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Identification of cell surface markers for acute myeloid leukemia prognosis based on multi-model analysis

Journal of Biomedical Research 2024年第4期38卷 397-412页

作者： Jiaqi Tang Lin Luo Bakwatanisa Bosco Ning Li Bin Huang Rongrong Wu Zihan Lin Ming Hong Wenjie Liu Lingxiang Wu Wei Wu Mengyan Zhu Quanzhong Liu Peng Xia Miao Yu Diru Yao Sali Lv Ruohan Zhang Wentao Liu Qianghu Wang Kening Li department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjingJiangsu 211166China department of hematology of the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University Northern Jiangsu Institute of Clinical MedicineHuai'anJiangsu 223300China Collaborative Innovation Center for Personalized Cancer Medicine Jiangsu Key Lab of Cancer BiomarkersPrevention and TreatmentNanjing Medical UniversityNanjingJiangsu 211166China department of hematology the First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingJiangsu 210029China Key Laboratory of hematology of Nanjing Medical University NanjingJiangsu 210029China department of Pharmacology School of Basic Medical SciencesNanjing Medical UniversityNanjingJiangsu 211166China The Affiliated Cancer Hospital of Nanjing Medical University Jiangsu Cancer HospitalJiangsu Institute of Cancer ResearchNanjingJiangsu 210002China

Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is *** surface markers(CSMs)have been shown to play an important role in AML leukemogenesis and *** the current study,we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas(TCGA)based on differential gene expression analysis and univariable Cox proportional hazards regression *** using multi-model analysis,including Adaptive LASSO regression,LASSO regression,and Elastic Net,we constructed a 9-CSMs prognostic model for risk stratification of the AML *** predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome *** Cox regression analysis showed that the risk score was an independent prognostic factor for the AML *** AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low ***,single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy ***,PI3K inhibitors were identified as potential treatments for these high-risk *** conclusion,we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.

关键词： acute myeloid leukemia cell surface markers prognosis drug sensitivity multi-model analysis

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Beyond the code:the role of histone methylation in cancer resistance and therapy

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2837-2839页

作者： Daniel Noerenberg Frederik Damm Charité–Universitätsmedizin Berlin corporate member of Freie Universität BerlinHumboldt Universität zu Berlinand Berlin Institute of HealthDepartment of HematologyOncologyand Cancer ImmunologyBerlinGermany German Cancer Consortium(Deutsches Konsortium für Translationale Krebsforschung DKTK)Partner SiteBerlinGermany

In a recently published paper in Nature,Yamagishi et *** a comprehensive exploration on the mechanistic basis and subsequent emergence of resistance of targeting histone H3 lysine trimethylation(H3K27me3)using the EZH... 详细信息

关键词： EZH2 resistance

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Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1665-1674页

作者： Jie Xiong Shu Cheng Xiao Gao Shan-He Yu Yu-Ting Dai Xin-Yun Huang Hui-Juan Zhong Chao-Fu Wang Hong-Mei Yi Hao Zhang Wei-Guo Cao Rong Li Wei Tang Yan Zhao Peng-Peng Xu Li Wang Wei-Li Zhao 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 MedicineShanghaiChina department of Nuclear Medicine Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Pathology Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Otolaryngology Shanghai Rujin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Radiation Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of hematology Navy Medical Center of PLAShanghaiChina Pole de Recherches Sino-Francais en Science du Vivant et Genomique Laboratory of Molecular PathologyShanghaiChina

Natural killer T cell lymphoma(NKTCL)is highly aggressive,with advanced stage patients poorly responding to intensive *** explore effective and safe treatment for newly diagnosed advanced stage NKTCL,we conducted a phase ll study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab(NCT04096690).Twenty-two patients with a median age of 51 years(range,24-74)were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days,followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 *** complete response and overall response rate after induction treatment were 59%(95%Cl,43-79%)and 68%(95%Cl,47-84%),*** a median follow-up of 30 months,the 2 year progression-free and overall survival rates were 68%(95%Cl,45-83%)and 86%(95%Cl,63-95%),*** most frequently grade 3/4 adverse events were neutropenia(32%,n=7)and hypofibrinogenemia(18%,n=4),which were manageable and led to no discontinuation of *** proportion score of PD-L1,peripheral blood high-density lipoprotein cholesterol,and apolipoprotein A-l correlated with good response,while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab *** conclusion,the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed,advanced stage *** lipid profle and immunosuppressive signature contributed to treatment resistance,providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

