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Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

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Neural Regeneration Research 2025年第1期20卷 265-276页

作者： Yao Yuan Lingqi Yu Xudong Zhuang Dongjing Wen Jin He Jingmei Hong Jiayu Xie Shengan Ling Xiaoyue Du Wenfeng Chen Xinrui Wang Institute of Life Sciences College of Biological Science and EngineeringFuzhou UniversityFuzhouFujian ProvinceChina NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primate(Fujian Maternity and Child Health Hospital) FuzhouFujian ProvinceChina Medical Research center Fujian Maternity and Child Health HospitalCollege of Clinical Medicine for Obstetrics&Gynecology and PediatricsFujian Medical UniversityFuzhouFujian ProvinceChina Department of Neurology and Institute of Neurology of The First Affiliated Hospital Institute of Neuroscienceand Fujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouFujian ProvinceChina

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory *** develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause *** located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)*** addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive *** these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut *** found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in *** heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal *** Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

关键词： ATP1A1 Atpα bang-sensitive paralysis Charcot-Marie-Tooth disease type 2 CRISPR/Cas9 homology-directed repair Na^(+)/K^(+)-ATPase point mutation seizures sodium pump

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Sintilimab-induced autoimmune diabetes:A case report and review of the literature

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World Journal of clinical Cases 2022年第4期10卷 1263-1277页

作者： Jing Yang Ying Wang Xiang-Min Tong clinical Laboratory center Zhejiang Provincial People’s HospitalHangzhou 310014Zhejiang ProvinceChina clinical Research Institute Zhejiang Provincial People’s HospitalHangzhou 310014Zhejiang ProvinceChina Department of Hematology Clinical Trial InstituteZhejiang Provincial People’s HospitalHangzhou 310014Zhejiang ProvinceChina

BACKGROUND With the widespread application of immune checkpoint inhibitor(ICI)therapy,the number of immune-related adverse effects(irAEs)has increased over the *** diabetes mellitus(DM)is a rare irAEs of ICIs and can be troublesome and life *** SUMMARY We report a 78-year-old woman with no history of diabetes who presented with hyperglycemia up to 23.4 mmol/L(random blood glucose level)after 14 courses of *** A1c was 8.2%,fasting insulin was 0.29 mIU/mL,and fasting C-peptide was decreased to a level with negative *** her medical history and laboratory examination,she was diagnosed with programmed cell death(PD)-1-inhibitor-induced,new-onset autoimmune *** controlling her blood glucose,she was treated with daily insulin by subcutaneous *** was allowed to continue anti-PD-1 therapy and she still obtained some therapeutic *** also reviewed some published cases(n=36)of PD-1/PD-ligand 1(PD-L1)inhibitor-induced *** also discuss potential pathogenic mechanisms,clinical features,prognostic markers(βcell antibodies,human leukocyte antigen type,PD-L1 Level)of this rare adverse *** It is important for all clinicians to be aware of DM as an irAEs of ICIs.

关键词： Sintilimab Immune related adverse effects Small cell lung cancer Autoimmune diabetes Case report

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Filamentation and inhibition of prokaryotic CTP synthase with ligands

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mLife 2024年第2期3卷 240-250页

作者： Chenjun Guo Zixuan Wang Ji‐Long Liu School of Life Science and Technology ShanghaiTech UniversityShanghaiChina Department of Physiology Anatomy and GeneticsUniversity of OxfordOxfordUK Shanghai clinical Research and trial center ShanghaiChina

Cytidine triphosphate synthase(CTPS)plays a pivotal role in the de novo synthesis of cytidine triphosphate(CTP),a fundamental building block for RNA and DNA that is essential for *** is capable of directly binding to all four nucleotide triphosphates:adenine triphosphate,uridine triphosphate,CTP,and guanidine ***,CTPS can form cytoophidia in vivo and metabolic filaments in vitro,undergoing regulation at multiple *** is considered a potential therapeutic target for combating invasions or infections by viral or prokaryotic *** cryo-electron microscopy,we determined the structure of Escherichia coli CTPS(ecCTPS)filament in complex with CTP,nicotinamide adenine dinucleotide(NADH),and the covalent inhibitor 6-diazo-5-oxo-L-norleucine(DON),achieving a resolution of *** constructed a phylogenetic tree based on differences in filament-forming interfaces and designed a variant to validate our hypothesis,providing an evolutionary perspective on CTPS filament *** computational analysis revealed a solvent-accessible ammonia tunnel upon DON *** comparative structural analysis,we discern a distinct mode of CTP binding of ecCTPS that differs from eukaryotic *** biochemical assays and structural analysis,we determined and validated the synergistic inhibitory effects of CTP with NADH or adenine on *** results expand our comprehension of the diverse regulatory aspects of CTPS and lay a foundation for the design of specific inhibitors targeting prokaryotic CTPS.

