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Clinical significance of mrp gene in primary hepatocellular carcinoma

Hepatobiliary & Pancreatic Diseases International 2003年第3期2卷 397-403页

作者： Bai-Lin Wang Xiao-Ping chen Shu-Ping Zhai de-feng chen the 3rd department of surgery, first affiliated hospital of guangzhou university of traditional medicine and pharmacy, guangzhou 510405, china the hepatic surgery center, tongji hospital, tongji medical college, huazhong university of science and technology, wuhan 430030, china The 3rd department of surgery First Affiliated Hospital of Guangzhou University of Traditional Medicine and Pharmacy Guangzhou 510405 China. wbl672000@***

OBJECTIVE: To study the relations among the expression of the multidrug resistance associated-protein (mrp) gene and clinicopathologic features, the influence of α-fetoprotein (AFP), and prognosis of patients who received adjuvant chemotherapy after resection of primary hepatocellular carcinoma (HCC). METHODS: The expression of the mrp gene encoding MRP and mRNAmrp was determined in tissues from 54 untreated patients with HCC, adjacent tissues from 24 patients with HCC and archival paraffin-embedded tissues from 12 patients with posthepatitic cirrhosis. The relationship between the mrp gene expression and the change level of AFP was analyzed in the 24 postoperative HCC patients whose AFP level was measured after 2 weeks. All of the HCC patients were followed up. RESULTS: The percentage of positive expressions of MRP and mRNAmrp in the three kinds of tissues was 57.40%, 25.00%, 16.67%, and 72.22%, 37.50%, 33.33% respectively. Significant difference was noted in the untreated HCC tissue, compared to the other two tissues (P 0.05), but the expression was related to the degree of differentiation of HCC (P3-, 5-year survival rates of HCC patients (P>0.05), the mean survival time of postoperative HCC patients or the negative mrp gene expression group was longer than that of the positive group (Pdetection of mrp gene expression is of great significance in accessing chemotherapeutic resistance of HCC, which provides evidence for reversing MDR in HCC. The mrp gene may be a useful marker in detecting prognosis of HCC p

关键词： hepatocellular carcinoma gene mrp MRP mrp RNV/messenger

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Chemokine-like factor 1 (CKLF1) is expressed in myocardial ischemia injury in vivo and in vitro

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BIOCELL 2024年第6期48卷 981-990页

作者： JULING feng HAODONG chen YANGBO LIU QIDI AI YANTAO YANG LEI ZHAO SHIfeng CHU NAIHONG chen School of pharmacy Department of PharmacyHunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction PiecesHunan University of Chinese MedicineChangsha410208China department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China department of Diagnostics Research Lab of Translational medicine Hengyang Medical CollegeUniversity of South ChinaHengyang421001China department of Gastrointestinal surgery The First Affiliated HospitalHengyang Medical CollegeUniversity of South ChinaHengyang421001China

Introduction:Chemokine-like factor 1(CKLF1)is a chemokine that is overexpressed in several *** previousﬁndings revealed a signiﬁcant increase in CKLF1 expression in the ischemic brain,suggesting its potential as a therapeutic target for ischemic ***:In this study,we examined the expression dynamics of CKLF1 in both in vivo and in vitro models of ischemic cardiac *** infarction(MI)was induced in vivo by ligation of the left anterior descending artery(LAD)of the rat *** levels of CKLF1,Creatine Kinase MB Isoenzyme(CK-MB),and Lactate dehydrogenase(LDH)in the serum were detected using Enzyme-linked immunosorbent assay(ELISA).The expression of CKLF1 in the infarcted area was detected by immunohistochemistry,immunoﬂuorescence,quantitative PCR(qPCR),and Western blotting(WB).H9C2 and AC16 cardiomyocytes cultured in vitro were subjected to oxygen and glucose deprivation(OGD).LDH was used to detect cell damage,and CKLF1 expression was detected by qPCR and ***:CKLF1 mRNA and protein expression were signiﬁcantly increased in h9c2 cells at 1.5 h and in AC16 cells at 4 h after *** serum CK-MB in rats increased signiﬁcantly on theﬁrst day after infarction,while the LDH concentration increased signiﬁcantly on the third day after ***1 blood levels signiﬁcantly increased on theﬁrst day following MI in ***1 expression notably increased in the infarct area on days 1,3,and 7 *** MI tissue,CKLF1 colocalizes with cardiomyocytes,macrophages,and ***:CKLF1 was substantially expressed during myocardial ischemia injury both in vivo and in vitro and was colocalized with macrophages and neutrophils,indicating that CKLF1 is expected to be a biomarker and a drug target for the treatment of myocardial infarction.

