Background:Hepatic artery occlusion(HAO)after liver transplantation(LT)is typically comprised of hepatic artery thrombosis(HAT)and stenosis(HAS),both of which are severe complications that coexist and interdependent.T...Background:Hepatic artery occlusion(HAO)after liver transplantation(LT)is typically comprised of hepatic artery thrombosis(HAT)and stenosis(HAS),both of which are severe complications that coexist and interdependent.This study aimed to evaluate an integrated endovascular treatment(EVT)strategy for the resolution of early HAO and identify the risk factors associated with early HAO as well as the procedural challenge encountered in the treatment strategy.Methods:Consecutive orthotopic LT recipients(n=366)who underwent transplantation between June 2017 and December 2018 were retrospectively investigated.EVT was performed using an integrated strategy that involved thrombolytic therapy,shunt artery embolization plus vasodilator therapy,percutaneous transluminal angioplasty,and/or stent placement.Simple EVT was defined as the clinical resolution of HAO by one round of EVT with thrombolytic therapy and/or shunt artery embolization plus vasodilator therapy.Otherwise,it was defined as complex EVT.Results:Twenty-six patients(median age 52 years)underwent EVT for early HAO that occurred within 30 days post-LT.The median interval from LT to EVT was 7(6–16)days.Revascularization time(OR=1.027;95%CI:1.005–1.050;P=0.018)and the need for conduit(OR=3.558;95%CI:1.241–10.203,P=0.018)were independent predictors for early HAO.HAT was diagnosed in eight patients,and four out of those presented with concomitant HAS.We achieved 100%technical success and recanalization by performing simple EVT in 19 patients(3 HAT+/HAS-and 16 HAT-/HAS+)and by performing complex EVT in seven patients(1 HAT+/HAS-,4 HAT+/HAS+,and 2 HAT-/HAS+),without major complications.The primary assisted patency rates at 1,6,and 12 months were all 100%.The cumulative overall survival rates at 1,6,and 12 months were 88.5%,88.5%,and 80.8%,respectively.Autologous transfusion<600 mL(94.74%vs.42.86%,P=0.010)and interrupted suture for hepatic artery anastomosis(78.95%vs.14.29%,P=0.005)were more prevalent in simple EVT.Conclusions:The integrated EVT strategy was a feasible approach providing effective resolution with excellent safety for early HAO after LT.Appropriate autologous transfusion and interrupted suture technique helped simplify EVT.展开更多
Background:Wernicke encephalopathy(WE)is an acute neurological disease resulting from vitamin B1 deficiency,and there are only very few case reports of WE after liver transplantation.The present study aimed to investi...Background:Wernicke encephalopathy(WE)is an acute neurological disease resulting from vitamin B1 deficiency,and there are only very few case reports of WE after liver transplantation.The present study aimed to investigate the clinical characteristics,etiology,magnetic resonance imaging(MRI)features,treatment and prognosis of patients with WE after liver transplantation.Methods:Twenty-three patients with WE after liver transplantation from the First Affiliated Hospital,Zhejiang University School of Medicine and Jiangxi Provincial People’s Hospital between January 2011 and December 2021 were retrospectively analyzed.Results:Among the 23 patients diagnosed with WE after liver transplantation,6(26%)had a classic triad of impaired consciousness,oculomotor palsy and ataxia,and 17(74%)had two features.The misdiagno-sis rate was 65%.After treatment with high-dose vitamin B1,19(83%)patients showed improvement,whereas 4(17%)showed no improvement,including 3 with residual short-term memory impairments and 1 with residual spatial and temporal disorientation and ataxia.Conclusions:The misdiagnosis rate is high in the early stage of WE,and the prognosis is closely asso-ciated with whether WE is diagnosed early and treated timely.High-dose glucose or glucocorticoids can trigger WE and cannot be administered before vitamin B1 treatment.Vitamin B1 is suggested to be used as a prophylactic treatment for patients with WE after liver transplantation.展开更多
Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the...Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.Methods:Gene Expression Omnibus(GEO)dataset(GSE15654,n=216)was analyzed to screen genes associated with progression of liver cirrhosis.A total of 181 plasma samples,including healthy control(HC,n=20),chronic hepatitis B(CHB,n=77)and HBV-related liver cirrhosis(LC,n=84),were enrolled for validation.In vitro and in vivo experiments were employed for the mechanistic investigation.Results:GEO dataset analysis showed that relatively low mRNA-expression of C–C motif chemokine ligand 16(CCL16)was associated with elevated Child-Pugh score(P=0.034)and worse prognosis(P=0.025).Plasma CCL16 level decreased in a stepwise pattern,with a median concentration of 10.29,6.57 and 4.47 ng/mL in the HC,CHB and LC groups,respectively(P<0.001).Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups(P<0.05).Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone.In vitro,CCL16 expression was downregulated by lipopolysaccharide and hypoxia.Overexpression of CCL16 from human normal liver cell line(LO2)reduced the extracellular matrix associated proteins(Col1 and Col4)in human hepatic stellate cell line(LX-2).In vivo,the pathological feature of cirrhosis was alleviated by the hepatocytespecific expression of CCL16.Conclusions:CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis.CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.展开更多
Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for om...Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.展开更多
Nanosecond pulsed electric field(nsPEF)is a novel,nonthermal,and minimally invasive modality that can ablate solid tumors by inducing apoptosis.Recent animal experiments show that nsPEF can induce the immunogenic cell...Nanosecond pulsed electric field(nsPEF)is a novel,nonthermal,and minimally invasive modality that can ablate solid tumors by inducing apoptosis.Recent animal experiments show that nsPEF can induce the immunogenic cell death of hepatocellular carcinoma(HCC)and stimulate the host’s immune response to kill residual tumor cells and decrease distant metastatic tumors.nsPEF-induced immunity is of great clinical importance because the nonthermal ablation may enhance the immune memory,which can prevent HCC recurrence and metastasis.This review summarized the most advanced research on the effect of nsPEF.The possible mechanisms of how locoregional nsPEF ablation enhances the systemic anticancer immune responses were illustrated.nsPEF stimulates the host immune system to boost stimulation and prevail suppression.Also,nsPEF increases the dendritic cell loading and inhibits the regulatory responses,thereby improving immune stimulation and limiting immunosuppression in HCC-bearing hosts.Therefore,nsPEF has excellent potential for HCC treatment.展开更多
The extracellular matrix(ECM)Is one of the major components of tumors that plays multiple crucial roles,including mechanical support,modulation of the microenvironment,and a source of signaling molecules.The quantity ...The extracellular matrix(ECM)Is one of the major components of tumors that plays multiple crucial roles,including mechanical support,modulation of the microenvironment,and a source of signaling molecules.The quantity and cross-linking status of ECM components are major factors determining tissue stiffness.During tumorigenesis,the interplay between cancer cells and the tumor microenvironment(TME)often results in the stiffness of the ECM,leading to aberrant mechanotransduction and further malignant transformation.Therefore,a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment.Herein,we summarized the knowledge concerning the following:(1)major ECM constituents and their functions in both normal and malignant conditions;(2)the interplay between cancer cells and the ECM in the TME;(3)key receptors for mechanotransduction and their alteration during carcinogenesis;and(4)the current therapeutic strategies targeting aberrant ECM for cancer treatment.展开更多
Background:The downstaging of hepatocellular carcinoma(HCC)has been confirmed to benefit liver transplantation(LT)patients whose tumors are beyond the transplantation criteria.Milan criteria(MC),a tumor size and numbe...Background:The downstaging of hepatocellular carcinoma(HCC)has been confirmed to benefit liver transplantation(LT)patients whose tumors are beyond the transplantation criteria.Milan criteria(MC),a tumor size and number-based assessment,is currently used as the endpoint in these patients.However,many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy.Hence,this study aimed to explore the feasibility of Hangzhou criteria(HC),which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number,as an endpoint of downstaging.Methods:We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy(LRT)as downstaging/bridge treatment prior to LT in three centers of China.Results:Recipients were divided into four groups:failed downstaging to the HC(group A,n=46),successful downstaging to the HC(group B,n=30),remained within the HC all the time(group C,n=113),and tumor progressed(group D,n=17).The 3-year HCC recurrence probabilities of groups B and C were not significantly different(10.3%vs.11.6%,P=0.87).The HCC recurrent rate was significantly higher in group A(52.3%)compared with that in group B/C(P<0.05).Seven patients(7/76,9.2%)whose tumor exceeded the the HC were successfully downstaged to the MC,and 39.5%(30/76)to the the HC.In group B,23 patients remained beyond the MC and their survivals were as well as those of patients within the MC.Conclusions:Compared to the MC,HC downstaging criteria can give more HCC patients access to LT and furthermore,the outcome of these patients is the same as those matching MC downstaging criteria.Hangzhou downstaging criteria therefore is applicable in clinical practice.展开更多
Amino acids are the building blocks of protein synthesis.They are structural elements and energy sources of cells necessary for normal cell growth,differentiation and function.Amino acid metabolism disorders have been...Amino acids are the building blocks of protein synthesis.They are structural elements and energy sources of cells necessary for normal cell growth,differentiation and function.Amino acid metabolism disorders have been linked with a number of pathological conditions,including metabolic diseases,cardiovascular diseases,immune diseases,and cancer.In the case of tumors,alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies.展开更多
