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Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia:a multicenter,randomized,open-label,phase 3 trial

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2669-2678页

作者： Biqi Zhou Jia Chen Tianhui Liu Yishan Ye Yanming Zhang Yiyang Ding Hong Liu MingQing Zhu Xiao Ma Xiaoli Li Longfei Zhao Zhihong Lin He Huang Yang Xu Depei Wu National Clinical Research center for Hematologic Diseases Jiangsu Institute of HematologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina institute of Blood and marrow transplantation Collaborative Innovation Center of HematologySoochow UniversitySuzhouChina bone marrow transplantation center The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Hematology The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’anHuai’anChina Soochow Hopes Hematology hospital SuzhouChina Department of Hematology Hygeia Suzhou Yongding HospitalSuzhouChina

Coinfusion of unrelated cord blood(UCB)units in haploidentical hematopoietic cell transplantation(haplo-HCT)(haplo-cord HCT)for hematopoietic malignancies showed promising results in previous reports,but the efficiency of haplo-cord HCT in acute myeloid leukemia(AML)still lacks sufficient *** multicenter,randomized,phase 3 trial(*** NCT03719534)aimed to assess the efficacy and safety of haplo-cord HCT in AML patients.A total of 268 eligible patients aged 18-60 years,diagnosed with measurable residual disease in AML(excluding acute promyelocytic leukemia),with available haploidentical donors and suitable for allotransplantation,were randomly allocated(1:1)to receive haplo-cord HCT(n=134)or haplo-HCT(n=134).The 3-year overall survival(OS)was the primary endpoint in this *** median follow-up was 36.50 months(IQR 24.75-46.50).The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group(80.5%,95%confidence interval[CI]:73.7-87.9 vs.67.8%95%CI 60.0-76.5,p=0.013).Favorable progression-free survival(70.3%,95%CI 62.6-78.8 vs.57.6%,95%CI 49.6-67.0,p=0.012)and cumulative incidence of relapse(12.1%,95%CI 12.0-12.2 vs.30.3%,95%CI 30.1-30.4,p=0.024)were observed in haplo-cord HCT *** 3-4 adverse events(AEs)within two years posttransplantation in the two groups were ***-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery(p=0.026)and increased T-cell reconstitution in the early period ***-cord HCT can improve OS in AML patients without excessive AEs,which may exert additional benefits for recipients of haplo-HCT.

关键词： hematopoietic acute phase

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Waldenström macroglobulinemia:a challenging case treated with anti-CD19 CAR-T cell therapy

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第8期25卷 719-722页

作者： Yang YANG Xiaolin GU Jingsong HE Yongxian HU Zhen CAI bone marrow transplantation center Department of Hematologythe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310006China Department of Hematology Putuo People’s HospitalZhoushan 316100China

Waldenström macroglobulinemia(WM)is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M(IgM)protein(Owen et al.,2003).Common signs and symptoms include fatigue due to anemia,lymph node enlargement,hepatosplenomegaly,thrombocytopenia,symptoms related to high viscosity,and peripheral neuropathy,among *** significant advances in WM treatment,this type of indolent lymphoma remains incurable,with a wide array of patient outcomes(Ruan et al.,2020).In recent years,chimeric antigen receptor T(CAR-T)cell therapy targeting cluster of differentiation 19(CD19)has shown unprecedented response rates and durability in the treatment of B-cell *** this report,we describe a challenging case of WM that involved multiple extramedullary sites,relapsed,and was refractory to chemotherapy,immunotherapy,and targeted *** anti-CD19 CAR-T cell therapy,the tumor burden significantly decreased and the patient’s condition remained stable at the writing of this report.

