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DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Congenital Heart Diseases

Congenital Heart Disease 2024年第2期19卷 247-256页

作者： shuliang Xia Huikang Tao shixin su Xinxin Chen Li Ma Jianru Li Bei Gao Xumei Liu Lei Pi Jinqing Feng Fengxiang Li Jia Li Zhiwei Zhang Guangdong Provincial People’s hospital Southern Medical UniversityGuangzhou510100China Department of Cardiovascular surgery Guangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangdong Provincial Clinical Research Center for Child HealthGuangzhou510623China Department of Pediatric Cardiology Guangdong Cardiovascular InstituteGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhou510100China Clinical Physiology Laboratory Institute of PediatricsGuangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangdong Provincial Key Laboratory of Research in Structural Birth Defect DiseaseGuangzhou510623China Department of Echocardiogram Guangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangdong Provincial Clinical Research Center for Child HealthGuangzhou510623China Department of Pediatrics Washington University School of MedicineSt.LouisMO63130USA Clinical Biological Resource Bank of Guangzhou Women and Children’s medical center Guangzhou Medical UniversityGuangzhou510623China

Aims:Multiple genes and environmental factors are known to be involved in congenital heart disease(CHD),but epigenetic variation has received little ***(MZ)twins with CHD provide a unique model for exploring this *** order to investigate the potential role of Deoxyribonucleic Acid(DNA)methyla-tion in CHD pathogenesis,the present study examined DNA methylation variation in MZ twins discordant for CHD,especially ventricular septal defect(VsD).Methods and Results:Using genome-wide DNA methylation profiles,we identified 4004 differentially methylated regions(DMRs)in 18 MZ twin pairs discordant for CHD,and 2826 genes were *** Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed a list of CHD-associated *** further investigate the role of DNA methylation in VsD,data from 7 pairs of MZ twins with VsD were *** identified 1614 DMRs corresponding to 1443 genes associated with arrhythmogenic right ventricular cardiomyopathy,cyclic guanosine monopho-sphate-protein kinase G(cGMP-PKG)signaling pathway by KEGG analysis,and cell-cell adhesion,calcium ion transmembrane transport by GO analysis.A proportion of DMR-associated genes were involved in calcium signaling *** methylation changes of calcium signaling genes might be related to VsD ***:CHD is associated with differential DNA methylation in MZ *** may be etiologically linked to DNA methylation,and methylation of calcium signaling genes may be involved in the development of VsD.

关键词： Congenital heart disease monozygotic twins methylation modification epigenetics

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New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis

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World Journal of Clinical Cases 2024年第6期12卷 1050-1062页

作者： Tsvetelina Velikova Boris Krastev Milena Gulinac Miroslav Zashev Vasko Graklanov Milena Peruhova medical Faculty Sofia University St.Kliment OhridskiSofia 1407Bulgaria medical center Nadezhda Medical Center NadezhdaSofia 1407Bulgaria General and Clinical Pathology Medical University of PlovdivPlovdiv 4002Bulgaria Department of General surgery University Hospital“Heart and Brain”Burgas 8000Bulgaria First Department of Internal Diseases Medical University of PlovdivPlovdiv 4000Bulgaria Department of Hematology University Hospital“St.George”Plovdiv 4000Bulgaria Division of Gastroenterology University Hospital“Heart and Brain”Burgas 1000Bulgaria

Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 *** this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes *** represents a unique challenge due to its immune-mediated nature and potential for severe ***,a precise picture of IMC pathophysiology is currently ***,we aimed to summarize the existing data while acknowledging the need for further *** comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and *** review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of ***,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.

关键词： Immune-checkpoint inhibitors Immune-checkpoint inhibitor-mediated colitis Inhibitor-mediated colitis management Immunotherapy-associated colitis Checkpoint inhibitor-induced colitis Gastrointestinal adverse effects Checkpoint inhibitor toxicity Inhibitor-mediated colitis therapy

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

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signal Transduction and Targeted Therapy 2024年第1期9卷 105-149页

