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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 {2. 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 2.15 and December 2.2. 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(Porgan allocation.

关键词： Sex liver transplantation hepatocellular carcinoma outcome recipient donor

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Differentiation and immunosuppressive function of CD19^(+)CD2.^(hi)CD2.^(+) regulatory B cells are regulated through the miR-2.a-3p/NFAT5 pathway

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Hepatobiliary & Pancreatic Diseases International 2024年第5期23卷 472-480页

作者： Jin-Yang Li Tian-Shuo Feng Ji Gao Xin-Xiang Yang Xiang-Cheng Li Zhen-Hua Deng Yong-Xiang Xia Zheng-Shan Wu Hepatobiliary Center the First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China key laboratory of Liver {2. Chinese Academy of Medical SciencesNanjing 210029China NHC key laboratory of Living Donor Liver {2. Nanjing Medical UniversityNanjing 210029China

Background: Regulatory B cells(Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs(miRNAs), mi R-2.a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and mi R-2.a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-2.a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs(m Bregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. Methods: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce mi R-2.a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-2.a-3p. Results: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of m Bregs in the circulating blood were significantly impaired. mi R-2.a-3p was found to be a regulator of m Bregs differentiation. Inhibition of miR-2.a-3p, which targeted nuclear factor of activated T cells 5(NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of m Bregs. The inhibition of mi R-2.a-3p in CD19~+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into m Bregs. In addition, the observed enhancement of differentiation and immunosuppressive function of m Bregs upon mi R-2.a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. Conclusions: mi R-2.a-3p was found to be a crucial regulator for m Bregs differentiation and immunosuppressive function. Silencing mi R-2.a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

关键词： Regulatory B cells miR-2.a-3p NFAT5 Liver transplantation

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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 {2. 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.,2.18;He et al.,2.2.).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,2.19).Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival(Voron et al.,2.15;van Vugt et al.,2.16).

关键词： cancer patients

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Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function:implication of miRNAs and microvesicles

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Military Medical Research 2024年第1期11卷 1-18页

作者： Zi-Sen Zhang Yi-Yan Liu Shuang-Shuang He Dai-Qin Bao Hong-Chen Wang Jie Zhang Xiao-Yong Peng Jia-Tao Zang Yu Zhu Yue Wu Qing-Hui Li Tao Li Liang-Ming Liu State key laboratory of Trauma Burns and Combined InjuryDepartment of Shock and TransfusionResearch Institute of SurgeryDaping HospitalArmy Medical UniversityChongqing 400042China

Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-{2. damage upon *** hypothesized that pericytes,a group of pluripotent cells that maintain vascular integrity and tension,are protective against sepsis via regulating vascular reactivity and *** We conducted a series of in vivo experiments using wild-type(WT),platelet-derived growth factor receptor-β(PDGFR-β)-Cre+mT/mG transgenic mice and Tie2.Cre+Cx43^(flox/flox)mice to examine the relative contribution of pericytes in sepsis,either induced by cecal ligation and puncture(CLP)or lipopolysaccharide(LPS)*** a separate set of experiments with Sprague-Dawley(SD)rats,pericytes were depleted using CP-673451,a selective PDGFR-βinhibitor,at a dosage of 40 mg/(kg·d)for 7 consecutive *** pericytes,vascular endothelial cells(VECs)and vascular smooth muscle cells(VSMCs)were used for mechanistic *** effects of pericytes and pericyte-derived microvesicles(PCMVs)and candidate miRNAs on vascular reactivity and barrier function were also *** CLP and LPS induced severe injury/loss of pericytes,vascular hyporeactivity and leakage(Ptransplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization(P2.to VSMCs and VECs,respectively,exerting a protective effect on vascular reactivity and barrier function after sepsis(P2.Sphk2./sphingosine-1-phosphate receptor(S1PR)1/phosphorylation of myosin light chain 2. pathway,whereas miR-132.effectively improved the barrier function of VECs by activating the Sphk2.S1PR2.zonula occludens-1 and vascular endothelial-cadherin *** Pericytes are protective a

关键词： Pericyte Vascular reactivity Vascular permeability Cx43 Microvesicle

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B cell development and antibody responses in human immune system mice:current status and future perspective

