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

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)therapy.Current targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in relapse.Therefore,novel targets for enhancing CAR-T cell therapy in MM remain needed.Fc 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 MM.To 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 1q21.Given 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 efficacy.Both 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 suppression.Our 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 body.Examples of systemic diseases encompass autoimmune disorders,infectious diseases,metabolic disorders,and chronic conditions like cancer.These 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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Skull and vertebral bone marrow in central nervous system inflammation

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Fundamental Research 2024年第2期4卷 246-250页

作者： Honglei Ren Qiang Liu Department of Neurology Tianjin Neurological InstituteTianjin Institute of ImmunologyState Key Laboratory of Experimental HematologyInternational Joint Laboratory of Ocular DiseasesMinistry of EducationHaihe Laboratory of Cell EcosystemTianjin Medical University General HospitalTianjin 300052China

Emerging evidence has highlighted the capacity of hematogenous cells in skull and vertebral bone marrow to enter the meningeal borders via ossified vascular channels and maintain immune homeostasis in the central nervous system(CNS).CNS-adjacent skull and vertebral bone marrow comprises hematopoietic niches that can sense CNS injury and supply specialized immune cells to fine-tune inflammatory responses.Here,we review recent advances in our understanding of skull and vertebral bone marrow-derived immune cells in homeostasis and inflammatory CNS diseases.Further,we discuss the implications for future development of therapies to mitigate CNS inflammation and its detrimental sequelae in neurological disorders.

关键词： Central nervous system Bone marrow Hematopoiesis Immune cells Neuroinflammation Stroke Multiple sclerosis

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Micelle-directed self-assembly of single-crystal-like mesoporous stoichiometric oxides for high-performance lithium storage

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National Science Review 2024年第4期11卷 195-205页

作者： Yanhua Wan Changyao Wang Xingmiao Zhang Yang Yin Mengmeng Liu Bing Ma Linlin Duan Yuzhu Ma Wei Zhang Changlin Zheng Dongliang Chao Fei Wang Yongyao Xia Wei Li Department of Chemistry Laboratory of Advanced Materials Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials State Key Laboratory of Molecular Engineering of Polymers College of Chemistry and Materials ScienceFudan University state key laboratory of Surface Physics and Department of Physics Fudan University

Due to their uncontrollable assembly and crystallization process,the synthesis of mesoporous metal oxide single crystals remains a formidable challenge.Herein,we report the synthesis of single-crystal-like mesoporous Li2TiSiO5by using soft micelles as templates.The key lies in the atomic-scale self-assembly and step-crystallization processes,which ensure the formation of single-crystal-like mesoporous Li2TiSiO5microparticles via an oriented attachment growth mechanism under the confinement of an in-situ formed carbon matrix.The mesoporous Li2TiSiO5anode achieves a superior rate capability(148 mAh g-1at5.0 A g-1) and outstanding long-term cycling stability(138 mAh g-1after 3000 cycles at 2.0 A g-1) for lithium storage as a result of the ultrafast Li+diffusion caused by penetrating mesochannels and nanosized crystal frameworks（5-10 nm）.In comparison,bulk Li2TiSiO5exhibits poor rate capability and cycle performance due to micron-scale diffusion lengths.This method is very simple and reproducible,heralding a new way of designing and synthesizing mesoporous single crystals with controllable frameworks and chemical functionalities.

关键词： mesoporous materials micelles single-crystal-like Li2TiSiO5 lithium-ion batteries

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Conversion of a single-layer ANN to photonic SNN for pattern recognition

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Science China(Information Sciences) 2024年第1期67卷 261-270页

作者： Yanan HAN Shuiying XIANG Tianrui ZHANG Yahui ZHANG Xingxing GUO Yuechun SHI state key laboratory of Integrated Service Networks State Key Discipline Laboratory of Wide Bandgap Semiconductor TechnologyXidian University Yongjiang laboratory

This work presents a complete conversion scheme for photonic spiking neural networks(SNNs).We verified that the output of an artificial neural network(ANN) trained with the simulated optical activation function can be directly converted into the spike rate of a photonic spiking neuron model.To reveal the feasibility of hardware implementation,we considered the effects of different bit precisions of data and weight,noise level,and bias current mismatch on the converted results.The proposed scheme was evaluated using the Deterding vowel,IRIS,TIDIGITS,and MNIST datasets for pattern recognition,and achieved mean accuracies of 95.80%,98.67%,96.19%,and 92.33%,respectively.The proposed scheme can convert an ANN into a photonic SNN with almost no precision loss,and the performance was comparable to that of an ANN trained with the rectified linear unit function.The proposed scheme can enable the high-performance implementation of photonic SNNs.