A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in ...A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in a drug-screening model has high value yet challenging to accomplish.Herein,we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters,and the culture of patient-derived tumor organoids(PDTOs)for personalized pre-clinical drug screening.The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo.As a result,18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs.These PDTOs,along with hepatocyte growth factor(HGF)of non-cellular components,preserve stromal cells,including cancer-associated fibroblasts(CAFs)and vascular endothelial cells(VECs).They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors.Drugs,including cabazitaxel,oxaliplatin,and sorafenib,were tested in PDTOs.The sensitivity of PDTOs to these drugs differs between individuals.The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging(MRI)and biochemical tests after oxaliplatin clinical treatment of the corresponding patient.Therefore,this approach is promising for economical,accurate,and high-throughput drug screening for personalized treatment.展开更多
The current treatment strategies in advanced malignancies remain limited.Notably,immunotherapies have raised hope for a successful control of these advanced diseases,but their therapeutic responses are suboptimal and ...The current treatment strategies in advanced malignancies remain limited.Notably,immunotherapies have raised hope for a successful control of these advanced diseases,but their therapeutic responses are suboptimal and vary considerably among individuals.Tumor-associated macrophages(TAMs)are a major component of the tumor microenvironment(TME)and are often correlated with poor prognosis and therapy resistance,including immunotherapies.Thus,a deeper understanding of the complex roles of TAMs in immunotherapy regulation could provide new insight into the TME.Furthermore,targeting of TAMs is an emerging field of interest due to the hope that these strategies will synergize with current immunotherapies.In this review,we summarize recent studies investigating the involvement of TAMs in immune checkpoint inhibition,tumor vaccines and adoptive cell transfer therapies,and discuss the therapeutic potential of targeting TAMs as an adjuvant therapy in tumor immunotherapies.展开更多
Background:Liver transplantation(LT)is one of the most effective surgical treatment for patients with end-stage liver disease.Steatosis is a contributor for inferior graft quality.But its impact and safety on transpla...Background:Liver transplantation(LT)is one of the most effective surgical treatment for patients with end-stage liver disease.Steatosis is a contributor for inferior graft quality.But its impact and safety on transplantation was less assessed in Chinese patients.Methods:Graft steatosis and related information involved in recipients,donors and surgical procedures were retrospectively collected from 239 patients.Results:Donor macrosteatosis(MaS)caused about 2.14 and 2.80 folds of increment on patient and graft mortality.Dose-response analysis revealed prominent risk of grafts on overall patient/organ mortality when MaS content exceeded 10%(P<0.05).Noteworthy,deaths were only observed in MaS group when concurrent with extremely higher post-transplant alanine aminotransferase(ALT,64%).However,microsteatosis(MiS)grafts didn’t affect outcomes after LT.In a cohort of Chinese patients,MaS had comprehensive effects on post-transplant outcomes with relatively lower safety threshold at 10%.Mortality gap caused by MaS grafts was observed in patients with severer ischemia reperfusion injury.Conclusions:Our study revealled the graft MaS affected the post-transplant outcomes in lower risk cutoff in Chinese patients.Further study is worthy to validate these results and investigate inner mechanism under the phenomenon.展开更多
Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investi...Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.Methods:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver can-cer.Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of patients.DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells.RNA sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis.Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.Results:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA methylation.SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer.SERPINE2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and angiogenesis.IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with EGFR.Mechanistically,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,c-Cbl.Additionally,EGFR was activated in liver cancer cells after sorafenib treatment,and SER-PINE2 knockdown-induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer.Furthermore,we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.Conclusions:SERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c-Cbl-mediated ubiquitination,suggesting that inhibition of the SERPINE2-EGFR axis may be a potential target for liver cancer treatment.展开更多
基金the National Major Science and Technology Projects of China(2017ZX10203201 and 2018ZX10301201)Project of Medical and Health Technology Program in Zhejiang Province(2016KYA073).
