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RNA modifications in cellular metabolism:implications for metabolism-targeted therapy and immunotherapy

Signal Transduction and Targeted Therapy 2024年第4期9卷 1565-1594页

作者： Wei-Wei Liu Si-Qing Zheng Tian Li Yun-Fei Fei Chen Wang Shuang Zhang Fei Wang Guan-Min Jiang Hao Wang department of Laboratory medicine The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina School of Clinical medicine Shandong UniversityJinanChina core Unit of National Clinical Research Center for Laboratory medicine HefeiChina Neurosurgical department The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina department of Clinical Laboratory The Fifth Affiliated HospitalSun Yat-sen UniversityZhuhaiChina

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of *** studies have been constantly making inroads in our understanding of pathophysiology,and inspiring development of *** a crucial component of epigenetics at post-transcription level,RNA modification significantly determines RNA fates,further affecting various biological processes and cellular *** be noted,immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological *** this review,we characterize the distribution features,modifying mechanisms and biological functions of 8 RNA modifications,including N6-methyladenosine(m6A),N6,2'-O-dimethyladenosine(m6Am),N1-methyladenosine(m1A),5-methylcytosine(m5C),N4-acetylcytosine(ac4C),N7-methylguanosine(m7G),Pseudouridine(V),adenosine-to-inosine(A-to-l)editing,which are relatively the most studied *** regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described,categorized as glucose,lipid,amino acid,and mitochondrial *** we highlight the regulation of RNA modifications on immunometabolism,further influencing immune *** all,we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy,progression of RNA modification-targeted agents,and its potential in RNAtargeted ***,we give legitimate perspectives for future researches in this field from methodological requirements,mechanistic insights,to therapeutic applications.

关键词： metabolism targeted alterations

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Telomeric DNA breaks in human induced pluripotent stem cells trigger ATR-mediated arrest and telomerase-independent telomere damage repair

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Journal of Molecular Cell Biology 2024年第3期16卷 46-60页

作者： Katrina N.Estep John W.Tobias Rafael J.Fernandez Brinley M.Beveridge F.Brad Johnson department of Pathology and Laboratory medicine University of PennsylvaniaPhiladelphiaPA 19104USA Quantiative Biosciences Merck&Co.Inc.West PointPA 19486USA Penn Genomic Analysis core University of PennsylvaniaPhiladelphiaPA 19104USA

Although mechanisms of telomere protection are well-defined in differentiated cells,how stem cells sense and respond to telomere dysfunction,in particular telomeric double-strand breaks(DSBs),is poorly ***,we report the DNA damage signaling,cell cycle,and transcriptome changes in human induced pluripotent stem cells(iPSCs)in response to telomere-internal *** engineer human iPSCs with an inducible TRF1-FokI fusion protein to acutely induce DSBs at *** this model,we demonstrate that TRF1-FokI DSBs activate an ATR-dependent DNA damage response,which leads to p53-independent cell cycle arrest in *** CRISPR–Cas9 to cripple the catalytic domain of telomerase reverse transcriptase,we show that telomerase is largely dispensable for survival and lengthening of TRF1-FokI-cleaved telomeres,which instead are effectively repaired by robust homologous recombination(HR).In contrast to HR-based telomere maintenance in mouse embryonic stem cells,where HR causes ZSCAN4-dependent extension of telomeres beyond their initial lengths,HR-based repair of telomeric breaks is sufficient to maintain iPSC telomeres at a normal length,which is compatible with sustained survival of the cells over several days of TRF1-FokI *** findings suggest a previously unappreciated role for HR in telomere maintenance in telomerase-positive iPSCs and reveal distinct iPSC-specific responses to targeted telomeric DNA damage.

关键词： telomeres telomerase alternative lengthening of telomeres pluripotent stem cells DNA damage double-strand breaks

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Developing a diagnostic model for predicting prostate cancer: a retrospective study based on Chinese multicenter clinical data

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Asian Journal of Andrology 2024年第1期26卷 34-40页

作者： Chang-Ming Wang Lei Yuan Xue-Han Liu Shu-Qiu Chen Hai-Feng Wang Qi-Fei Dong Bin Zhang Ming-Shuo Huang Zhi-Yong Zhang Jun Xiao Tao Tao department of Urology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China department of Radiology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China core Facility Center for Medical Sciences The First Affiliated Hospital of USTcDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China department of Urology Affiliated Zhongda Hospital of Southeast UniversityNanjing 210009China department of Urology Shanghai East HospitalTongji University School of MedicineShanghai 200120China department of Urology Shanghai Changhai HospitalSecond Military Medical UniversityShanghai 200000China department of Urology Affiliated Anhui Provincial Hospital of Anhui Medical UniversityHefei 230001China

