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High-throughput screening of novel TFEB agonists in protecting against acetaminopheninduced liver injury in mice

Acta Pharmaceutica Sinica B 2024年第1期14卷 190-206页

作者： Xiaojuan Chao Mengwei Niu Shaogui Wang Xiaowen Ma Xiao Yang Hua Sun Xujia Hu Hua Wang Li Zhang Ruili Huang Menghang Xia Andrea Ballabio Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China department of Oncology the First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China national Center for Advancing Translational Sciences National Institutes of HealthBethesdaMD 20892USA Telethon Institute of Genetics and Medicine TIGEMPozzuoliNaples 80131Italy medical Genetics Department of Translational MedicineFederico II UniversityNaples 80131Italy department of Molecular and Human Genetics Baylor College of MedicineHoustonTX 77030USA department of Internal Medicine Division of GastroenterologyHepatology&MotilityUniversity of Kansas Medical CenterKansas CityKS 66160USA

Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and *** studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein *** lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with *** the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse *** loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,***,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against *** also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB *** these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in *** conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

关键词： Autophagy DILI Drug screening Hepatotoxicity Lysosome Mitochondria Mitophagy NRF2

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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

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Signal Transduction and Targeted Therapy 2024年第2期9卷 738-750页

作者： Yun Zhang Lijun Du Chenxi Wang Zhangsheng Jiang Qingchi Duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen Key Laboratory of Chinese medicine rheumatology of Zhejiang Province Research Institute of Chinese Medical Clinical Foundation and ImmunologyCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Cancer Center of Zhejiang university Hangzhou 310029China department of pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Chongqing International Institute for Immunology Chongqing 400038China

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to *** dysregulation of double-negative(DN)T cells is considered as a crucial commander during ***,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune ***,the function of neddylation in SLE is still ***,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus *** investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus *** double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus *** findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus ***,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was ***,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation ***,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE ***,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

关键词： inactivation double finding

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A circular single-stranded DNA mycovirus infects plants and confers broad-spectrum fungal resistance

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Molecular Plant 2024年第6期17卷 955-971页

作者： Xianhong Wang Ioly Kotta-Loizou Robert H.A.Coutts Huifang Deng Zhenhao Han Ni Hong Karim Shafik Liping Wang Yashuang Guo Mengmeng Yang Wenxing Xu Guoping Wang national Key Laboratory for Germplasm Innovation&Utilization of Horticultural Crops Wuhan 430070China Hubei Hongshan Laboratory Wuhan 430070China College of Plant Science and Technology Huazhong Agricultural UniversityWuhan 430070China Key Lab of Plant pathology of Hubei Province Wuhan 430070China department of Life Sciences Faculty of Natural SciencesImperial College LondonLondon SW72AZUK department of Clinical Pharmaceutical and Biological ScienceSchool of Life and Medical SciencesUniversity of HertfordshireHatfield AL109ABUK department of Plant pathology Faculty of AgricultureAlexandria UniversityAlexandria 21526Egypt

Circular single-stranded DNA(ssDNA)viruses have been rarely found in fungi,and the evolutionary and ecological relationships among ssDNA viruses infecting fungi and other organisms remain *** this study,a novel circular ssDNA virus,tentatively named Diaporthe sojae circular DNA virus 1(DsCDV1),was identified in the phytopathogenic fungus Diaporthe sojae isolated from pear ***1 has a monopartite genome(3185 nt in size)encapsidated in isometric virions(21-26 nm in diameter).The genome comprises seven putative open reading frames encoding a discrete replicase(Rep)split by an intergenic region,a putative capsid protein(CP),several proteins of unknown function(P1-P4),and a long intergenic ***,the two split parts of DsCDV1 Rep share high identities with the Reps of Geminiviridae and Genomoviridae,respectively,indicating an evolutionary linkage with both *** analysis based on Rep or CP sequences placed DsCDV1 in a unique cluster,supporting the establishment of a new family,tentatively named Gegemycoviridae,intermediate to both ***1 significantly attenuates fungal growth and nearly erases fungal virulence when transfected into the host ***,DsCDV1 can systematically infect tobacco and pear seedlings,providing broad-spectrum resistance to fungal *** localization analysis revealed that DsCDV1 P3 is systematically localized in the plasmodesmata,while its expression in trans-complementation experiments could restore systematic infection of a movement-deficient plant virus,suggesting that P3 is a movement ***1 exhibits unique molecular and biological traits not observed in other ssDNA viruses,serving as a link between fungal and plant ssDNA viruses and presenting an evolutionary connection between ssDNA viruses and *** findings contribute to expanding our understanding of ssDNA virus diversity and evolution,offering potential biocontrol applications for managing crucial plant d

