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M2-type macrophage membrane-mediated delivery of Carvedilol nanocomplex for acute liver failure treatment and remodeling inflammatory microenvironment

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Nano Research 2024年第7期17卷 6362-6375页

作者： Mingge Shang Yaohui Zhang Junjie Qian Wenchao Wang Xizhi Yu Jiacheng Huang Lin Zhou shusen zheng Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China NHC Key Laboratory of Combined Multi-organ Transplantation Key Laboratory of Organ TransplantationHangzhou 310003China Key Laboratory of the diagnosis and treatment of organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical Sciences(2019RU019)Hangzhou 310003China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesHangzhou 310003China Department of Thyroid Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College Hangzhou 310000China

Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure(ALF).Hence,reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting *** group found Carvedilol possessed potential anti-inflammatory property previously,which had been scarcely reported in *** present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4(IL-4)and IL-10 at *** Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform(termed as M2M@CNP)to evade reticuloendothelial system(RES)and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species(ROS),further prolonging its circulation and *** released Carvedilol produced anti-inflammatory,antioxidant and anti-apoptosis effects,combining local M2-type cell membranes(M2-CM)inhibited pro-inflammatory cytokines and ROS levels,which in turn promoted and amplified M1 to M2 phenotype polarization *** study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.

关键词： acute liver failure hepatic drug delivery M2 macrophage-camouflaged nanoplatform inflammatory microenvironment macrophage polarization

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Deep learning-based radiomics allows for a more accurate assessment of sarcopenia as a prognostic factor in hepatocellular carcinoma

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 83-90页

作者： Zhikun LIU Yichao WU Abid Ali KHAN Lun LU Jianguo WANG Jun CHEN Ningyang JIA shusen zheng Xiao XU Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou310006China Zhejiang University School of Medicine Hangzhou310058China Department of Radiology Easter Hepatobiliary Surgery HospitalNaval Medical UniversityShanghai200438China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China NHC Key Laboratory of Combined Multi-organ Transplantation Hangzhou310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou310022China

Hepatocellular carcinoma(HCC)is one of the most common malignancies and is a major cause of cancer-related mortalities worldwide(Forner et al.,2018;He et al.,2023).Sarcopenia is a syndrome characterized by an accelerated loss of skeletal muscle(SM)mass that may be age-related or the result of malnutrition in cancer patients(Cruz-Jentoft and Sayer,2019).Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival(Voron et al.,2015;van Vugt et al.,2016).

关键词： cancer patients

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Integrative analysis of the transcriptome and metabolome reveals the importance of hepatokine FGF21 in liver aging

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Genes & Diseases 2024年第5期11卷 407-427页

作者： Wenchao Wang Junjie Qian Mingge Shang Yiting Qiao Jiacheng Huang Xinxin Gao Zhou Ye Xinyu Tong Kangdi Xu Xiang Li zhengtao Liu Lin Zhou shusen zheng Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang 310003China NHC Key Laboratory of Combined Multi-organ Transplantation HangzhouZhejiang 310003China Key Laboratory of the Diagnosis and Treatment of Organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical Sciences(2019RU019)HangzhouZhejiang 310003China Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiang 310003China Shulan International Medical College Zhejiang Shuren UniversityHangzhouZhejiang 310015China Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College HangzhouZhejiang 310000China

Aging is a contributor to liver ***,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly *** our study,the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted *** aged rat liver model was established with D-galactose,and two other senescent hepatocyte models were established by treating HepG2 cells with D-galactose and *** then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte *** livers,genes related to peroxisomes,fatty acid elongation,and fatty acid degradation exhibited down-regulated expression with aging,and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these *** senescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also ***,the expressions of cell cycle-related genes were significantly down-regulated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription *** then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging *** successfully validated the results from cellular and animal experiments using human liver and blood *** study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.

