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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 determined.This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC.Methods:Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed.The 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 studied.Results: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 donors.Multivariate 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(Porgan 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 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 sig

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

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Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges

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hepatobiliary & Pancreatic Diseases International 2024年第2期23卷 117-122页

作者： Xin Yang Lu Lu Wen-Wei Zhu Yi-Feng Tao Cong-Huan Shen Jin-Hong Chen Zheng-Xin Wang Lun-Xiu Qin hepatobiliary Surgery and Liver transplantation Centers Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan UniversityShanghai 200040China

Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic veins.Ex vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation.Due to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation.The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar echinococcosis.Recently,the application of ELRA for liver malignances has gained more attention.However,standardization of clinical practice norms and international consensus are still lacking.The prognostic impact in these oncologic patients also needs further evaluation.In this review,we summarized the principles and recent progresses on ELRA.

关键词： Ex vivo liver resection Liver auto-transplantation Oncology Liver malignancies

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Artificial kidney: Challenges and opportunities

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World Journal of transplantation 2024年第1期14卷 42-47页

作者： Filippos F Karageorgos Stavros Neiros Konstantina-Eleni Karakasi Stella Vasileiadou Georgios Katsanos Nikolaos Antoniadis Georgios Tsoulfas department of transplantation Surgery Center for Research and Innovation in Solid Organ TransplantationAristotle University School of MedicineThessaloniki 54642Greece

This review aims to present the developments occurring in the field of artificial organs and particularly focuses on the presentation of developments in artificial kidneys.The challenges for biomedical engineering involved in overcoming the potential difficulties are showcased,as well as the importance of interdisciplinary collaboration in this marriage of medicine and technology.In this review,modern artificial kidneys and the research efforts trying to provide and promise artificial kidneys are presented.But what are the problems faced by each technology and to what extent is the effort enough to date?

关键词： Artificial kidney Implantable kidney Hemodialysis Peritoneal dialysis Endstage kidney disease

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Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma:A comprehensive review

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World Journal of Hepatology 2024年第4期16卷 537-549页

作者： Jing-Jing Li Jia-Xi Mao Han-Xiang Zhong Yuan-Yu Zhao Fei Teng Xin-Yi Lu Li-Ye Zhu Yang Gao Hong Fu Wen-Yuan Guo department of Liver Surgery and organ transplantation Shanghai Changzheng HospitalNaval Medical UniversityShanghai 200003China

The tumor microenvironment is a complex network of cells,extracellular matrix,and signaling molecules that plays a critical role in tumor progression and metastasis.Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits.However,recent studies have shown that lymphatic endothelial cells(LECs)and blood endothelial cells(BECs)also play multifaceted roles in the tumor microenvironment beyond their structural functions,particularly in hepatocellular carcinoma(HCC).This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC,including their involvement in angiogenesis,immune modulation,lymphangiogenesis,and metastasis.By providing a detailed account of the complex interplay between LECs,BECs,and tumor cells,this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

关键词： Lymphatic endothelial cells Blood endothelial cells Hepatocellular carcinoma Tumor microenvironment

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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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Pleural empyema with endobronchial mass due to Rhodococcus equi infection after renal transplantation: A case report and review of literature

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World Journal of Clinical Cases 2024年第1期12卷 224-231页

作者： Guo-Fu Liang Sheng Chao Zhou Sun Ke-Jing Zhu Qian Chen Lei Jia Yu-Lin Niu department of organ transplantation School of Clinical MedicineGuizhou Medical UniversityGuiyang 550025Guizhou ProvinceChina department of organ transplantation The Affiliated Hospital of Guizhou Medical UniversityGuiyang 550000Guizhou ProvinceChina

BACKGROUND Kidney transplantation is the best option for patients with end-stage renal disease.However,the need for lifelong immunosuppression results in renal transplant recipients being susceptible to various infections.Rhodococcus equi(R.equi)is a rare opportunistic pathogen in humans,and there are limited reports of infection with R.equi in post-renal transplant recipients and no uniform standard of treat-ment.This article reports on the diagnosis and treatment of a renal transplant recipient infected with R.equi 21 mo postoperatively and summarizes the charac-teristics of infection with R.equi after renal transplantation,along with a detailed review of the literature.Here,we present the case of a 25-year-old man who was infected with R.equi 21 mo after renal transplantation.Although the clinical features at the time of presentation were not specific,chest computed tomography(CT)showed a large volume of pus in the right thoracic cavity and right middle lung atelectasis,and fiberoptic bronchoscopy showed an endobronchial mass in the right middle and lower lobe orifices.Bacterial culture and metagenomic next-generation sequen-cing sequencing of the pus were suggestive of R.equi infection.The immunosup-pressive drugs were immediately suspended and intravenous vancomycin and azithromycin were administered,along with adequate drainage of the abscess.The endobronchial mass was then resected.After the patient’s clinical symptoms and chest CT presentation resolved,he was switched to intravenous ciprofloxacin and azithromycin,followed by oral ciprofloxacin and azithromycin.The patient was re-hospitalized 2 wk after discharge for recurrence of R.equi infection.He recovered after another round of adequate abscess drainage and intravenous ciprofloxacin and azithromycin.CONCLUSION Infection with R.equi in renal transplant recipients is rare and complex,and the clinical presentation lacks specificity.Elaborate antibiotic therapy is required,and adequate abscess drainage and surgical excision are necessary.Given the recurre