作者： Yumin Wang Jing Hu shuang Wu Joshua s.Fleishman Yulin Li Yinshi Xu Wailong Zou Jinhua Wang Yukuan Feng Jichao Chen Hongquan Wang Department of Respiratory and Critical Care Medicine Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Department of Pathogen Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300060PR China Department of Neurology Zhongnan Hospital of Wuhan UniversityWuhan 430000PR China Department of Pharmaceutical sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Department of Outpatient Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Beijing Key Laboratory of Drug Target and screening Research Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050PR China Department of Pancreatic Cancer Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060PR China

Ferroptosis,a unique modality of cell death with mechanistic and morphological differences from other cell death modes,plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug *** epigenetic modifications and posttranslational modifications(PTMs)promote anticancer drug resistance,cancer progression,and *** studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases(NsDs),cardiovascular diseases(CVDs),liver diseases,lung diseases,and kidney *** this review,we first summarize the core molecular mechanisms of ***,the roles of epigenetic processes,including histone PTMs,DNA methylation,and noncoding RNA regulation and PTMs,such as phosphorylation,ubiquitination,sUMOylation,acetylation,methylation,and ADP-ribosylation,are concisely *** roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases,including cancers,NsD,CVDs,liver diseases,lung diseases,and kidney diseases,as well as the application of epigenetic and PTM modulators in the therapy of these diseases,are then discussed in *** the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other *** addition,these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

关键词： diseases epigenetic overcome

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Retinal artery/arteriole occlusion risks after endovascular treatment for unruptured intracranial aneurysm

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stroke & Vascular Neurology 2024年第3期9卷 295-305,I0251-I0263页

作者： Hae Rang Kim Min Jeoung Kim sunyeup Kim Myung soo Chang Dong Joon Kim Byung Moon Kim Keun Young Park Yong Bae Kim Christopher seungkyu Lee suk Ho Byeon sung soo Kim seung Won Lee Yong Joon Kim Department of Ophthalmology CHA Bundang Medical CenterCHA University College of MedicineSeongnamKorea(the Republic of) Department of Neurosurgery Severance Stroke CenterSeverance HospitalYonsei University College of MedicineSeoulKorea(the Republic of) Department of Neurosurgery Uijeongbu St.Mary’s HospitalThe Catholic University of Korea College of MedicineUijeongbuKorea(the Republic of) Department of medical AI Sungkyunkwan University School of MedicineSuwonKorea(the Republic of) Department of Ophthalmology Institute of Vision ResearchYonsei University College of MedicineSeoulKorea(the Republic of) Department of Radiology Severance Stroke CenterSeverance HospitalYonsei University College of MedicineSeoulKorea(the Republic of) Department of Precision Medicine Sungkyunkwan University School of MedicineSuwonKorea(the Republic of)

Background To evaluate the association between retinal artery/arteriole occlusion(RAO)and unruptured intracranial aneurysm(UIA).Methods Incident UIA patients from a nationwide cohort(n=253240)were categorised into three groups based on subsequent treatment:observation(n=208993),microsurgical clipping(n=14168)and endovascular treatment(EVT)groups(n=30079).The incidence and the incident time of RAO were *** of RAO and associated risk factors were ***,a hospital cohort comprising 2569 consecutive UIA patients treated at a tertiary hospital was analysed with detailed clinical information of *** In the nationwide cohort analysis,the incidence of RAO was significantly higher in EVT group than in observation and clipping groups,especially within 60 days(early RAO(within 60 days):HR=4.00,95%CI:2.44 to 6.56);delayed RAO(after 60 days:HR=1.74,95%CI:1.13 to 2.68).Multivariable analysis showed that the presence of chronic kidney disease(p=0.009)and use of a balloon microcatheter during the procedure(p=0.013)were associated with a higher risk of *** hospital cohort analysis,11(0.8%)cases of RAO occurred after EVT,whereas none occurred after microsurgical clipping(ps with RAO were younger and received balloon microcatheters more frequently than their *** cases of RAO(90.9%)occurred in paraclinoid aneurysms,where EVT was preferred over microsurgical *** Performing EVT for UIA may increase the risk of subsequent *** should be taken when treating paraclinoid aneurysms with balloon microcatheters.

