臨床最常見的表徵之一,其中臉部血管纖維瘤發生機率為百分之七十五。結節硬化症主要涉及mTOR 路徑(mammalian target of rapamycin pathway),是一個生物學上非常重要的領域,掌管了細胞增生、血管生成、蛋白合成及代謝等重要功能。已知的結節硬化症兩個致病基因,TSC1(製造Hamartin) 及TSC2(製造Tuberin)皆為 mTOR 的抑制分子。Rapamycin其功能與TSC複合蛋白一樣具有調控mTOR的訊息傳遞,且已運用在臨床治療。迄今為止,臨床對結節硬化症皮膚表現的治療,仍以傳統的外科式的方式治療,例如電燒或手術切除,但會有外科手術副作用的風險,如疼痛、傷口感染,或是產生疤痕,執行上也麻煩許多,且小朋友的局部麻醉不容易進行,全身麻醉又有比較大的健康風險。若以雷射方式治療,治療所需的費用較高,且患部復發機率高需重複治療,所以臨床治療臉部血管纖維瘤還有非常大需要改進的空間。
本次研究使用rapamycin (0.1%)合併calcitriol (3 mcg/g)、rapamycin (0.1%)或calcitriol (3 mcg/g)外用藥膏來治療結節硬化症皮膚表現,為期36週,評估其療效以及副作用,並以次世代定序(Next-generation Sequencing)為方式做受試者基因檢測。本研究針對第一階段納入的11位受試者在第12週解盲做評估。解盲後藥物使用以rapamycin (0.1%)合併calcitriol (3 mcg/g) 和使用單方rapamycin治療臉部血管纖維瘤皆有明顯效果。11位受試者沒有明顯的副作用與不適症狀發生,只有輕微皮膚搔癢和輕微的刺痛感的情況發生。以次世代定序分析受試者基因,帶有TSC2基因突變的有9位(82%),未偵測到帶有TSC1(0%)突變,2位(18%)未發現帶有突變點。 臺大醫院結節硬化症門診,是目前全台結節硬化症就診人數最多的門診,希望透過這次試驗,提供病患以方便、簡單、費用較低和安全的外用藥膏治療臉部血管纖維瘤,讓結節硬化症病患得到更完善的照護。 | zh_TW |
dc.description.abstract | Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease. It is a syndrome characterized by multiple organs involvement such as skin, brain, kidneys, heart, eyes and lungs with hamartomas. One third of people are hereditary and two thirds are sporadic cause by de novo mutation. Most people with TSC have changes in their skin. Facial angiofibroma is one of skin features which appear in up to 75%. mTOR (mammalian target of rapamycin) pathway is associated with cellular proliferation, angiogenesis, protein synthesis and transcription. Mutation of TSC1or TSC2 causes abnormality of hamartin or tuberin and therefore results in the defects in mTOR pathway inhibition. Rapamycin is a mTOR pathway inhibitor; ingestion of rapamycin has been shown to improve TSC symptoms and/or signs, including skin lesions. At present, available treatment options for facial angiofibroma are limited to surgical therapies such as excision or dermabrasion and laser therapy. However, these therapies often cause pain, discomfort, infection or produce scar, have to be repeated many times, and therefore often require repeated general anesthesia in younger patients. And laser therapy is quite expensive.