关键词： Kidney transplantation Rhodococcus equi Pleural empyema Pulmonary atelectasis Immunosuppression Case report

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Clinical application of COVID-19 vaccine in liver transplant recipients

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hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 339-343页

作者： Feng-Chao Liu Man Xie Wei Rao Division of Hepatology Liver Disease CenterThe Affiliated Hospital of Qingdao UniversityQingdao 266000China organ transplantation Center The Affiliated Hospital of Qingdao UniversityQingdao 266000China Institute of organ Donation and transplantation of Qingdao University Qingdao 266000China department of Gastroenterology The Affiliated Hospital of Qingdao UniversityQingdao 266000China

Background:Solid organ transplant(SOT)activities,such as liver transplant,have been greatly influenced by the pandemic of coronavirus disease 2019(COVID-19),a disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Immunosuppressed individuals of liver transplant recipients(LTRs)tend to have a high risk of COVID-19 infection and related complications.Therefore,COVID-19 vaccination has been recommended to be administered as early as possible in LTRs.Data sources:The keywords“liver transplant”,“SARS-CoV-2”,and“vaccine”were used to retrieve articles published in PubMed.Results:The antibody response following the 1st and 2nd doses of vaccination was disappointingly low,and the immune responses among LTRs remarkably improved after the 3rd or 4th dose of vaccination.Although the 3rd or 4th dose of COVID-19 vaccine increased the antibody titer,a proportion of patients remained unresponsive.Furthermore,recent studies showed that SARS-CoV-2 vaccine could trigger adverse events in LTRs,including allograft rejection and liver injury.Conclusions:This review provides the recently reported data on the antibody response of LTRs following various doses of vaccine,risk factors for poor serological response and adverse events after vaccination.

关键词： Liver transplant COVID-19 SARS-CoV-2 Vaccine Antibody response

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Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase(G6PD) by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis

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Science China Life Sciences 2024年第8期 1648-1665页

作者： Jie Gao Xiaoyi Shi Yaohui Sun Xudong Liu Feng Zhang Chengcheng Shi Xiao Yu Zhiping Yan Long Liu Shizhe Yu Jiacheng Zhang Xiaodan Zhang Shuijun Zhang Wenzhi Guo department of hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou University Henan Diagnosis & Treatment League for Hepatopathy The First Affiliated Hospital of Zhengzhou University Henan Innovative Research Group for hepatobiliary & Pancreatic Surgery and Digestive organ transplantation Henan organ transplantation Quality Control Centre Henan Engineering Technology Research Center for organ transplantation department of Pharmacy The First Affiliated Hospital of Zhengzhou University department of General Surgery Huashan HospitalFudan University Cancer Metastasis Institute Fudan University

Betaine-homocysteine methyltransferase（BHMT） regulates protein methylation and is correlated with tumorigenesis;however,the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored.Here,we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma（HCC） using tissue samples from 198 patients.BHMT was to be frequently found（86.6%） expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC.Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo,whereas complete knockout of Bhmt(Bhmt-/-) produced the opposite effect.We combined proteomics,metabolomics,and molecular biological strategies and detected that Bhmt-/-promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase（G6PD）and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models.In contrast,restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis.Additionally,coimmunoprecipitation identified monomethylated modifications of the G6PD,and BHMT regulated the methylation of G6PD.Protein sequence analysis,generation and application of specific antibodies,and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246.Furthermore,we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD,thereby inhibiting G6PD activity,which in turn suppressed hepatocarcinogenesis.Taken together,this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency,suggesting a potential therapeutic strategy for HCC treatment.

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Dynamic immune recovery process after liver transplantation revealed by single-cell multi-omics analysis

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The Innovation 2024年第3期5卷 55-68页

作者： Rui Wang Xiao Peng Yixin Yuan Baojie Shi Yuan Liu Hengxiao Ni Wenzhi Guo Qiwei Yang Pingguo Liu Jie Wang Zhaojie Su Shengnan Yu Dehua Liu Jinyan Zhang Junjie Xia Xueni Liu Hao Li Zhengfeng Yang Zhihai Peng organ transplantation Clinical Medical Center of Xiamen University Department of General SurgeryXiang’an Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen 361102China organ transplantation Institute of Xiamen University Xiamen Human Organ Transplantation Quality Control CenterXiamen Key Laboratory of Regeneration MedicineFujian Provincial Key Laboratory of Organ and Tissue RegenerationSchool of MedicineXiamen UniversityXiamen 361102China department of General Surgery Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China department of hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000China department of hepatobiliary&Pancreatic Surgery The National Key Clinical SpecialtyZhongshan Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen 361102China Precision Research Center for Refractory Diseases Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 201620China

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.

关键词： process analysis precise

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