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Science China(Life Sciences) 2024年第4期67卷 645-652页

作者： Tao Zhang Wentao Liu Yong-Guang Yang key laboratory of {2. Regeneration&transplantation of the Ministry of Education The First Hospital of Jilin UniversityChangchun 130061China National-Local Joint Engineering laboratory of Animal Models for Human Diseases Jilin UniversityChangchun 130061China International Center of Future Science Jilin UniversityChangchun 130061China

Humanized immune system(HIS)mice have been developed and used as a small surrogate model to study human immune function under normal or disease *** variations are found between models,most HIS mice show robust human T cell ***,there has been unsuccessful in constructing HIS mice that produce high-affinity human antibodies,primarily due to defects in terminal B cell differentiation,antibody affinity maturation,and development of primary follicles and germinal *** this review,we elaborate on the current knowledge about and previous attempts to improve human B cell development in HIS mice,and propose a potential strategy for constructing HIS mice with improved humoral immunity by transplantation of human follicular dendritic cells(FDCs)to facilitate the development of secondary follicles.

关键词： humanized immune system mouse humoral immunity germinal center B cell follicular dendritic cell

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Skeletal stem cells in bone development,homeostasis,and disease

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Protein & Cell 2024年第8期15卷 559-574页

作者： Guixin Yuan Xixi Lin Ying Liu Matthew B.Greenblatt Ren Xu The First Affliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell State Key Laboratory of Cellular Stress BiologySchool of MedicineFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361005China Xiamen key laboratory of Regeneration Medicine Fujian Provincial Key Laboratory of Organ and Tissue RegenerationOrgan Transplantation InstituteSchool of MedicineXiamen UniversityXiamen 361102China Department of Pathology and laboratory Medicine Weill Cormell Medical CollegeNew YorkNY 10065USA Research Division Hospital for Special SurgeryNew YorkNY10065USA

Tissue-resident stem cells are essential for development and repair,and in the skeleton,this function is fulfilled by recently identified skeletal stem cells(SSCs).However,recent work has identified that SSCs are not monolithic,with long bones,craniofacial sites,and the spine being formed by distinct stem *** studies have utilized techniques such as fluorescence-activated cell sorting,lineage tracing,and single-cell sequencing to investigate the involvement of ssCs in bone development,homeostasis,and *** investigations have allowed researchers to map the lineage commitment trajectory of ssCs in different parts of the body and at different time ***,recent studies have shed light on the characteristics of ssCs in both physiological and pathological *** review focuses on discussing the spatiotemporal distribution of ssCs and enhancing our understanding of the diversity and plasticity of ssCs by summarizing recent discoveries.

关键词： skeletal stem cells bone development endochondral ossification intramembranous ossification lineage tracing

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Elimination of GGTA1,CMAH,β4GalNT2.and CIITA genes in pigs compromises human versus pig xenogeneic immune reactions

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Animal Models and Experimental Medicine 2024年第4期7卷 584-590页

作者： Jing Xu Jilong Ren Kai Xu Minghui Fang Meina Ka Fei Xu Xin Wang Jing Wang Zhiqiang Han Guihai Feng Ying Zhang Tang Hai Wei Li Zheng Hu State key laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijingChina key laboratory of {2. Regeneration and Reconstruction Chinese Academy of SciencesBeijingChina University of Chinese Academy of Sciences BeijingChina Beijing Institute for Stem Cell and Regenerative Medicine BeijingChina key laboratory of {2. Regeneration and transplantation of the Ministry of Education The First HospitalJilin UniversityChangchunChina Beijing Farm Animal Research Center Institute of ZoologyChinese Academy of SciencesBeijingChina

Background:Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic,while immunogenic genes need to be eliminated to improve the immune compatibility between humans and *** knockout strategies are mainly aimed at the genes causing hyperacute immune rejection(HAR)that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure,in which process the MHCⅡmolecule plays critical ***:Thus,we generate a 4-gene(GGTA1,CMAH,β4GalNT2.and CIITA)knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions ***:We successfully obtained 4KO piglets with deficiency in all alleles of genes,and at cellular and tissue ***,the safety of our animals after gene editing was verified by using whole-genome sequencing and *** have survived for more than one year in the barrier,and also survived for more than 3 months in the conventional environment,suggesting that the piglets without MHCⅡcan be raised in the barrier and then gradually mated in the conventional ***:4KO piglets have lower immunogenicity,are safe in genomic level,and are easier to breed than the model with both MHCⅠandⅡdeletion.