关键词： circular single-stranded DNA virus mycovirus virus evolution Genomoviridae Gegemycoviridae Diaporthe sojae circular DNA virus 1

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CD97 inhibits osteoclast differentiation via Rap1a/ERK pathway under compression

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International Journal of Oral Science 2024年第1期16卷 134-144页

作者： Xuan Zhou Xinjia Cai Fengyang Jing Xuefen Li Jianyun Zhang Heyu Zhang Tiejun Li department of Oral pathology Peking University School and Hospital of Stomatology&National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Laboratory for Digital and Material Technology of Stomatology&Beijing Key Laboratory of Digital Stomatology&Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health&NMPA Key Laboratory for Dental MaterialsBeijingChina Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions Chinese Academy of Medical Sciences(2019RU034)BeijingChina Central Laboratory Peking University School and Hospital of StomatologyBeijingChina

Acceleration of tooth movement during orthodontic treatment is challenging, with osteoclast-mediated bone resorption on the compressive side being the rate-limiting step. Recent studies have demonstrated that mechanoreceptors on the surface of monocytes/macrophages, especially adhesion G protein-coupled receptors (aGPCRs), play important roles in force ***, its role in the regulation of osteoclast differentiation remains unclear. Herein, through single-cell analysis, we revealed that CD97, a novel mechanosensitive aGPCR, was expressed in macrophages. Compression upregulated CD97 expression and inhibited osteoclast differentiation;while knockdown of CD97 partially rescued osteoclast differentiation. It suggests that CD97 may be an important mechanosensitive receptor during osteoclast differentiation. RNA sequencing analysis showed that the Rap1a/ERK signalling pathway mediates the effects of CD97 on osteoclast differentiation under compression. Consistently, we clarified that administration of the Rap1a inhibitor GGTI298 increased osteoclast activity, thereby accelerating tooth movement. In conclusion,our results indicate that CD97 suppresses osteoclast differentiation through the Rap1a/ERK signalling pathway under orthodontic compressive force.

关键词： CD97 osteoclast inhibited

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Novel DNA methylation markers for early detection of gastric cardia adenocarcinoma and esophageal squamous cell carcinoma

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Science China Life Sciences 2024年

作者： Zhiyuan Fan Jiajie Hao Feifan He Hao Jiang Jinwu Wang Minjuan Li Xinqing Li Ru Chen Wenqiang Wei Office of national Central Cancer Registry National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Molecular Oncology Center for Cancer Precision MedicineNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College school of Population Medicine and Public Health Chinese Academy of Medical Sciences and Peking Union Medical College department of pathology Linzhou Cancer Hospital department of Orthopedic Surgery Beijing Jishuitan HospitalCapital Medical University Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical University

Gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) present significant health challenges in China,often diagnosed at advanced stages with poor ***,effective biomarkers for early detection remain *** study aimed to integrate methylome and transcriptome data to identify DNA methylation markers for the early detection of GCA and *** the discovery stage,we conducted Infinium MethylationEPIC array analysis on 36 paired GCA and non-tumor adjacent tissues (NAT),identifying differentially methylated CpG sites (DMCs) between GCA/ESCC and NAT through combined analyses of in-house and publicly available *** the validation stage,targeted pyrosequencing and quantitative real-time RT-PCR were performed on paired tumor and NAT samples from 50GCA and 50 ESCC *** the application stage,an independent set of 438 samples,including GCA,ESCC,high-and low-grade dysplasia(HGD/LGD),and normal controls,was tested for selected DMCs using *** analysis validated three GCA-specific,two ESCC-specific,and one tumor-shared DMCs,exhibiting significant hypermethylation and decreased expression of target genes in tumor samples compared with *** these DMCs,we developed a GCA-specific 4-marker panel (cg27284428,cg11798358,cg07880787,and cg00585116) with an area under the receiver operating characteristic curve (AUC) of 0.917,effectively distinguishing between cardia HGD/GCA patients and cardia LGD/normal ***,an ESCC-specific 3-marker panel (cg14633892,cg04415798,and cg00585116)achieved an AUC of 0.865 in distinguishing esophageal HGD/ESCC ***,integrating cg00585116,age,and alcohol consumption yielded a tumor-shared logistic model with good discrimination for two cancer/HGD (AUC,0.767;95%confidence interval,0.720–0.813).The mean AUC of the model after 5-fold cross-validation was *** summary,our study identifies novel DNA methylation markers capable of accurately distinguishing

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Exploring unconventional attributes of red blood cells and their potential applications in biomedicine

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Protein & Cell 2024年第5期15卷 315-330页

作者： Alkmini T.Anastasiadi Vasiliki-Zoi Arvaniti Krystalyn E.Hudson Anastasios G.Kriebardis Constantinos Stathopoulos Angelo D’Alessandro Steven L.Spitalnik Vassilis L.Tzounakas department of Biochemistry School of MedicineUniversity of Patras26504 PatrasGreece department of pathology and Cell Biology Columbia University Irving Medical CenterNew York CityNY 10032USA Laboratory of Reliability and Quality Control in Laboratory Hematology(HemQcR) Department of Biomedical SciencesSchool of Health&Caring SciencesUniversity of West Attica(UniWA)12243 EgaleoGreece department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus13001 AuroraCOUSA Present address:Institute for Fundamental Biomedical Research(IFBR) Biomedical Sciences Research Center“Alexander Fleming”Vari11527 AthensGreece

We need to talk about red blood *** cells are defined as cells containing distinct nuclei and other membranous ***,red blood cells(RBCs)lack a nucleus and organelles—perhaps to limit the generation of reactive oxygen species(Zhang et al.,2011)—and are filled with hemoglobin(Hb).This oxygen carrier is limited to the cytosol by the cell membrane and cytoskeleton,which maintain cellular integrity and deformability as RBCs pass through narrow capillaries(Gratzer,1994)to perform their primary function of gas exchange.

关键词： membranous maintain

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Infectious causes of fever of unknown origin in developing countries: An international ID-IRI study

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Journal of Intensive Medicine 2024年第1期4卷 94-100页