文摘Background:Hepatic artery occlusion(HAO)after liver transplantation(LT)is typically comprised of hepatic artery thrombosis(HAT)and stenosis(HAS),both of which are severe complications that coexist and interdependent.This study aimed to evaluate an integrated endovascular treatment(EVT)strategy for the resolution of early HAO and identify the risk factors associated with early HAO as well as the procedural challenge encountered in the treatment strategy.Methods:Consecutive orthotopic LT recipients(n=366)who underwent transplantation between June 2017 and December 2018 were retrospectively investigated.EVT was performed using an integrated strategy that involved thrombolytic therapy,shunt artery embolization plus vasodilator therapy,percutaneous transluminal angioplasty,and/or stent placement.Simple EVT was defined as the clinical resolution of HAO by one round of EVT with thrombolytic therapy and/or shunt artery embolization plus vasodilator therapy.Otherwise,it was defined as complex EVT.Results:Twenty-six patients(median age 52 years)underwent EVT for early HAO that occurred within 30 days post-LT.The median interval from LT to EVT was 7(6–16)days.Revascularization time(OR=1.027;95%CI:1.005–1.050;P=0.018)and the need for conduit(OR=3.558;95%CI:1.241–10.203,P=0.018)were independent predictors for early HAO.HAT was diagnosed in eight patients,and four out of those presented with concomitant HAS.We achieved 100%technical success and recanalization by performing simple EVT in 19 patients(3 HAT+/HAS-and 16 HAT-/HAS+)and by performing complex EVT in seven patients(1 HAT+/HAS-,4 HAT+/HAS+,and 2 HAT-/HAS+),without major complications.The primary assisted patency rates at 1,6,and 12 months were all 100%.The cumulative overall survival rates at 1,6,and 12 months were 88.5%,88.5%,and 80.8%,respectively.Autologous transfusion<600 mL(94.74%vs.42.86%,P=0.010)and interrupted suture for hepatic artery anastomosis(78.95%vs.14.29%,P=0.005)were more prevalent in simple EVT.Conclusions:The integrated EVT strategy was a feasible approach providing effective resolution with excellent safety for early HAO after LT.Appropriate autologous transfusion and interrupted suture technique helped simplify EVT.
基金approved by Jiangxi Provincial People’s Hospital and First Affiliated Hospital,Zhejiang University School of Medicine(2022068 and 2022370).Written informed consent was obtained from all participants.
文摘Background:Wernicke encephalopathy(WE)is an acute neurological disease resulting from vitamin B1 deficiency,and there are only very few case reports of WE after liver transplantation.The present study aimed to investigate the clinical characteristics,etiology,magnetic resonance imaging(MRI)features,treatment and prognosis of patients with WE after liver transplantation.Methods:Twenty-three patients with WE after liver transplantation from the First Affiliated Hospital,Zhejiang University School of Medicine and Jiangxi Provincial People’s Hospital between January 2011 and December 2021 were retrospectively analyzed.Results:Among the 23 patients diagnosed with WE after liver transplantation,6(26%)had a classic triad of impaired consciousness,oculomotor palsy and ataxia,and 17(74%)had two features.The misdiagno-sis rate was 65%.After treatment with high-dose vitamin B1,19(83%)patients showed improvement,whereas 4(17%)showed no improvement,including 3 with residual short-term memory impairments and 1 with residual spatial and temporal disorientation and ataxia.Conclusions:The misdiagnosis rate is high in the early stage of WE,and the prognosis is closely asso-ciated with whether WE is diagnosed early and treated timely.High-dose glucose or glucocorticoids can trigger WE and cannot be administered before vitamin B1 treatment.Vitamin B1 is suggested to be used as a prophylactic treatment for patients with WE after liver transplantation.