关键词： CTP synthase Cryo-electron microscopy cytoophidium metabolic filament species specific inhibition

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Combined chemo-endocrine therapy as a potential new option for HR+/HER2−advanced breast cancer:a prospective study of fulvestrant plus oral vinorelbine

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Cancer Biology & Medicine 2023年第4期20卷 287-296页

作者： Xue Wang Jian Yue Yikun Kang Zhong Dai Jie Ju Jiayu Wang Pin Zhang Fei Ma Binghe Xu Peng Yuan Department of VIP Medical Services National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Comprehensive Oncology Huanxing Cancer HospitalBeijing 100026China Department of Medical Oncology and clinical trial center National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in *** study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast ***:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and ***:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 *** overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),*** adverse events reported were of grade 1/2,and none were of grade 4/***:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast *** combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.

关键词： HR+/HER2−breast cancer recurrence metastasis fulvestrant oral vinorelbine

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Dietary carbohydrate intake and risk of type 2 diabetes:a 16-year prospective cohort study

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Science China Life Sciences 2025年

作者： Lu Gan Yi Yang Bin Zhao Kai Yu Kehua Guo Fang Fang Zhiguang Zhou Demetrius Albanes Jiaqi Huang Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University CSU-Sinocare Research Center for Nutrition and Metabolic Health Xiangya School of Public Health Central South UniversityFurong Laboratory Division of Cancer Epidemiology and Genetics National Cancer Institute NIH Department of Health and Human Services School of Computer Science and Engineering Central South University Institute of Environmental Medicine Karolinska Institute National clinical Research center for Metabolic Diseases Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University

Despite considerable research underscoring the importance of carbohydrate intake in relation to the risk of type 2 diabetes(T2D), a comprehensive assessment of this relationship is currently lacking. We aimed to examine the associations of various types and food sources of dietary carbohydrate intake with the risk of T2D, to evaluate potential effect modification by other factors, including genetic susceptibility,and to explore the potential mediators for such associations. The present study included 161,872 participants of the UK Biobank who were free of prevalent cancer, cardiovascular disease, or diabetes, and had at least one validated 24-h dietary recall assessment. Multivariableadjusted age-stratified Cox proportional hazard regression models were applied to estimate hazard ratios(HRs) and 95% confidence intervals(CI) for the associations of various types and food sources of dietary carbohydrate intake with risk of T2D. During a median follow-up of13.6 years, 4,176 incident cases of T2D were identified. In the multivariable-adjusted models, a greater intake of fiber, carbohydrates from whole grains, and carbohydrates from non-starchy vegetables was significantly associated with a lower risk of T2D(highest vs. lowest quantile, HR [95% CI]=0.70 [0.62–0.79], 0.74 [0.67–0.82], and 0.83 [0.75–0.92], respectively, all P for trend <0.005). In contrast, a higher intake of starch and carbohydrate from starchy vegetables was associated with an increased risk of T2D(highest vs. lowest quantile, HR [95%CI]=1.31 [1.16–1.48] and 1.19 [1.09–1.31], respectively, both P for trend <0.005). Replacing one serving of refined grains or starchy vegetables with an equal amount of whole grains or non-starchy vegetables was associated with 4% to 10% lower risk of T2D(all P values <0.001).The observed associations were generally similar across population subgroups, including individuals with different genetic susceptibility to T2D. Mediation analyses of the inverse association between T

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TRMT6 and TRMT61A facilitated acute pancreatitis severity via regulation of neutrophil function

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Science China Life Sciences 2025年

作者： Yuan Dong Li Su Sin Man Lam Cen Yan Yalan Deng Guotao Lu Jinkui Yang Guanghou Shui Yingmei Feng Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University Department of Science and Development Beijing Youan HospitalCapital Medical University Laboratory for clinical Medicine Capital Medical University Neuroscience Research Institute Peking University Center of Medical and Health AnalysisPeking University State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of Sciences Pancreatic center Department of GastroenterologyAffiliated Hospital of Yangzhou UniversityYangzhou University Beijing Key Laboratory of Diabetes Research and Care Department of EndocrinologyBeijing Tongren HospitalCapital Medical University

Dear Editor,Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for increased severity in acute pancreatitis (AP)(Mikóet al,2018).However,to date,no studies have simultaneously included healthy individuals,T2DM patients,and AP patients to investigate which diabetes-associated metabolites are linked to AP severity.

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Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology

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Neural Regeneration Research 2025年第9期20卷 2589-2590页

作者： Mikio Shimizu Tatsusada Okuno Department of Neurology Osaka University Graduate School of MedicineSuitaJapan Department of Neurology Osaka General Medical CenterOsakaJapan

Amyotrophic lateral sclerosis(ALS)is a devastating neurological disease characterized by the accumulation of aberrant proteins in motor neurons of the brain and spinal *** with ALS develop skeletal muscle weakness,resulting in death from respiratory paralysis,which usually occurs 2-4 years after clinical onset(Goutman et al.,2022).

