{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:21:23Z","timestamp":1791998483957,"version":"4.4.0"},"reference-count":268,"publisher":"Impact Journals, LLC","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging"],"published-print":{"date-parts":[[2020,2,4]]},"DOI":"10.18632\/aging.102777","type":"journal-article","created":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T00:40:42Z","timestamp":1580863242000},"page":"3053-3094","source":"Crossref","is-referenced-by-count":44,"title":["New landscapes and horizons in hepatocellular carcinoma therapy"],"prefix":"10.18632","volume":"12","author":[{"given":"Melchiorre","family":"Cervello","sequence":"first","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Emma","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppa","family":"Augello","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Cusimano","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Giannitrapani","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy"},{"name":"Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Soresi","sequence":"additional","affiliation":[{"name":"Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaw M.","family":"Akula","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Abrams","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda S.","family":"Steelman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Gulino","sequence":"additional","affiliation":[{"name":"Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Belmonte","sequence":"additional","affiliation":[{"name":"Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Montalto","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy"},{"name":"Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"McCubrey","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"7892","published-online":{"date-parts":[[2020,2,4]]},"reference":[{"key":"1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.","volume":"6","author":"Jemal","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"2","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.18632\/aging.101531","article-title":"Integrated analysis of the impact of age on genetic and clinical aspects of hepatocellular carcinoma.","volume":"1","author":"Ren","year":"2018","journal-title":"Aging (Albany NY)"},{"key":"3","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1586\/17474124.2015.1028363","article-title":"The evolving epidemiology of hepatocellular carcinoma: a global perspective.","volume":"9","author":"Adams","year":"2015","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"4","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1053\/j.gastro.2007.04.061","article-title":"Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.","volume":"13","author":"Rudolph","year":"2007","journal-title":"Gastroenterology"},{"key":"5","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1056\/NEJMra1001683","article-title":"Hepatocellular carcinoma.","volume":"36","author":"El-Serag","year":"2011","journal-title":"N Engl J Med"},{"key":"6","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1016\/j.bpg.2014.08.007","article-title":"Hepatocellular carcinoma epidemiology.","volume":"2","author":"La Vecchia","year":"2014","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"7","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1111\/liv.13204","article-title":"The evolutionary scenario of hepatocellular carcinoma in Italy: an update.","volume":"3","author":"Borzio","year":"2017","journal-title":"Liver Int"},{"key":"8","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1002\/hep.29913","article-title":"Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases.","volume":"6","author":"Heimbach","year":"2018","journal-title":"Hepatology"},{"key":"9","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma.","volume":"14","author":"El-Serag","year":"2012","journal-title":"Gastroenterology"},{"key":"10","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/nrgastro.2010.100","article-title":"Hepatocellular carcinoma: A global view.","volume":"7","author":"Roberts","year":"2010","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"11","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.ejim.2009.12.011","article-title":"Hepatocellular carcinoma: comparison of two different periods at the same center.","volume":"2","author":"Montalto","year":"2010","journal-title":"Eur J Intern Med"},{"key":"12","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1111\/liv.12208","article-title":"Rise and fall of HCV-related hepatocellular carcinoma in Italy: a long-term survey from the ITA.LI.CA centres.","volume":"3","author":"Giannini","year":"2013","journal-title":"Liver Int"},{"key":"13","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1097\/MCG.0b013e3182872f29","article-title":"Epidemiology of hepatocellular carcinoma: consider the population.","volume":"4","author":"El-Serag","year":"2013","journal-title":"J Clin Gastroenterol"},{"key":"14","unstructured":"https:\/\/www.registri-tumori.it\/cms\/sites\/default\/files\/pubblicazioni\/2018_NumeriCancro-operatori.pdf."