关键词： treatment nationwide balloon

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IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

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Genes & Diseases 2024年第1期11卷 464-478页

作者： Mengtian Fan Nana Geng Xingyue Li Danyang Yin Yuyou Yang Rong Jiang Cheng Chen Naibo Feng Li Liang Xiaoli Li Fengtao Luo Huabing Qi Qiaoyan Tan Yangli Xie Fengjin Guo Laboratory of Developmental Biology Department of Cell Biology and GeneticsSchool of Basic Medical ScienceChongqing Medical UniversityChongqing 400016China Laboratory of stem Cells and Tissue Engineering School of Basic Medical ScienceChongqing Medical UniversityChongqing 400016China Department of Orthopedics The 1st Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Wound Repair and Rehabilitation Medicine State Key Laboratory of TraumaBurns and Combined InjuryTrauma CenterResearch Institute of SurgeryDaping HospitalArmy Medical UniversityChongqing 400042China

Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is *** inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage ***,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains ***,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone ***1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth *** deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and ***1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage ***,ER stress cannot be activated normally in ERN1-deficient *** conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER ***1 may have a potential role as a new target for cartilage growth and maturation.

关键词： Cartilage development ER stress ERN1 IHH PTHrP/PTH1R

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Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen species/NF-κB signaling

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Journal of Clinical and Translational Hepatology 2024年第6期12卷 539-550页

作者： Xiaohui Xu Jinmei Feng Xin Wang Xin Zeng Ying Luo Xinyu He Meihua Yang Tiewei Lv Zijuan Feng Liming Bao Li Zhao Daochao Huang Yi Huang Institute of Pediatrics Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Pediatric Metabolism and Inflammatory DiseasesChongqingChina Department of Cardiology Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersNational Clinical Key Cardiovascular SpecialtyLaboratory of Children’s Important Organ Development and Diseases of Chongqing Municipal Health CommissionChongqingChina Department of Laboratory Medicine Chongqing Western HospitalChongqingChina Key Laboratory of Molecular Biology for Infectious Diseases Ministry of EducationInstitute for Viral HepatitisChongqing Medical UniversityChongqingChina Department of Laboratory Medicine The Third People’s Hospital of ChengduChengduSichuanChina Departments of Neurology Epilepsy CenterBarnes-Jewish Hospital and Washington University School of MedicineSt.LouisMOUSA Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College of Cornell UniversityNew YorkNYUSA Departments of Medicine(Oncology) Washington University School of MedicineSt.LouisMOUSA

Background and Aims:Hepatic fibrosis(HF)is a critical step in the progression of hepatocellular carcinoma(HCC).Gene associated with retinoid-IFN-induced mortality 19(GRIM19),an essential component of mitochondrial respiratory chain complex I,is frequently attenuated in various human cancers,including ***,we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF ***:GRIM19 expression was evaluated in normal liver tissues,hepatitis,hepatic cirrhosis,and HCC using human liver disease spectrum tissue *** studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats(CRIsPR)/CRIsPR-associated protein-9(Cas9)lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in *** performed flow cytometry,immunofluorescence,immunohistochemistry,western blotting,and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced ***:Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues,including hepatitis,cirrhosis,and HCC ***-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in *** addition,GRIM19 loss caused chronic liver injury through reactive oxygen species(ROs)-mediated oxidative stress,resulting in aberrant NF-κB activation via an IKK/IKB partner in ***-more,GRIM19 loss activated NLRP3-mediated IL33 signaling administration of the NLRP3 inhibitor MCC950 dramatically via the ROs/NF-κB pathway in *** alleviated GRIM19 loss-driven HF in ***:The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROs/NF-κB signaling,providing potential therapeutic approaches for earlier HF prevention.

关键词： Liver fibrosis GRIM19 Reactive Oxygen species NF-κB NLRP3 inflammasome IL33.

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spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma

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International Journal of Oral science 2024年第1期16卷 110-121页

作者： Zheqi Liu Zhen Zhang Yu Zhang Wenkai Zhou Xu Zhang Canbang Peng Tong Ji Xin Zou Zhiyuan Zhang Zhenhu Ren Department of Oral and Maxillofacial-Head and Neck Oncology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyShanghaiChina Department of Oral and Maxillofacial surgery Zhongshan HospitalFudan UniversityShanghaiChina school and hospital of stomatology Kunming Medical UniversityKunmingChina center for Tumor Diagnosis&Therapy Jinshan HospitalFudan UniversityShanghaiChina Department of Pathology Jinshan HospitalFudan UniversityShanghaiChina Hainan Western Central hospital Academician Zhang Zhiyuan Team Innovation CenterDanzhouChina

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OsCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OsCC, single cell (sC) and spatial transcriptomics (st) sequencing of OsCC tissues were performed. The proportion of TME in the st data was obtained through sPOTlight deconvolution using sC and GsE103322 data. The metabolic activity of each spot was calculated using scMetabolism,and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-βexpression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OsCC using sC, st and TCGA bulk data, and highlights potential targets for therapy.