In this study, we performed a double-blind clinical trial comparing the efficacy and side effects of rapamycin (0.1%) combined with calcitriol (3 mcg/g)、rapamycin (0.1%) alone and calcitriol (3 mcg/g) alone for treatment of facial angiofibroma during a period of 36 weeks. And we applied the next-generation sequencing (NGS) technology for the genetic diagnosis by testing TSC1 and TSC2 genes. Rapamycin (0.1%) combine calcitriol (3 mcg/g) and rapamycin (0.1%) alone showed the best efficacy in our 11 patients at week 12. There were no severe side effects except for mild pruritus, burning sensation or stinging sensation. There were 9 cases with TSC2 mutation and 2 cases with no mutation identified. There was no case with mutation at TSC1. The Joint Tuberous Sclerosis Complex Clinic at the National Taiwan University Hospital is the biggest Joint TSC clinic in Taiwan. Through this experiment, it is hoped that the clinic can provide convenient, cost-effective and safe topical ointments to TSC patients with facial angiofibromas in order to give them a more comprehensive care. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T16:29:05Z (GMT). No. of bitstreams: 1 ntu-104-P02448004-1.pdf: 2047419 bytes, checksum: b438a7b256e65ab6b8644955dddf9472 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 口試委員會審定書 i
致謝 ii 中文摘要 iii Abstract v 第一章 研究背景與動機 1 1.1結節硬化症疾病簡介 1 1.2結節硬化症發現與進展 2 1.3 結節硬化症臨床特徵 4 1.3.1皮膚表徵 4 1.3.2口腔表徵 5 1.3.3眼部表徵 5 1.3.4神經系統表徵 5 1.3.5心血管表徵 6 1.3.6肺臟表徵 6 1.3.7腎臟表徵 7 1.3.8其他表徵 7 1.4 結節硬化症的診斷及檢查 8 1.4.1基因診斷 8 1.4.2臨床診斷 8 1.4.3臨床診斷檢查 9 1.5結節硬化症的治療 11 1.6結節硬化症基因與Rapamycin之作用機轉 12 1.7 Calcitriol作用機轉 13 1.8遺傳諮詢 14 1.9研究目的 15 第二章 研究方法 17 2.1 研究對象來源及條件 17 2.1.1受試者來源 17 2.1.2受試者條件 17 2.2 試驗藥物 19 2.2.1藥物名稱 19 2.2.2劑型 19 2.2.3劑量 19 2.2.4試藥配製 19 2.2.5試藥與設備 20 2.3外用藥試驗程序 21 2.4療效評估指標 24 2.4.1主要評估指標 24 2.4.2次要評估標準 24 2.5次世代定序檢測 25 2.5.1 DNA的萃取 25 2.5.2次世代定序分析 25 第三章 研究結果 29 3.1人口統計與臨床表徵 29 3.2解盲後藥效評估 32 3.2.1臉部血管纖維瘤嚴重度指標(FASI)改善評估 32 3.2.2臉部血管纖維瘤紅斑、大小、丘疹及範圍改善評估 35 3.2.2.1紅斑 35 3.2.2.2大小 37 3.2.2.3丘疹 39 3.2.2.4範圍 41 3.2.3解盲後用藥統計 42 3.3外用藥膏副作用評估 46 3.4次世代定序基因檢測 48 3.5遺傳諮詢案例 49 3.5.1案例一 49 3.5.2案例二 50 第四章 討論 51 第五章 結論 53 參考文獻 54 附錄 59 附錄一、個案報告表 59 附錄二、病患日誌卡 60 附錄三、TSC1/TSC2基因引子序列 61 圖目錄 圖一、mTOR pathway 12 圖二、臉部血管纖維瘤外用藥試驗流程圖 23 圖三A、臉部血管纖維瘤嚴重度指標總分數改變百分比折線圖 34 圖三B、臉部血管纖維瘤嚴重度指標平均分數差異之柱狀圖 34 圖四A、臉部血管纖維瘤紅斑總分數改變百分比折線圖 36 圖四B、臉部血管纖維瘤紅斑平均分數差異之柱狀圖 36 圖五A、臉部血管纖維瘤大小總分數改變百分比折線圖。 38 圖五B、臉部血管纖維瘤大小平均分數差異之柱狀圖 38 圖六A、臉部血管纖維瘤丘疹總分數改變百分比折線圖。 40 圖六B、臉部血管纖維瘤丘疹平均分數差異之柱狀圖 40 圖七、血管纖維瘤面積平均分數差異之柱狀圖 41 圖八、受試者R001左右兩側用藥比較圖 43 圖九、受試者R004左右兩側用藥比較圖 44 圖十、受試者R003左右兩側用藥比較圖 45 表目錄 表一、副作用標準表 22 表二、人口統計學 30 表三、臨床表徵 31 表四、受試者左右兩側用藥表 33 表五、解盲後藥物使用比 42 表六、副作用評估表 47 表七、基因突變 48 | |
dc.language.iso | zh-TW | |
dc.title | 結節硬化症患者外用rapamycin合併calcitriol於皮膚病灶之臨床試驗 | zh_TW |
dc.title | Topical Rapamycin and Calcitriol Therapy Trial for Cutaneous Lesions in Tuberous Sclerosis Complex (TSC) Patients | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 陳沛隆 | |
dc.contributor.oralexamcommittee | 謝豐舟,廖怡華 | |
dc.subject.keyword | 結節硬化症,臉部血管纖維瘤,mTOR 路徑,rapamycin,calcitriol,次世代定序, | zh_TW |
dc.subject.keyword | Tuberous sclerosis complex (TSC),Facial angiofibroma,mTOR pathway,rapamycin,calcitriol,next-generation sequencing (NGS), | en |
dc.relation.page | 64 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-08-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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