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

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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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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Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2^(-/-)Mice and Human Intrahepatic Cholangiocyte Organoid Models

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Research 2024年第2期2023卷 355-372页

作者： Qigu Yao Wenyi Chen Yingduo Yu Feiqiong Gao Jiahang Zhou Jian Wu Qiaoling Pan Jinfeng Yang Lingling Zhou Jiong Yu Hongcui Cao Lanjuan Li State key laboratory for the diagnosis and treatment of Infectious diseases Cllaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affliated HospitalZhejang University School of Medicine79 Qingchun Rd.Hangzhou 310003China National Clinical Research Center for Infectious diseases HangzhouChina key laboratory of diagnosis and treatment of Aging and Physic-chemical Injury diseases of zhejiang province 79 Qingchun Rd.Hangzhou 310003China Jjinan Microecological Biomedicine Shandong laboratory Jinan 250117China

Primary sclerosing cholangitis(PSC)is a biliary disease accompanied by chronic inflammation of the liver and biliary *** stem cells(MSCs)are used to treat liver diseases because of their immune regulation and regeneration-promoting *** study was performed to explore the therapeutic potential of human placental MSCs(hP-MSCs)in PSC through the Takeda G protein-coupled receptor 5(TGR5)receptor *** tissues were collected from patients with PSC and healthy donors(n=4)for RNA sequencing and intrahepatic cholangiocyte organoid ***-MSCs were injected via the tail vein into Mdr2^(-/-),bile duct ligation(BDL),and 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary *** in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry(LC-MS/MS).Compared with healthy controls,liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis,and marked downregulation of bile acid receptor TGR5 ***-MSC treatment apparently reduced the inflammation,cholestasis,and fibrosis in Mdr2^(-/-),BDL,and DDC model *** activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway,hP-MSC treatment promoted the proliferation of cholangiocytes,and affected the transcription of downstream nuclear factorκB through regulation of the binding of TGR5 and Pellino3,thereby affecting the cholangiocyte inflammatory phenotype.

关键词： inflammation TGR5 Human

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Addressing chemoresistance with a lipid gemcitabine nanotherapeutic strategy for effective treatment of pancreatic cancer

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Nano Research 2024年第9期17卷 8377-8388页

作者： Jiawei Hong Shiyun Xian Shusen Zheng Hangxiang Wang Donghai Jiang The First Affiliated Hospital NHC Key Laboratory of Combined Multi-Organ TransplantationCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for Diagnosis and Treatment of Infectious DiseasesSchool of MedicineZhejiang UniversityHangzhou 310003China Jinan Microecological Biomedicine Shandong laboratory Jinan 250117China

Resistance to gemcitabine in pancreatic cancer poses a significant clinical *** investigation is warranted to assess whether nano-formulation strategy can be employed to enhance the sensitivity of resistant strains to gemcitabine *** this study,using gemcitabine-resistant pancreatic cancer cell lines,we examined the therapeutic potential of a gemcitabine nanodelivery platform and assessed the ability to overcome drug resistance against resistant *** of human equilibrative nucleoside transporter 1(hENT1)led to reduced cellular uptake of gemcitabine,resulting in chemoresistance in pancreatic *** nanoparticles circumvented the entry blockade caused by hENT1 silencing through *** entry via clathrin-mediated endocytosis increased intracellular gemcitabine accumulation in gemcitabine-resistant pancreatic cancer ***,gemcitabine nanoparticles are preferential in vivo delivery to tumor tissues,likely due to the enhanced permeability and retention *** comparison to free gemcitabine,gemcitabine nanoparticles demonstrate a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells,with favorable *** study improved the efficacy of gemcitabine through nanotechnology,providing a novel strategy to address gemcitabine-resistant pancreatic cancer.

