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Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease

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中华医学杂志(英文版) 2024年第10期137卷 1207-1217页

作者： Pan Tianzhong Ding Peng Huang Aijie Tang Baolin Song Kaidi Sun Guangyu Wu Yue Yang Shiying Chen Xingchi Wang Dongyao Zhu Xiaoyu Department of Hematology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China Anhui Provincial Key Laboratory of Blood Research and Applications Hefei Anhui China Blood and Cell Therapy Institute Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China division of life sciences and Medicine University of Science and Technology of China Hefei Anhui China The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China

Background: With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation (UCBT), the correlation between immune reconstitution (IR) after UCBT and graft-versus-host disease (GVHD) has been reported successively, but reports on double-negative T (DNT) cell reconstitution and its association with acute GVHD (aGVHD) after UCBT are lacking.Methods: A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology, the First Affiliated Hospital of USTC, between August 2018 and June 2021. IR differences were compared between the patients with and without aGVHD.Results: The absolute number of DNT cells in the healthy Chinese population was 109 (70-157)/μL, accounting for 5.82 (3.98-8.19)% of lymphocytes. DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation. Importantly, the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year (F = 4.684,P = 0.039 andF = 5.583,P = 0.026, respectively). In addition, the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased, and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD (HR = 0.46, 95% confidence interval [CI]: 0.23-0.93;P = 0.031).Conclusions: Compared to the number of DNT cells in Chinese healthy people, the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow. In addition, the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

关键词： Umbilical cord blood transplantation Graft-versus-host disease Immune reconstitution Double negative T Hematological Malignancies Treg cell Breg cell

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NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma

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Current Medical science 2024年第1期44卷 168-179页

作者： Wei XUE Ting WANG Wen-jing TIAN Si-qi PANG Hua-feng ZHANG Wei-dong JIA Department of General Surgery The First Affiliated Hospital of University of Science and Technology of ChinaDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China Institute of health and Medicine Hefei Comprehensive National Science CenterHefei 230601China The Chinese Academy of sciences Key Laboratory of Innate Immunity and Chronic Disease School of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China

Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients,and the underlying mechanism remains largely unknown.The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC,explore the potential molecular mechanism,and propose combinatorial therapeutic targets for HCC management.Methods Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol.RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant(LR)cells.The upregulated genes were analyzed by GO and KEGG analyses.Then,qPCR and Western blotting were employed to determine the relative gene expression levels.Afterwards,the intracellular reactive oxygen species(ROS)and apoptosis were detected by flow cytometry.Results PLC-LR and Hep3B-LR were established.There was a total of 116 significantly upregulated genes common to both LR cell lines.The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities,and reactive oxygen species pathways.Notably,NAD(P)H:quinone oxidoreductase 1(NQO1)was highly expressed in LR cells,and was involved in the lenvatinib resistance.The high expression of NQO1 decreased the production of ROS induced by lenvatinib,and subsequently suppressed the apoptosis.The combination of lenvatinib and NQO1 inhibitor,dicoumarol,reversed the resistance of LR cells.Conclusion The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels,thereby promoting lenvatinib resistance in HCC cells.

关键词： hepatocellular carcinoma lenvatinib resistance NAD(P)H quinone oxidoreductase 1 reactive oxygen species apoptosis dicoumarol

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Super-Resolution Fluorescence Microscopy for Cilia Investigation and Ciliopathy Diagnosis(Invited)

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激光与光电子学进展 2024年第6期61卷 260-271页

作者： Liu Zhen Wu Yang division of life science The Hong Kong University of Science and TechnologyHong KongChina

The last two decades have witnessed the invention and development of super-resolution microscopy(SRM)that breaks the diffraction limit of light and pushes the fluorescence microscopy resolution to several nanometers.While SRM is widely used in biological studies,such as resolving subdiffraction structures,molecular mapping,tracking single molecules,probing protein-protein interactions,and observing organelle dynamics,its direct application in translational medicine,such as disease diagnosis,is still preliminary.Despite their small size,cilia play a crucial role as organelles in cell signaling and motility,with defects in cilia leading to ciliopathy.Similar to other miniature organelles and macromolecular complexes,cilia are ideal for super-resolution imaging.In this review,we will 1)introduce cilia and ciliopathy,2)show how SRM extends our knowledge of cilia,and 3)focus on how SRM improves the diagnosis of motile ciliopathies.

