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Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes

Acta Pharmaceutica Sinica B 2024年第4期14卷 1693-1710页

作者： Xiong Chen Jinfu Qian Shiqi Liang Jianchang Qian Wu Luo Yujuan Shi Hong Zhu Xiang Hu Gaojun Wu Xiaokun Li Guang Liang Department of Endocrinology the First Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China Chemical Biology Research Center School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325035China Department of Wound Repair the First Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China Department of Cardiology the First Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China School of Pharmaceutical Sciences Hangzhou Medical CollegeHangzhou 311399China

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

关键词： Diabetic cardiomyopathy Protein tyrosine kinases FGFR1 Cardiomyocytes Inflammatory responses Toll-like receptor4 c-Src NFkB

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Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis

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Journal of Pharmaceutical Analysis 2024年第5期14卷 744-757页

作者： Lifan Lin Xinmiao Li Yifei Li Zhichao Lang Yeping Li Jianjian Zheng Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China Department of Urology The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China

Liver fibrosis is primarily driven by the activation of hepatic stellate cells(HSCs),a process associated with *** Rb1(GRb1),a major active component extracted from Panax ginseng,inhibits HSC ***,the potential role of GRb1 in mediating HSC ferroptosis remains *** study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro,using CCl4-induced liver fibrosis mouse model and primary HSCs,LX-2 *** findings revealed that GRb1 effectively inactivated HSCs in vitro,reducing alpha-smooth muscle actin(a-SMA)and type I collagen(Col1A1)***,GRb1 significantly alleviated CCl4-induced liver fibrosis in *** a mechanistic standpoint,the ferroptosis pathway appeared to be central to the antifibrotic effects of ***,GRb1 promoted HSC ferroptosis both in vivo and in vitro,characterized by increased glutathione depletion,malondialdehyde production,iron overload,and accumulation of reactive oxygen species(ROS).Intriguingly,GRb1 increased Beclin 1(BECN1)levels and decreased the System Xc-key subunit *** experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by ***,BECN1 could directly interact with SLC7A11,initiating HSC *** conclusion,the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in ***,this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation,at least partly through its modulation of BECN1 and SLC7A11.

关键词： Ginsenoside Rb1 Ferroptosis Liver fibrosis Hepatic stellate cells

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Profibrotic role of the SOX9-MMP10-ECM biosynthesis axis in the tracheal fibrosis after injury and repair

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Genes & Diseases 2024年第5期11卷 360-373页

作者： Lei Gu Anmao Li Chunyan He Rui Xiao Jiaxin Liao Li Xu Junhao Mu Xiaohui Wang Mingjin Yang Jinyue Jiang Yang Bai Xingxing Jin Meiling Xiao Xia Zhang Tairong Tan Yang Xiao Jing Lin Yishi Li Shuliang Guo Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Soochow UniversitySuzhou 215006China Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Infection Disease The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang 325000China

Fibroblast activation and extracellular matrix(ECM)deposition play an important role in the tracheal abnormal repair process and *** a transcription factor,SOX9 is involved in fibroblast activation and ECM ***,the mechanism of how SOX9 regulates fibrosis after tracheal injury remains *** investigated the role of SOX9 in TGF-b1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast(RTF)***9 overexpression adenovirus(Ad-SOX9)and siRNA were transfected into RTF *** found that SOX9 expression was up-regulated in RTF cells treated with ***9 overexpression activated fibroblasts and promoted ECM *** SOX9 inhibited cell proliferation,migration,and ECM deposition,induced G2 arrest,and increased apoptosis in RTF ***-seq and chromatin immunoprecipitation sequencing(ChIP-seq)assays identified MMP10,a matrix metalloproteinase involved in ECM deposition,as a direct target of SOX9,which promotes ECM degradation by increasing MMP10 expression through the Wnt/b-catenin signaling ***,in vivo,SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis,as manifested by reduced tracheal *** conclusion,our findings indicate that SOX9 can drive fibroblast activation,cell proliferation,and apoptosis resistance in tracheal fibrosis via the Wnt/b-catenin signaling *** SOX9eMMP10 eECM biosynthesis axis plays an important role in tracheal injury and *** SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

