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Cavalletto L, Bertoli E, Mescoli C, Aliberti C, Quaranta MG, Kondili L, Chemello L. Long-Term Risk of Hepatic and Extrahepatic-Related Events After Direct Antiviral Therapy for Chronic Hepatitis C: A Prospective Long-Term Study Cohort. Cancers (Basel) 2025; 17:1528. [PMID: 40361459 PMCID: PMC12071134 DOI: 10.3390/cancers17091528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/02/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
Novel direct antiviral-acting (DAA) molecules significantly improved efficacy and ameliorated outcomes of patients with chronic hepatitis C (CHC). The extensive use of DAA from 2015, due to large access to therapy, maximized rates of viral eradication with a safety profile in the majority of cases. AIMS We evaluated risk factors and the incidence of related clinical events and hepatocellular carcinoma (HCC) in cases with sustained virologic response (SVR) after DAA. We also aimed to apply a score assessment to identify the individual patient with unfavorable outcomes during an average follow-up (FU) of five years. METHODS In total, 470 cases consecutively recruited with CHC have been compared by non-invasive tests (NIT), as APRI, FORNS, FIB-4, LSPS, and transient elastography (TE) liver stiffness measurement (LSM), to identify cutoff related to major event onset. RESULTS Grouping of cases without or with related events development of both types hepatic (HE) (i.e., HCC or further cirrhosis decompensation or/with hospitalized septic state) or extrahepatic (EHE) (i.e., other tumors, bleeding, or thrombotic episodes and other organs pathologic conditions not liver related)allowed us to select the parameters to propose a novel risk stratification system (RISS) for the identification of the remnant individual patient's risk for HCC occurrence, orthotopic liver transplant (OLT) need, or death during long-term follow-up (FU). CONCLUSIONS Patients with cirrhosis and portal hypertension (PH) maintained a higher LSM mean value (>25 kPa), showed the lowest reduction of NIT scores, and developed events in 80/108 (74%) cases (67 and 13 of HE and EHE type), even after long-term successful DAA therapy. Furthermore, cases with RISS score ≥ 8 demonstrated a significant incidence of HCC (37/46, 80.4%) and a reduction in survival rate to 65.4% at 5-year FU.
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Affiliation(s)
- Luisa Cavalletto
- UOC Clinica Medica 5, Regional Center for Liver Disease Outpatient Unit, Department of Medicine—DIMED, University of Padova, 35128 Padova, Italy
| | - Eleonora Bertoli
- Unit of Emergency Medicine, Department of Systems Medicine—DIDAS, University of Padova, 35128 Padova, Italy;
| | - Claudia Mescoli
- Unit of Pathology, Department of Medicine—DIMED, University of Padova, 35128 Padova, Italy;
| | - Camillo Aliberti
- Unit of Radiology, Pederzoli Hospital Peschiera del Garda, 37019 Verona, Italy;
| | | | - Loreta Kondili
- Istituto Superiore di Sanità, Global Health Center, 00161 Rome, Italy; (M.G.Q.); (L.K.)
| | - Liliana Chemello
- UOC Clinica Medica 5, Regional Center for Liver Disease Outpatient Unit, Department of Medicine—DIMED, University of Padova, 35128 Padova, Italy
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Hashimoto M, Kobayashi T, Ohira M, Okimoto S, Abe T, Inoue M, Onoe T, Honmyo N, Kuroda S, Ohdan H. Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024; 31:318-328. [PMID: 38135908 DOI: 10.1002/jhbp.1406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/23/2023] [Accepted: 11/15/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND/PURPOSE The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. METHODS We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. RESULTS SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. CONCLUSIONS There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.