作者： Hakan Erdem Jaffar AAl-Tawfiq Maha Abid Wissal Ben Yahia George Akafity Manar Ezzelarab Ramadan Fatma Amer Amani El-Kholy Atousa Hakamifard Bilal Ahmad Rahimi Farouq Dayyab Hulya Caskurlu Reham Khedr Muhammad Tahir Lysien Zambrano Mumtaz Ali Khan Aun Raza Nagwa Mostafa El-Sayed Magdalena Baymakova Aysun Yalci Yasemin Cag Umran Elbahr Aamer Ikram department of Infectious Diseases&Clinical Microbiology Gulhane School of MedicineTurkish Health Sciences UniversityAnkaraTurkey Specialty Internal Medicine and Quality and Patient Safety department Johns Hopkins Aramco HealthcareDhahranSaudi Arabia Division of Infectious Diseases Indiana University School of MedicineIndianapolisINUSA department of Infectious Diseases Farhat Hached University HospitalIbn El Jazzar Medical SchoolUniversity of SousseSousseTunisia Internal Medicine department Farhat Hached University HospitalIbn El Jazzar Medical SchoolUniversity of SousseSousseTunisia Cape Coast Teaching Hospital Cape CoastGhana medical Parasitology Faculty of MedicineSuez UniversitySuezEgypt department of medical Microbiology and Immunology Faculty of MedicineZagazig UniversityZagazigEgypt department of Clinical pathology Faculty of MedicineCairo UniversityGizaEgypt department of Infectious Diseases School of MedicineIsfahan University of Medical SciencesIsfahanIran department of Infectious Diseases Kandahar University Medical FacultyTeaching HospitalKandaharAfghanistan department of Infectious Diseases Mohammed Bn Khalifa Bn Salman Alkhalifa Specialist Cardiac CenterAwaliBahrain department of Infectious Diseases and Clinical Microbiology Faculty of MedicineIstanbul Medeniyet UniversityIstanbulTurkey department of Pediatric Oncology National Cancer Institute–Cairo UniversityChildren Cancer Hospital EgyptCairoEgypt department of Medicine Federal General HospitalIslamabadPakistan Institute for Research in medical Sciences and Right to Health(ICIMEDES) Scientific Research Unit(UIC)Faculty of Medical Sciences(FCM)National Autonomous University of Honduras(UNAH)TegucigalpaHonduras national Institute of Health IslamabadPakistan Shaukat Khanum Memorial Cancer Hospital and Research Center LahorePakistan medical Parasitology department Research Institute of OphthalmologyGizaEgypt department of Infectious Diseases Military Medical AcademySofiaBulgaria department of Infecti

Background:Fever of unknown origin(FUO)in developing countries is an important dilemma and further research is needed to elucidate the infectious causes of ***:A multi-center study for infectious causes of FUO in lower middle-income countries(LMIC)and lowincome countries(LIC)was conducted between January 1,2018 and January 1,*** total,15 participating centers from seven different countries provided the data,which were collected through the Infectious DiseasesInternational Research Initiative *** adult patients with confirmed infection as the cause of FUO were included in the *** severity parameters were quick Sequential Organ Failure Assessment(qSOFA)≥2,intensive care unit(ICU)admission,vasopressor use,and invasive mechanical ventilation(IMV).Results:A total of 160 patients with infectious FUO were included in the ***,148(92.5%)patients had community-acquired infections and 12(7.5%)had hospital-acquired *** most common infectious syndromes were tuberculosis(TB)(n=27,16.9%),infective endocarditis(n=25,15.6%),malaria(n=21,13.1%),brucellosis(n=15,9.4%),and typhoid fever(n=9,5.6%).Plasmodium falciparum,Mycobacterium tuberculosis,Brucellae,Staphylococcus aureus,Salmonella typhi,and Rickettsiae were the leading infectious agents in this study.A total of 56(35.0%)cases had invasive procedures for *** mean qSOFA score was 0.76±0.94{median(interquartile range[IQR]):0(0–1)}.ICU admission(n=26,16.2%),vasopressor use(n=14,8.8%),and IMV(n=10,6.3%)were not ***,38(23.8%)patients had at least one of the severity *** mortality rate was 15(9.4%),and the mortality was attributable to the infection causing FUO in 12(7.5%)***:In LMIC and LIC,tuberculosis and cardiac infections were the most severe and the leading infections causing FUO.

关键词： Developing countries Fever of unknown origin Infection

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Injectable“cocktail”hydrogel with dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic effect

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SmartMat 2024年第2期5卷 43-53页

作者： Li Zhao Jiawen Xu Yao Tong Pengyu Gong Fucheng Gao Hui Li Yanyan Jiang Key Laboratory for Liquid-Solid Structural Evolution&Processing of Materials(Ministry of Education) School of Materials Science and EngineeringShandong UniversityJinanChina department of pathology Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina department of Clinical Laboratory The Second HospitalCheeloo College of MedicineShandong UniversityJinanChina

The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HER-2)overexpressing breast cancer ***,insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical ***,an in situ forming gold nanorods(AuNRs)-sodium alginate(ALG)hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable,dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic *** photothermal agent AuNRs,anticancer drug DOX,and anticancer antibody HCT were mixed in ALG solution,and after injection,the soluble ALG was quickly transformed into a hydrogel in the presence of Ca^(2+)in the ***,the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70%under 808 nm laser *** thermal effect can also provide photothermal stimulation to trigger the drug release from the gel *** addition,the drug release rate and the releasing degree are also sensitive to the *** vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 *** vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor *** proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.