关键词： Antioxidant capability FGF21 Liver aging Liver regeneration Multiomics analysis

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Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma:a multicenter cohort study in China

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Cancer Biology & Medicine 2024年第4期21卷 347-362页

作者： Jian Chen Zhe Yang Fengqiang Gao Zhisheng Zhou Junli Chen Di Lu Kai Wang Meihua Sui zhengxin Wang Wenzhi Guo Guoyue Lyu Haizhi Qi Jinzhen Cai Jiayin Yang shusen zheng Xiao Xu Zhejiang University School of Medicine Hangzhou 310030China Institute of Organ Transplantation Zhejiang UniversityHangzhou 310030China Department of Hepatobiliary and Pancreatic Surgery Shulan Hospital of HangzhouHangzhou 310006China National Center for Healthcare Quality Management in Liver Transplant Hangzhou 310003China Department of General Surgery Huashan HospitalFudan UniversityShanghai 200040China Department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Hepatobiliary and Pancreatic Surgery The First Hospital of Jilin UniversityChangchun 130021China Department of Liver Transplantation Second Xiangya HospitalCentral South UniversityChangsha 410008China Department of Organ Transplantation Center The Affiliated Hospital of Qingdao UniversityQingdao 266003China Department of Liver Surgery and Liver Transplantation Center West China HospitalSichuan UniversityChengdu 610044China NHC Key Laboratory of Combined Multi-organ Transplantation Hangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Objective:Sex-specific differences are observed in various liver diseases,but the influence of sex on the outcomes of hepatocellular carcinoma(HCC)after liver transplantation(LT)remains to be *** study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with ***:Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were *** associations between donor,recipient,or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching(PSM).The survival associated with different sex-based donor-recipient transplant patterns was further ***:Among 3,769 patients enrolled in this study,the 1-,3-,and 5-year overall survival(OS)rates of patients with HCC after LT were 96.1%,86.4%,and 78.5%,respectively,in female recipients,and 95.8%,79.0%,and 70.7%,respectively,in male recipients after PSM(P=0.009).However,the OS was comparable between recipients with female donors and male *** analysis indicated that male recipient sex was a risk factor for post-LT survival(HR=1.381,P=0.046).Among the donor-recipient transplant patterns,the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival(P<0.05).Conclusions:Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients,and the male-male donor-recipient transplant pattern was associated with the poorest post-LT *** from male donors may provide the most benefit to female *** results indicate that sex should be considered as a critical factor in organ allocation.

关键词： Sex liver transplantation hepatocellular carcinoma outcome recipient donor

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SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation

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Cancer Communications 2024年第3期44卷 384-407页

作者： Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie shusen zheng Penghong Song Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China National Health Commission Key Laboratory of Combined Multi-organ Transplantation HangzhouZhejiangP.R.China Key Laboratory of the Diagnosis and Treatment of Organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical SciencesHangzhouZhejiangP.R.China Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiangP.R.China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China

Background:Liver cancer is a malignancy with high morbidity and mortality *** family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many *** this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer ***: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 *** 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 *** methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and *** 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 ***-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using ***:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA ***2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver ***2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and ***/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with ***,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,***,EGFR was activated in liver cancer cells after sorafenib treatment,and SER

关键词： liver cancer metastasis DNA methylation SERPINE2 EGFR c-Cbl ubiquitination

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Gut Microbiota Modulation:A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation

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Engineering 2023年第10期29卷 59-72页

作者： Ze Xiang Jian Wu Jiarui Li shusen zheng Xuyong Wei Xiao Xu Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s HospitalSchool of MedicineZhejiang UniversityHangzhou 310006China School of Medicine Zhejiang UniversityHangzhou 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Affiliated Hangzhou First People’s HospitalSchool of MedicineZhejiang UniversityHangzhou 310006China Department of Clinical Laboratory The Affiliated Suzhou Hospital of Nanjing Medical University&Suzhou Municipal HospitalGusu SchoolNanjing Medical UniversitySuzhou 215008China Shulan(Hangzhou)Hospital Zhejiang Shuren University School of MedicineHangzhou 310022China National Health Commission(NHC)Key Laboratory of Combined Multi-organ Transplantation the First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China

