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Outcomes of haploidentical bone marrow transplantation in patients with severe aplastic anemia-II that progressed from non-severe acquired aplastic anemia

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Frontiers of Medicine 2021年第5期15卷 718-727页

作者： Hongchen Liu Xiaoli Zheng Chengtao Zhang Jiajun Xie Beibei Gao Jing Shao Yan Yang Hengxiang Wang Jinsong Yan Department of hematology Liaoning Medical Center for Hematopoietic Stem Cell TransplantationDalian Key Laboratory of HematologyLiaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational MedicineDiamond Bay Institute of Hematologythe Second Hospital of Dalian Medical UniversityDalian 116027China Department of hematology Air Force Medical CenterPLABeijing 100142China Department of Environmental Health and Toxicology Liaoning Medical Center for Hematopoietic Stem Cell TransplantationLiaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational MedicineSchool of Public HealthDalian Medical UniversityDalian 116044China

Severe aplastic anemia II(SAA-II)progresses from non-severe aplastic anemia(NSAA).The unavailability of efficacious treatment has prompted the need for haploidentical bone marrow transplantation(haplo-BMT)in patients lacking a human leukocyte antigen(HLA)-matched *** study aimed to investigate the efficacy of haplo-BMT for patients with ***-two patients were included and followed up,and FLU/BU/CY/ATG was used as conditioning *** these patients,21 were successfully engrafted,19 of whom survived after *** patients experienced grade II–IV aGvHD,including two with grade III–IV *** patients experienced chronic GvHD,among whom four were mild and two were *** patients experienced infections during *** was diagnosed with post-transplant lymphoproliferative disorder and one with probable EBV disease,and both recovered after rituximab ***-BMT achieved 3-year overall survival and disease-free survival rate of 86.4%±0.73%after a median follow-up of 42 months,indicating its effectiveness as a salvage *** promising outcomes may support haplo-BMT as an alternative treatment strategy for patients with SAA-II lacking HLA-matched donors.

关键词： severe aplastic anemia non-severe acquired aplastic anemia haploidentical bone marrow transplantation outcomes

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Combined prednisone and levothyroxine improve treatment of severe thrombocytopenia in hepatitis B with compensatory cirrhosis accompanied by subclinical and overt hypothyroidism

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Science China(Life Sciences) 2018年第8期61卷 924-933页

作者： Jing Xue Ru Feng Haixia Fu Qian Jiang Hao Jiang Jing Lu Hui Liu Jingwen Wang Ting Niu Xin Wang YANDi Xie Hao Wang Lanping Xu Kaiyan Liu Xiaojun Huang Xiaohui Zhang Peking University People's Hospital Peking University Institute of Hematology Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation Collaborative Innovation Center of Hematology Peking University Departments of hematology Beijing HospitalNational Center of Gerontology Department of hematology Beijing Tongren Hospital Department of hematology Sichuan University West China Medical Center Department of hematology Shandong Provincial Hospital Peking University People's Hospital Institute of Hepatic Diseases

The aim of the present study was to investigate the relationship between hypothyroidism and thrombocytopenia in hepatitis Brelated compensatory liver cirrhosis and to determine whether treatment with levothyroxine and prednisone is superior in a multicenter, open-label, observational study in China. In total, 125 consecutive hepatitis B-related compensated liver cirrhosis patients with severe thrombocytopenia accompanied by hypothyroidism were included. The patients were divided into four groups according to treatment strategy: a control group(n=29), a prednisone group(n=25), a levothyroxine group(n=32) and a prednisone plus levothyroxine group(n=39). Severe thrombocytopenia was more prevalent in hepatitis B-associated compensatory liver cirrhosis patients with hypothyroidism than in euthyroid patients(29.6% vs. 14.7%, Ptherapy, serum thyroid stimulating hormone and combination treatment with prednisone and levothyroxine were associated with bleeding events. Therefore, the present study suggests that hypothyroidism is associated with severe thrombocytopenia in hepatitis B-associated compensatory liver cirrhosis. Treatment with prednisone plus levothyroxine may present a novel approach in these patients.