关键词： killer metabolism lymphoma

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Exercise-induced microbial changes in preventing type 2 diabetes

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Science China(Life Sciences) 2024年第5期67卷 892-899页

作者： Ting Yao Hui Wang Kaiqing Lin Ruwen Wang Shanshan Guo Peijie Chen Hao Wu Tiemin Liu Ru Wang School of Exercise and Health Shanghai Frontiers Science Research Base of Exercise and Metabolic HealthShanghai University of SportShanghai 200438China department of Physiology and pathophysiology School of Basic Medical SciencesXi’an Jiaotong University School of MedicineXi’an 710061China Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism&Integrative BiologyFudan UniversityShanghai 200433China State Key Laboratory of Genetic Engineering Human Phenome InstituteFudan Microbiome Centerand Department of Bariatric and Metabolic SurgeryHuashan HospitalFudan UniversityShanghai 201203China State Key Laboratory of Genetic Engineering Department of Endocrinology and MetabolismHuman Phenome Instituteand School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China

The metabolic benefits associated with long-term physical activity are well appreciated and growing evidence suggests that it involves the gut *** we re-evaluated the link between exercise-induced microbial changes and those associated with prediabetes and *** found that the relative abundances of substantial amounts of diabetes-associated metagenomic species associated negatively with physical fitness in a Chinese athlete students *** additionally showed that those microbial changes correlated more with handgrip strength,a simple but valuable biomarker suggestive of the diabetes states,than maximum oxygen intake,one of the key surrogates for endurance ***,the causal relationships among exercise,risks for diabetes,and gut microbiota were explored based on mediation *** propose that the protective roles of exercise against type 2 diabetes are mediated,at least partly,by the gut microbiota.

关键词： gut microbiota body fat diabetes handgrip maximum oxygen intake

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Therapeutic genome editing of an aberrant splice site inβ-thalassemia by CRISPR/Cas9 with multiple sgRNAs

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Genes & Diseases 2024年第1期11卷 15-18页

作者： Fei Yang Shuqian Xu Chao Huang Zhiqiang Shao Yuefen Hu Yang Yang Yongrong Lai Qing Ke Dan Liang Yuxuan Wu Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China department of Obstetrics and Gynecology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui 230022China NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract(Anhui Medical University) HefeiAnhui 230032China department of hematology Qilu HospitalCheeloo College of MedicineShandong UniversityJinanShandong 250012China BRLMedicine Inc. Shanghai 201108China department of hematology The First Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530000China department of Neurology The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China

Genetic mutations cause aberrant splicing,one of the important molecular mechanisms in human ***2-654,a mutation causing aberrant splicing ofβ-globin premRNA and contributing toβ-globin deficiency,is one of the most common diseases in Southeast Asia and China."In our previous work,we found a TTTV protospacer adjacent motif(PAM)by the Cas12a system and the editing efficiency of Ivs2-654 C>T achieving 76.7%.

关键词： CRISPR/Cas9 China thalassemia

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Identification and characterization of human hematopoietic mesoderm

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Science China(Life Sciences) 2024年第2期67卷 320-331页

作者： Yuqi Wen Jingjing Zhao Runqing Zhang Fan Liu Xiaoyuan Chen Dan Wu Mengge Wang Cuicui Liu Pei Su Panpan Meng Yiyue Zhang Xin Gao Lu Wang Hongtao Wang Jiaxi Zhou State Key Laboratory of Experimental hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Tianjin institutes of Health Science Tianjin 301600China CAMS Center for Stem Cell Medicine PUMC Department of Stem Cell and Regenerative MedicineTianjin 300020China Division of Cell Developmental and Integrative BiologySchool of MedicineSouth China University of TechnologyGuangzhou 510006China

The embryonic mesoderm comprises heterogeneous cell subpopulations with distinct lineage *** is unclear whether a bias for the human hematopoietic lineage emerges at this early developmental *** this study,we integrated single-cell transcriptomic analyses of human mesoderm cells from embryonic stem cells and embryos,enabling us to identify and define the molecular features of human hematopoietic mesoderm(HM)cells biased towards hematopoietic *** discovered that BMP4 plays an essential role in HM specification and can serve as a marker for HM ***,BMP4 acts as a downstream target of HDAC1,which modulates the expression of BMP4 by deacetylating its *** of HDAC significantly enhances HM specification and promotes subsequent hematopoietic cell *** conclusion,our study identifies human HM cells and describes new mechanisms for human hematopoietic development.