关键词： CXCL12 microenvironment squamous

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Classification of musical hallucinations and the characters along with neural-molecular mechanisms of musical hallucinations associated with psychiatric disorders

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World Journal of Psychiatry 2024年第9期14卷 1386-1396页

作者： Xin Lian Wei song Tian-Mei si Naomi Zheng Lian Department of Radiology and Biomedical Imaging Shanxi Bethune HospitalShanxi Academy of Medical SciencesTaiyuan 030032Shanxi ProvinceChina Department of Psychiatry and Behavioral Neurosciences McMaster UniversityHamilton L8S 4L8ONCanada Department of Psychopharmacology Peking University Sixth HospitalBeijing 100191China Department of Psychiatry Hartford HealthCareSt Vincent’s Medical CenterWestportCT 06088United States

BACKGROUND Musical hallucinations(MH)involve the false perception of music in the absence of external stimuli which links with different *** pathomechanisms of MH encompass various *** etiological classification of MH is of particular importance and offers valuable insights to understand MH,and further to develop the effective treatment of *** the recent decades,more MH cases have been reported,revealing newly identified medical and psychiatric causes of *** imaging studies reveal that MH activates a wide array of brain *** up-to-date analysis on MH,especially on MH comorbid psychiatric conditions is *** To propose a new classification of MH;to study the age and gender differences of MH in mental disorders;and neuropathology of *** Literatures searches were conducted using keywords such as“music hallucination,”“music hallucination and mental illness,”“music hallucination and gender difference,”and“music hallucination and psychiatric disease”in the databases of PubMed,Google scholar,and Web of *** cases were collected and categorized based on their *** t-test and ANOVA were employed(Ps of MH different etiological *** neuroimaging studies of neural networks regulating MH and their possible molecular mechanisms were *** Among the 357 yielded publications,294 MH cases were *** average age of MH cases was 67.9 years,with a predominance of females(66.8%females vs 33.2%males).MH was classified into eight groups based on their etiological *** analysis of MH cases indicates varying associations with psychiatric *** We carried out a more comprehensive review of MH *** the first time according to our knowledge,we demonstrated the psychiatric conditions linked and/or associated with MH from statistical,biological and molecular point of view.

关键词： Pathomechanism Etiological factors Classification Gender difference Neuropathway Psychotic musical hallucination and non-psychotic musical hallucination Neuropathway Biological and molecular mechanism

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Moxibustion of Zusanli(st36)and shenshu(BL23)alleviates the inflammation of rheumatoid arthritis in rats through regulating macrophage migration inhibitory factor/glucocorticoids signaling

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Journal of Traditional Chinese Medicine 2024年第2期44卷 353-361页

作者： ZHANG Linlin ZHONG Yumei LU Wenting sHANG Yanan GUO Yanding LUO Xiaochao CHEN Yang LUO Kun HU Danhui YU Huiling ZHOU Haiyan Acupuncture and Moxibustion College Chengdu University of Traditional Chinese MedicineChengdu 610075China Department of Painology First People's Hospital of ChengduChengdu 610095China Chinese Evidence-Based Medicine Centre West China HospitalSichuan UniversityChengdu 610044China Traditional Chinese Medicine College Chongqing Medical UniversityChongqing 400016China External treatment center First People's Hospital of ChengduChengdu 610095China

