Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not be...Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.展开更多
Background and Aims:Liver transplantation(LT)using ABO-incompatible(ABOi)grafts can extend the donor pool to a certain extent and hence reduce the waiting time for transplantation.However,concerns of the impending pro...Background and Aims:Liver transplantation(LT)using ABO-incompatible(ABOi)grafts can extend the donor pool to a certain extent and hence reduce the waiting time for transplantation.However,concerns of the impending prognosis associated with this option,especially for patients with liver failure and higher model for end-stage liver disease(MELD)scores,who tend to be more fragile during the waiting period before LT.Methods:Recipients undergoing LT for acute-onchronic liver failure or acute liver failure were retrospectively enrolled at four institutions.Overall survival was compared and a Cox regression analysis was performed.Propensity score matching was performed for further comparison.Patients were stratified by MELD score and cold ischemia time(CIT)to determine the subgroups with survival benefits.Results:Two hundred ten recipients who underwent ABOi LT and 1,829 who underwent ABO compatible(ABOc)LT were enrolled.The 5-year overall survival rate was significantly inferior in the ABOi group compared with the ABOc group after matching(50.6%vs.75.7%,p<0.05).For patients with MELD scores≤30,using ABOi grafts achieved a comparable overall survival rate as using ABOc grafts(p>0.05).Comparison of the survival rates revealed no statistically significant difference for patients with MELD scores≥40(p>0.05).For patients with MELD scores of 31-39,the overall survival rate was significantly inferior in the ABOi group compared with the ABOc group(p<0.001);however,the rate was increased when the liver graft CIT was<8 h.Conclusions:For recipients with MELD scores≤30,ABOi LT had a prognosis comparable to that of ABOc LT and can be regarded as a feasible option.For recipients with MELD scores≥40,ABOi should be adopted with caution in emergency cases.For recipients with MELD scores of 31-39,the ABOi LT prognosis was worse.However,those patients benefited from receiving ABOi grafts with a CIT of<8 h.展开更多
Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that h...Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism.However,their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear.In this study,we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins(SREBPs)and miR-33a.Our in silico and experimental analyses identified miR-33a as a direct target of circFASN.Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro.Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation.Clinically,the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a(46.3%vs.18.8%p=0.012,n=73).Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis.MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia,providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.展开更多
基金supported by grants from the National Science and Technology Major Project of China(No.2017ZX10203205)the National Natural Science Funds for Distinguished Young Scholar of China(No.81625003)+1 种基金Key Program National Natural Science Foundation of China(No.81930016)Key Research&Development Plan of Zhejiang Province(No.2019C03050)。
文摘Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.
基金This research was partially supported by National Natural Science Funds for Distinguished Young Scholar of China,(No.81625003)Key Program,National Natural Science Foundation of China,(No.81930016,No.81570589,No.81702858)+1 种基金Youth Program of National Natural Science Foundation of Zhejiang Province(No.LQ17H160006)National S&T Major Project(No.2017ZX10203205).
文摘Background and Aims:Liver transplantation(LT)using ABO-incompatible(ABOi)grafts can extend the donor pool to a certain extent and hence reduce the waiting time for transplantation.However,concerns of the impending prognosis associated with this option,especially for patients with liver failure and higher model for end-stage liver disease(MELD)scores,who tend to be more fragile during the waiting period before LT.Methods:Recipients undergoing LT for acute-onchronic liver failure or acute liver failure were retrospectively enrolled at four institutions.Overall survival was compared and a Cox regression analysis was performed.Propensity score matching was performed for further comparison.Patients were stratified by MELD score and cold ischemia time(CIT)to determine the subgroups with survival benefits.Results:Two hundred ten recipients who underwent ABOi LT and 1,829 who underwent ABO compatible(ABOc)LT were enrolled.The 5-year overall survival rate was significantly inferior in the ABOi group compared with the ABOc group after matching(50.6%vs.75.7%,p<0.05).For patients with MELD scores≤30,using ABOi grafts achieved a comparable overall survival rate as using ABOc grafts(p>0.05).Comparison of the survival rates revealed no statistically significant difference for patients with MELD scores≥40(p>0.05).For patients with MELD scores of 31-39,the overall survival rate was significantly inferior in the ABOi group compared with the ABOc group(p<0.001);however,the rate was increased when the liver graft CIT was<8 h.Conclusions:For recipients with MELD scores≤30,ABOi LT had a prognosis comparable to that of ABOc LT and can be regarded as a feasible option.For recipients with MELD scores≥40,ABOi should be adopted with caution in emergency cases.For recipients with MELD scores of 31-39,the ABOi LT prognosis was worse.However,those patients benefited from receiving ABOi grafts with a CIT of<8 h.
基金supported by the National Natural Science Foundation of China(General Program)[Grant number:81570589]the National Natural Science Funds for Distinguished Young Scholars of China[Grant number:81625003]+1 种基金the National Natural Science Foundation of China(Key Program)[Grant number:81930016]the Cheung Kong Scholars Program of China and National Science and Technology Major Project[Grant number:2017ZX100203205].
文摘Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism.However,their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear.In this study,we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins(SREBPs)and miR-33a.Our in silico and experimental analyses identified miR-33a as a direct target of circFASN.Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro.Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation.Clinically,the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a(46.3%vs.18.8%p=0.012,n=73).Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis.MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia,providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.