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Affiliation(s)
- Masakazu Hashimoto
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, Hiroshima, Japan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Sho Okimoto
- Department of Surgery, Chugoku Rosai Hospital, Kure, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Tomoyuki Abe
- Department of Surgery, JA Onomichi General Hospital, Onomichi, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Masashi Inoue
- Department of Surgery, National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Takashi Onoe
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Naruhiko Honmyo
- Department of Surgery, Hiroshima City North Medical Center, Asa Citizens Hospital, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
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Hafez HA, Atoom AM, Khafaga RHM, Shaker SA, Kamel MA, Assem NM, Mahmoud SA. Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats. Int J Mol Sci 2023; 24:15844. [PMID: 37958828 PMCID: PMC10647297 DOI: 10.3390/ijms242115844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/28/2023] [Accepted: 10/28/2023] [Indexed: 11/15/2023] Open
Abstract
(1) Background: Hepatitis C virus (HCV) infection is endemic in Egypt, with the highest prevalence rate worldwide. Sofosbuvir (SOF) is a nucleos(t)ide analog that specifically inhibits HCV replication. This study aimed to explore the possible effects of the therapeutic dose of SOF on the mitochondrial biogenesis and functions of the liver, muscle, and ovarian tissues of young normal female rats. (2) Methods: This study was conducted on 20 female Wistar rats, classified into two groups, the control group and the exposed group; the latter was orally supplemented with 4 mg/kg/day of SOF for 3 months. (3) Results: The exposure to SOF impairs mitochondrial biogenesis via mitochondrial DNA copy number decline and suppressed mitochondrial biogenesis-regulated parameters at mRNA and protein levels. Also, SOF suppresses the DNA polymerase γ (POLG) expression, citrate synthase activity, and mitochondrial NADH dehydrogenase subunit-5 (ND5) content, which impairs mitochondrial functions. SOF increased lipid peroxidation and oxidative DNA damage markers and decreased tissue expression of nuclear factor erythroid 2-related factor 2 (Nfe2l2). (4) Conclusions: The present findings demonstrate the adverse effects of SOF on mitochondrial biogenesis and function in different tissues of young female rats, which mostly appeared in ovarian tissues.
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Affiliation(s)
- Hala A. Hafez
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt; (R.H.M.K.); (S.A.S.); (N.M.A.); (S.A.M.)
| | - Ali M. Atoom
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19111, Jordan;
| | - Rana H. M. Khafaga
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt; (R.H.M.K.); (S.A.S.); (N.M.A.); (S.A.M.)
| | - Sara A. Shaker
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt; (R.H.M.K.); (S.A.S.); (N.M.A.); (S.A.M.)
| | - Maher A. Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt; (R.H.M.K.); (S.A.S.); (N.M.A.); (S.A.M.)
| | - Nagwa M. Assem
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt; (R.H.M.K.); (S.A.S.); (N.M.A.); (S.A.M.)
| | - Shimaa A. Mahmoud
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt; (R.H.M.K.); (S.A.S.); (N.M.A.); (S.A.M.)
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Jafari S, Ravan M, Karimi-Sani I, Aria H, Hasan-Abad AM, Banasaz B, Atapour A, Sarab GA. Screening and identification of potential biomarkers for pancreatic cancer: An integrated bioinformatics analysis. Pathol Res Pract 2023; 249:154726. [PMID: 37591067 DOI: 10.1016/j.prp.2023.154726] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/26/2023] [Accepted: 07/26/2023] [Indexed: 08/19/2023]
Abstract
Pancreatic cancer is one of the highly invasive and the seventh most common cause of death among cancers worldwide. To identify essential genes and the involved mechanisms in pancreatic cancer, we used bioinformatics analysis to identify potential biomarkers for pancreatic cancer management. Gene expression profiles of pancreatic cancer patients and normal tissues were screened and downloaded from The Cancer Genome Atlas (TCGA) bioinformatics database. The Differentially expressed genes (DEGs) were identified among gene expression signatures of normal and pancreatic cancer, using R software. Then, enrichment analysis of the DEGs, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, was performed by an interactive