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Susceptibility Gene Identification and Genome-Based Drug Repurposing in Hepatocellular Carcinoma

為了解決th-55jx650w mobile01的問題，作者lalu Muhammad irham 這樣論述：

This thesis consists of two component of studies which were to investigate the role of genomic variants mediated hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients and utilizing the genomic information of HCC associated variants to repurpose drugs for HCC disease. The first study,

we examined the role of genomic variation in progression of HCC in patients with CHB infection. Hepatitis B virus (HBV) replication in CHB patients often mediated HCC progression (HBV replication requires the calcium (Ca2+) signaling pathway), calcium enters non-excitable cells such as immune cells

and cancer cells through store-operated channels (SOCs). STIM1 and ORAI1 genes are two basic components of store-operated calcium signaling. However, the roles of these two variation genes (STIM1 and ORAI1) mediated HCC in CHB patients are still uncertain. Therefore, we carried out an HBV cohort st

udy with long-term follow-up process. This study is part of REVEAL-HBV cohort study with total participants 3631 patients with chronic hepatitis B from Taiwanese population (345 patients with HCC progression and 3286 patients without HCC progression). Axiom CHB1 genome-wide array was utilized to ide

ntify the genetic variants of the STIM1 and ORAI1 genes. Through this study, we successfully identified the clinical associations of 40 variants of STIM1 and ORAI1 genes and those variants will be leveraged for further analysis. The trend of being associated with HCC development was presented in thr

ee variants of the STIM1 (rs6578418, rs7116520, and rs11030472) and one variant of ORAI1 (rs6486795) (p0.05) after correction for multiple testing; our study revealed that, neither STIM1 nor ORAI1 showed a significant association mediated HCC progression in CHB patients. Interestingly, our functiona

l studies (total internal reflection fluorescence images and transwell migration assay) confirmed that the store-operated calcium has critical roles mediated signaling in the HCC migration. In conclusion, although calcium signaling is essential for HBV replication, genetic polymorphisms of store-ope

rated calcium pathway (STIM1 and ORAI1) genes are not associated with HCC progression.In the second part of this study, we focused on the leveraging of genomic variation associated with HCC for drug repurposing for HCC treatment using multiple bioinformatics databases. Curing HCC disease by current

therapies is still not probable, 70%~80% of HCC disease treatments are still ineffective and inefficient due to diagnosis occurring at advanced stages. In addition, there are not many drugs approved for HCC treatment. Currently, a large number of genomic risk loci for various human diseases have bee

n identified and further widely cataloged; however, strategies for guiding clinical research by integrating the extensive results of genomic studies and biological resources are still limited. Moreover, integrative analyses that provide novel insights of the genomic associated with the diseases base

d on the susceptibility of genes are expected to be particularly useful for drug repurposing (genomic driven-drug repurposing). Major obstacles to developing new clinical drugs for HCC are the long-term processes and huge amounts of money required. An alternative strategy with shorter times and lowe

r costs for discovering new treatments by finding new indications for approved drugs is called drug repurposing. In this study, we repurposed marketed drugs for HCC by omics data mining from PubMed and in silico databases. We prioritized the biological HCC-risk genes for target drugs based on six fu

nctional annotation criteria: missense or nonsense mutations, cis-expression quantitative trait loci (cis-eQTLs), molecular pathway analyses, gene ontology biological processes, genetic overlap with mammalian phenotype ontology, and primary immunodeficiency. The biological HCC-risk genes were furthe

r integrated with somatic mutation from COSMIC dataset. Interestingly, we found almost all the biological HCC-risk genes were overlap with the somatic mutation. STRING database was harnessed to identify the drug target genes expanded from biological HCC-risk genes. Herein, we identified 20 drug targ

et genes that overlapped with 127 drugs according to the DrugBank and Therapeutic Target Database. Of these 20 drug-targeted genes, we identified four drug-targeted genes known to overlap with 11 available drugs used in the clinic for HCC disease and eight known drug-targeted genes that overlapped w

ith 17 drugs for other diseases, suggesting their potential for drug repurposing for HCC. In addition, four known drug-targeted genes with seven drugs are currently in preclinical investigations for HCC disease. Subsequently, we prioritized these drugs for other diseases using the Connectivity Map (

CMap) database-based approach, and we found the top five drugs, i.e. meloxicam, pioglitazone, celecoxib, gefitinib, and rosiglitazone, which were the most promising drugs that might be repurposed for HCC treatment. Taken together, we integrated a crucial HCC profile between germline variants and som

atic mutation into clinical situations to further shed light on clinical applications of genomic-based therapies and provide a guide for HCC drug discovery.