关键词： paralysis sclerosis

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Current state and future of co-inhibitory immune checkpoints for the treatment of glioblastoma

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Cancer Biology & Medicine 2020年第3期17卷 555-568页

作者： Shaoping Shen Ling Chen Jialin Liu Lin Yang Mengna Zhang Lingxiong Wang Rong Zhang Yasushi Uemura Qiyan Wu Xinguang Yu Tianyi Liu Department of Neurosurgery Chinese PLA General HospitalBeijing 100853China Pediatric center Chinese PLA General HospitalBeijing 100853China Key Laboratory of Cancer center Chinese PLA General HospitalBeijing 100853China Division of Cancer Immunotherapy Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwa 277-8577Japan

In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are *** checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on *** date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some ***,glioblastoma(GBM)still lacks an effective ***,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to ***,the use of immune checkpoints in the treatment of GBM still faces many ***,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be ***,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be *** of these concerns require extensive basic research and clinical *** this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.

关键词： Immunotherapy glioblastoma co-inhibitory immune checkpoint checkpoint inhibitors combination therapy

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Bioequivalence of two esomeprazole magnesium enteric-coated formulations in healthy Chinese subjects

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World Journal of clinical Cases 2020年第22期8卷 5518-5528页

作者： Zheng-Zhi Liu Qing Ren Yan-Nan Zhou Hai-Miao Yang Phase I clinical trial Laboratory Affiliated Hospital of Changchun University of Chinese MedicineChangchun 130021Jilin ProvinceChina

BACKGROUND The pharmacokinetics and bioequivalence of esomeprazole in healthy Chinese subjects and the effects of food on the pharmacokinetics have not been well *** To evaluate the pharmacokinetic characteristics of esomeprazole magnesium(Eso)enteric-coated capsule in the healthy subjects in China and the bioequivalence of the two *** This study was conducted in the Phase I clinical trial Unit of the Affiliated Hospital of Changchun University of Chinese Medicine.A total of 64 healthy subjects were enrolled in the ***-two subjects fasted or fed,took the test or reference formulation Eso enteric-coated capsule by a four-cycle,two-sequence crossover of fasting/fed,self-controlled *** liquid chromatographymass spectrometry was performed to determine the drug plasma concentration at 16 different time points within 12 h after drug *** pharmacokinetic parameters Cmax,area under the curve(AUC)0-t,and AUC0-inf were calculated to evaluate the *** Pharmacokinetic parameters were evaluated after subjects took the test formulation and control formulation under fasting *** ratio of geometric means of Cmax was 104.15%,with a confidence interval(CI)of 98.20-110.46%.The ratio of geometric means of AUC0-t was 105.26%,with a CI of 99.80-111.01%.The ratio of geometric means of AUC0-inf was 105.37%,with a CI of 99.97-111.06%.The pharmacokinetic parameters were also evaluated after subjects took the reference formulation of Eso enteric-coated capsule after *** upper limit of 95%CI of the geometric mean ratio of pharmacokinetic parameters of Eso enteric-coated capsules in the postprandial state Cmax was-0.1689,and the point estimate was 0.9509(0.80-1.25).The upper limit of 95%CI of the geometric mean ratio of pharmacokinetic parameters of Eso enteric-coated capsules in the postprandial state AUC0-t was-0.1015(≤0),and the point estimate was 0.9003(0.80-1.25).The upper limit of 95%CI of the geometric

关键词： Esomeprazole Proton pump inhibitor Bioequivalence Pharmacodynamics Gastroesophageal reflux disease

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Hsa-miR-214-3p inhibits breast cancer cell growth and improves the tumor immune microenvironment by downregulating B7H3

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Oncology research 2025年第1期33卷 103-121页

作者： Yan Lu Kang Wang Yuanhong Peng Meng Chen Lin Zhong Luji Huang F U Cheng Xindan Sheng Xin Yang Manzhao Ouyang George A Calin Zhiwei He China-America Cancer Research Institute Guangdong Medical University Dongguan 523808 China. GCP center Shunde Hospital Southern Medical University (The First People's Hospital of Shunde Foshan) Shunde 528300 China. Department of Gastrointestinal Surgery Shunde Hospital Southern Medical University (The First People's Hospital of Shunde Foshan) Shunde 528300 China. The Second School of clinical Medicine Southern Medical University Guangzhou 510080 China. Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA. Department of Oncology Shunde Hospital Southern Medical University (The First People's Hospital of Shunde Foshan) Shunde 528300 China.

Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors, but the currently used immune checkpoint inhibitors targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) show limited clinical efficacy in many breast cancers. B7H3 has been widely reported as an immunosuppressive molecule, but its immunological function in breast cancer patients remains unclear.Methods:We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO) databases. MicroRNAs were selected using the TarBase, miRTarBase, and miRBase databases. The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays, which identified the specific action sites of interaction. The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR (qPCR). experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis. Additionally, the regulatory impact of hsa-miR-214-3p on B7H3 was examined. Enzyme-linked immunosorbent assays (ELISA) and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells (PBMCs) on immune cells and associated cytokines.Results:In breast cancer tissues, the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p, as well as with the regulatory effects on breast cancercell behavior. Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3. Importantly, our research identified, for the first time, two binding sites for hsa-miR-214-3p on the 3' UTR of B7H3, both of which exert similar effects independently. Co-culture experime

关键词： B7H3 Breast cancer Hsa-miR-214-3p Immunotherapy

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