and collaborative HTML5 gene list enrichment analysis tool (enrichr) and ToppGene. The protein-protein interaction (PPI) network was also constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and ToppGenet web based tool followed by identifying hub genes of the top 100 DEGs in pancreatic cancer using Cytoscape software. Over 2000 DEGs with variable log2 fold (LFC) were identified among 34,706 genes. Principal component analysis showed that the top 20 DEGs, including H1-4, H1-5, H4C3, H4C2, RN7SL2, RN7SL3, RN7SL4P, RN7SKP80, SCARNA12, SCARNA10, SCARNA5, SCARNA7, SCARNA6, SCARNA21, SCARNA9, SCARNA13, SNORA73B, SNORA53, SNORA54 might distinguish pancreatic cancer from normal tissue. GO analysis showed that the top DEGs have more enriched in the negative regulation of gene silencing, negative regulation of chromatin organization, negative regulation of chromatin silencing, nucleosome positioning, regulation of chromatin silencing, and nucleosomal DNA binding. KEGG analysis identified an association between pancreatic cancer and systemic lupus erythematosus, alcoholism, neutrophil extracellular trap formation, and viral carcinogenesis. In PPI network analysis, we found that the different types of histone-encoding genes are involved as hub genes in the carcinogenesis of pancreatic cancer. In conclusion, our bioinformatics analysis identified genes that were significantly related to the prognosis of pancreatic cancer patients. These genes and pathways could serve as new potential prognostic markers and be used to develop treatments for pancreatic cancer patients.
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Affiliation(s)
- Somayeh Jafari
- Department of Molecular Medicine, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Milad Ravan
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Karimi-Sani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran; Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amin Moradi Hasan-Abad
- Autoimmune Diseases Research Center, Shahid Beheshti Hospital, Kashan University of Medical Sciences, Kashan, Iran
| | - Bahar Banasaz
- Internal Medicine Department, Babol University of Medical Sciences, Babol, Iran.
| | - Amir Atapour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Gholamreza Anani Sarab
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
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García-Crespo C, Francisco-Recuero I, Gallego I, Camblor-Murube M, Soria ME, López-López A, de Ávila AI, Madejón A, García-Samaniego J, Domingo E, Sánchez-Pacheco A, Perales C. Hepatitis C virus fitness can influence the extent of infection-mediated epigenetic modifications in the host cells. Front Cell Infect Microbiol 2023; 13:1057082. [PMID: 36992689 PMCID: PMC10040758 DOI: 10.3389/fcimb.2023.1057082] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
IntroductionCellular epigenetic modifications occur in the course of viral infections. We previously documented that hepatitis C virus (HCV) infection of human hepatoma Huh-7.5 cells results in a core protein-mediated decrease of Aurora kinase B (AURKB) activity and phosphorylation of Serine 10 in histone H3 (H3Ser10ph) levels, with an affectation of inflammatory pathways. The possible role of HCV fitness in infection-derived cellular epigenetic modifications is not known.MethodsHere we approach this question using HCV populations that display a 2.3-fold increase in general fitness (infectious progeny production), and up to 45-fold increase of the exponential phase of intracellular viral growth rate, relative to the parental HCV population.ResultsWe show that infection resulted in a HCV fitness-dependent, average decrease of the levels of H3Ser10ph, AURKB, and histone H4 tri-methylated at Lysine 20 (H4K20m3) in the infected cell population. Remarkably, the decrease of H4K20m3, which is a hallmark of cellular transformation, was significant upon infection with high fitness HCV but not upon infection with basal fitness virus.DiscussionHere we propose two mechanisms ─which are not mutually exclusive─ to explain the effect of high viral fitness: an early advance in the number of infected cells, or larger number of replicating RNA molecules per cell. The implications of introducing HCV fitness as an influence in virus-host interactions, and for the course of liver disease, are warranted. Emphasis is made in the possibility that HCV-mediated hepatocellular carcinoma may be favoured by prolonged HCV infection of a human liver, a situation in which viral fitness is likely to increase.