OBJECTIVE:To test the hypothesis that moxibustion may inhibit rheumatoid arthritis(RA)synovial inflammation by regulating the expression of macrophage migration inhibitory factor(MIF)/glucocorticoids(GCs).METHODs:Fifty male sprague-Dawley rats were randomly divided into five groups(n=10 each):blank Control(CON)group,RA Model(RA)group,Moxibustion(MOX)group,MIF inhibitor(s,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester(IsO-1)group,and Moxibustion+MIF inhibitor IsO-1(MOX+IsO-1)*** in the IsO-1 group and IsO-1+MOX group were intraperitoneally injected with the inhibitor *** rats in the RA group,IsO-1 group,MOX group,and IsO-1+MOX group were injected with Freund's complete adjuvant(FCA)in the right hind footpad to establish an experimental RA rat *** the MOX group and MOX+IsO-1 group,rats were treated with *** thickness of the footpads of the rats in each group was measured at three-time points before,after modeling and after moxibustion *** contents of serum MIF,corticosterone(CORT),tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)were detected by enzyme-linked immunosorbent assay;and the contents of synovial MIF were detected by Western ***-eosin(HE)staining method was used to observe the pathological changes of synovial tissue under a section light microscope,and pathological scoring was performed according to the grading standard of the degree of synovial tissue ***:Moxibustion was found to reduce the level of MIF and alleviate inflammation in RA rats in this *** addition,after inhibiting the expression of MIF,the level of CORT increased,and the level of TNF-α *** RA rats with inhibited MIF by moxibustion,the level of CORT was almost unchanged,but the level of TNF-α further *** correlation analysis data suggested that MIF was positively related to the expression of TNF-α and negatively correlated with the expression of ***:Reducing MIF to

关键词： rheumatoid arthritis macrophage migration inhibitory factor moxibustion corticosterone glucocorticoids

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Optimal sequential therapy using tyrosine kinase inhibitors as the first-line treatment in patients with metastatic renal cell carcinoma: A nationwide multicenter study

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Asian Journal of Urology 2024年第3期11卷 450-459页

作者： Jung Ki Jo seong Il seo MinYong Kang Jinsoo Chung Cheol Kwak sung-Hoo Hong Cheryn song Jae Young Park Chang Wook Jeong seok Hwan Choi sung Han Kim Eu Chang Hwang Chan Ho Lee Hakmin Lee Department of Urology Medical and Digital EngineeringCollege of MedicineHanyang UniversitySeoulRepublic of Korea Department of Urology Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea Department of Urology National Cancer CenterGoyangRepublic of Korea Department of Urology Seoul National University HospitalSeoulRepublic of Korea Department of Urology Kangnam St Mary’s HospitalSeoulRepublic of Korea Department of Urology Asan Medical CenterSeoulRepublic of Korea Department of Urology Korea University Ansan HospitalAnsanRepublic of Korea Department of Urology Kyungpook National University HospitalDaeguRepublic of Korea Department of Urology Chonnam National University Hwasun HospitalHwasunRepublic of Korea Department of Urology Inje University Busan Paik HospitalBusanRepublic of Korea Department of Urology Seoul National University Bundang HospitalSeongnamRepublic of Korea

Objective:The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor(TKI)as the first-line therapy for patients with metastatic renal cell carcinoma(mRCC)in terms of overall survival(Os),progression-free survival(PFs),and rates of discontinuation and adverse effects during the treatment ***:This is a retrospective,nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December *** focused on patients at either“favorable”or“intermediate”risk according to the International mRCC Database Consortium criteria,and they were followed up(median 335 days).Finally,a total of 1409 patients were selected as the study *** generated a Cox proportional hazard model adjusted for covariates,and the different therapy schemes were statistically tested in terms of Os as well as *** addition,frequencies of discontinuation and adverse events were compared among the therapy ***:Of the primary patterns of treatment sequences(24 sequences),“sunitinib epazopanib”and“sunitinibeeverolimuseimmunotherapy”showed the most beneficial results in both Os and PFs with significantly lower hazards than“sunitinib”,which is the most commonly treated agent in *** that the“TKIeTKI”structure showed relatively higher discontinuation rates with higher adverse effects,the overall beneficial sequence would be“sunitinibeeverolimuseimmunotherapy”.Conclusion:Among several sequential therapy starting with TKIs,“sunitinibeeverolimuse immunotherapy”was found to be the best scheme for mRCC patients with“favorable”or“intermediate”risks.

关键词： Tyrosinekinase inhibitor Metastaticrenalcell carcinoma Overall survival Progression-free survival

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