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Effects of different concentrations of nicotinamide on hematopoietic stem cells cultured in vitro

World Journal of Stem Cells 2024年第2期16卷 163-175页

作者： Yan Ren Yan-Ni Cui Hong-Wei Wang The Second Clinical Medical College Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina Department of hematology The Second Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina Department of hematology Key Laboratory of Molecular Diagnosis and Treatment of Blood Diseases in Shanxi ProvinceTaiyuan 030001Shanxi ProvinceChina

BACKGROUND In vitro expansion to increase numbers of hematopoietic stem cells(HSCs)in cord blood could improve clinical efficacy of this vital ***(NAM)can promote HSC expansion ex vivo,but its effect on hematopoietic stem and progenitor cells(HSPCs,CD34^(+)CD38)and functional subtypes of HSCs-shortterm repopulating HSCs(ST-HSCs,CD34^(+)CD38CD45RACD49f^(+))and long-term repopulating HSCs(LT-HSCs,CD34^(+)CD38CD45RACD49f^(+)CD90^(+))is not yet *** a sirtuin 1(SIRT1)inhibitor,NAM participates in regulating cell adhesion,polarity,migration,proliferation,and ***,SIRT1 exhibits dual effects by promoting or inhibiting differentiation in different tissues or *** propose that the concentration of NAM may influence proliferation,differentiation,and SIRT1 signaling of *** To evaluate the effects and underlying mechanisms of action of different concentrations of NAM on HSC proliferation and *** CD34^(+)cells were purified from umbilical cord blood using MacsCD34 beads,and cultured for 10-12 d in a serum-free medium supplemented with cytokines,with different concentrations of NAM added according to experimental *** cytometry was used to detect phenotype,cell cycle distribution,and apoptosis of the cultured ***-time polymerase chain reaction was used to detect the transcription levels of target genes encoding stemness-related factors,che mokines,components of hypoxia pathways,and antioxidant ***-dihydro-fluorescein diacetate probes were used to evaluate intracellular production of reactive oxygen species(ROS).Determination of the effect of different culture conditions on the balance of cytokine by cytometric bead *** Compared with the control group,the proportion and expansion folds of HSPCs(CD34^(+)CD38)incubated with 5 mmol/L or 10 mmol/L NAM were significantly increased(all P<0.05).The ST-HSCs ratio and fold expansion of the 5 mmol/L NAM group were significantly

关键词： Hematopoietic stem cells Nicotinamide Concentration Proliferation Differentiation Sirtuin 1

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Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

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Current Medical Science 2024年第2期44卷 298-308页

作者： Zhen LU Qian LAI Zhi-feng LI Meng-ya ZHONG Yue-long JIANG Li-ying FENG Jie ZHA Jing-wei YAO Yin LI Xian-ming DENG Bing XU Department of hematology The First Affiliated Hospital of Xiamen University and Institute of HematologySchool of MedicineXiamen UniversityXiamen361005China Key laboratory of Xiamen for diagnosis and Treatment of Hematological Malignancy Xiamen361005China Department of Oncology The First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhou510630China State Key laboratory of Cellular Stress Biology Innovation Center for Cell Signaling NetworkSchool of Life SciencesXiamen UniversityXiamen361003China

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient *** present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL ***:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were *** addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in ***:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor *** of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these ***:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

关键词： B-cell acute lymphoblastic leukemia dual-target inhibitor NF-kB c-Myc PI3K/AKT p53

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Acquired immune thrombotic thrombocytopenic purpura(TTP)associated with inactivated COVID-19 vaccine CoronaVac

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Frontiers of Medicine 2024年第4期18卷 744-751页

作者： Zhangbiao Long Suyu Jiang Honglei Xin Lu Zhang Ruinan Lu Fengqi Liu Yong Xu Linv Wang Jun Wang Xuezhong Zhang Hui Liao Jinning Shi Xue Yan Xiang Zhu Ruonan Shao Zijian Li Yilin Zhu Han Yan Jiao Wu Chao Fang Xiaodong Xi Xiaofeng Shi Department of hematology The First Affiliated Hospital of Anhui Medical UniversityHefei230022China Department of hematology The Second Affiliated Hospital of Nanjing Medical UniversityNanjing210003China Department of hematology The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjing210029China Department of hematology Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing210008China Department of hematology The Affiliated Hospital of Nanjing University of Chinese MedicineThe First Clinical Medical College of Nanjing University of Chinese MedicineNanjing210009China Department of hematology Zhongda Hospital of Southeast UniversityNanjing210044China Department of hematology Nanjing First HospitalNanjing Medical UniversityNanjing210006China Department of hematology The Air Force Hospital of Eastern Theater commandNanjing210016China Department of hematology Jiangning Hospital Affiliated of Nanjing Medical UniversityNanjing211199China Department of hematology Nanjing Hospital of Chinese MedicineNanjing210006China Department of Pharmacology School of Basic MedicineTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science and TechnologyThe Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei ProvinceWuhan430030China Shanghai Institute of hematology State Key Laboratory of Medical GenomicsRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China