Hepatocellular carcinoma(HCC)is the most common malignancy of the liver,posing a significant threat to public *** liver transplantation(LT)is an effective treatment for HCC,ischemia–reperfusion(I/R)injury,transplant rejection,and complications after LT can greatly reduce its *** recent years,transplant oncology has come into being,a comprehensive discipline formed by the intersection and integration of surgery,oncology,immunology,and other related *** microbiota,an emerging field of research,also plays a crucial *** the microbiome–gut–liver axis,the gut microbiota has an impact on the onset and progression of HCC as well as *** review summarizes the mechanisms by which the gut microbiota affects HCC and its bidirectional interactions with chronic liver disease that can develop into HCC as well as the diagnostic and prognostic value of the gut microbiota in *** addition,gut microbiota alterations after LT were reviewed,and the relationship between the gut microbiota and liver I/R injury,the efficacy of immunosuppressive drugs used,and complications after LT were *** the era of LT oncology,the role of the gut microbiota in HCC and LT should be emphasized,which can provide new insights into the management of HCC and LT via gut microbiota modulation.

关键词： Gut microbiota Hepatocellular carcinoma(HCC) Liver transplantation(LT) Clinical value Mediating mechanism

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Recent Progress and Future Direction for the Application of Multiomics Data in Clinical Liver Transplantation

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Journal of Clinical and Translational Hepatology 2022年第2期10卷 363-373页

作者： zhengtao Liu Jun Xu Shuping Que Lei Geng Lin Zhou Adil Mardinoglu shusen zheng Shulan International Medical College Zhejiang Shuren UniversityHangzhouZhejiangChina Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiangChina NHC Key Laboratory of Combined Multi-organ Transplantation Key Laboratory of the diagnosis and treatment of organ TransplantationCAMSFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiangChina Key Laboratory of Organ Transplantation Zhejiang ProvinceFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiangChina DingXiang Clinics HangzhouZhejiangChina Science for Life Laboratory KTH-Royal Institute of TechnologyStockholmSweden Centre for Host-Microbiome Interactions Faculty of DentistryOral&Craniofacial SciencesKing’s College LondonLondonUK

Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver *** purpose of this study was to review the current application and future direction for omics in *** reviewed the use of multiomics to elucidate the pathogenesis leading to LT and *** directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in *** molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft *** emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be *** also outlined the ideal workflow for omics in *** step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower *** should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.

关键词： Multiomic analysis Transcriptomics Proteomics Metabolomics Liver transplantation EAD

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Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors

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Journal of Clinical and Translational Hepatology 2023年第1期11卷 219-230页

作者： Yimou Lin Haitao Huang Lifeng Chen Ruihan Chen Jimin Liu shusen zheng Qi Ling Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Clinical Engineering and Information Technology the First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Pathology and Molecular Medicine Faculty of Health SciencesMcMaster UniversityHamiltonOntarioCanada Key Laboratory of Combined Multiorgan Transplantation Ministry of Public HealthHangzhouZhejiangChina

Liver transplantation(LT)is the final treatment option for patients with end-stage liver *** increasing donor shortage results in the wide usage of grafts from extended criteria donors across the *** such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases,which significantly reduce recipient *** several clinical factors have been demonstrated to impact donor liver quality,accurate,comprehensive,and effective assessment systems to guide decision-making for organ usage,restoration or discard are *** addition,the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft ***,such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality *** on donors and grafts,we updated potential biomarkers in donor blood,liver tissue,or perfusates that predict graft quality following LT,and summarized strategies for restoring graft function in the era of extended criteria *** this review,we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

关键词： Liver transplantation Extended criteria donors Graft quality Assessment Biomarkers Restoration

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MiR-516a-3p is a Novel Mediator of Hepatocellular Carcinoma Oncogenic Activity and Cellular Metabolism

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Engineering 2022年第9期16卷 162-175页

作者： Tao Rui Xueyou Zhang Shi Feng Haitao Huang Shaowei Zhan Haiyang Xie Lin Zhou shusen zheng Qi Ling Department of Surgery Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou 310003China Department of Surgery Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseasesthe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesZhejiang ProvinceHangzhou 310003China