台灣飲食及環境健促與慢性疾病防治相關研究

為了解決th-55jx650w mobile01的問題，作者林旻樺 這樣論述：

背景：人口老齡化正成為世界日益嚴重的趨勢。預計臺灣2025年超高齡社會65歲以上人口將達20%。老化伴隨肌肉質量減少，導致心肺和生理功能下降及生活品質下降。全球發展中的國家快速城市化發展，人們生活型態趨向身體活動量不足、久坐、不健康飲食等因素，導致體位肥胖問題，衍生非傳染性疾病已成為全球十大死亡威脅之一。在臺灣糖尿病近十年排行國人十大死因第5位。臺灣幼兒部分，過去幾十年來異位性皮膚炎的盛行率逐年有顯著上升趨勢，由於種群遺傳變異性不會以如此快的速度變化，基於“衛生假說”假設現代的西方生活方式以及沒有暴露於微生物的現象，環境因素的變化很可能是異位性皮膚炎數量增加原因。目的：(一)以渥太華憲章五個

行動綱領應用於醫院建立健康公共政策發展為全院式糖尿病健康促進醫院，希望醫院員工能養成健康飲食和規律運動的健康生活方式，預防糖尿病發生，鼓勵員工成為糖尿病志工到社區照顧糖尿病患者自我照護行為，強化社區糖尿病人落實健康生活型態，以延緩糖尿病併發症發生，進而提高糖尿病患者的生活品質滿意度。(二)評估慢性腎臟病個案使用史它丁類藥物與首次診斷肌肉減少症的風險，以預防延緩失能，活躍老化。(三)調查學齡前兒童尿液三氯沙濃度暴露與過敏性疾病，特定疾病的免疫球蛋白E(IgE)濃度和兒童性別之間的關係，找出環境致敏風險因子，提供衛生單位制定政策參考。重要性：本研究是台灣第一個將《渥太華憲章》五個行動綱領應用於公共

衛生的全院式糖尿病促進計劃。本研究發現慢性腎臟疾病個案使用史它丁類藥物治療似乎可以減少肌少症發生，且更高劑量的史它丁類藥物可能可以降低慢性腎臟病患確診肌肉減少症的風險比。本研究發現學齡前幼兒暴露三氯沙與免疫球蛋白E濃度和兒童特異反應性疾病的潛在高風險有關。我們的研究結果可以提供衛生福利部和醫療組織做為非傳染性疾病防治參考。材料與方法： (一)以《渥太華憲章》五個行動綱領應用全院式糖尿病健康促進計畫，於2011年選擇台灣中部某健康促進醫院為研究醫院，培訓全院員工糖尿病健康促進技能包含體重控制、糖尿病護理和糖尿病品質管理。招募醫院員工成為志工，並培訓其擔任糖尿病防治志工到社區為糖尿病患者提供糖尿病

照護和指導。計劃前後以世界衛生組織生活質量（WHOQOL）-BREF -台灣版對糖尿病患者進行問卷調查。請醫院員工填寫健康促進生活型態量表。以統計方法分析調查數據。(二)以流行病學為基礎，從台灣國家健康保險研究數據庫中選取了1997年至2011年之間臨床醫師確診為慢性腎臟疾病共計75,637例。研究對象的納入包括出院診斷紀錄慢性腎臟疾病超過1次或在門診就診一年內主診斷有慢性腎臟疾病紀錄。在考慮了排除因素之患者後，最終研究共納入67,001例慢性腎臟病病例。研究使用Cox比例風險模式，初步分析慢性腎臟病個案使用史它丁類藥物減少新診斷肌少症發生之效果。為了考慮個體用藥的時間差異，採用了具有時間依賴

性協變量的Cox比例風險模式並在控制性別，年齡，收入和城市化程度之後，計算風險比(hazard ratio, HR)和95%信賴區間。(三)“三氯沙對兒童過敏性疾病發病機制的影響”從兒童環境與過敏性疾病研究(CEAS:2010)中取得453個兒童，其尿液和血液樣本用於分析三氯沙和免疫球蛋白E(IgE)濃度(3歲組）。三年後，再次從3歲組獲得臨床數據為”6歲組”。評估了3歲組和6歲組尿液三氯沙濃度與免疫球蛋白E濃度和過敏性疾病的相關性。主要成果：(一)以渥太華五大行動綱領推動全院式糖尿病健康促進計畫，結果(1)糖尿病患者對”健康”和”與健康相關的生活品質”的滿意度顯著提高，並且在健康促進和自我管

理行為方面的顯著改善(p < 0.05)。(2)醫院員工在健康促進行為包括“三餐定時定量”，“不吃人工添加物”，“有人指導運動課程，“運動時會測自己脈搏，“做延展操每周至少3次”，“每周至少做3次每次20-30分鐘運動”，“參加個人健康照顧課程”，“知道壓力源所在”，“檢查膽固醇”，“重視成就感”等項目有顯著改善(p