},{"key":"15","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.ejim.2016.10.012","article-title":"Characteristics of liver cirrhosis in Italy: evidence for a decreasing role of HCV aetiology.","volume":"3","author":"Gaeta","year":"2017","journal-title":"Eur J Intern Med"},{"key":"16","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1002\/hep.21492","article-title":"Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.","volume":"4","author":"Persico","year":"2007","journal-title":"Hepatology"},{"key":"17","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1002\/hep.28123","article-title":"Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.","volume":"6","author":"Hunt","year":"2015","journal-title":"Hepatology"},{"key":"18","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41571-018-0073-4","article-title":"Molecular therapies and precision medicine for hepatocellular carcinoma.","volume":"1","author":"Finn","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"19","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.canlet.2015.07.018","article-title":"Heterogeneity of liver cancer and personalized therapy.","volume":"37","author":"Wang","year":"2016","journal-title":"Cancer Lett"},{"key":"20","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.cell.2017.05.046","article-title":"Electronic address: wheeler@bcm.edu, and Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma.","volume":"16","author":"Moore","year":"2017","journal-title":"Cell"},{"key":"21","doi-asserted-by":"publisher","first-page":"7385","DOI":"10.1158\/0008-5472.CAN-09-1089","article-title":"Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.","volume":"6","author":"Friedman","year":"2009","journal-title":"Cancer Res"},{"key":"22","doi-asserted-by":"publisher","first-page":"236","DOI":"10.18632\/oncotarget.466","article-title":"Targeted therapy for hepatocellular carcinoma: novel agents on the horizon.","volume":"3","author":"Montalto","year":"2012","journal-title":"Oncotarget"},{"key":"23","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1615\/ForumImmunDisTher.2015013982","article-title":"From targets to targeted therapies in hepatocellular carcinoma.","volume":"5","author":"Cusimano","year":"2014","journal-title":"For Immunopathol Dis Therap"},{"key":"24","doi-asserted-by":"publisher","first-page":"2358","DOI":"10.2174\/1381612822666160304151011","article-title":"Critical roles of EGFR family members in breast cancer and breast cancer stem cells: targets for therapy.","volume":"2","author":"Fenga","year":"2016","journal-title":"Curr Pharm Des"},{"key":"25","doi-asserted-by":"publisher","first-page":"4603","DOI":"10.18632\/oncotarget.2209","article-title":"Deregulation of the EGFR\/PI3K\/PTEN\/Akt\/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.","volume":"5","author":"Gizak","year":"2014","journal-title":"Oncotarget"},{"key":"26","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1002\/hep.26898","article-title":"Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma.","volume":"5","author":"Gupta","year":"2014","journal-title":"Hepatology"},{"key":"27","doi-asserted-by":"publisher","first-page":"E30","DOI":"10.3390\/ijms17010030","article-title":"EGFR signaling in liver diseases.","volume":"1","author":"Sibilia","year":"2015","journal-title":"Int J Mol Sci"},{"key":"28","doi-asserted-by":"publisher","first-page":"e8122","DOI":"10.1097\/MD.0000000000008122","article-title":"Hepatocellular carcinoma treated with anti-epidermal growth factor receptor antibody nimotuzumab: A case report.","volume":"9","author":"Zhang","year":"2017","journal-title":"Medicine (Baltimore)"},{"key":"29","first-page":"4143","article-title":"Gefitinib in advanced unresectable hepatocellular carcinoma: Results from the eastern cooperative oncology group\u2019s study E1203.","volume":"2","author":"Benson","year":"2006","journal-title":"J Clin Oncol"},{"key":"30","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1634\/theoncologist.2011-0253","article-title":"Phase II trial of erlotinib and docetaxel in advanced and refractory hepatocellular and biliary cancers: Hoosier Oncology Group GI06-101.","volume":"1","author":"Loehrer","year":"2012","journal-title":"Oncologist"},{"key":"31","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.1002\/cncr.26556","article-title":"Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.","volume":"11","author":"Erlichman","year":"2012","journal-title":"Cancer"},{"key":"32","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/35077225","article-title":"Oncogenic kinase signalling.","volume":"41","author":"Hunter","year":"2001","journal-title":"Nature"},{"key":"33","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s10549-018-4664-7","article-title":"The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence.","volume":"16","author":"Ryd\u00e9n","year":"2018","journal-title":"Breast Cancer Res Treat"},{"key":"34","first-page":"3857","article-title":"GLI2 induces PDGFRB expression and modulates cancer stem cell properties of gastric cancer.","volume":"2","author":"Lai","year":"2017","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"35","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1158\/1078-0432.CCR-0930-03","article-title":"Aberrant expression of neuropilin-1 and -2 in human pancreatic cancer cells.","volume":"1","author":"Korc","year":"2004","journal-title":"Clin Cancer Res"},{"key":"36","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1007\/s10147-005-0528-3","article-title":"Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma.","volume":"1","author":"Yanaga","year":"2006","journal-title":"Int