关键词： diagnosis limit spite

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Impact of exercise on markers of B cell-related immunity:A systematic review

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Journal of Sport and health science 2024年第3期13卷 339-352,I0002页

作者： David Walzik Sergen Belen Karen Wilisch Marie Kupjetz Silvana Kirschke Tobias Esser Niklas Joisten Alexander Schenk Sebastian Proschinger Philipp Zimmer division of Performance and health(Sports Medicine) Institute for Sport and Sport ScienceTU Dortmund UniversityDortmund 44227Germany

Background:B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins.Exercise alters B cell counts and immunoglobulin levels,but evidence-based conclusions on potential benefits for adaptive immunity are lacking.This systematic review assessed current literatures on the impact of acute exercise and exercise training on B cells,immunoglobulins,and markers of secretory immunity in human biofluids.Methods:According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,MEDLINE,Web of science,and Embase were searched on March 8,2023.Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions,immunoglobulin levels,salivary flow rate,or secretory immunoglobulin A secretion rate were included.Quality and reporting of exercise training studies were assessed using the Tool for the Assessment of Study Quality and reporting in Exercise.Study characteristics,outcome measures,and statistically significant changes were summarized tabularly.Results:Of the 67 eligible studies,22 applied acute exercise and 45 applied exercise training.All included outcomes revealed significant alterations over time in acute exercise and exercise training context,but only a few investigations showed significant differences compared to control conditions.Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training.Conclusion:B cell-related outcomes are altered by acute exercise and exercise training,but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities.Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

关键词： Antibody B-lymphocyte Exercise Humoral immunity Immune system

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Super Resolution Fluorescence Microscopy for Cilia Investigation and Ciliopathy Diagnosis

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激光与光电子学进展 2024年

作者： Zhen LIU Yang WU division of life science The Hong Kong University of Science and Technology

The last two decades have witnessed the invention and development of superresolution microscopy(SRM), which breaks the diffraction limit of light and pushes the resolution of fluorescence microscopy to several nanometers. SRM is now widely applied in biological studies such as resolving subdiffraction structures, molecular mapping, single molecule tracking, probing protein-protein interactions, and observing organelle dynamics. However, its direct application in translational medicine such as disease diagnosis is still preliminary. Despite their small size, cilia play a crucial role as organelles in cell signaling and motility, and defects in cilia lead to ciliopathy. Like other miniature organelles and macromolecular complexes, cilia are ideal for superresolution imaging. In this review, we will 1) introduce cilia and ciliopathy, 2) show how SRM extends our knowledge of cilia, and 3) focus on how SRM improves the diagnosis of motile ciliopathies.

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Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1624-1643页

作者： Can Cheng Hanhui Yao Heng Li Jingwen Liu Zhengyi Liu Yang Wu Liang Zhu Hejie Hu Zhengdong Fang Liang Wu Department of General Surgery the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Comprehensive Surgery Anhui Provincial Cancer HospitalWest District of the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Anhui Provincial Hospital health Management Center the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Breast Surgery Henan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityPeople's Hospital of Henan UniversityZhengzhou 450003China

HMGA2,a pivotal transcription factor,functions as a versatile regulator implicated in the progression of diverse aggressive malignancies.In this study,mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2,and USP48 was identified as a deubiquitinating enzyme of HMGA2.The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation,while the deprivation of USP48 promoted HMGA2 degradation,thereby suppressing tumor invasion and metastasis.We discovered that USP48 undergoes SUMOylation at lysine 258,which enhances its binding affinity to HMGA2.Through subsequent phenotypic screening of small molecules,we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48.Interestingly,the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2.Clinically,upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer(CRC).Collectively,our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC,but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