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Affiliation(s)
- Carlos García-Crespo
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Irene Francisco-Recuero
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Isabel Gallego
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Marina Camblor-Murube
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - María Eugenia Soria
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Ana López-López
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Ana Isabel de Ávila
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Madejón
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria “La Paz”, Madrid, Spain
| | - Javier García-Samaniego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria “La Paz”, Madrid, Spain
| | - Esteban Domingo
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Esteban Domingo, ; Aurora Sánchez-Pacheco, ; Celia Perales,
| | - Aurora Sánchez-Pacheco
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
- *Correspondence: Esteban Domingo, ; Aurora Sánchez-Pacheco, ; Celia Perales,
| | - Celia Perales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
- Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- *Correspondence: Esteban Domingo, ; Aurora Sánchez-Pacheco, ; Celia Perales,
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Hoyt JE, Teja N, Jiang T, Rozema L, Gui J, Watts BV, Shiner B, Gradus JL. Changes in Alcohol Consumption following Direct-Acting Antiviral Treatment for Hepatitis C in VA Patients with Comorbid Alcohol Use Disorder and PTSD. J Dual Diagn 2022; 18:185-198. [PMID: 36151743 PMCID: PMC9719291 DOI: 10.1080/15504263.2022.2123119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
OBJECTIVE To investigate whether direct-acting antivirals (DAA) for hepatitis C viral infection (HCV): glecaprevir/pibrentasvir (GLE/PIB), ledipasvir/sofosbuvir (LDV/SOF), and sofosbuvir/velpatasvir (SOF/VEL) are associated with reduced alcohol consumption among veterans with alcohol use disorder (AUD) and co-occurring post-traumatic stress disorder (PTSD). METHODS We measured change in Alcohol Use Disorder Identification Test-Consumption Module (AUDIT-C) scores in a retrospective cohort of veterans with PTSD and AUD receiving DAAs for HCV. RESULTS One thousand two hundred and eleven patients were included (GLE/PIB n = 174, LDV/SOF n = 808, SOF/VEL n = 229). Adjusted frequencies of clinically meaningful improvement were 30.5% for GLE/PIB, 45.5% for LDV/SOF, and 40.5% for SOF/VEL. The frequency was lower for GLE/PIB than for LDV/SOF (OR = 0.59; 95% CI [0.40, 0.87]) or SOF/VEL (OR = 0.66; 95% CI [0.42, 1.04]). CONCLUSIONS DAA treatment for HCV was associated with a substantial reduction in alcohol use in patients with AUD and co-occurring PTSD. Further exploration of the role of DAAs in AUD treatment is warranted.
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Affiliation(s)
- Jessica E Hoyt
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
| | - Nikhil Teja
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
| | - Tammy Jiang
- Boston University School of Public Health, Boston, Massachusetts, USA
| | - Luke Rozema
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
| | - Jiang Gui
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
- Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Bradley V Watts
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
- Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Brian Shiner
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
- Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
- Veterans Administration National Center for PTSD, White River Junction, Vermont, USA
| | - Jaimie L Gradus
- Boston University School of Public Health, Boston, Massachusetts, USA
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Atif M, Mustaan MA, Falak S, Ghaffar A, Munir B. Targeting the effect of sofosbuvir on selective oncogenes expression level of hepatocellular carcinoma Ras/Raf/MEK/ERK pathway in Huh7 cell line. Saudi J Biol Sci 2022; 29:103332. [PMID: 35813116 PMCID: PMC9256646 DOI: 10.1016/j.sjbs.2022.103332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 04/21/2022] [Accepted: 05/29/2022] [Indexed: 11/29/2022] Open
Abstract
Direct acting antiviral agents are emerging line of treatment to eradicate Hepatitis C virus. Recent controversy over whether direct acting antiviral agents increase rate of hepatocellular carcinoma in HCV patients or prevent it, has increased the need to elaborate underlying mechanisms on molecular basis. This work was aimed to investigate the effect of sofosbuvir on the expression of selected oncogenes from the Ras/Raf/MEK/ERK pathway in Huh7 cell line. Results found concrete molecular evidence that sofosbuvir has significantly altered the expression of selected genes when huh7 cell line was treated with sofosbuvir. Nine genes related to HCC were found to be affected by sofosbuvir in a mixed effect manner. The relative expression of growth factors (VEGF, PDGFRB and HGF) was increased in sofosbuvir treated cell lines. The kinase family genes H-RAS, B-RAF, MET except MAPK1 were downregulated. Similarly, DUSP1 was upregulated and SPRY2 was slightly downregulated; both were negative feedback inhibitors of ERK signalling cascade. Sofosbuvir upregulated the growth factors and MAPK1 which suggests it to be a carcinogen. The downregulation of kinases and upregulation of DUSP1 make it an anticancer drug. Hence, the results from this study are important to prove that sofosbuvir neither reduce nor induce hepatocellular carcinoma.