关键词： Chemokine-like factor 1 Overexpression Myocardial infarction

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development and validation of a nomogram to predict allograft survival after pediatric liver transplantation

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World Journal of Pediatrics 2024年第3期20卷 239-249页

作者： Guang-Xiang Gu Shu-Ting Pan Yi-chen Fan chen chen Qiang Xia department of Liver surgery Renji HospitalShanghai Jiaotong University School of MedicineNo.160 Pujian RoadPudong New DistrictShanghai 200128China department of Liver Transplantation Sun Yet-Sen Memorial HospitalSun Yat-Sen UniversityNo.107 Yanjiang West RoadGuangzhou 510080China Clinical center for Investigation Renji HospitalShanghai Jiaotong University School of MedicineShanghaiChina department of Anesthesiology Renji HospitalShanghai Jiaotong University School of MedicineShanghaiChina

Background Liver transplantation is the main treatment for cholestatic liver disease and some metabolic liver diseases in ***,no accurate prediction model to determine the survival probability of grafts prior to surgery *** study aimed to develop an effective prognostic model for allograft survival after pediatric liver *** This retrospective cohort study included 2032 patients who underwent pediatric liver transplantation between January 1,2006,and January 1,2020.A nomogram was developed using Cox regression and validated based on bootstrap *** and discriminatory accuracies were determined using the concordance index and visualized using calibration curves;net benefits were calculated for model *** online Shiny application was developed for easy access to the *** Multivariable analysis demonstrated that preoperative diagnosis,recipient age,body weight,graft type,preoperative total bilirubin,interleukin-1β,portal venous blood flow direction,spleen thickness,and the presence of heart disease and cholangitis were independent factors for survival,all of which were selected in the *** of the nomogram indicated that the 1-,3-,and 5-year predicted survival rates agreed with the actual survival *** concordance indices for graft survival at 1,3,and 5 years were 0.776,0.757,and 0.753,respectively,which were significantly higher than those of the Pediatric End-Stage Liver Disease and Child-Pugh scoring *** allograft dysfunction risk of a recipient could be easily predicted using the following URL:https://***/ASPELT/l Conclusion The allograft survival after pediatric liver transplantation(ASPELT)score model can effectively predict the graft survival rate after liver transplantation in children,providing a simple and convenient evaluation method for clinicians and patients.

关键词： Allograft survival Nomogram Pediatric liver transplantation

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IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

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Chinese Journal of Cancer Research 2024年第2期36卷 103-113页

作者： Yi-Long Wu Shun Lu Gongyan chen Jianxing He Jifeng feng Yiping Zhang Liyan Jiang Hongming Pan Jianhua Chang Jian Fang Amy Cai Lilian Bu Jane Shi Jinjing Xia Guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People's Hospital&Guangdong Academy of Medical SciencesSouthern Medical UniversityGuangzhou 510080China Shanghai Lung Cancer center Shanghai Chest HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200025China department of Respiration Harbin Cancer HospitalHarbin Medical UniversityHarbin 150081China department of Thoracic Oncology and surgery the First Affliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China department of medical Oncology Jiangsu Cancer HospitalNanjing 210009China department of medical Oncology Zhejiang Cancer HospitalHangzhou 330022China department of Pulmonary medicine Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China department of medical Oncology Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China department of medical Oncology Shenzhen HospitalCancer Hospital of Chinese Academy of Medical SciencesShenzhen 518116China department of Thoracic Oncology Beijing Cancer HospitalBeijing 100142China Product development Shanghai Roche Pharmaceutical LtdShanghai 201203China