关键词： CD19 globulin durability

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Insights from TARGET-seq:Inflammation drives TP53-mediated clonal evolution

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The Innovation 2024年第2期5卷 7-8页

作者： Yeqian Zhao Wenxuan Huo Yue Liang Xiaodong Mo Shanshan Pei Yanmin Zhao bone marrow transplantation center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Liangzhu Laboratory Zhejiang University Medical CenterHangzhou 311121China institute of Hematology Zhejiang UniversityHangzhou 311121China Peking University People’s hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing 100044China

Approximately 10%–20%myeloproliferative neoplasms(MPNs)can progress into blast-phase MPNs,also termed secondary acute myeloid leukemias(sAMLs),presenting dismal *** exhibits a distinctive clinical and pathological profile compared to de novo AML,marked by a higher incidence of erythroid leukemias and reduced responsive to conventional chemotherapies,resulting in a median survival of approximately 6 ***53 alterations are prevalent adverse events in leukemic transformation(LT),occurring in around one-third of sAML subjects.

关键词： TP53 neoplasms alterations

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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 ***,COVID-19 vaccination has been recommended to be administered as early as possible in *** sources:The keywords“liver transplant”,“SARS-CoV-2”,and“vaccine”were used to retrieve articles published in ***: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 *** the 3rd or 4th dose of COVID-19 vaccine increased the antibody titer,a proportion of patients remained ***,recent studies showed that SARS-CoV-2 vaccine could trigger adverse events in LTRs,including allograft rejection and liver ***: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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Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor

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National Science Review 2024年第4期11卷 206-215页

作者： Ziyan Liao Jie Jiang Wei Wu Jiaqi Shi Yanfang Wang Yuejun Yao Tao Sheng Feng Liu Wei Liu Peng Zhao Feifei Lv Jie Sun Hongjun Li Zhen Gu National Key Laboratory of Advanced Drug Delivery and Release Systems College of Pharmaceutical Sciences Zhejiang University Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province College of Pharmaceutical SciencesZhejiang University Liangzhu Laboratory Zhejiang University bone marrow transplantation center of the first affiliated hospital and Department of Cell Biology Zhejiang University School of Medicine Department of Medical Oncology The First Affiliated Hospital School of Medicine Zhejiang University Department of Laboratory Medicine The First Affiliated Hospital Zhejiang University School of Medicine Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated HospitalSchool of MedicineZhejiang University Jinhua institute of Zhejiang University MOE Key Laboratory of Macromolecular Synthesis and Functionalization of Ministry of Education Department of Polymer Science and EngineeringZhejiang University Department of General Surgery Sir Run Run Shaw Hospital School of Medicine Zhejiang University

The limited infiltration and persistence of chimeric antigen receptor(CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading,delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

关键词： drug delivery cell therapy bioinspired biomaterials cancer immunotherapy

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Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires

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Cancer Innovation 2024年第3期3卷 1-21页

作者： Yulin Xu Wei Shan Qian Luo Meng Zhang Dawei Huo Yijin Chen Honghu Li Yishan Ye Xiaohong Yu Yi Luo He Huang bone marrow transplantation center The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Liangzhu Laboratory Zhejiang UniversityHangzhouChina institute of Hematology Zhejiang UniversityHangzhouChina Zhejiang Province Engineering Research center for Stem Cell and Immunity Therapy HangzhouChina School of Medicine Zhejiang UniversityHangzhouChina

Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast ***,approaches to obtain cancer-reactive TCR-T cells have been ***:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune *** steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized *** human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and *** fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 ***,human T cells were processed for TCRβ-chain(TRB)sequencing *** the repertoires had been constructed,features such as the fraction,diversity,and immune signature were ***:The results demonstrated an increase in diversity and clonality of T cells after *** preferential usage and features of TRBV,TRBJ,and the V–J combination were also *** stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 *** burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized ***:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T *** platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.