基金This work was supported by grants from the National Science and Technology Major Project of China[2017ZX10203205]the National Natural Science Funds for Distinguished Young Scholar of China[81625003]+2 种基金Projects of Medical and Health Technology Program in Zhejiang Province[WKJ-ZJ-1514]China Postdoctoral Science Foundation[2017M612014]Zhejiang Medical and Technological Program[2018263185].
文摘Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.Methods:Gene Expression Omnibus(GEO)dataset(GSE15654,n=216)was analyzed to screen genes associated with progression of liver cirrhosis.A total of 181 plasma samples,including healthy control(HC,n=20),chronic hepatitis B(CHB,n=77)and HBV-related liver cirrhosis(LC,n=84),were enrolled for validation.In vitro and in vivo experiments were employed for the mechanistic investigation.Results:GEO dataset analysis showed that relatively low mRNA-expression of C–C motif chemokine ligand 16(CCL16)was associated with elevated Child-Pugh score(P=0.034)and worse prognosis(P=0.025).Plasma CCL16 level decreased in a stepwise pattern,with a median concentration of 10.29,6.57 and 4.47 ng/mL in the HC,CHB and LC groups,respectively(P<0.001).Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups(P<0.05).Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone.In vitro,CCL16 expression was downregulated by lipopolysaccharide and hypoxia.Overexpression of CCL16 from human normal liver cell line(LO2)reduced the extracellular matrix associated proteins(Col1 and Col4)in human hepatic stellate cell line(LX-2).In vivo,the pathological feature of cirrhosis was alleviated by the hepatocytespecific expression of CCL16.Conclusions:CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis.CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.
基金supported by Innovative Research Groups of National Natural Science Foundation of China(81721091)Major Program of National Natural Science Foundation of China(91542205)+8 种基金National S&T Major Project(2017ZX 10203205)National Natural Science Foundation of China(81902813)Zhejiang International Science and Technology Cooperation Project(2016C04003)Zhejiang Provincial Natural Science Foundation of China(LY18H030002)Zhejiang Medical Association(grant no.2019ZYC-A81)International Youth Exchange Programme by China Association for Science and Technology(2019),Tianqing Liver Diseases Research Fund(TQGB20200114)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(2021KY145)Organ Transplantation Overseas Training for Youth Talents from Shulan Excellent Talent Project,CSCO(Chinese Society Of Clinical Oncology)-Bayer Tumor Research Funding(Y-bayer202001/zb-0003)Open Fund of Key laboratory of High-Incidence-Tumor Prevention&Treatment(Guangxi Medical University)belonged to Ministry of Education.
文摘Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.
基金National S&T Major Project(No.2018ZX10301201)Innovative Research Groups of National Natural Science Foundation of China(No.81721091)。
文摘Nanosecond pulsed electric field(nsPEF)is a novel,nonthermal,and minimally invasive modality that can ablate solid tumors by inducing apoptosis.Recent animal experiments show that nsPEF can induce the immunogenic cell death of hepatocellular carcinoma(HCC)and stimulate the host’s immune response to kill residual tumor cells and decrease distant metastatic tumors.nsPEF-induced immunity is of great clinical importance because the nonthermal ablation may enhance the immune memory,which can prevent HCC recurrence and metastasis.This review summarized the most advanced research on the effect of nsPEF.The possible mechanisms of how locoregional nsPEF ablation enhances the systemic anticancer immune responses were illustrated.nsPEF stimulates the host immune system to boost stimulation and prevail suppression.Also,nsPEF increases the dendritic cell loading and inhibits the regulatory responses,thereby improving immune stimulation and limiting immunosuppression in HCC-bearing hosts.Therefore,nsPEF has excellent potential for HCC treatment.