J Clin Oncol"},{"key":"37","first-page":"55","article-title":"Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer.","volume":"1","author":"Filho","year":"2013","journal-title":"Cancer Genomics Proteomics"},{"key":"38","doi-asserted-by":"publisher","first-page":"3144","DOI":"10.12659\/MSM.894617","article-title":"Prognostic Value of VEGF in hepatocellular carcinoma patients treated with sorafenib: A meta-analysis.","volume":"2","author":"Li","year":"2015","journal-title":"Med Sci Monit"},{"key":"39","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.clinre.2016.11.006","article-title":"Co-expression of PDGF-B and VEGFR-3 strongly correlates with poor prognosis in hepatocellular carcinoma patients after hepatectomy.","volume":"4","author":"Dai","year":"2018","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"40","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1756-9966-32-16","article-title":"Expression and prognostic value of VEGFR-2, PDGFR-\u03b2, and c-Met in advanced hepatocellular carcinoma.","volume":"3","author":"Xu","year":"2013","journal-title":"J Exp Clin Cancer Res"},{"key":"41","doi-asserted-by":"publisher","first-page":"39534","DOI":"10.18632\/oncotarget.17134","article-title":"Platelet-derived growth factor receptor \u03b1 in hepatocellular carcinoma is a prognostic marker independent of underlying liver cirrhosis.","volume":"8","author":"Lee","year":"2017","journal-title":"Oncotarget"},{"key":"42","doi-asserted-by":"publisher","first-page":"1925315","DOI":"10.1155\/2019\/1925315","article-title":"Predictive value of diminished serum PDGF-BB after curative resection of hepatocellular cancer.","volume":"201","author":"Imoto","year":"2019","journal-title":"J Oncol"},{"key":"43","doi-asserted-by":"publisher","first-page":"6605","DOI":"10.1038\/onc.2017.260","article-title":"The PDGFR\u03b1-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma.","volume":"3","author":"Roskams","year":"2017","journal-title":"Oncogene"},{"key":"44","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1586\/era.09.41","article-title":"Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial.","volume":"9","author":"Santoro","year":"2009","journal-title":"Expert Rev Anticancer Ther"},{"key":"45","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.jhep.2018.04.010","article-title":"Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial.","volume":"6","author":"Sun","year":"2018","journal-title":"J Hepatol"},{"key":"46","doi-asserted-by":"publisher","first-page":"4078","DOI":"10.1200\/JCO.2017.35.15_suppl.4078","article-title":"Efficacy of regorafenib (reg) in patients with hepatocellular carcinoma (hcc) in the phase III resorce trial according to alpha-fetoprotein (afp) and c-met levels as predictors of poor prognosis.","volume":"3","author":"Bruix","year":"2017","journal-title":"J Clin Oncol"},{"key":"47","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1158\/1535-7163.MCT-03-0156","article-title":"Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248.","volume":"5","author":"Mendel","year":"2006","journal-title":"Mol Cancer Ther"},{"key":"48","doi-asserted-by":"publisher","first-page":"3027","DOI":"10.1200\/JCO.2008.20.9908","article-title":"Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.","volume":"2","author":"Clark","year":"2009","journal-title":"J Clin Oncol"},{"key":"49","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/S1470-2045(09)70171-8","article-title":"Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study.","volume":"1","author":"Cheng","year":"2009","journal-title":"Lancet Oncol"},{"key":"50","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1634\/theoncologist.2009-0316","article-title":"Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77\/06).","volume":"1","author":"Bodoky","year":"2010","journal-title":"Oncologist"},{"key":"51","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1002\/cncr.27758","article-title":"Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma.","volume":"11","author":"Ricker","year":"2013","journal-title":"Cancer"},{"key":"52","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1200\/JCO.2013.54.3298","article-title":"Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.","volume":"3","author":"Qian","year":"2015","journal-title":"J Clin Oncol"},{"key":"53","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1158\/1078-0432.CCR-10-2011","article-title":"Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma.","volume":"1","author":"Raoul","year":"2011","journal-title":"Clin Cancer Res"},{"key":"54","doi-asserted-by":"publisher","first-page":"2090","DOI":"10.1158\/1078-0432.CCR-11-1991","article-title":"Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma.","volume":"1","author":"Park","year":"2012","journal-title":"Clin Cancer Res"},{"key":"55","doi-asserted-by":"publisher","first-page":"3517","DOI":"10.1200\/JCO.2012.48.4410","article-title":"Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.","volume":"3","author":"Boucher","year":"2013","journal-title":"J Clin Oncol"},{"key":"56","doi-asserted-by":"publisher","first-page":"3509","DOI":"10.1200\/JCO.2012.47.3009","article-title":"Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.","volume":"3","author":"Lin","year":"2013","journal-title":"J Clin