关键词： dual-stimuli-responsive drug release HER-2 overexpressing breast cancer injectable hydrogel photothermal therapy synergistic effect

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Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 2060-2073页

作者： Jing Zhou Mei-Ying Zhang Ai-Ai Gao Cheng Zhu Tao He James G Herman Ming-Zhou Guo school of Medicine NanKai UniversityTianjin 300071China department of Gastroenterology and Hepatology The First Medical CenterChinese PLA General HospitalBeijing 100853China departments of pathology Characteristic Medical Center of The Chinese People’s Armed Police ForceTianjin 300162China The Hillman Cancer Center University of Pittsburgh Cancer InstitutePittsburghPA 15213United States national Key Laboratory of Kidney Diseases Chinese PLA General HospitalBeijing 100853China

BACKGROUND Targeting DNA damage response(DDR)pathway is a cutting-edge *** has been reported that Schlafen-11(SLFN11)contributes to increase chemosensitivity by participating in ***,the detailed mechanism is *** To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 *** To reach the purpose,eight esophageal squamous carcinoma cell lines,142 esophageal dysplasia(ED)and 1007 primary esophageal squamous cell carcinoma(ESCC)samples and various techniques were utilized,including methylationspecific polymerase chain reaction,CRISPR/Cas9 technique,Western blot,colony formation assay,and xenograft mouse *** Methylation of SLFN11 was exhibited in 9.15%of(13/142)ED and 25.62%of primary(258/1007)ESCC cases,and its expression was regulated by promoter region ***11 methylation was significantly associated with tumor differentiation and tumor size(both P<0.05).However,no significant associations were observed between promoter region methylation and age,gender,smoking,alcohol consumption,TNM stage,or lymph node *** DNA damaged model induced by low dose cisplatin,SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways,while inhibiting the ATM/CHK2 signaling *** silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor(AZD0156),both in vitro and in *** SLFN11 is frequently methylated in human *** of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

关键词： Schlafen-11 Esophageal squamous cell carcinoma DNA methylation Synthetic lethality AZD0156

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Targeting proprotein convertase subtilisin/kexin type 9(PCSK9):from bench to bedside

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Signal Transduction and Targeted Therapy 2024年第2期9卷 509-557页

作者： Xuhui Bao Yongjun Liang Hanman Chang Tianji Cai Baijie Feng Konstantin Gordon Yuekun Zhu Hailian Shi Yundong He Liyi Xie Institute of Therapeutic Cancer Vaccines Fudan University Pudong Medical CenterShanghaiChina Shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghaiChina department of Oncology Fudan University Pudong Medical CenterShanghaiChina Center for Clinical Research Fudan University Pudong Medical CenterShanghaiChina Clinical Research Center for Cell-based Immunotherapy Fudan UniversityShanghaiChina department of pathology Duke University Medical CenterDurhamNCUSA Center for medical Research and Innovation Fudan University Pudong Medical CenterShanghaiChina Institute for Food Safety and Health Illinois Institute of TechnologyChicagoILUSA department of Sociology University of MacaoTaipaMacaoChina medical Institute Peoples’Friendship University of RussiaMoscowRussia A.Tsyb medical Radiological Research Center ObninskRussia department of Colorectal Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineZhangjiang Hi-tech ParkShanghaiChina department of Radiation Oncology Fudan University Shanghai Cancer CenterShanghaiChina department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina

Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,*** exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular *** also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient *** advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular *** therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular ***,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer *** review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer *** conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms acr

关键词： PCSK9 metabolism convert

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