关键词： Extracellular matrix deposition Fibroblast activation MMP10 SOX9 Tracheal fibrosis

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Impact of High Sodium Diet on Neovascularization and Osseointegration around Titanium Implant:An in Vivo and in Vitro Study

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Biomedical and Environmental Sciences 2024年第7期37卷 739-753页

作者： Keyuan Xu Xiaoting Tang Yun Xiang Yiding Shen Zhennan Deng Pingping Ma Xinkun Shen Department of Orthopaedics The Third Affiliated Hospital of Wenzhou Medical University(Ruian People’s Hospital)Wenzhou 325016ZhejiangChina School and hospital of Stomatology Wenzhou Medical UniversityWenzhou 325027ZhejiangChina

Objective A high sodium(HS)diet is believed to affect bone metabolism *** its impact on osseointegration of titanium(Ti)implants holds significant implications for postoperative dietary management of implanted *** This investigation probed the impact of sodium ions(Na^(+))on neovascularization and osteogenesis around Ti implants in vivo,utilizing micro-computed tomography,hematoxylin and eosin staining,and immunohistochemical ***,in vitro experiments assessed the effects of varied Na^(+)concentrations and exposure durations on human umbilical vein endothelial cells(HUVECs)and MC3T3-E1 *** In vivo,increased dietary sodium(0.8%-6.0%)led to a substantial decline in CD34 positive HUVECs and new bone formation around Ti implants,alongside an increase in inflammatory *** vitro,an increase in Na^(+)concentration(140-150 mmol/L)adversely affected the proliferation,angiogenesis,and migration of HUVECs,especially with prolonged *** MC3T3-E1 cells initially exhibited less susceptibility to high Na^(+)concentrations compared to HUVECs during short-term exposure,prolonged exposure to a HS environment progressively diminished their proliferation,differentiation,and osteogenic *** These findings suggest that HS diet had a negative effect on the early osseointegration of Ti implants by interfering with the process of postoperative vascularized bone regeneration.

关键词： High-sodium Implants Vascularization Osseointegration

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Identification of differentially expressed mRNAs as novel predictive biomarkers for gastric cancer diagnosis and prognosis

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1947-1964页

作者： Jian-Wei Zhou Yi-Bing Zhang Zhi-Yang Huang Yu-Ping Yuan Jie Jin Department of Gastroenterology Wenzhou Central HospitalDingli Clinical College of Wenzhou Medical UniversityThe Second Affiliated Hospital of Shanghai UniversityWenzhou 325000Zhejiang ProvinceChina

BACKGROUND Gastric cancer(GC)has a high mortality rate *** significant progress in GC diagnosis and treatment,the prognosis for affected patients still remains *** To identify important candidate genes related to the development of GC and iden-tify potential pathogenic mechanisms through comprehensive bioinformatics *** The Gene Expression Omnibus database was used to obtain the GSE183136 dataset,which includes a total of 135 GC *** limma package in R software was employed to identify differentially expressed genes(DEGs).Thereafter,enrichment analyses of Gene Ontology(GO)terms and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways were performed for the gene modules using the clusterProfile package in R *** protein-protein interaction(PPI)networks of target genes were constructed using STRING and visualized by Cytoscape *** common hub genes that emerged in the cohort of DEGs that was retrieved from the GEPIA database were then screened using a Venn *** expression levels of these overlapping genes in stomach adenocarcinoma samples and non-tumor samples and their association with prognosis in GC patients were also obtained from the GEPIA database and Kaplan-Meier ***,real-time quantitative polymerase chain reaction(RT-qPCR)and western blotting were performed to determine the mRNA and protein levels of glutamic-pyruvic transaminase(GPT)in GC and normal immortalized cell *** addition,cell viability,cell cycle distribution,migration and invasion were evaluated by cell counting kit-8,flow cytometry and transwell ***,we also conducted a retrospective analysis on 70 GC patients diagnosed and surgically treated in wenzhou Central hospital,Dingli Clinical college of wenzhou medical University,The Second affiliated hospital of Shanghai University between January 2017 to December *** tumor and adjacent normal samples were collected from the patients to determine the