Hepatocellular carcinoma(HCC)remains one of the most lethal *** previously demonstrated that the chromosome 19 microRNA cluster(C19MC)was associated with tumor burden and prognosis in patients with *** the current study,we aim to explore the role of miR-516a-3p-an identical mature microRNA(miRNA)co-spliced by four oncogenic pre-miRNAs of C19MC(i.e.,mir-516a-1,mir-516a-2,mir-516b-1,and mir-516b-2)-in *** our cohort of HCC patients,miR-516a-3p was highly expressed in HCC tissues in comparison with adjacent non-tumor *** expression of tumor miR-516a-3p significantly correlated with advanced tumor stages,distinguished high HCC recurrence and mortality,and independently predicted poor *** further found that miR-516a-3p enhanced the proliferation,migration,and invasiveness of HCC cells in vitro and promoted tumor growth and metastasis in *** cancer cells,miR-516a-3p could be delivered via exosomes or extracellular vesicles and increased the oncogenic activity of recipient ***,we performed comprehensive transcriptomics,proteomics,and metabolomics analysis on the potential mechanism underlying miR-516a-3p-promoted *** DIABLO analysis showed a close correlation and strong cluster consistency between the proteomics and metabolomics *** further confirmed six proteins(i.e.,LMBR1,CHST9,RBM3,SLC7A6,PTGFRN,and NOL12)as the direct targets of miR-516a-3p and as central players in miR-516a-3p-mediated metabolism *** integrated multi-omics and co-enriched pathway analysis showed that miR-516a-3p regulates the metabolic pathways of HCC cells,particularly purine and pyrimidine *** conclusion,our findings suggest that miR-516a-3p promotes malignant behaviors in HCC cells by regulating cellular metabolism and affecting neighboring cells via the exosome delivery ***,we suggest miR-516a-3p as a novel molecular target for HCC therapy.

关键词： Hepatocellular carcinoma MicroRNA cluster Exosome Multi-omics

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When immunotherapy meets liver transplantation for hepatocellular carcinoma: A bumpy but promising road

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Chinese Journal of Cancer Research 2023年第2期35卷 92-107页

作者： Yufeng Gu Shengjun Xu zhengxin Wang Jiayin Yang shusen zheng Qiang Wei Zhikun Liu Xiao Xu The Fourth School of Clinical Medicine Zhejiang Chinese Medical UniversityHangzhou 310053China Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou 310006China Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Hangzhou 310006China Department of General Surgery Huashan HospitalFudan UniversityShanghai 200040China Department of Liver Surgery Liver Transplantation CenterWest China Hospital of Sichuan UniversityChengdu 610044China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou 311112China Westlake Laboratory of Life Sciences and Biomedicine Hangzhou 310024China

Liver transplantation(LT)is a highly curative therapy for patients with hepatocellular carcinoma(HCC).However,due to the shortage of donor livers and rapid progression of HCC,a majority of patients are dropped out from the ***,immunotherapy has shown great promise in the treatment of advanced ***,the use of immunotherapy is limited in LT mainly due to the potentially increasing risk of graft *** of the main challenges for researchers is the protection of donor graft from an immunotherapy-boosted immune response mounted by the ***,the safety,availability,and costs of immunotherapy are other challenges that need to be ***,we reviewed the literature involving patients who received immunotherapy prior to transplant to avoid waitlist dropouts and following transplantation to prevent the progression of tumor recurrence and ***,the incidence of rejection was 25.0%pre-transplant and 18.5%*** on the review of these clinical studies,we can conclude that conducting clinical trials on the safety and efficacy of currently available immunotherapy drugs and identifying novel immunotherapy targets through extensive research may be promising for patients who do not meet the selection criteria for LT and who experience post-transplant *** date,the clinical experience on the use of immunotherapy before or after LT comes from individual case *** some of the reported results are promising,they are not sufficient to support the standardized use of immunotherapy in clinical practice.

关键词： Liver transplantation hepatocellular carcinoma immunotherapy immune checkpoint inhibitors adoptive cell therapy

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