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab *** as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian ***: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT ***: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel ***: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

关键词： Atezolizumab East Asia non-small cell lung cancer programmed death-ligand 1 inhibitors monoclonal antibody

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Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1302-1316页

作者： Xinyuan Xu Qian Zhang Xufeng Wang Jing Jin chengwei Wu Li feng Xiuyan Yang Mingzhu Zhao Yingyi chen Shaoyong Lu Zhen Zheng Xiaobing Lan Yi Wang Yan Zheng Xuefeng Lu Qiufen Zhang Jian Zhang State Key Laboratory of medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Medicinal Chemistry and Bioinformaticscenter Shanghai Jiao Tong University School of MedicineShanghai 200025China department of General surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefei 230026China department of Assisted Reproduction Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China college of pharmacy Ningxia Medical UniversityYinchuan 750004China department of Pancreatic surgery Shanghai General HospitalShanghai Key Laboratory of Pancreatic DiseaseInstitute of Pancreatic DiseaseShanghai Jiao Tong University School of MedicineShanghai 200080China

Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour ***6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic ***,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be ***,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/***,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/*** allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural ***,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver *** our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic *** not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

关键词： SIRT6 Inhibitor Allosteric Selectivity Cocrystal Pancreatic cancer metastasis

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Disruption of PABPN1 phase separation by SNRPD2 drives colorectal cancer cell proliferation and migration through promoting alternative polyadenylation of CTNNBIP1

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science china(Life sciences) 2024年第6期67卷 1212-1225页

作者： Zhijie Hu Mengxia Li Yufeng chen Liutao chen Yuting Han chengyong chen Xin Lu Nan You Yawen Lou Yingye Huang Zhanfeng Huo Chao Liu cheng Liang Susu Liu Ke deng Liangfu chen Shangwu chen Guohui Wan Xiaojian Wu Yonggui Fu Anlong Xu State Key Laboratory of Biocontrol Guangdong Province Key Laboratory of Pharmaceutical Functional GenesDepartment of BiochemistrySchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China department of General surgery(Colorectal surgery)&Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases&Biomedical Innovation center The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation National Engineering Research Center for New Drug and Druggability(cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China School of Life sciences Beijing University of Chinese MedicineBeijing 100029China

Generally shortened 3′UTR due to alternative polyadenylation(APA)is widely observed in cancer,but its regulation mechanisms for cancer are not well ***,with profiling of APA in colorectal cancer tissues and poly(A)signal editing,we firstly identified that the shortened 3′UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and *** found that liquid-liquid phase separation(LLPS)of PABPN1 is reduced albeit with higher expression in cancer,and the reduction of LLPS leads to the shortened 3′UTR of CTNNBIP1and promotes cell proliferation and ***,the splicing factor SNRPD2 upregulated in colorectal cancer,can interact with glutamic-proline(EP)domain of PABPN1,and then disrupt LLPS of PABPN1,which attenuates the repression effect of PABPN1 on the proximal poly(A)*** results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1,suggesting that regulation of APA by interfering LLPS of 3′end processing factor may have the potential as a new way for the treatment of cancer.