Corona virus disease 2019(COVID-19)due to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has affected the whole *** thrombotic thrombocytopenic purpura(TTP)has been reported after administration of mRNA-or adenoviral vector-based COVID-19 vaccines,including ***2-S,BNT162b2,mRNA-1273,and ChAdOx1 ***,whether inactivated vaccines,such as CoronaVac,could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are *** this study,two cases were *** cases developed TTP after the second CoronaVac vaccination shot,but not the *** demonstrated symptoms of fever,neurological abnormalities,renal dysfunction,thrombocytopenia,and *** patients achieved complete remission through several sessions of plasma exchanges and immune *** incidence of TTP in Nanjing area was *** number of patients with TTP was 12 in 2019,6 in 2020,16 in 2021,and 19 in *** the authors’knowledge,this report is the first report of TTP associated with inactivated COVID-19 vaccine(CoronaVac).The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based *** plasma exchange is a vital treatment for CoronaVac-related TTP,similar to activated vaccine-related TTP.

关键词： thrombotic thrombocytopenia purpura(TTP) corona virus disease 2019(COVID-19) CoronaVac acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccine

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Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-βsignaling

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Frontiers of Medicine 2024年第1期18卷 128-146页

作者： Yuanyuan Hao Panpan Chen Shanshan Guo Mengyuan Li Xueli Jin Minghuan Zhang Wenhai Deng Ping Li Wen Lei Aibin Liang Wenbin Qian Department of hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou310009China Department of hematology Henan Provincial People’s HospitalZhengzhou University People’s HospitalZhengzhou450003China Key laboratory of laboratory Medicine Ministry of EducationSchool of Laboratory Medicine and Life SciencesWenzhou Medical UniversityWenzhou325000China Department of hematology Tongji Hospital of Tongji UniversityShanghai200065China

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

关键词： tumor-derived exosome chimeric antigen receptor T-cell lymphoma TGF-β

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Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

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Signal Transduction and Targeted Therapy 2024年第2期9卷 724-737页

作者： Zhengyu Yu Hexian Li Qizhong Lu Zongliang Zhang Aiping Tong Ting Niu Department of hematology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)*** targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in ***,novel targets for enhancing CAR-T cell therapy in MM remain *** receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for *** further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome *** the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and *** in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor *** results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

关键词： directed thereby offering

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Towards a blood ecosystem approach to dissect systemic diseases

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Science China(Life Sciences) 2024年第7期67卷 1528-1531页

作者： Hong Wang Tao Cheng State Key laboratory of Experimental hematology Haihe Laboratory of Cell EcosystemNational Clinical Research Center for Blood DiseasesInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Tianjin Institutes of Health Science Tianjin 301600China

Systemic diseases,in contrast to localized ailments,exert widespread effects and can impact the entire *** of systemic diseases encompass autoimmune disorders,infectious diseases,metabolic disorders,and chronic conditions like *** diseases often entail intricate interactions among diverse organs,tissues,and physiological systems,influenced by a myriad of factors.

关键词： diseases organs autoimmune

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Method for the extraction of circulating nucleic acids based on MOF reveals cell-free RNA signatures in liver cancer

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National Science Review 2024年第1期11卷 94-106页

作者： Yuqing Sun Haixin Yu Shaoqing Han Ruoxi Ran Ying Yang Yongling Tang Yuhao Wang Wenhao Zhang Heng Tang Boqiao Fu Boshi Fu Xiaocheng Weng Song-Mei Liu Hexiang Deng Shuang Peng Xiang Zhou College of Chemistry and Molecular Sciences Key Laboratory of Biomedical Polymers-Ministry of Education Wuhan University Department of Digestive Surgical Oncology Union Hospital Tongji Medical College Huazhong University of Science and Technology Cancer Center Union HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Clinical laboratory Center for Gene Diagnosis and Program of Clinical Laboratory Zhongnan Hospital of Wuhan University College of Chemistry and Materials Science Hubei Engineering University Department of Pharmacology School of Pharmacy China Medical University Taikang Center for Life and Medical Sciences Wuhan University Department of hematology Zhongnan Hospital of Wuhan University

Cell-free RNA(cf RNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cf RNA isolation technologies due to the low abundance and instability of cf ***, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids(containing cf RNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework(MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cf RNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cf RNA in serum from patients with liver cancer was described and a cf RNA signature with six cf RNAs was identified to diagnose liver cancer with high diagnostic efficiency(area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer.

