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

為了解決Lee Hi SEVENTEEN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.