关键词： hepatitis B cirrhosis thrombocytopenia hypothyroidism treatment

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Immunotherapy in hematologic malignancies:achievements,challenges and future prospects

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Signal Transduction and Targeted therapy 2023年第9期8卷 4043-4081页

作者： Lu Tang Zhongpei Huang Heng Mei Yu Hu Institute of hematology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology430022 WuhanChina Hubei Clinical Medical Center of cell therapy for Neoplastic Disease 430022 WuhanChina Key Laboratory of Biological Targeted therapy the Ministry of Education430022 WuhanChina Hubei Key Laboratory of Biological Targeted therapy Union HospitalTongji Medical CollegeHuazhong University of Science and Technology430022 WuhanChina

The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of *** categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers,including stem cell transplantation,immune checkpoint inhibitors,antigen-targeted antibodies,antibody-drug conjugates,tumor vaccines,and adoptive cell *** immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical *** immunotherapeutic approaches have their advantages but also shortcomings that need to be *** provide clinicians with timely information on these revolutionary therapeutic approaches,the comprehensive review provides historical perspectives on the applications and clinical considerations of the ***,we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic *** further discuss the specific mechanisms of action,summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies,as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.

关键词： clinical treatment shortcomings

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Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer

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Military Medical Research 2024年第5期11卷 717-746页

作者： Lu Tang Zhong-Pei Huang Heng Mei Yu Hu Institute of hematology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Hubei Clinical Medical Center of cell therapy for Neoplastic Disease Wuhan430022China Key Laboratory of Biological Targeted therapy The Ministry of EducationWuhan430022China Hubei Key Laboratory of Biological Targeted therapy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China

Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic ***,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical *** evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical *** information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and *** this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing *** further outline recent advances in the application of single-cell analyses in CAR-T ***,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.

关键词： Single-cell sequencing Cancer immunotherapy CAR-T therapy cell heterogeneity Trajectory inference Tumor microenvironment

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Loop CD20/CD19 CAR-T cells eradicate B-cell malignancies efficiently

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Science China(Life Sciences) 2023年第4期66卷 754-770页

作者： Zhaoqi Chen Yan Liu Nianci Chen Haiyan Xing Zheng Tian Kejing Tang Qing Rao Yingxi Xu Ying Wang Min Wang Jianxiang Wang State Key Laboratory of Experimental hematology Institute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China National Clinical Research Center for Blood Diseases Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Haihe Laboratory of cell Ecosystem Institute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Tianjin Key Laboratory of cell therapy for Blood Diseases Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China

CD19 chimeric antigen receptor(CAR)T cells have shown robust efficacy in relapsed and refractory acute lymphoblastic leukemia(R/R ALL),but compromising result in chronic lymphoblastic leukemia(CLL)and non-Hodgkin’s lymphoma(NHL).CD19-relapse and the lack of CAR-T cell persistence which result in treatment failure are considerable obstacles to ***-T targeting CD20 is an option for salvaging CD19 CAR-T *** studies have established variant structures of bispecific CAR-T which could avoid antigen-loss and immune ***,we constructed tandem and loop CAR structures targeting both CD19 and CD20 *** CAR-T cells could eliminate either CD19 or CD20 negative lymphoma cells,suggesting they exhibited dual antigen targeting of CD19 and *** comparing the efficiency of four bispecific CAR modified T cells,it was found that loop2019 CAR was the best structure among them to eradicate lymphoma cell lines and patients’primary lymphoma or CLL cells in a very low dose in vitro and prolong the survival time dramatically in lymphoma xenograft mice *** data highlighted the potential of loop2019 CAR-T in clinical treatment.