关键词： alternative polyadenylation colorectal cancer CTNNBIP1 PABPN1 liquid-liquid phase separation SNRPD2

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ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3027-3048页

作者： Mengdie Dong Yunjia Zhang Minghong chen Yongkang Tan Jiao Min Xian He Fuhao Liu Jiaming Gu Hong Jiang Longbin Zheng Jiajing chen Quanwen Yin Xuesong Li Xiang chen Yongfeng Shao Yong Ji Hongshan chen department of Cardiovascular surgery the First Affiliated Hospital of Nanjing Medical Universityand Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNational Vaccine Innovation PlatformNanjing Medical UniversityNanjing 211166China Key Laboratory of Cardiovascular and Cerebrovascular medicine School of PharmacyNanjing Medical UniversityNanjing 211166China department of Clinical medicine Nanjing Medical University TIANYUAN Honors SchoolNanjing Medical UniversityNanjing 211166China department of Anesthesiology Sir Run Run HospitalNanjing Medical UniversityNanjing 211166China department of Cardiovascular surgery the First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166China Key Laboratory of Cardiovascular and Cerebrovascular medicine Key Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineState Key Laboratory of Reproductive MedicineSchool of Pharmacythe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversityNanjing 211166China National Key Laboratory of Frigid Zone Cardiovascular Diseases(NKLFZCD) Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China)College of PharmacyKey Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial IschemiaChinese Ministry of EducationNHC Key Laboratory of Cell Transplantationthe Central Laboratory of the First Affiliated HospitalHarbin Medical UniversityHarbin 150081China Key Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China department of Cardiology Huai’an First People’s Hospital Affiliated with Nanjing Medical UniversityHuai’an 223399China

Endothelial-to-mesenchymal transition(EndMT)is a key driver of *** glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate *** lactylation,mediated by lactate,can regulate gene expression and participate in disease ***,whether histone lactylation is involved in atherosclerosis remains ***,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’***,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting *** found that deletion of ASF1A inhibited EndMT and improved endothelial *** analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis *** of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced *** study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.

关键词： Histone lactylation Atherosclerosis Endothelial-tomesenchymal transition ASF1A SNAI1 Endothelial dysfunction Lactate Epigenetic

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GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

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Acta Pharmaceutica Sinica B 2024年第2期14卷 698-711页

作者： Qiwei Jiang Yong Li Songwang Cai Xingyuan Shi Yang Yang Zihao Xing Zhenjie He Shengte Wang Yubin Su Meiwan chen Zhesheng chen Zhi Shi department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineState Key Laboratory of Bioactive Molecules and Druggability AssessmentMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China department of Gastrointestinal surgery&General surgery the Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080China department of Thoracic surgery The First Affiliated Hospital of Jinan UniversityGuangzhou 510632China department of Radiation Oncology The Fifth Hospital of Guangzhou Medical UniversityGuangzhou 510150China State Key Laboratory of Quality Research in Chinese medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 519000China department of Pharmaceutical sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

关键词： Gastric cancer GLUL N-Cadherin β-Catenin Enzyme

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The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions:insights from a single-arm,phase II trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2202-2214页

作者： Bo cheng Caichen Li Jianfu Li Longlong Gong Peng Liang Ying chen Shuting Zhan Shan Xiong Ran Zhong Hengrui Liang Yi feng Runchen Wang Haixuan Wang Hongbo Zheng Jun Liu chengzhi Zhou Wenlong Shao Yuan Qiu Jiancong Sun Zhanhong Xie Zhu Liang chenglin Yang Xiuyu Cai Chunxia Su Wei Wang Jianxing He Wenhua Liang department of Thoracic surgery and Oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina medical department Genecast Biotechnology Co.LtdWuxiChina department of Radiation Oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina department of Respiratory medicine the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina department of Cardiothoracic surgery Affiliated Hospital of Guangdong Medical UniversityZhanjiangChina department of Thoracic surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina department of VIP Inpatient Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaSun Yat-sen UniversityGuangzhouChina department of medical Oncology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina

Immune checkpoint inhibitors targeting the programmed cell death-1(PD-1)protein significantly improve survival in patients with advanced non-small-cell lung cancer(NSCLC),but its impact on early-stage ground-glass opacity(GGO)lesions remains *** is a single-arm,phase II trial(NCT04026841)using Simon’s optimal two-stage design,of which 4 doses of sintilimab(200 mg per 3 weeks)were administrated in 36 enrolled multiple primary lung cancer(MPLC)patients with persistent high-risk(Lung-RADS category 4 or had progressed within 6 months)*** primary endpoint was objective response rate(ORR).T/B/NK-cell subpopulations,TCR-seq,cytokines,exosomal RNA,and multiplexed immunohistochemistry(mIHC)were monitored and compared between responders and ***,two intent-to-treat(ITT)lesions(pure-GGO or GGO-predominant)showed responses(ORR:5.6%,2/36),and no patients had progressive disease(PD).No grade 3-5 TRAEs *** total response rate considering two ITT lesions and three non-intent-to-treat(NITT)lesions(pure-solid or solid-predominant)was 13.9%(5/36).The proportion of CD8^(+)T cells,the ratio of CD8^(+)/CD4^(+),and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over ***,the mIHC analysis showed more CD8^(+)T cells infiltrated in ***,responders’cytokine concentrations of EGF and CTLA-4 increased during *** exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among ***,PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety *** effects were associated with specific T-cell re-distribution,EGF/CTLA-4 cytokine compensation,and regulation of metabolism pathways.

关键词： lesions metabolism doses

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RNA m^(6)A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression

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Genes & Diseases 2024年第1期11卷 382-396页

作者： Zheng Zhang Keren Zhou Li Han Andrew Small Jianhuang Xue Huilin Huang Hengyou Weng Rui Su Brandon Tan Chao Shen Wei Li Zhicong Zhao Ying Qing Xi Qin Kitty Wang Keith Leung Mark Boldin Chun-Wei chen David Ann Zhijian Qian Xiaolan deng Jianjun chen Zhenhua chen department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA 91016USA Irell and Manella Graduate School of Biological sciences Beckman Research Institute of City of HopeDuarteCA 91010USA Gehr Family center for Leukemia Research City of HopeDuarteCA 91010USA Sun Yat-sen university Cancer center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060China guangzhou Laboratory GuangzhouGuangdong 510005China Bioland Laboratory GuangzhouGuangdong 51005China department of Liver surgery Renji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China department of Diabetes Complications and Metabolism Beckman Research Institute of City of HopeDuarteCA 91010USA department of Biochemistry and Molecular Biology University of FloridaGainesvilleFL 32603USA tongji hospital affiliated to tongji university Frontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China School of pharmacy China Medical UniversityShenyangLiaoning 110001China

As the most common internal modification of mRNA,Ne-methyladenosine(m^(6)A)and its regulators modulate gene expression and play critical roles in various biological and patholog-ical processes including *** was reported previously that m^(6)A methyltransferase(writer),methyltransferase-like 3(METTL3)adds m^(6)A in primary microRNAs(pri-miRNAs)and fa-cilitates its processing into precursor miRNAs(pre-miRNAs).However,it is unknown whether m^(6)A modification also plays a role in the maturation process of pre-miRNAs and(if so)whether such a function contributes to ***,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in ***,YTHDF2 promotes expression of miR-126-3p(also known as miR-126,as it is the main product of precursor miR-126(pre-miR-126)),a miRNA that was reported as an oncomiRNA in AML,through facilitating the processing of pre-miR-126 into mature ***,YTHDF2 recognizes m^(6)A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of ***2 posi-tively and negatively correlates with miR-126 and miR-126's downstream target genes,respec-tively,in AML patients,and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis,indi-cating that miR-126 is a functionally important target of YTHDF2 in ***,our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the ther-apeutic potential of targeting this axis for AML treatment,but also suggest that m^(6)A plays a role in pre-miRNA processing that contributes to tumorigenesis.

关键词： AML miR-126 N^(6)-methyladenosine Pre-miRNA maturation YTHDF2

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