关键词： CD4 T cell genetically edited pig immune rejection major histocompatibility complex II xenotransplantation

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Hydrogel-Assisted Electrokinetics for High-Resolution and Non-invasive Flow Monitoring in Microfluidic Chips

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Chinese Journal of Chemistry 2024年第6期42卷 571-577页

作者： Na Zhao Yanni Ma Zehua Yu Jun Huang Xiangqian Fu Tao Qiu Kang Liu MOE key laboratory of Hydraulic Machinery Transients School of Power and Mechanical EngineeringWuhan UniversityWuhanHubei430072 China Department of Urology Renmin Hospital of Wuhan UniversityWuhanHubei430072 China Department of organ transplantation Renmin Hospital of Wuhan UniversityWuhanHubei430072 China

Convenient non-invasive flow monitoring would facilitate the operation and control in microfluidic chips,but is challenging due to the small space of microchannels and complex operation required in traditional optical *** this work,we propose a novel non-invasive strategy to probe microfluidic flows via streaming potential *** sealing one side of the microchannel with a piece of hydrogel film,streaming potential inside the channel can be clearly detected by electrodes at outer surface of the hydrogel due to ion diffusion in the *** is detected without sensors contacting with the internal ***,the electrodes shape like a tiny probe,which can move around mapping the flow distribution in a chip with the spatial resolution of 1 mm and flow rate detection limit of 3μL·min–*** inside the channels can also be detected,due to the fluctuation of streaming voltage when gas-liquid interface flows through the electrode,showing an easy and potential way for multi-functional flow monitoring in microfluidic chips.

关键词： Microfluidics Hydrogels Electrokinetics Flow monitoring Non-invasive Sensor Charge transport

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Diagnosis and therapy of tacrolimus toxicity in a liver transplant recipient during COVID-19 treatment

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 326-330页

作者： Feng Zhu Yi-Ming Wang Ming Ni Yuan Liang Jie-Hui Huang Xue-Hao Wang Feng Cheng Ling Lu Hepatobiliary Center The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Liver TransplantationResearch Unit of Liver Transplantation and Transplant ImmunologyChinese Academy of Medical SciencesNanjing 210000China Department of Respiratory and Critical Care Medicine Wuxi Fifth People’s HospitalWuxi 214000China Jiangsu key laboratory of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing 210000China

To the Editor:SARS-CoV-2.the pathogen responsible for the pandemic of coronavirus disease 2.19(COVID-19),has had profound impacts on human health,and its antagonist Paxlovid is a commonly used treatment option[1].However,treatment selection for immunosuppressed patients,such as liver recipients,remains uncertain due to potential drug interactions and the risk of immunosuppressant dosage adjustment,which can cause liver injury[2..

关键词： dosage treatment antagonist

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A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

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Acta Pharmaceutica Sinica B 2024年第1期14卷 223-240页

作者： Lei Sun Arabella H.Wan Shijia Yan Ruonian Liu Jiarui Li Zhuolong Zhou Ruirui Wu Dongshi Chen Xianzhang Bu Jingxing Ou Kai Li Xiongbin Lu Guohui Wan Zunfu Ke Department of Pathology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-Local Joint Engineering laboratory of Druggability and New Drug Evaluation National Engineering Research Center for New Drug and Druggability(Cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Department of Hepatic Surgery and Liver transplantation Center Third Affiliated HospitalOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhou 510630China Guangdong Provincial key laboratory of Liver Disease Research Guangzhou 510630China Department of Ultrasound Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Melvin and Bren Simon Comprehensive Cancer Center Indiana UniversityIndianapolisIN 46202USA

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug ***,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),{2.oids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant *** and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing *** screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO ***,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX ***,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

关键词： Lenvatinib Drug resistance High-throughput screening Drug discovery Patient-derived model Romidepsin EGFR Liver cancer

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