关键词： Colorectal cancer Invasion and metastasis Post-translational modification Ubiquitination SUMOylation USP48 HMGA2 Specific inhibitors

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Integration of multiple flexible electrodes for realtime detection of barrier formation with spatial resolution in a gut-on-chip system

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Microsystems & Nanoengineering 2024年第1期10卷 105-114页

作者： Mara Lucchetti Gabriel Werr Sofia Johansson Laurent Barbe Léa Grandmougin Paul Wilmes Maria Tenje Luxembourg Centre for Systems Biomedicine(LCSB) University of LuxembourgEsch-sur-Alzette L-4362Luxembourg division of Biomedical Engineering Department of Materials Science and EngineeringScience for Life LaboratoryUppsala University75121 UppsalaSweden Department of life sciences and Medicine Faculty of ScienceTechnology and MedicineUniversity of LuxembourgEsch-sur-Alzette L-4362Luxembourg

In healthy individuals,the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation.To study the effect of probiotics,dietary compounds and drugs on gut barrier formation and disruption,human gut epithelial and bacterial cells can be cocultured in an in vitro model called the human microbial crosstalk(HuMiX)gut-on-a-chip system.Here,we present the design,fabrication and integration of thin-film electrodes into the HuMiX platform to measure transepithelial electrical resistance(TEER)as a direct readout on barrier tightness in realtime.As various aspects of the HuMiX platform have already been set in their design,such as multiple compressible layers,uneven surfaces and nontransparent materials,a novel fabrication method was developed whereby thin-film metal electrodes were first deposited on flexible substrates and sequentially integrated with the HuMiX system via a transfer-tape approach.Moreover,to measure localized TEER along the cell culture chamber,we integrated multiple electrodes that were connected to an impedance analyzer via a multiplexer.We further developed a dynamic normalization method because the active measurement area depends on the measured TEER levels.The fabrication process and system setup can be applicable to other barrier-on-chip systems.As a proof-of-concept,we measured the barrier formation of a cancerous Caco-2 cell line in real-time,which was mapped at four spatially separated positions along the HuMiX culture area.

关键词： barrier system multiple

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Development and validation of a nomogram model for predicting the risk of pre-hospital delay in patients with acute myocardial infarction

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World Journal of Cardiology 2024年第2期16卷 80-91页

作者： Jiao-Yu Cao Li-Xiang Zhang Xiao-Juan Zhou Department of Cardiology The First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230001Anhui ProvinceChina

BACKGROUND Acute myocardial infarction(AMI)is a severe cardiovascular disease caused by the blockage of coronary arteries that leads to ischemic necrosis of the myocardium.Timely medical contact is critical for successful AMI treatment,and delays increase the risk of death for patients.Pre-hospital delay time(PDT)is a significant challenge for reducing treatment times,as identifying high-risk patients with AMI remains difficult.This study aims to construct a risk prediction model to identify high-risk patients and develop targeted strategies for effective and prompt care,ultimately reducing PDT and improving treatment outcomes.AIM To construct a nomogram model for forecasting pre-hospital delay(PHD)likelihood in patients with AMI and to assess the precision of the nomogram model in predicting PHD risk.METHODS A retrospective cohort design was employed to investigate predictive factors for PHD in patients with AMI diagnosed between January 2022 and September 2022.The study included 252 patients,with 180 randomly assigned to the development group and the remaining 72 to the validation group in a 7:3 ratio.Independent risk factors influencing PHD were identified in the development group,leading to the establishment of a nomogram model for predicting PHD in patients with AMI.The model's predictive performance was evaluated using the receiver operating characteristic curve in both the development and validation groups.RESULTS Independent risk factors for PHD in patients with AMI included living alone,hyperlipidemia,age,diabetes mellitus,and digestive system diseases(P<0.05).A characteristic curve analysis indicated area under the receiver operating characteristic curve values of 0.787(95%confidence interval:0.716–0.858)and 0.770(95%confidence interval:0.660-0.879)in the development and validation groups,respectively,demonstrating the model's good discriminatory ability.The Hosmer–Lemeshow goodness-of-fit test revealed no statistically significant disparity between the anticipated and observed incidence of PHD in both