基金This study was supported by the National Natural Science Foundation of China(No.81903143)Innovative Research Groups of National Natural Science Foundation of China(No.81721091)+3 种基金National S&T Major Project(No.2017ZX10203205)Zhejiang International Science and Technology Cooperation Project(No.2016C04003)Research Unit Project of Chinese Academy of Medical Sciences(2019-I2M-5-030)Major Program of National Natural Science Foundation of China(No.91542205).
文摘The extracellular matrix(ECM)Is one of the major components of tumors that plays multiple crucial roles,including mechanical support,modulation of the microenvironment,and a source of signaling molecules.The quantity and cross-linking status of ECM components are major factors determining tissue stiffness.During tumorigenesis,the interplay between cancer cells and the tumor microenvironment(TME)often results in the stiffness of the ECM,leading to aberrant mechanotransduction and further malignant transformation.Therefore,a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment.Herein,we summarized the knowledge concerning the following:(1)major ECM constituents and their functions in both normal and malignant conditions;(2)the interplay between cancer cells and the ECM in the TME;(3)key receptors for mechanotransduction and their alteration during carcinogenesis;and(4)the current therapeutic strategies targeting aberrant ECM for cancer treatment.
基金grants from the National Science and Technology Major Project of China(No.2017ZX10203205)the National Natural Science Founds for Distinguished Young Scholar of China(No.81625003)+1 种基金the State Key Program of National Natural Science Foundation of China(No.81930016)the National Natural Science Foundation of China(No.81902407).
文摘Background:The downstaging of hepatocellular carcinoma(HCC)has been confirmed to benefit liver transplantation(LT)patients whose tumors are beyond the transplantation criteria.Milan criteria(MC),a tumor size and number-based assessment,is currently used as the endpoint in these patients.However,many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy.Hence,this study aimed to explore the feasibility of Hangzhou criteria(HC),which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number,as an endpoint of downstaging.Methods:We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy(LRT)as downstaging/bridge treatment prior to LT in three centers of China.Results:Recipients were divided into four groups:failed downstaging to the HC(group A,n=46),successful downstaging to the HC(group B,n=30),remained within the HC all the time(group C,n=113),and tumor progressed(group D,n=17).The 3-year HCC recurrence probabilities of groups B and C were not significantly different(10.3%vs.11.6%,P=0.87).The HCC recurrent rate was significantly higher in group A(52.3%)compared with that in group B/C(P<0.05).Seven patients(7/76,9.2%)whose tumor exceeded the the HC were successfully downstaged to the MC,and 39.5%(30/76)to the the HC.In group B,23 patients remained beyond the MC and their survivals were as well as those of patients within the MC.Conclusions:Compared to the MC,HC downstaging criteria can give more HCC patients access to LT and furthermore,the outcome of these patients is the same as those matching MC downstaging criteria.Hangzhou downstaging criteria therefore is applicable in clinical practice.
基金The National Natural Science Foundation of China(82073144,J.W.)the Health Commission of Zhejiang Province(JBZX-202004,J.W.)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(LHDMD22H310005,J.W.).
文摘Amino acids are the building blocks of protein synthesis.They are structural elements and energy sources of cells necessary for normal cell growth,differentiation and function.Amino acid metabolism disorders have been linked with a number of pathological conditions,including metabolic diseases,cardiovascular diseases,immune diseases,and cancer.In the case of tumors,alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies.
基金the Key Research and Development Plan of Zhejiang Province(No.2020C04003)the National Natural Science Foundation of China(No.82070652,No.81870434,NO.T2125009,NO.92048302,NO.11822207 and NO.12102388)+1 种基金the Natural Science Foundation of Zhejiang Province(NO.LR18A020001)the Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022007B).
文摘A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in a drug-screening model has high value yet challenging to accomplish.Herein,we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters,and the culture of patient-derived tumor organoids(PDTOs)for personalized pre-clinical drug screening.The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo.As a result,18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs.These PDTOs,along with hepatocyte growth factor(HGF)of non-cellular components,preserve stromal cells,including cancer-associated fibroblasts(CAFs)and vascular endothelial cells(VECs).They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors.Drugs,including cabazitaxel,oxaliplatin,and sorafenib,were tested in PDTOs.The sensitivity of PDTOs to these drugs differs between individuals.The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging(MRI)and biochemical tests after oxaliplatin clinical treatment of the corresponding patient.Therefore,this approach is promising for economical,accurate,and high-throughput drug screening for personalized treatment.