关键词： cancer-targeted T-cell receptor T(TCR-T)cells circulating hematopoietic stem and progenitor cells(HSPCs) humanized mouse model steady-state peripheral blood T-cell receptorβ-chain(TRB) three-dimensional culture

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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67卷 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 UniversityZhengzhou 450052China Henan Diagnosis&Treatment League for Hepatopathy The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Henan Innovative Research Group for Hepatobiliary&Pancreatic Surgery and Digestive Organ transplantation Zhengzhou 450052China Henan Organ transplantation Quality Control Centre Zhengzhou 450052China Henan Engineering Technology Research center for Organ transplantation Zhengzhou 450052China Department of Pharmacy The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of General Surgery Huashan HospitalFudan University Shanghai 200040China Cancer Metastasis institute Fudan UniversityShanghai 200040China

Betaine-homocysteine methyltransferase(BHMT)regulates protein methylation and is correlated with tumorigenesis;however,the effects and regulation of BHMT in hepatocarcinogenesis remain largely ***,we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma(HCC)using tissue samples from 198 *** 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 *** overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo,whereas complete knockout of Bhmt(Bhmt^(−/−))produced the opposite *** 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 *** contrast,restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated ***,coimmunoprecipitation identified monomethylated modifications of the G6PD,and BHMT regulated the methylation of *** sequence analysis,generation and application of specific antibodies,and site-directed mutagenesis indicated G6PD methylation at the arginine residue ***,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 *** together,this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency,suggesting a potential therapeutic strategy for HCC treatment.

关键词： HCC BHMT arginine methylation G6PD PPP metabolism

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Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

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World Journal of Gastroenterology 2024年第1期30卷 34-49页

作者： Yu-Wei Zhou Yue Ren Miao-Miao Lu Ling-Ling Xu Wei-Xin Cheng Meng-Meng Zhang Lin-Ping Ding Dong Chen Jian-Guo Gao Juan Du Ci-Liang Jin Chun-Xiao Chen Yun-Fei Li Tao Cheng Peng-Lei Jiang Yi-Da Yang Peng-Xu Qian Peng-Fei Xu Xi Jin Department of Gastroenterology The First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Gastroenterology The Second Hospital of JiaxingJiaxing 314000Zhejiang ProvinceChina Endoscopy center Children’s Hospital of Zhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Gastroenterology The Second People’s Hospital of Yuhang DistrictHangzhou 310000Zhejiang ProvinceChina Department of Gastroenterology Hangzhou Shangcheng District People’s HospitalHangzhou 310003Zhejiang ProvinceChina Department of Colorectal Surgery The First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Gastroenterology The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina Women’s hospital and institute of Genetics Zhejiang University School of MedicineHangzhou 310000Zhejiang ProvinceChina center of Stem Cell and Regenerative Medicine and Bone Marrow Transplantation CenterThe First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Infectious Disease The First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

Crohn’s disease(CD)is caused by immune,environmental,and genetic *** can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains *** biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known *** achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost *** this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary *** supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid *** benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic *** importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

关键词： Inflammatory bowel disease Crohn’s disease Lymphatic system Inside-out model Immune cells Zebrafish

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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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PRC2 primes bivalent genes for transcription induction independent of histone methyltransferase activity

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Science China(Life Sciences) 2024年第9期67卷 2033-2035页

作者： Meihan Gong Ye Yuan Zhongye Dai Xuejiao Lv Jiacheng Su Dawei Huo Lin Niu Xu Chen Xudong Wu State Key Laboratory of Experimental Hematology The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical EpigeneticsKey Laboratory of Immune Microenvironment and Disease(Ministry of Education)Department of Cell BiologySchool of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China bone marrow transplantation center the First Affiliated HospitalZhejiang University School of MedicineLiangzhu LaboratoryInstitute of HematologyZhejiang UniversityHangzhou 311113China

Dear Editor,Polycomb group proteins,conserved epigenetic transcriptional repressors,are crucial for orchestrating diverse developmental gene expression programs(Schuettengruber et al.,2017).The polycomb repressive complex 2(PRC2)catalyzes H3 lysine-27 trimethylation(H3K27me3)to establish a delicate balance with H3K4me3,forming a bivalent chromatin state at target gene promoters and thereby poising them for subsequent transcription activation(Bernstein et al.,2006).

关键词： valent thereby subsequent

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