BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma(HCC).AIM To comprehensively analyze and characterize all publicly available genomic...BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma(HCC).AIM To comprehensively analyze and characterize all publicly available genomic,gene expression,methylation,miRNA and proteomic data in HCC,covering 85 studies and 3355 patient sample profiles,to identify the key dysregulated genes and pathways they affect.METHODS We collected and curated all well-annotated and publicly available highthroughput datasets from PubMed and Gene Expression Omnibus derived from human HCC tissue.Comprehensive pathway enrichment analysis was performed using pathDIP for each data type(genomic,gene expression,methylation,miRNA and proteomic),and the overlap of pathways was assessed to elucidate pathway dependencies in HCC.RESULTS We identified a total of 8733 abstracts retrieved by the search on PubMed on HCC for the different layers of data on human HCC samples,published until December 2016.The common key dysregulated pathways in HCC tissue across different layers of data included epidermal growth factor(EGFR)andβ1-integrin pathways.Genes along these pathways were significantly and consistently dysregulated across the different types of high-throughput data and had prognostic value with respect to overall survival.Using CTD database,estradiol would best modulate and revert these genes appropriately.CONCLUSION By analyzing and integrating all available high-throughput genomic,transcriptomic,miRNA,methylation and proteomic data from human HCC tissue,we identified EGFR,β1-integrin and axon guidance as pathway dependencies in HCC.These are master regulators of key pathways in HCC,such as the mTOR,Ras/Raf/MAPK and p53 pathways.The genes implicated in these pathways had prognostic value in HCC,with Netrin and Slit3 being novel proteins of prognostic importance to HCC.Based on this integrative analysis,EGFR,andβ1-integrin are master regulators that could serve as potential therapeutic targets in HCC.展开更多
Osteoarthritis(OA)is a degenerative multifactorial disease with concomitant structural,inflammatory,and metabolic changes that fluctuate in a temporal and patient-specific manner.This complexity has contributed to ref...Osteoarthritis(OA)is a degenerative multifactorial disease with concomitant structural,inflammatory,and metabolic changes that fluctuate in a temporal and patient-specific manner.This complexity has contributed to refractory responses to various treatments.MsCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression.Here,we evaluated 15 randomized controlled clinical trials(RCTs)and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA,and we found net positive effects of MSCs on mitigating pain and symptoms(improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints)and on cartilage protection and/or repair(18/21 clinical studies).We examined MsC dose,tissue of origin,and autologous vs.allogeneic origins as well as patient clinical phenotype,endotype,age,sex and level of OA severity as key parameters in parsing MSC clinical effectiveness.The relatively small sample size of 610 patients limited the drawing of definitive conclusions.Nonetheless,we noted trends toward moderate to higher doses of MsCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation.Evidence from preclinical studies is supportive of MsC anti-inflammatory and immunomodulatory effects,but additional investigations on immunomodulatory,chondroprotective and other clinical mechanisms of action are needed.We hypothesize that MsC basal immunomodulatory"fitness"correlates with OA treatment efficacy,but this hypothesis needs to be validated in future studies.We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory"ft"or engineered-to-be-fit-for-OA MsCs in well-designed,data-intensive clinical trials to advance the field.展开更多
文摘BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma(HCC).AIM To comprehensively analyze and characterize all publicly available genomic,gene expression,methylation,miRNA and proteomic data in HCC,covering 85 studies and 3355 patient sample profiles,to identify the key dysregulated genes and pathways they affect.METHODS We collected and curated all well-annotated and publicly available highthroughput datasets from PubMed and Gene Expression Omnibus derived from human HCC tissue.Comprehensive pathway enrichment analysis was performed using pathDIP for each data type(genomic,gene expression,methylation,miRNA and proteomic),and the overlap of pathways was assessed to elucidate pathway dependencies in HCC.RESULTS We identified a total of 8733 abstracts retrieved by the search on PubMed on HCC for the different layers of data on human HCC samples,published until December 2016.The common key dysregulated pathways in HCC tissue across different layers of data included epidermal growth factor(EGFR)andβ1-integrin pathways.Genes along these pathways were significantly and consistently dysregulated across the different types of high-throughput data and had prognostic value with respect to overall survival.Using CTD database,estradiol would best modulate and revert these genes appropriately.CONCLUSION By analyzing and integrating all available high-throughput genomic,transcriptomic,miRNA,methylation and proteomic data from human HCC tissue,we identified EGFR,β1-integrin and axon guidance as pathway dependencies in HCC.These are master regulators of key pathways in HCC,such as the mTOR,Ras/Raf/MAPK and p53 pathways.The genes implicated in these pathways had prognostic value in HCC,with Netrin and Slit3 being novel proteins of prognostic importance to HCC.Based on this integrative analysis,EGFR,andβ1-integrin are master regulators that could serve as potential therapeutic targets in HCC.
基金funded by the Canadian Institutes of Health Research(CIHR)(PJT-166089)the Natural Sciences and Engineering Research Council of Canada(NSERC)(RGPIN-2018-05737)supported by the Schroeder Arthritis Institute via the Toronto General and Western Hospital Foundation(University Health Network).
文摘Osteoarthritis(OA)is a degenerative multifactorial disease with concomitant structural,inflammatory,and metabolic changes that fluctuate in a temporal and patient-specific manner.This complexity has contributed to refractory responses to various treatments.MsCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression.Here,we evaluated 15 randomized controlled clinical trials(RCTs)and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA,and we found net positive effects of MSCs on mitigating pain and symptoms(improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints)and on cartilage protection and/or repair(18/21 clinical studies).We examined MsC dose,tissue of origin,and autologous vs.allogeneic origins as well as patient clinical phenotype,endotype,age,sex and level of OA severity as key parameters in parsing MSC clinical effectiveness.The relatively small sample size of 610 patients limited the drawing of definitive conclusions.Nonetheless,we noted trends toward moderate to higher doses of MsCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation.Evidence from preclinical studies is supportive of MsC anti-inflammatory and immunomodulatory effects,but additional investigations on immunomodulatory,chondroprotective and other clinical mechanisms of action are needed.We hypothesize that MsC basal immunomodulatory"fitness"correlates with OA treatment efficacy,but this hypothesis needs to be validated in future studies.We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory"ft"or engineered-to-be-fit-for-OA MsCs in well-designed,data-intensive clinical trials to advance the field.