基金supported by the National Science Fund for Distinguished Young Scholars(81625003)National Science and Technology Major Project(2017ZX10203205)+2 种基金National Science and Technology Key Program(81930016)Key R&D Project of Zhejiang Province(2019C03050)the National Natural Science Foundation of China(81801824).
文摘The current treatment strategies in advanced malignancies remain limited.Notably,immunotherapies have raised hope for a successful control of these advanced diseases,but their therapeutic responses are suboptimal and vary considerably among individuals.Tumor-associated macrophages(TAMs)are a major component of the tumor microenvironment(TME)and are often correlated with poor prognosis and therapy resistance,including immunotherapies.Thus,a deeper understanding of the complex roles of TAMs in immunotherapy regulation could provide new insight into the TME.Furthermore,targeting of TAMs is an emerging field of interest due to the hope that these strategies will synergize with current immunotherapies.In this review,we summarize recent studies investigating the involvement of TAMs in immune checkpoint inhibition,tumor vaccines and adoptive cell transfer therapies,and discuss the therapeutic potential of targeting TAMs as an adjuvant therapy in tumor immunotherapies.
基金This study is supported by Innovative Research Groups of National Natural Science Foundation of China(81721091)Major program of National Natural Science Foundation of China(91542205)+7 种基金National S&T Major Project(2017ZX10203205)National Natural Science Foundation of China(81902813)Zhejiang International Science and Technology Cooperation Project(2016C04003)Zhejiang Provincial Natural Science Foundation of China(LY18H030002)Zhejiang Medical Association(2019ZYC-A81)International Youth Exchange Programme by China Association for Science and Technology(2019)Tianqing Liver Diseases Research Fund(TQGB20200114)Open Fund of Key laboratory of High-Incidence-Tumor Prevention&Treatment(Guangxi Medical University),Ministry of Education.
文摘Background:Liver transplantation(LT)is one of the most effective surgical treatment for patients with end-stage liver disease.Steatosis is a contributor for inferior graft quality.But its impact and safety on transplantation was less assessed in Chinese patients.Methods:Graft steatosis and related information involved in recipients,donors and surgical procedures were retrospectively collected from 239 patients.Results:Donor macrosteatosis(MaS)caused about 2.14 and 2.80 folds of increment on patient and graft mortality.Dose-response analysis revealed prominent risk of grafts on overall patient/organ mortality when MaS content exceeded 10%(P<0.05).Noteworthy,deaths were only observed in MaS group when concurrent with extremely higher post-transplant alanine aminotransferase(ALT,64%).However,microsteatosis(MiS)grafts didn’t affect outcomes after LT.In a cohort of Chinese patients,MaS had comprehensive effects on post-transplant outcomes with relatively lower safety threshold at 10%.Mortality gap caused by MaS grafts was observed in patients with severer ischemia reperfusion injury.Conclusions:Our study revealled the graft MaS affected the post-transplant outcomes in lower risk cutoff in Chinese patients.Further study is worthy to validate these results and investigate inner mechanism under the phenomenon.
基金This work was supported by grants from the National Nat-ural Science Foundation of China(82070652 and 81870434)Department of Science and Technology of Zhejiang Province(2020C04003)+2 种基金the Chinese Academy of Medi-cal Sciences(019-I2M-5-030)the Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022007B)the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases(zz202302).
文摘Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.Methods:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver can-cer.Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of patients.DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells.RNA sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis.Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.Results:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA methylation.SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer.SERPINE2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and angiogenesis.IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with EGFR.Mechanistically,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,c-Cbl.Additionally,EGFR was activated in liver cancer cells after sorafenib treatment,and SER-PINE2 knockdown-induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer.Furthermore,we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.Conclusions:SERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c-Cbl-mediated ubiquitination,suggesting that inhibition of the SERPINE2-EGFR axis may be a potential target for liver cancer treatment.