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Affiliation(s)
- Muhammad Atif
- Department of Biochemistry, Government College University, Faisalabad 38000, Pakistan
| | | | - Sadia Falak
- Department of Biochemistry, University of Jhang, Jhang 35200, Pakistan
| | - Abdul Ghaffar
- Department of Biochemistry, Government College University, Faisalabad 38000, Pakistan
| | - Bushra Munir
- Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
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Tsai WL, Cheng JS, Liu PF, Chang TH, Sun WC, Chen WC, Shu CW. Sofosbuvir induces gene expression for promoting cell proliferation and migration of hepatocellular carcinoma cells. Aging (Albany NY) 2022; 14:5710-5726. [PMID: 35833210 PMCID: PMC9365546 DOI: 10.18632/aging.204170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 05/13/2022] [Indexed: 11/29/2022]
Abstract
Direct-acting antivirals (DAAs) have achieved a sustained virological response (SVR) rate of 95–99% in treating HCV. Several studies suggested that treatment with sofosbuvir (SOF), one type of DAAs, may be associated with increased risk of developing HCC. The aim of this study is to investigate the potential mechanisms of SOF on the development of HCC. OR-6 (harboring full-length genotype 1b HCV) and Huh 7.5.1 cells were used to examine the effects of SOF on cell proliferation and migration of HCC cells. SOF-upregulated genes in OR-6 cells were inspected using next generation sequencing (NGS)and the clinical significance of these candidate genes was analyzed using The Cancer Genome Atlas (TCGA) database. We found that SOF increased cell proliferation and cell migration in OR-6 and Huh 7.5.1 cells. Several SOF-upregulated genes screened from NGS were confirmed by real-time PCR in OR-6 cells. Among these genes, PHOSPHO2, KLHL23, TRIM39, TSNAX-DISC1 and RPP21 expression were significantly elevated in the tumor tissues compared with the non-tumor tissues of HCC according to TCGA database. High expression of PHOSPHO2 and RPP21 was associated with poor overall survival of HCC patients. Moreover, knockdown of PHOSPHO2-KLHL23, TSNAX-DISC1, TRIM39 and RPP21 diminished cell proliferation and migration increased by SOF in OR-6 and Huh 7.5.1 cells. In conclusion, SOF-upregulated genes promoted HCC cell proliferation and migration, which might be associated with the development of HCC.