The overdiagnosis of prostate cancer(PCa)caused by nonspecific elevation serum prostate-specific antigen(PSA)and the overtreatment of indolent PCa have become a global problem that needs to be solved *** aimed to construct a prediction model and provide a risk stratification system to reduce unnecessary *** this retrospective study,clinical data of 1807 patients from three Chinese hospitals were *** final model was built using stepwise logistic regression *** apparent performance of the model was assessed by receiver operating characteristic curves,calibration plots,and decision curve ***,a risk stratification system of clinically significant prostate cancer(csPCa)was created,and diagnosis-free survival analyses were *** multivariable screening and evaluation of the diagnostic performances,a final diagnostic model comprised of the PSA density and Prostate Imaging-Reporting and Data System(PI-RADS)score was *** validation in the development cohort and two external cohorts showed excellent discrimination and ***,we created a risk stratification system using risk thresholds of 0.05 and 0.60 as the cut-off *** follow-up results indicated that the diagnosis-free survival rate for csPCa at 12 months and 24 months postoperatively was 99.7%and 99.4%,respectively,for patients with a risk threshold below O.05 after the initial negative prostate biopsy,which was significantly better than patients with higher *** diagnostic model and risk stratification system can achieve a personalized risk calculation of *** provides a standardized tool for Chinese patients and physicians when considering thenecessity of prostatebiopsy.

关键词： nomogram prostate biopsy prostate cancer Prostate Imaging-Reporting and Data System prostate-specific antigen density

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Simulation-based assessment for the emergency medicine milestones: a national survey of simulation experts and program directors

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World Journal of Emergency medicine 2024年第4期15卷 301-305页

作者： Afrah A Ali Ashley Crimmins Hegang Chen Danya Khoujah department of Emergency medicine University of Maryland School of MedicineBaltimore 21201USA department of Epidemiology and Public Health University of Maryland School of MedicineBaltimore 21201USA department of Emergency medicine AdventHealth TampaTampa 33606USA

The focus of outcome-based education has shifted from the process of training to the end“product”of *** has necessitated a reframing of the teaching,learning,and ***,in 2013,the Accreditation Council for Graduate Medical Education(ACGME)implemented the educational milestones for all accredited residencies and fellowship programs.[1]The milestones have been described as“developmentally based,specialty-specific achievements that residents are expected to demonstrate at established intervals as they progress through training.”[1]Milestones are based on the six core competencies established by the ACGME and American Board of Medical Specialties(ABMS),which consist of medical knowledge(MK),patient care(PC),interpersonal and communication skills(ICS),practice-based learning and improvement(PBLI),professionalism(PROF),and systems-based practice(SBP).[2,3]ACGME,in conjunction with the American Board of Emergency medicine(ABEM),drafted 23 detailed subcompetencies relevant to emergency medicine(EM).[4]

关键词： Miles milestone education

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Protective mechanism of quercetin in alleviating sepsis-related acute respiratory distress syndrome based on network pharmacology and in vitro experiments

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World Journal of Emergency medicine 2024年第2期15卷 111-120页

作者： Weichao Ding Wei Zhang Juan Chen Mengmeng Wang Yi Ren Jing Feng Xiaoqin Han Xiaohang Ji Shinan Nie Zhaorui Sun department of Emergency medicine Jinling HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210002China department of Emergency medicine Jinling Clinical Medical College of Nanjing University of Chinese MedicineNanjing 210002China department of Emergency medicine the Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002China department of Emergency medicine Xuzhou Municipal Hospital Affiliated to Xuzhou Medical UniversityXuzhou 221000China

BACKGROUND:Sepsis-related acute respiratory distress syndrome(ARDS)has a high mortality rate,and no effective treatment is available *** is a natural plant product with many pharmacological activities,such as antioxidative,anti-apoptotic,and anti-inflammatory *** study aimed to elucidate the protective mechanism of quercetin against sepsis-related ***:In this study,network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related *** targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro ***:A total of 4,230 targets of quercetin,360 disease targets of sepsis-related ARDS,and 211 intersection targets were obtained via database *** the 211 intersection targets,interleukin-6(IL-6),tumor necrosis factor(TNF),albumin(ALB),AKT serine/threonine kinase 1(AKT1),and interleukin-1β(IL-1β)were identified as the core targets.A Gene Ontology(GO)enrichment analysis revealed 894 genes involved in the inflammatory response,apoptosis regulation,and response to *** Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified 106 *** eliminating and generalizing,the hypoxia-inducible factor-1(HIF-1),TNF,nuclear factor-κB(NF-κB),and nucleotide-binding and oligomerization domain(NOD)-like receptor signaling pathways were *** docking revealed that quercetin had good binding activity with the core ***,quercetin blocked the HIF-1,TNF,NF-κB,and NODlike receptor signaling pathways in lipopolysaccharide(LPS)-induced murine alveolar macrophage(MH-S)*** also suppressed the inflammatory response,oxidative reactions,and cell ***:Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1,TNF,NF-κB,and NOD-like receptor signaling pathways to reduce inflammation,cell apoptosis,and oxidative