关键词： hematopoietic mesoderm human pluripotent stem cells human embryos BMP4 HDAC1

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mtDNA-triggered pH response signal-amplified fluorescent probe for multiple cell discrimination

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Chinese Chemical Letters 2024年第3期35卷 363-368页

作者： Tianping Xia Yanxian Hou Zhuoran Xia Gengwen Chen Peichen Tang Jiangli Fan Xiaojun Peng State Key Laboratory of Fine Chemicals Frontiers Science Center for Smart Materials Oriented Chemical EngineeringDalian University of TechnologyDalian 116024China hematology Reagent R&D department Mindray Bio-medical Electronics Co.Ltd.Shenzhen 518132China Research institute of Dalian University of Technology in Shenzhen Shenzhen 518057China

Developing fluorescence probes with multiple responses has vital significance but remains ***,for the first time,we present a mitochondrial DNA(mtDNA)-triggered pH response signalamplified fluorescent probe(QCY-DBT)for multiple cell *** probe exhibited a large stokes shift(229 nm),excellent DNA selectivity over RNA,and ultrasensitivity of detection limit(DL;74.0 ng/mL).Thus,QCY-DBT was successfully applied to analyze multiple human peripheral blood cells and visualize mtDNA in healthy and apoptotic *** the tumor acidic environment(pH 6.0–7.0),the absorbance of QCY-DBT at 436 nm increased,and the fluorescence signal(665 nm)was amplified by mtDNA,which enabled the direct observation of tumor *** study provides help in designing smart probes with multiple responses for efficient abnormal cell detection.

关键词： Fluorescence probe Mitochondrial DNA pH response Peripheral blood cells Multiple cell detection

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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

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Genes & Diseases 2024年第1期11卷 397-412页

作者： Zhe Chen Qian Guo Shichen Huang Lei Li Feng Wu Zhilong Liu Zhigang Li Tao Chen Guanbin Song Shuangnian Xu Jieping Chen Yu Hou department of hematology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China institute of Life Sciences Chongqing Medical UniversityChongqing 400016China Key Laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400044China Chongqing Foreign Language School Chongqing 400039China

Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML ***,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive *** metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of ***,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of *** a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA *** synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft *** results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.

关键词： AML Combinatorial inhibition FOXO3A GNG7 mTOR

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New insights on the role of chondroitin sulfate proteoglycans in neural stem cell–mediated repair in spinal cord injury

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Neural Regeneration Research 2025年第6期20卷 1699-1700页

作者： Seyed Mojtaba Hosseini Soheila Karimi-Abdolrezaee department of Physiology and pathophysiology Spinal Cord Research CentreRady Faculty of Health SciencesUniversity of ManitobaWinnipegMBCanada Manitoba Multiple Sclerosis Research Center WinnipegMBCanada Children Hospital Research institute of Manitoba WinnipegMBCanada

Extensive neurodegeneration is a hallmark of traumatic spinal cord injury (SCI) that underlies permanent sensorimotor and autonomic impairments (Alizadeh et al.,2019).Following the primary impact,the spinal cord undergoes a cascade of secondary injury mechanisms that are driven by disruption of the blood-spinal cord ba rrier,vascula r inju ry,glial reactivity,neu roinfla mmation,oxidative stress,lipid peroxidation,and glutamate excitotoxicity that culminate in neuronal and oligodendroglial cell death,demyelination,and axonal damage(Alizadeh et al.,2019).To achieve a meaningful functional recovery after SCI,regeneration of new neurons and oligodendrocytes and their successful growth and integration within the neural network are critical steps for reconstructing the damaged spinal cord tissue (Fischer et al.,2020).

关键词： peroxidation Fischer injury

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EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1187-1203页

作者： Yongyun Li Tianyu Zhu Jie Yang Qianqian Zhang Shiqiong Xu Shengfang Ge Renbing Jia Jianming Zhang Xianqun Fan department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200001China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200001China National Research Center for Translational Medicine(Shanghai) State Key Laboratory of Medical GenomicsShanghai Institute of HematologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China institute of Translational Medicine Zhangjiang Institute for Advanced StudyShanghai Jiao Tong UniversityShanghai 200240China

Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular *** search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer ***,elevated expression of EHMT2 had been validated in UM ***,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T *** immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of *** transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA *** constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic *** blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key *** summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.

关键词： Uveal melanoma EHMT2 RhoA pathway ARHGAP29 G protein GNAQ GNA11

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