关键词： MOF circulating cell-free RNA biomarker liver cancer diagnosis

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LATS1 Promotes B-ALL Tumorigenesis by Regulating YAP1 Phosphorylation and Subcellular Localization

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Current Medical Science 2024年第1期44卷 81-92页

作者： Feng ZHANG Mohammed Awal Issah Hai-ying FU Hua-rong ZHOU Ting-bo LIU Jian-zhen SHEN Fujian Provincial Key laboratory on hematology Fujian Medical Center of HematologyFujian Institute of HematologyClinical Research Center for Hematological Malignancies of Fujian ProvinceFujian Medical University Union HospitalFuzhou 350001China Tamale Technical University Faculty of Allied Health and Pharmaceutical SciencesDepartment of Medical Laboratory TechnologyTamale NS-011-2000Ghana Department of hematology The Third Affiliated People's Hospital of Fujian University of Traditional Chinese MedicineThe Third People's Hospital of Fujian ProvinceFuzhou 350122China

Objective YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors;differentiating between these roles may depend on the YAP1 phosphorylation *** specific function of YAP1 in B cell acute lymphoblastic leukemia(B-ALL),however,is currently ***,in the present study,the role of YAP1 in B-ALL was investigated using relevant cell lines and patient *** The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting,quantitative real-time polymerase chain reaction,flow cytometry,immunostaining,and nude mouse subcutaneous tumorigenesis *** expression levels of Hippo pathway-related molecules before and after verteporfin(VP)treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 *** Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation ***1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells;YAP1 was distributed in the nuclei in NALM6 *** of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 *** and after VP treatment,the expression of the upstream gene LATS1 was upregulated;its overexpression promoted YAP1-Ser127 ***,YAP1 was distributed in the *** LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function;thus,VP,which targets this axis,may serve as a new therapeutic method for improving the outcomes for B-ALL patients.

关键词： acute lymphoblastic leukemia large tumor suppressor kinase 1 phosphorylation RNA-Seq Yesl-associated protein

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Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo

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Oncology Research 2024年第6期32卷 1109-1118页

作者： ZHIGANG XIA MENGYAO TIAN YUCAI CHENG WENFANG YI ZEFAN DU TIANWEN LI YUCHEN WEN LINDI LI YONG LIU CHUN CHEN Pediatric hematology laboratory Division of Hematology/OncologyDepartment of PediatricsThe Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen518107China Scientific Research Center The Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen518107China

Background:Chimeric antigen receptor T(CAR-T)cell therapy has achieved marked therapeutic success in ameliorating hematological ***,there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T(CAR-T)cell therapy,as well as the optimal timing for CAR-T cell infusion *** and Methods:We employed cell-derived tumor xenograft(CDX)murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell ***,transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment ***:Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine,followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy,exerts the most efficacious therapeutic effect in B-cell hematological ***,RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism,primarily through the inhibition of key mitochondrial targets,such as C-Jun Kinase enzyme(C-JUN).Conclusion:In summary,the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

关键词： CD19 CAR-T B-cell hematologic malignancies Metabolism In vivo

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Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia

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Frontiers of Medicine 2024年第2期18卷 327-343页

作者： Niu Qiao Yizhu Lyu Feng Liu Yuliang Zhang Xiaolin Ma Xiaojing Lin Junyu Wang Yinyin Xie Ruihong Zhang Jing Qiao Hongming Zhu Li Chen Hai Fang Tong Yin Zhu Chen Qiang Tian Saijuan Chen Shanghai Institute of hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of hematology Second Hospital of Dalian Medical UniversityDalian116021China

The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine *** an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly ***,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction *** study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma *** was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/***,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular ***,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

关键词： acute promyelocytic leukemia plasma proteomics plasma metabolomics cross-sectional correlation network pathogenesis treatment

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