关键词： pancreatic cancer gemcitabine resistance gemcitabine nanoparticle human equilibrative nucleoside transporter 1

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Severe liver injury and clinical characteristics of occupational exposure to 2-amino-5-chloro-N,3-dimethylbenzamide: A case series

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Hepatobiliary & Pancreatic diseases International 2024年第2期23卷 186-194页

作者： Meng-Xiao Feng Hua Zou Yuan-Qiang Lu Department of Emergency Medicine The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China key laboratory for diagnosis and treatment of Aging and Physic-chemical Injury diseases of zhejiang province Hangzhou 310003China Occupational Health and Radiation Protection Institute Zhejiang Provincial Center for Disease Control and PreventionHangzhou 310051China

Background:The 2-amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of pesticides and ***,no literature currently exists on 2-amino-5-chloro-N,3-dimethylbenzamide poisoning in *** study aimed to reveal the health hazard of this chemical for humans and summarize the clinical characteristics of patients with occupational 2-amino-5-chloro-N,3-dimethylbenzamide ***:This observational study included four patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning from June 2022 to July *** entire course of the incidents was described in *** 2-amino-5-chloro-N,3-dimethylbenzamide concentrations were detected by a mass ***-toxylin and eosin staining was performed to assess liver injury,and immunofluorescence was used to evaluate hepatic ***:The 2-amino-5-chloro-N,3-dimethylbenzamide powder(99%purity)entered the human body mainly via the skin and respiratory tract due to poor personal protective *** typical course of 2-amino-5-chloro-N,3-dimethylbenzamide poisoning was divided into latency,rash,fever,organic dam-age,and recovery phases in accordance with the clinical *** and fever may be the important premonitory symptoms for further organ *** chemical was detected in the blood of all patients and caused multiple organ injuries,predominantly liver injury,including kidney,myocardium,and *** patients recovered smoothly after comprehensive treatments,including artificial liver therapy,continuous renal replacement therapy,glucocorticoids,and other symptomatic and supportive *** patient survived by liver *** postoperative pathological findings of the removed liver showed acute liver failure,and immunofluorescence staining confirmed the abundance of mitophagy in residual ***:This study is the first to elaborate the clinical characteristics of patients with 2-amino-5-chloro-N,

关键词： 2-amino-5-chloro-N,3-dimethylbenzamide Poisoning Clinical characteristics Liver injury

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Bioactive Hydrogels with Pro-coagulation Effect for Hemostasis

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Chinese Journal of Chemistry 2024年第1期42卷 87-103,I0004页

作者： Quanshi Guo Yihang Ding Lisha Yu Zongrui Tong Zhengwei Mao MOE key laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and EngineeringZhejiang UniversityHangzhouZhejiang 310058China Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang 310009China key laboratory of Precision diagnosis and treatment for Hepatobiliary and Pancreatic Tumor of zhejiang province HangzhouZhejiang 310009China

Hemostatic hydrogels are widely applied for wound management of damaged tissues,traumatic wounds,and surgical *** hydrogels composed of bioactive components,including fibrin and thrombin,showed great promise in the clinic due to their good pro-coagulation *** the expanding knowledge of cascade reaction of blood coagulation and emerging bioactive substances,massive bioactive hydrogels consisting of peptides,hemocoagulase,polyphosphate(polyP),etc.,have been developed as effective hemostatic *** on the coagulation process and mechanism,we summarize the role of reported bioactive hydrogels in hemostasis in this *** conclude the key points in the coagulation process,including activation of coagulation factors,fibrinogen polymerization,etc.,then discuss how to design bioactive hydrogels to accelerate coagulation targeted to these ***,we conclude the progress and propose a perspective of bioactive hydrogels with a pro-coagulation effect for hemostasis.

关键词： Hemostasis Biological activity Biomaterials Enzyme catalysis Composites

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MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 119-134页

作者： Wenyi Chen Feiyan Lin Xudong Feng Qigu Yao Yingduo Yu Feiqiong Gao Jiahang Zhou Qiaoling Pan Jian Wu Jinfeng Yang Jiong Yu Hongcui Cao Lanjuan Li State key laboratory for the diagnosis and treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Medical Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Jinan Microecological Biomedicine Shandong laboratory Jinan 250117China key laboratory of diagnosis and treatment of Aging and Physic-chemical Injury diseases of zhejiang province Hangzhou 310003China

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage *** placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver ***,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC *** results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in ***,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular ***,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

关键词： Mesenchymal stem cell Exosomes Primary sclerosing cholangitis Fibrosis Organoids Th17

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Impact of short-term ambient air pollution exposure on the risk of severe COVID-19

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Journal of Environmental Sciences 2024年第1期135卷 610-618页