关键词： Pre-hospital delay Acute myocardial infarction Risk prediction Nomogram

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METTL9-catalyzed histidine methylation of S100A9 suppresses the anti-Staphylococcus aureus activity of neutrophils

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Protein & Cell 2024年第3期15卷 223-229页

作者： Dan Cao Mengyue Lv Chi Hu Shukai Li Siwen Wang Chao Xu Wen Pan Department of Digestive Disease The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technologyof ChinaHefei230001China division of life sciences and Medicine The CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesInstitute of ImmunologyUniversity of Science and Technology of ChinaHefei 230027China division of life sciences and Medicine MOE Key Laboratory for Cellular DynamicsHefei National Center for Cross-Disciplinary SciencesUniversity of Science and Technology of ChinaHefei 230027China

Dear Editor,Protein histidine methylation has been found to be a widespread post-translational modification(PTM)in mammalian cells and represents more than 13%of all protein methylation events in the human methylome(Ning et al.,2016;Kapell and Jakobsson,2021).Recently,we and other groups independently identified METTL9 as the first broad-specificity histidine N1 methyltransferase in mammals(Davydova et al.,2021;Lv et al.,2021).METTL9 methylates a variety of substrates with a common x-His-x-His motif(His is for histidine;the second x is preferably small amino acids:A/C/G/S)and catalyzes methyl transfer to the last histidine.

关键词： S100A9 specificity

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Solid-state atomic hydrogen as a broad-spectrum RONS scavenger for accelerated diabetic wound healing

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National science Review 2024年第2期11卷 196-206页

作者： Man Luo Qin Wang Gang Zhao Wei Jiang Cici Zeng Qingao Zhang Ruyu Yang Wang Dong Yunxi Zhao Guozhen Zhang Jun Jiang Yucai Wang Qing Zhu Key Laboratory of Precision and Intelligent Chemistry School of Chemistry and Materials Science University of Science and Technology of China Department of Radiology The First Affiliated Hospital of University of Science and Technology of China Division of Life Sciences and Medicine University of Science and Technology of China Shenzhen Senior High School Institute of Intelligent Innovation Henan Academy of Sciences

Hydrogen therapy shows great promise as a versatile treatment method for diseases associated with the overexpression of reactive oxygen and nitrogen species（RONS）. However, developing an advanced hydrogen therapy platform that integrates controllable hydrogen release, efficient RONS elimination, and biodegradability remains a giant technical challenge. In this study, we demonstrate for the first time that the tungsten bronze phase H0.53WO3（HWO） is an exceptionally ideal hydrogen carrier, with salient features including temperature-dependent highly-reductive atomic hydrogen release and broad-spectrum RONS scavenging capability distinct from that of molecular hydrogen. Moreover, its unique p H-responsive biodegradability ensures post-therapeutic clearance at pathological sites. Treatment with HWO of diabetic wounds in an animal model indicates that the solid-state atomic H promotes vascular formation by activating M2-type macrophage polarization and anti-inflammatory cytokine production, resulting in acceleration of chronic wound healing. Our findings significantly expand the basic categories of hydrogen therapeutic materials and pave the way for investigating more physical forms of hydrogen species as efficient RONS scavengers for clinical disease treatment.

关键词： atomic hydrogen RONS scavenger inflammatory regulation diabetic wound healing hydrogen therapy

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