关键词： Quercetin Sepsis-related acute respiratory distress syndrome Network pharmacology

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RNA modifications in the progression of liver diseases:from fatty liver to cancer

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Science China(Life Sciences) 2024年第10期67卷 2105-2119页

作者： Simiao Li Wajahat Z Mehal Xinshou Ouyang department of Internal medicine Section of Digestive DiseasesYale University School of MedicineNew Haven CT 06520USA

Non-alcoholic fatty liver disease(NAFLD)has emerged as a prominent global health concern associated with high risk of metabolic syndrome,and has impacted a substantial segment of the *** disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis(NASH),which can progress to cirrhosis and hepatocellular carcinoma(HCC)and is increasingly becoming a prevalent indication for liver *** existing therapeutic options for NAFLD,NASH,and HCC are limited,underscoring the urgent need for innovative treatment *** into gene expression,particularly RNA modifications such as N6methyladenosine(m^(6)A),hold promising avenues for *** modifications play integral roles in RNA metabolism and cellular functions,encompassing the entire NAFLD-NASH-HCC *** review will encompass recent insights on diverse RNA modifications,including m^(6)A,pseudouridine(Ψ),N^(1)-methyladenosine(m^(1)A),and 5-methylcytidine(m^(5)C)across various RNA *** will uncover their significance in crucial aspects such as steatosis,inflammation,fibrosis,and ***,prospective research directions and therapeutic implications will be explored,advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

关键词： m^(6)A RNA modification NASH NAFLD HCC fatty liver

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Cav3.2 channel regulates cerebral ischemia/reperfusion injury:a promising target for intervention

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Neural Regeneration Research 2024年第11期19卷 2480-2487页

作者： Feibiao Dai Chengyun Hu Xue Li Zhetao Zhang Hongtao Wang Wanjun Zhou Jiawu Wang Qingtian Geng Yongfei Dong Chaoliang Tang Graduate School Wannan Medical CollegeWuhuAnhui ProvinceChina department of Anesthesiology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina core Facility Center for Medical Sciences The First Affiliated Hospital of USTC(Anhui Provincial Hospital)HefeiAnhui ProvinceChina department of Pharmacy The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina department of Neurosurgery The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina

Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion *** calcium channels are involved in cerebral ischemia/reperfusion ***3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain ***,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains ***,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal *** results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal *** further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion ***3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion ***,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal *** the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion *** findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 *** from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.

关键词： calcineurin Cav3.2 channel cerebral ischemia/reperfusion hippocampus hypoxia/reoxygenation inflammatory response nuclear factor of activated T cells 3 oxidative stress primary hippocampal neurons stroke

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Frequentist and Bayesian Sample Size Determination for Single-Arm Clinical Trials Based on a Binary Response Variable: A Shiny App to Implement Exact Methods

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Open Journal of Statistics 2024年第1期14卷 90-105页

作者： Susanna Gentile Valeria Sambucini department of statistical Sciences Sapienza University of Rome Rome Italy

Sample size determination typically relies on a power analysis based on a frequentist conditional approach. This latter can be seen as a particular case of the two-priors approach, which allows to build four distinct power functions to select the optimal sample size. We revise this approach when the focus is on testing a single binomial proportion. We consider exact methods and introduce a conservative criterion to account for the typical non-monotonic behavior of the power functions, when dealing with discrete data. The main purpose of this paper is to present a Shiny App providing a user-friendly, interactive tool to apply these criteria. The app also provides specific tools to elicit the analysis and the design prior distributions, which are the core of the two-priors approach.