作者： Baihuan Feng Jiangshan Lian Fei Yu Dan Zhang Weizhen Chen QiWang Yifei Shen Guoliang Xie Ruonan Wang Yun Teng Bin Lou Shufa Zheng Yida Yang Yu Chen Department of laboratory Medicine The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China key laboratory of Clinical In Vitro Diagnostic Techniques of zhejiang province Hangzhou 310000China Institute of laboratory Medicine Zhejiang UniversityHangzhou 310000China Department of Infectious diseases The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China State key laboratory for diagnosis and treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseasesthe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China

Ecological studies suggested a link between air pollution and severe COVID-19 outcomes,while studies accounting for individual-level characteristics are *** the present study,we aimed to investigate the impact of short-term ambient air pollution exposure on disease severity among a cohort of 569 laboratory confirmed COVID-19 patients admitted to designated hospitals in zhejiang province,China,from January 17 to March 3,2020,and elucidate the possible biological processes involved using *** with mild cases,severe cases had higher proportion of medical conditions as well as unfavorable results in most of the laboratory tests,and manifested higher air pollution exposure *** exposure to air pollutants was associated with increased risk of severe COVID-19 with odds ratio(OR)of 1.89(95%confidence interval(CI):1.01,3.53),2.35(95%CI:1.20,4.61),2.87(95%CI:1.68,4.91),and 2.01(95%CI:1.10,3.69)for PM_(2.5),PM_(10),NO_(2)and CO,*** for NO_(2)remained significant in two-pollutant models after adjusting for other *** analysis showed 884 differentially expressed genes which mainly were enriched in virus clearance related biological processes between patients with high and low NO_(2)exposure levels,indicating that compromised immune response might be a potential underlying mechanistic *** findings highlight the impact of shortterm air pollution exposure,particularly for NO_(2),on COVID-19 severity,and emphasize the significance in mitigating the COVID-19 burden of commitments to improve air quality.

关键词： Air pollution COVID-19 Severity Transcriptomics Immune response

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Screening for metabolic dysfunction-associated fatty liver disease:Time to discard the emperor’s clothes of normal liver enzymes?

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World Journal of Gastroenterology 2024年第22期30卷 2839-2842页

作者： Chen-Xiao Huang Xiao-Dong Zhou Calvin Q Pan Ming-Hua Zheng Metabolic Dysfunction-Associated Fatty Liver disease Research Center Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina Department of cardiovascular Medicine The Key Laboratory of Cardiovascular Diseases of WenzhouThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina Division of Gastroenterology and Hepatology Department of MedicineNew York University Langone HealthNew York University Grossman School of MedicineNew YorkNY 11355United States Institute of Hepatology Wenzhou Medical UniversityKey Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang ProvinceWenzhou 325000Zhejiang ProvinceChina

Metabolic dysfunction-associated fatty liver disease(MAFLD)is the most prevalent chronic liver condition *** liver enzyme-based screening methods have limitations that may missed diagnoses and treatment *** Chen et al,the risk of developing MAFLD remains elevated even when alanine aminotransferase levels fall within the normal ***,there is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of MAFLD diagnosis and enable early *** paper proposes two potential screening methods for identifying individuals who may be at risk of developing MAFLD:Lowering these thresholds and promoting the use of noninvasive liver fibrosis scores.

关键词： Metabolic dysfunction-associated fatty liver disease Non-alcoholic fatty liver disease Alanine aminotransferase Liver enzymes Screening Noninvasive liver fibrosis scores

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SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation

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Cancer Communications 2024年第3期44卷 384-407页

作者： Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie Shusen Zheng Penghong Song Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China National Health Commission key laboratory of Combined Multi-organ Transplantation HangzhouZhejiangP.R.China key laboratory of the diagnosis and treatment of Organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical SciencesHangzhouZhejiangP.R.China key laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiangP.R.China State key laboratory for diagnosis and treatment of Infectious diseases First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China

Background:Liver cancer is a malignancy with high morbidity and mortality *** family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many *** this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer ***:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver *** from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of *** methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and *** sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer ***-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using ***:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA ***2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver ***2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and ***/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with ***,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,***,EGFR was activated in liver cancer cells after sorafenib treatment,and SER

关键词： liver cancer metastasis DNA methylation SERPINE2 EGFR c-Cbl ubiquitination

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