关键词： chimeric antigen receptor CD19 CD20 bispecific targeting CLL lymphoma

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Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma

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Signal Transduction and Targeted therapy 2021年第10期6卷 3045-3061页

作者： Jiajun Xie Zifeng Wang Wenjun Fan Youping Liu Fang Liu Xiangbo Wan Meiling Liu Xuan Wang Deshun Zeng Van Wang Bin He Min Yan Zijian Zhang Mengjuan Zhang Zhijie Hou Chunli Wang Zhijie Kang Wenfeng Fang Li Zhang Eric W-F Lam Xiang Guo Jinsong Yan Yixin Zeng Mingyuan Chen Quentin Liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangzhouChina Institute of Cancer Stem cell Cancer CenterDalian Medical UniversityDalianChina Department of hematology Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational MedicineLiaoning Medical Center for Hematopoietic Stem Cell TransplantationDalian Key Laboratory of HematologyDiamond Bay Institute of HematologyThe Affiliated Second Hospital of Dalian Medical UniversityDalianChina Department of Radiation Oncology The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Sun Yat-sen Institute of hematology The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been *** carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)***,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of ***,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone *** inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft *** fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

关键词： LMP1 cancer plasticity

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NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions

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Science China(Life Sciences) 2015年第12期58卷 1288-1298页

作者： WANG YaJie CHEN Chen DONG Fang MA ShiHui XU Jing GONG YueMin CHENG Hui ZHOU Yuan CHENG Tao HAO Sha State Key Laboratory of Experimental hematology Institute of Hematology& Blood Diseases Hospital Collaborative Innovation Center for Cancer Medicine Center for Stem cell Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Department of Stem cell and Regenerative Medicine Chinese Academy of Medical Sciences & Peking Union Medical College

Acute myeloid leukemia(AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3(MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen(i.e., CD47) and the down-regulation of active antigens(i.e., CD86, CD54, retinoic acid early transcript(RAE), histocompatibility 2, D region locus b(H2-Db) and H2-Dd). Natural killer(NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells.

关键词： acute myeloid leukemia natural killer cell immunosurveillance

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Inhibition of NF-κB by mutant IκBα enhances TNF-α-induced apoptosis in HL-60 cells by controlling bcl-x_L expression

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Chinese Medical Journal 2004年第7期117卷 972-977页

作者：曹文静张瑶珍张东华李登举唐锦治 Department of hematology

Backgound The aim of this study was to explore whether the inhibition of nuclear factor-κB (NF-κB) activation by mutant IκBα (S32,36→A) can enhance TNF-α-induced apoptosis of leukemia cells and to investigate the possible *** The mutant IκBα gene was transfected into HL-60 cells by liposome-mediated techniques. G418 resistant clones stably expressing mutant IκBα were obtained by the limiting dilution method. TNF-α-induced NF-κB activation was measured by electrophoretic mobility shift assay (EMSA). The expression of bcl-x L was detected by RT-PCR and Western blot after 4 hours exposure of parental HL-60 and transfected HL-60 cells to a variety of concentrations of TNF-α. The percentage of apoptotic leukemia cells was evaluated by flow cytometry (FCM). Results Mutant IκBα protein was confirmed to exist by Western blot. The results of EMSA showed that NF-κB activation by TNF-α in HL-60 cells was induced in a dose-dependent manner, but was almost completely inhibited by mutant IκBα repressor in transfected cells. The levels of bcl-x L mRNA and protein in HL-60 cells increased after exposure to TNF-α, but changed very little in transfected HL-60 cells. The inhibition of NF-κB activation by mutant IκBα enhanced TNF-α-induced apoptosis. The cytotoxic effects of TNF-α were amplified in a time- and dose-dependent *** NF-κB activation plays an important role in the resistance to TNF-α-induced apoptosis. The inhibition of NF-κB by mutant IκBα could provide a new approach that may enhance the anti-leukemia effects of TNF-α or even of other cytotoxic agents.