关键词： Gastric cancer Differentially expressed genes Bioinformatics Hub genes Prognosis

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The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

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Neural Regeneration Research 2024年第4期19卷 800-806页

作者： Xinxin Wang Yushu Hu Renshi Xu medical college of Nanchang University Department of Neurology Jiangxi Provincial People's HospitalThe First Affiliated Hospital of Nanchang Medical CollegeThe Clinical College of Nanchang Medical College

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory ***,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the *** disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized *** TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral *** review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

关键词： amyotrophic lateral sclerosis axonal transport liquid-liquid phase separation noncellular autonomous functions oxidative stress pathogenesis post-translational modification protein quality control system stress granules TAR DNA-binding protein 43(TDP-43)

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Plexin domain-containing 1 may be a biomarker of poor prognosis in hepatocellular carcinoma patients,may mediate immune evasion

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 2091-2112页

作者： Ming-Yue Tang Xue Shen Run-Sheng Yuan Hui-Yuan Li Xin-Wei Li Yi-Ming Jing Yue Zhang Hong-Hong Shen Zi-Shu Wang Lei Zhou Yun-Chuan Yang He-Xin Wen Fang Su Department of medical Oncology The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233000Anhui ProvinceChina Otolaryngology and Head and Neck Surgery The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233000Anhui ProvinceChina Department of Neurology The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233000Anhui ProvinceChina Department of Hepatobiliary Surgery The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233000Anhui ProvinceChina Department of Gastrointestinal Surgery The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233000Anhui ProvinceChina

BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in *** Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in *** immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our *** prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint ***,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining *** Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor *** and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic *** HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation *** enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 *** high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor *** As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.

关键词： Plexin domain-containing 1 Biomarker Immune evasion Prognosis Immunotherapy Hepatocellular carcinoma

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Predictive value of neutrophil-to-lymphocyte ratio in coronary chronic total occlusion patients

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Journal of Geriatric Cardiology 2024年第5期21卷 542-549页

作者： Qian LI Yue YU Ya-Qiong ZHOU Yi ZHAO Jin WU Yuan-Jing WU Bin DU Pei-Jian WANG Tao ZHENG Department of Cardiovascular Medicine the First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina Department of Cardiology First Affiliated Hospital of Chengdu Medical CollegeChengduChina Department of Neurology the First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina

BACKGROUND The neutrophil to lymphocyte ratio(NLR)has been reported as a novel predictor for atherosclerosis and car-diovascular *** study aimed to determine the effects of NLR on long-term clinical outcomes of chronic total occlusion(CTO)*** A total of 670 patients with CTO who met the inclusion criteria were included at the end of the follow-up *** were divided into tertiles according to their baseline NLR levels at admission:low(n=223),intermediate(n=223),and high(n=224).The incidence of major adverse cardiac events(MACEs)during the follow-up period,including all-cause death,nonfatal myocardial infarction(MI),or ischemia-driven revascularization,were compared among the three *** Major adverse cardiac events were observed in 27 patients(12.1%)in the low tertile,40(17.9%)in the intermediate tertile,and 61(27.2%)in the high NLR tertile(P<0.001).Kaplan-Meier analysis demonstrated a significantly higher incidence of MACE,ischemia-driven coronary revascularization,non-fatal MI,and mortality in patients within the high tertile than those in the low and intermediate groups(all P<0.001).Multivariable COX regression analysis showed that the high tertile of baseline NLR level showed a strong association with the risk of MACE(hazard ratio[HR]=2.21;95%confidence interval[CI]:1.21-4.03;P=0.009),ischemia-driven coronary revascularization(HR=3.19;95%CI:1.56-6.52;P=0.001),MI(HR=2.61;95%CI:1.35-5.03;P=0.043)and mortality(HR=3.78;95%CI:1.65-8.77;P=0.001).CONCLUSION Our findings suggest that NLR is an inexpensive and readily available biomarker that can independently pre-dict cardiovascular risk in patients with CTO.