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Affiliation(s)
- Wei-Lun Tsai
- Division of General Internal Medicine, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,School of Nursing, Fooyin University, Kaohsiung, Taiwan
| | - Jin-Shiung Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Tsung-Hsien Chang
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Chih Sun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wen-Chi Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chih-Wen Shu
- Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
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Tajiri K, Ito H, Kawai K, Kashii Y, Hayashi Y, Murayama A, Minemura M, Takahara T, Shimizu Y, Yasuda I. Direct-acting antivirals for hepatitis C virus-infected patients with hepatocellular carcinoma. World J Hepatol 2022; 14:1190-1199. [PMID: 35978673 PMCID: PMC9258255 DOI: 10.4254/wjh.v14.i6.1190] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/18/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients has a high risk of recurrence. Although eradication of HCV is expected to reduce this risk, the risk in patients with a history of HCC may be high after treatment with direct-acting antivirals (DAAs). AIM To determine the risk factors for HCC recurrence in patients with HCV and a history of HCC. METHODS The risk of HCC recurrence in patients with a history of HCC and/or of HCC occurrence in patients without a history of HCC after DAA therapy was retrospectively analyzed in 311 HCV patients treated at our institution and several neighboring hospitals. The frequency and predictors of HCC recurrence/ occurrence after DAA treatment were included in these analyses. The clinical course of HCC before and after DAA treatment was also evaluated. RESULTS HCV patients with a history of HCC were older and had greater progression of liver fibrosis and diabetes than patients without a history of HCC. Median recurrence-free survival (RFS) was 1092 d in patients with a history of HCC, and post-DAA HCC recurrence/occurrence was observed in 29 patients (53.7%) with and 5 (1.9%) without a history of HCC over 6 years (P < 0.001). RFS in patients with a history of HCC did not differ significantly before and after DAA treatment. The frequency of HCC recurrence/occurrence in patients with a history of HCC was lower after than before DAA treatment. Multivariate analysis showed that the incidence rate of HCC recurrence/occurrence before DAA treatment was the only independent predictor of HCC recurrence/occurrence after DAA treatment. Liver function was well preserved and clinical course was good in patients with HCC recurrence/occurrence after DAA therapy. CONCLUSION DAA therapy in patients infected with HCV is also effective in patients with a history of HCC. Curative treatment for HCC is desirable before DAA therapy. The frequency of HCC recurrence/occurrence before DAA therapy was associated with a significantly increased risk of HCC recurrence after DAA therapy. Careful observation after DAA therapy is required in patients with a history of HCC.
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Affiliation(s)
- Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama 930-0194, Japan.
| | - Hiroyuki Ito
- Department of Gastroenterology, Takaoka Municipal Hospital, Takaoka 933-8550, Japan
| | - Kengo Kawai
- Gastroenterology Center, Nanto Municipal Hospital, Nanto 932-0211, Japan
| | - Yoshiro Kashii
- Department of Gastroenterology, Saiseikai Toyama Hospital, Toyama 931-8533, Japan
| | - Yuka Hayashi
- Department of Gastroenterology, Toyama University Hospital, Toyama 930-0194, Japan
| | - Aiko Murayama
- Department of Gastroenterology, Toyama University Hospital, Toyama 930-0194, Japan
| | - Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, Toyama 930-0194, Japan
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, Toyama 930-0194, Japan
| | - Yukihiro Shimizu
- Gastroenterology Center, Nanto Municipal Hospital, Nanto 932-0211, Japan
| | - Ichiro Yasuda
- Department of Gastroenterology, Toyama University Hospital, Toyama 930-0194, Japan
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10
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The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma. Medicina (B Aires) 2022; 58:medicina58020259. [PMID: 35208582 PMCID: PMC8875284 DOI: 10.3390/medicina58020259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives: The impact of direct-acting antiviral (DAA)-based regimens on the recurrence of hepatocellular carcinoma (HCC) after successful curative hepatectomy is controversial. Aims: This study aimed to assess the association between DAAs treatment and recurrence risk in HCC after resection. Materials and Methods: We retrospectively assessed 152 cases of early stage (BCLC stage 0/A) hepatitis C virus (HCV)-related HCC (HCV-HCC) that underwent resection with curative intent between 2001 and 2019 at Kaohsiung Chang Gung Memorial Hospital; 48 cases achieved a sustained virological response (SVR) by DAA, and 104 cases were not treated with any antiviral therapy (non-treatment group). Recurrence-free survival (RFS) following curative resection was analyzed by using the log-rank test and Kaplan–Meier method. A Cox proportional hazards model was used to analyze the factors that impacted RFS and OS. Results: Five patients (10.4%) experienced HCC recurrence after DAA therapy. The cumulative HCC recurrence rate was significantly lower in the DAA group than the non-treatment group (p < 0.001). Multivariate analysis revealed a significant difference in RFS between the non-treatment group and DAA group (p = 0.001; hazard ratio (HR), 4.978; 95% CI, 1.976–12.542); liver cirrhosis (p = 0.005; HR, 2.062; 95% CI, 1.247–3.410), microvascular invasion (p = 0.001; HR, 2.331; 95% CI, 1.408–3.860) and AFP > 15 ng/mL (p = 0.022; HR, 1.799; 95% CI, 1.089–2.970) were also independent factors for HCC recurrence. ALBI stage II/III (p = 0.005; HR, 3.249; 95% CI, 1.418–7.443) and microvascular invasion (p < 0.001; HR, 4.037 95% CI, 2.071–7.869) were independent factors for OS; no significant difference in OS was observed between the DAA and no DAA treatment groups. Conclusions: DAA treatment could reduce the risk of recurrence after curative treatment for early stage HCC.