关键词： mutant IκBα · nuclear fector-κB · TNF-α · cell line HL-60 · apoptosis · bcl-x L

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Molecular pathogenesis of acute myeloid leukemia: A diversedisease with new perspectives

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Frontiers of Medicine 2010年第4期4卷 356-362页

作者： Felicitas THOL Arnold GANSER Department of hematology HemostasisOncologyand Stem Cell TransplantationHannover Medical SchoolHannover 30625Germany

Acute myeloid leukemia(AML)is a very heterogeneous neoplasm of the hematopoietic stem *** important achievements in the treatment of AML,the long term survival of patients with the disease remains *** the pathogenesis of AML better is crucial forﬁnding new treatment *** AML development,hematopoietic precursor cells undergo clonal transformation in a multistep process through acquisition of chromosomal rearrangements and/or different gene *** recent years,novel gene mutations have been found in patients with *** mutations can be divided into two important categories,class I mutations that confer a proliferation advantage and class II mutations that inhibit myeloid *** for some of these mutations is now part of the initial diagnostic work-up in newly diagnosed AML *** about the mutation status of speciﬁc genes is useful for risk-stratiﬁcation,minimal residual disease(MRD)monitoring and increasingly also for targeted therapy,especially for patients with cytogenetically normal AML(CN-AML).Besides chromosomal rearrangements and gene mutations,epigenetic regulation of genes–meaning changes in gene expression by mechanisms other than changes in the underlying DNA sequence–also represents an important mechanism of *** article reviews some of the most common mutations in CN-AML and gives a perspective of the translation of these discoveries from bench to bedside.

关键词： acute myeloid leukemia mutations risk stratiﬁcation

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Fetal kidney stem cells ameliorate cisplatin induced acute renal failure and promote renal angiogenesis

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World Journal of Stem cells 2015年第4期7卷 776-788页

作者： Ashwani Kumar Gupta Sachin H Jadhav Naresh Kumar Tripathy Soniya Nityanand Stem cell Research Facility Department of HematologySanjay Gandhi Post-Graduate Institute of Medical Sciences

AIM: To investigate whether fetal kidney stem cells(f KSC) ameliorate cisplatin induced acute renal failure(ARF) in rats and promote renal ***: The f KSC were isolated from rat fetuses of gestation day 16 and expanded in vitro up to 3rd passage. They were characterized for the expression of mesenchymal and renal progenitor markers by flow cytometry and immunocytochemistry, respectively. The in vitro differentiation of f KSC towards epithelial lineage was evaluated by the treatment with specific induction medium and their angiogenic potential by matrigel induced tube formation assay. To study the effect of f KSC in ARF, f KSC labeled with PKH26 were infused in rats with cisplatin induced ARF and, the blood and renal tissues of the rats were collected at different time points. Blood biochemical parameters were studied to evaluate renal function. Renal tissues were evaluated for renal architecture, renal cell proliferation and angiogenesis by immunohistochemistry, renal cell apoptosis by terminal deoxynucleotidyl transferase nickend labeling assay and early expression of angiogenic molecules viz. vascular endothelial growth factor(VEGF), hypoxia-inducible factor(HIF)-1α and endothelial nitric oxide synthase(eN OS) by western ***: The fK SC expressed mesenchymal markers viz. CD29, CD44, CD73, CD90 and CD105 as well asrenal progenitor markers viz. Wt1, Pax2 and Six2. They exhibited a potential to form CD31 and Von Willebrand factor expressing capillary-like structures and could be differentiated into cytokeratin(CK)18 and CK19 positive epithelial cells. Administration of fK SC in rats with ARF as compared to administration of saline alone, resulted in a significant improvement in renal function and histology on day 3(2.33 ± 0.33 vs 3.50 ± 0.34, P < 0.05) and on day 7(0.83 ± 0.16 vs 2.00 ± 0.25, P < 0.05). The infused PKH26 labeled fK SC were observed to engraft in damaged renal tubules and showed increased proliferation and reduced apoptosis(P <

关键词： Fetal kidney stem cells Mesenchymal andrenal progenitor markers Acute renal failure Stem celltherapy Angiogenesis

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