关键词： photonic SNN conversion optical computing pattern recognition artificial neural network

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The risk factors and threshold level of subchronic inhalation exposure of reclaimed water

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Journal of Environmental Sciences 2024年第3期137卷 639-650页

作者： Jiayang Kong Yun Lu Yunru Ren Menghao Chen Gang Liu Liangliang Shi state key Joint laboratory of Environment Simulation and Pollution Control State Environment Protection Key Laboratory of Microorganism Application and Risk ControlSchool of EnvironmentTsinghua UniversityBeijing 100084China

Inhalation of reclaimed water is known to cause lung infammation,and free endotoxins have been shown to be a major risk factor for acute exposure.Subchronic exposure has also been shown to induce infammatory responses with visible tissue damage.However,subchronic risk factors have yet to be identified,and a threshold for the protection of occupational populations during urban reuse is necessary.In this study,potential risk factors in reclaimed water were examined by subchronic exposure with fractionated reclaimed water,and the health risk threshold was tested with a series of diluted reclaimed water.Accordingly,following a 12-week exposure,macromolecules and microorganisms were found to be two major risk factors in reclaimed water that could cause pulmonary infammation,including increased proportion of polymorphonuclear leukocytes in bronchoalveolar fuid,formation of inducible bronchus-associated lymphoid tissue,and elevation of Immunoglobulin A levels.Moreover,infammation persisted after a 4-week recovery period.The calculated threshold of reclaimed water exposure for mice was 31.8 Endotoxin Unit(EU)/(kg·day)under when exposed to 50%additional relative humidity from reclaimed water at 25℃ for 2 hr/day.Meanwhile,the subchronic threshold estimate for humans under the same exposure conditions was found to be 12.2 EU/(kg·day),corresponding to endotoxin levels of 61.7 EU/mL in reclaimed water.The threshold level of endotoxin was lower than that in most non-potable reclaimed water.The findings of this study suggest that occupational exposure of reclaimed water can serve as a potential risk to workers.

关键词： Reclaimed water Inhalation exposure Risk factor Threshold Infammation Endotoxin

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REDH:A database of RNA editome in hematopoietic differentiation and malignancy

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Chinese Medical Journal 2024年第3期137卷 283-293页

作者： Jiayue Xu Jiahuan He Jiabin Yang Fengjiao Wang Yue Huo Yuehong Guo Yanmin Si Yufeng Gao Fang Wang Hui Cheng Tao Cheng Jia Yu Xiaoshuang Wang Yanni Ma state key laboratory of Common Mechanism Research for Major Diseases Haihe Laboratory of Cell EcosystemInstitute of Basic Medical SciencesChinese Academy of Medical SciencesBeijing 100005China key laboratory of RNA and Hematopoietic Regulation Chinese Academy of Medical SciencesBeijing 100005China Department of Biochemistry and Molecular Biology Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China state key laboratory of experimental hematology National Clinical Research Center for Blood DiseasesInstitute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300020China Institute of Blood Transfusion Chinese Academy of Medical SciencesChengduSichuan 610052China

Background:The conversion of adenosine(A)to inosine(I)through deamination is the prevailing form of RNA editing,impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species.Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases,providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets.However,the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking.Methods:We downloaded RNA sequencing(RNA-seq)data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information(NCBI)Gene Expression Omnibus(GEO)database,and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used.We performed sequence alignment,identified RNA editing sites,and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases.Results:We established a new database,"REDH",represents RNA editome in hematopoietic differentiation and malignancy.REDH is a curated database of associations between RNA editome and hematopoiesis.REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts(human).Through the Differentiation,Disease,Enrichment,and knowledge modules,each A-to-I editing site is systematically integrated,including its distribution throughout the genome,its clinical information(human sample),and functional editing sites under physiological and pathological conditions.Furthermore,REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control.Conclusions:REDH is accessible at http://***/.This user-friendly database would aid in understanding the mechanisms of RNA editing in hema