关键词： Binomial Proportion Frequentist and Bayesian Power Functions Exact Sample Size Determination Shiny App Two-Priors Approach

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Impact of Social Determinants of Health on Self-Perceived Resilience: An Exploratory Study of Two Cohorts of Adults with Congenital Heart Disease

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Congenital Heart Disease 2024年第1期19卷 33-48页

作者： Albert Osom Krysta S.Barton Katie Sexton Lyndia Brumback Joyce P.Yi-Frazier Abby R.Rosenberg Ruth Engelberg Jill M.Steiner department of Biostatistics University of WashingtonSeattleWA98195USA Biostatistics Epidemiology and Analytics for Research(BEAR)core Seattle Children’s Research InstituteSeattleWA98101USA College of medicine University of WashingtonSeattleWA98195USA Center for Clinical and Translational Research Seattle Children’s Research InstituteSeattleWA98101USA department of Psychosocial Oncology and Palliative Care Dana-Farber Cancer InstituteDepartment of MedicineBoston Children’s HospitalBostonMA02215USA department of Pediatrics Harvard Medical SchoolBostonMA02215USA Division of Pulmonary Critical Care and Sleep MedicineDepartment of Medicine&Cambia Palliative Care Center of ExcellenceUniversity of WashingtonHarborview Medical CenterSeattleWA98104USA Division of Cardiology Department of Medicine&Cambia Palliative Care Center of ExcellenceUniversity of WashingtonSeattleWA98195USA

Social determinants of health(SDOH)affect quality of *** investigated SDOH impacts on self-perceived resilience among people with adult congenital heart disease(ACHD).Secondary analysis of data from two com-plementary studies:a survey study conducted May 2021–June 2022 and a qualitative study conducted June 2020–August *** was assessed through CD-RISC10 score(range 0–40,higher scores reﬂect greater self-perceived resilience)and interview *** and SDOH(education,employment,living situa-tion,monetary stability,ﬁnancial dependency,area deprivation index)data were collected by healthcare record review and *** used linear regression with robust standard errors to analyze survey data and performed a thematic analysis of interview *** participants(N=127)mean age was 42±14 years;51%were female,87%*** was moderate(75%)or complex(25%);41%functional class C or ***(mean 30±7)varied by monetary stability:compared to people with difﬁculty paying bills,resilience was 15.0 points higher(95%CI:6.9–23.1,p<0.001)for people reporting having enough money and 14.2 points higher(95%CI:5.9–22.4,p=0.001)for those reporting just enough *** participants’(N=25)mean age was 32 years(range 22–44);52%were female,72%*** was moderate(56%)or complex(44%);76%functional class C or *** discussed factors affecting resilience aligned with each of the major SDOH,prominently,economic stability and healthcare access and *** stability may be important for supporting self-perceived resi-lience in *** knowledge can inform the development of resilience interventions for this population.

关键词： Social determinants of health adult congenital heart disease resilience ﬁnancial stability

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Treatment with intravenous alteplase in ischaemic stroke patients with onset time between 4.5 and 24 hours(HOPE):protocol for a randomised,controlled,multicentre study

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Stroke & Vascular Neurology 2024年第3期9卷 318-323,I0274-I0282页

作者： Zhongyu Luo Ying Zhou Yaode He Shenqiang Yan Zhicai Chen Xuting Zhang Yi Chen Lu-Sha Tong Wansi Zhong Haitao Hu Kemeng Zhang Jiansheng Yang Bruce C V Campbell Min Lou department of Neurology Zhejiang University School of Medicine Second Affiliated HospitalHangzhouZhejiangChina department of medicine and Neurology Melbourne Brain Centre at Royal Melbourne HospitalParkvilleVictoriaAustralia

Background While intravenous thrombolysis is recommended for patients who had an acute ischaemic stroke(AIS)within 4.5hours of symptom onset,there are few randomised trials investigating the benefits of thrombolysis beyond this therapeutic *** To determine whether patients who had an AIS selected with the presence of potentially salvageable tissue on CT perfusion at 4.5–24hours after stroke onset(for stroke with unknown onset time,the midpoint of the time last known to be well and symptom recognition time;for wake-up stroke,the midpoint of the time last known to be well or sleep onset and wake up time)will benefit from intravenous *** HOPE is a prospective,multicentre,randomised,open-label blinded endpoint trial with the stage of phase *** treatment allocation employs 1:1 *** treatment arm under investigation is alteplase with standard therapy,the control arm is standard *** imaging criteria include ischaemic core volume≤70mL,penumbra≥10mL and mismatch≥20%.Study outcomes The primary outcome is non-disabled functional outcome(assessed as modified Rankin Scale score of 0–1 at 90 days).Discussion HOPE is the first trial to investigate whether intravenous thrombolysis with alteplase offers benefits in patients who had an AIS presenting within 4.5–24hours,which has the potential to extend time window and expand eligible population for thrombolysis therapy.

关键词： patients intravenous centre

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