关键词： patients coronary occlusion

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Establishing and clinically validating a machine learning model for predicting unplanned reoperation risk in colorectal cancer

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World Journal of Gastroenterology 2024年第23期30卷 2991-3004页

作者： Li-Qun Cai Da-Qing Yang Rong-Jian Wang He Huang Yi-Xiong Shi Department of Colorectal and Anal Surgery Whenzhou Central HospitalWenzhou 325000Zhejiang ProvinceChina Department of Colorectal and Anorectal Surgery The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina

BACKGROUND Colorectal cancer significantly impacts global health,with unplanned reoperations post-surgery being key determinants of patient *** predictive models for these reoperations lack precision in integrating complex clinical *** To develop and validate a machine learning model for predicting unplanned reoperation risk in colorectal cancer *** Data of patients treated for colorectal cancer(n=2044)at the first affiliated hospital of wenzhou medical University and wenzhou Central hospital from March 2020 to March 2022 were retrospectively *** were divided into an experimental group(n=60)and a control group(n=1984)according to unplanned reoperation *** were also divided into a training group and a validation group(7:3 ratio).We used three different machine learning methods to screen characteristic variables.A nomogram was created based on multifactor logistic regression,and the model performance was assessed using receiver operating characteristic curve,calibration curve,Hosmer-Lemeshow test,and decision curve *** risk scores of the two groups were calculated and compared to validate the *** More patients in the experimental group were≥60 years old,male,and had a history of hypertension,laparotomy,and hypoproteinemia,compared to the control *** logistic regression analysis confirmed the following as independent risk factors for unplanned reoperation(P<0.05):Prognostic Nutritional Index value,history of laparotomy,hypertension,or stroke,hypoproteinemia,age,tumor-node-metastasis staging,surgical time,gender,and American Society of Anesthesiologists *** operating characteristic curve analysis showed that the model had good discrimination and clinical *** This study used a machine learning approach to build a model that accurately predicts the risk of postoperative unplanned reoperation in patients with colorectal cancer,which can improve tr

关键词： Colorectal cancer Postoperative unplanned reoperation Unplanned reoperation Clinical validation Nomogram Machine learning models

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Construction of CDKN2A-related competitive endogenous RNA network and identification of GAS5 as a prognostic indicator for hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1514-1531页

作者： Yong Pan Yi-Ru Zhang Ling-Yun Wang Li-Na Wu Ying-Qiu Ma Zhou Fang Shi-Bo Li Department of Infectious Disease Zhoushan HospitalWenzhou Medical UniversityZhoushan 316021Zhejiang ProvinceChina State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital of Zhejiang UniversityHangzhou 310003Zhejiang ProvinceChina Department of Infectious Disease The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325035Zhejiang ProvinceChina

BACKGROUND Competitive endogenous RNA(ceRNA)is an innovative way of gene expression modulation,which plays a crucial part in ***,the intricacy and behavioral characteristics of the ceRNA network in hepatocellular carcinoma(HCC)remain *** To establish a cyclin dependent kinase inhibitor 2A(CDKN2A)-related ceRNA network and recognize potential prognostic indicators for *** The mutation landscape of CDKN2A in HCC was first explored using the cBioPortal *** expression analysis was implemented between CDKN2Ahigh and CDKN2Alow expression HCC *** targeted microRNAs were predicted by lncBasev3.0,and the targeted mRNAs were predicted by miRDB,and Targetscan *** univariate and multivariate analysis were utilized to identify independent prognostic *** CDKN2A was frequently mutated and deleted in *** single-cell RNA-sequencing analysis revealed that CDKN2A participated in cell cycle *** CDKN2A-related ceRNA network-growth arrest specific 5(GAS5)/miR-25-3p/SRY-box transcription factor 11(SOX11)was successfully ***5 was recognized as an independent prognostic biomarker,whose overexpression was correlated with a poor prognosis in HCC *** association between GAS5 expression and methylation,immune infilt-ration was ***,traditional Chinese medicine effective components targeting GAS5 were *** This CDKN2A-related ceRNA network provides innovative insights into the molecular mechanism of HCC formation and ***,GAS5 might be a significant prognostic biomarker and therapeutic target in HCC.

关键词： Hepatocellular carcinoma Competitive endogenous RNA Molecular mechanism Prognosis Biomarker

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