关键词： RNA editing Hematopoietic differentiation Hematopoietic malignancy Database management systems

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Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia:a prospective,single arm,phase I trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2250-2259页

作者： Yunfei Chen Yanmei Xu Ying Chi Ting Sun Yuchen Gao Xueqing Dou Zhibo Han Feng Xue Huiyuan Li Wei Liu Xiaofan Liu Huan Dong Rongfeng Fu Mankai Ju Xinyue Dai Wentian Wang Yueshen Ma Zhen Song Jundong Gu Wei Gong Renchi Yang Lei Zhang state key laboratory of experimental hematology National Clinical Research Centre for Blood DiseasesHaihe Laboratory of Cell EcosystemTianjin Key Laboratory of Gene Therapy for Blood DiseasesCAMS Key Laboratory of Gene Therapy for Blood DiseasesInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Tianjin Institutes of Health Science Tianjin 301600China National Clinical Research Center for Hematologic Diseases Jiangsu Institute of HematologyThe First Affiliated Hospital of Soochow UniversitySuzhou 215006China National Engineering Research Centre of Cell Products Tianjin Key Laboratory of Engineering Technologies for Cell PharmaceuticalAmCellGene Engineering Co.LtdTianjin 300457China School of Population Medicine and Public Health Chinese Academy of Medical Sciences and Peking Union Medical College100730 BeijingChina

Patients with refractory immune thrombocytopenia(ITP)frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies.Umbilical cord-derived mesenchymal stem cells(UC-MSCs)present a promising alternative,capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders.This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP.The research design included administering UC-MSCs at escalating doses of 0.5×10^(6)cells/kg,1.0×10^(6)cells/kg,and 2.0×10^(6)cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase,followed by a dose of 2.0×10^(6)cells/kg weekly for the dose-expansion phase.Adverse events,platelet counts,and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period.Ultimately,12(with an addition of three patients in the 2.0×10^(6)cells/kg group due to dose-limiting toxicity)and six patients were enrolled in the dose-escalation and dose-expansion phase,respectively.Thirteen patients(13/18,72.2%)experienced one or more treatment emergent adverse events.Serious adverse events occurred in four patients(4/18,22.2%),including gastrointestinal hemorrhage(2/4),profuse menstruation(1/4),and acute myocardial infarction(1/4).The response rates were 41.7%in the dose-escalation phase(5/12,two received 1.0×10^(6)cells/kg per week,and three received 2.0×10^(6)cells/kg per week)and 50.0%(3/6)in the dose-expansion phase.The overall response rate was 44.4%(8/18)among all enrolled patients.To sum up,UC-MSCs are effective and well tolerated in treating refractory ITP(ClinicalTrials.gov ID:NCT04014166).

关键词： doses immunity treatment

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Microbes in mass extinction: an accomplice or a savior?

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National Science Review 2024年第1期11卷 12-15页

作者： Genming Luo Deng Liu Hao Yang China University of Geosciences (Wuhan) state key laboratory of Geobiology and Environmental Geology

Microbes include various types of organisms that are invisible to the naked eye,e.g. bacteria, archaea and microeukaryotes. Although the precise number remains largely unknown, microbes are recognized as the unseen majority of our biosphere [1]. As a group of organisms classified by body size, microbes cover a considerable spectrum of metabolisms,

关键词： AFTERMATH

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Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H:quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase

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Chinese Journal of Natural Medicines 2024年第1期22卷 75-88页

作者： SONG Jiangzhou ZOU Guiqing ZHAO Zhou ZHU Ya XUE Jiayu AO Lanjia SUN Huiyong HAO Haiping ZHANG Bo XU Xiaowei state key laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China state key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer cells.NQO1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)production.This ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell death.Nicotinamide phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer therapy.The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+depletion.In this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT.Among these,compound T8 demonstrated potent antitumor properties.Specifically,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT.This discovery offers a promising new molecular entity for advancing anticancer research.

关键词： NQO1 ROS NAMPT NAD^(+) T8

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