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Yahya G, Hashem Mohamed N, Pijuan J, Seleem NM, Mosbah R, Hess S, Abdelmoaty AA, Almeer R, Abdel‐Daim MM, Shulaywih Alshaman H, Juraiby I, Metwally K, Storchova Z. Profiling the physiological pitfalls of anti-hepatitis C direct-acting agents in budding yeast. Microb Biotechnol 2021; 14:2199-2213. [PMID: 34378349 PMCID: PMC8449668 DOI: 10.1111/1751-7915.13904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/05/2023] Open
Abstract
Sofosbuvir and Daclatasvir are among the direct-acting antiviral (DAA) medications prescribed for the treatment of chronic hepatitis C (CHC) virus infection as combination therapy with other antiviral medications. DAA-based therapy achieves high cure rates, reaching up to 97% depending on the genotype of the causative hepatitis C virus (HCV). While DAAs have been approved as an efficient and well-tolerated therapy for CHC, emerging concerns about adverse cardiac side effects, higher risk of recurrence and occurrence of hepatocellular carcinoma (HCC) and doubts of genotoxicity have been reported. In our study, we investigated in detail physiological off-targets of DAAs and dissected the effects of these drugs on cellular organelles using budding yeast, a unicellular eukaryotic organism. DAAs were found to disturb the architecture of the endoplasmic reticulum (ER) and the mitochondria, while showing no apparent genotoxicity or DNA damaging effect. Our study provides evidence that DAAs are not associated with genotoxicity and highlights the necessity for adjunctive antioxidant therapy to mitigate the adverse effects of DAAs on ER and mitochondria.
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Affiliation(s)
- Galal Yahya
- Department of Microbiology and ImmunologyFaculty of PharmacyZagazig UniversityAl Sharqia44519Egypt
- Department of Molecular GeneticsFaculty of BiologyTechnical University of KaiserslauternPaul‐Ehrlich Str. 24Kaiserslautern67663Germany
| | | | - Jordi Pijuan
- Laboratory of Neurogenetics and Molecular Medicine ‐ IPERInstitut de Recerca Sant Joan de DéuBarcelona08950Spain
| | - Noura M. Seleem
- Department of Microbiology and ImmunologyFaculty of PharmacyZagazig UniversityAl Sharqia44519Egypt
| | - Rasha Mosbah
- Infection Control UnitHospitals of Zagazig UniversityAl SharqiaEgypt
| | - Steffen Hess
- Department of Cell BiologyFaculty of BiologyTechnical University of KaiserslauternKaiserslauternGermany
| | - Ahmed A. Abdelmoaty
- Department of Tropical MedicineFaculty of MedicineZagazig UniversityZagazig44519Egypt
| | - Rafa Almeer
- Department of ZoologyCollege of ScienceKing Saud UniversityP.O. Box 2455Riyadh11451Saudi Arabia
| | - Mohamed M. Abdel‐Daim
- Department of ZoologyCollege of ScienceKing Saud UniversityP.O. Box 2455Riyadh11451Saudi Arabia
- Pharmacology DepartmentCollege of Veterinary MedicineSuez Canal UniversityIsmailiaEgypt
| | | | - Ibrahim Juraiby
- General Directorate of Health AffairsMinistry of HealthJazan82723Saudi Arabia
| | - Kamel Metwally
- Department of Pharmaceutical ChemistryFaculty of PharmacyTabuk UniversityTabuk47713Saudi Arabia
- Department of Medicinal ChemistryFaculty of PharmacyZagazig UniversityZagazig44519Egypt
| | - Zuzana Storchova
- Department of Molecular GeneticsFaculty of BiologyTechnical University of KaiserslauternPaul‐Ehrlich Str. 24Kaiserslautern67663Germany
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12
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Reungoat E, Grigorov B, Zoulim F, Pécheur EI. Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis. Cancers (Basel) 2021; 13:cancers13092270. [PMID: 34065048 PMCID: PMC8125929 DOI: 10.3390/cancers13092270] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary In the era of direct-acting antivirals against the hepatitis C virus (HCV), curing chronic hepatitis C has become a reality. However, while replicating chronically, HCV creates a peculiar state of inflammation and oxidative stress in the infected liver, which fuels DNA damage at the onset of HCV-induced hepatocellular carcinoma (HCC). This cancer, the second leading cause of death by cancer, remains of bad prognosis when diagnosed. This review aims to decipher how HCV durably alters elements of the extracellular matrix that compose the liver microenvironment, directly through its viral proteins or indirectly through the induction of cytokine secretion, thereby leading to liver fibrosis, cirrhosis, and, ultimately, HCC. Abstract Chronic infection by the hepatitis C virus (HCV) is a major cause of liver diseases, predisposing to fibrosis and hepatocellular carcinoma. Liver fibrosis is characterized by an overly abundant accumulation of components of the hepatic extracellular matrix, such as collagen and elastin, with consequences on the properties of this microenvironment and cancer initiation and growth. This review will provide an update on mechanistic concepts of HCV-related liver fibrosis/cirrhosis and early stages of carcinogenesis, with a dissection of the molecular details of the crosstalk during disease progression between hepatocytes, the extracellular matrix, and hepatic stellate cells.
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13
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Lee HW, Han DH, Shin HJ, Lee JS, Kim SU, Park JY, Kim DY, Ahn SH, Kim BK. Hepatocellular Carcinoma Risk According to Regimens for Eradication of Hepatitis C Virus; Interferon or Direct Acting Antivirals. Cancers (Basel) 2020; 12:3414. [PMID: 33217965 PMCID: PMC7698608 DOI: 10.3390/cancers12113414] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/09/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
By pegylated interferon (PegIFN)-free direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection, a sustained virological response (SVR) rate >95% can be attained with a satisfactory tolerability and shorter treatment duration. However, it remains controversial whether there is any difference in prognosis depending on regimens-PegIFN or DAAs. We compared the probabilities of hepatocellular carcinoma (HCC) development between patients achieving an SVR by PegIFN/ribavirin (PegIFN group, n = 603) and DAAs (DAAs group, n = 479). The DAAs group was significantly older and had a higher proportion of cirrhosis than the PegIFN group. Before adjustment, the DAAs group had a higher HCC incidence than the PegIFN group (p < 0.001). However, by multivariate analyses, the DAAs (vs. PegIFN) group was not associated with HCC risk (adjusted hazard ratio 0.968, 95% confidence interval 0.380-2.468; p = 0.946). Old age, male, higher body mass index, cirrhosis, and lower platelet count were associated with increased HCC risk (all p < 0.05). After propensity score matching (PSM), a similar HCC risk between the two groups was observed (p = 0.372). We also compared HCC incidences according to sofosbuvir (SOF)-based and SOF-free DAAs, showing a similar risk in both groups before adjustment (p = 0.478) and after PSM (p = 0.855). In conclusion, post-SVR HCC risks were comparable according to treatment regimens; PegIFN- vs. DAA-based regimens and SOF-based vs. SOF-free DAA regimens. Further studies with a longer follow-up period are required.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
| | - Dai Hoon Han
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of medicine, Seoul 03722, Korea
| | - Hye Jung Shin
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.W.L.); (J.S.L.); (S.U.K.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Korea;
- Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul 03722, Korea
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