Oncol"},{"key":"57","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/hep.27290","article-title":"Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial.","volume":"6","author":"Wu","year":"2014","journal-title":"Hepatology"},{"key":"58","doi-asserted-by":"publisher","first-page":"2959","DOI":"10.1158\/1078-0432.CCR-13-2620","article-title":"Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET.","volume":"2","author":"Chen","year":"2014","journal-title":"Clin Cancer Res"},{"key":"59","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMoa1717002","article-title":"Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.","volume":"37","author":"Kl\u00fcmpen","year":"2018","journal-title":"N Engl J Med"},{"key":"60","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.","volume":"39","author":"Komov","year":"2018","journal-title":"Lancet"},{"key":"61","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1111\/j.1478-3231.2008.01762.x","article-title":"Targeting vascular endothelial growth factor with the monoclonal antibody bevacizumab inhibits human hepatocellular carcinoma cells growing in an orthotopic mouse model.","volume":"2","author":"Busuttil","year":"2009","journal-title":"Liver Int"},{"key":"62","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s00432-010-0914-8","article-title":"Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression.","volume":"13","author":"Tang","year":"2011","journal-title":"J Cancer Res Clin Oncol"},{"key":"63","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1634\/theoncologist.2011-0465","article-title":"Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma.","volume":"1","author":"Farace","year":"2012","journal-title":"Oncologist"},{"key":"64","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s11523-016-0467-0","article-title":"Phase I\/II randomized trial of sorafenib and bevacizumab as first-line therapy in patients with locally advanced or metastatic hepatocellular carcinoma: north central cancer treatment group trial N0745 (Alliance).","volume":"1","author":"Alberts","year":"2017","journal-title":"Target Oncol"},{"key":"65","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1038\/sj.bjc.6605580","article-title":"Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma.","volume":"10","author":"Cheng","year":"2010","journal-title":"Br J Cancer"},{"key":"66","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1200\/JCO.2008.18.3301","article-title":"Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma.","volume":"2","author":"Abbruzzese","year":"2009","journal-title":"J Clin Oncol"},{"key":"67","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1148\/radiol.2015142140","article-title":"Hepatocellular carcinoma: A phase II randomized controlled double-blind trial of transarterial chemoembolization in combination with biweekly intravenous administration of bevacizumab or a placebo.","volume":"27","author":"Peck-Radosavljevic","year":"2015","journal-title":"Radiology"},{"key":"68","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/S1470-2045(15)00050-9","article-title":"Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.","volume":"1","author":"Trojan","year":"2015","journal-title":"Lancet Oncol"},{"key":"69","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/S1470-2045(18)30937-9","article-title":"Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased \u03b1-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.","volume":"2","author":"Ohno","year":"2019","journal-title":"Lancet Oncol"},{"key":"70","doi-asserted-by":"publisher","first-page":"27277","DOI":"10.1074\/jbc.M704244200","article-title":"Liver-specific activities of FGF19 require Klotho beta.","volume":"28","author":"Desnoyers","year":"2007","journal-title":"J Biol Chem"},{"key":"71","doi-asserted-by":"publisher","first-page":"57633","DOI":"10.18632\/oncotarget.9328","article-title":"Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.","volume":"7","author":"Leong","year":"2016","journal-title":"Oncotarget"},{"key":"72","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1042\/BJ20101603","article-title":"Fibroblast growth factors and their receptors in cancer.","volume":"43","author":"Haugsten","year":"2011","journal-title":"Biochem J"},{"key":"73","doi-asserted-by":"publisher","first-page":"5165","DOI":"10.1074\/jbc.M109.068783","article-title":"FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation.","volume":"28","author":"Li","year":"2010","journal-title":"J Biol Chem"},{"key":"74","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13046-016-0478-9","article-title":"FGF19\/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib.","volume":"3","author":"Teng","year":"2017","journal-title":"J Exp Clin Cancer Res"},{"key":"75","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1471-2407-12-56","article-title":"Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.","volume":"1","author":"Miyazaki","year":"2012","journal-title":"BMC Cancer"},{"key":"76","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.1111\/liv.14055","article-title":"Klotho-beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma.","volume":"3","author":"Cheng","year":"2019","journal-title":"Liver Int"},{"key":"77","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1158\/1535-7163.MCT-16-0589","article-title":"Discovery and pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor.","volume":"1","author":"Saxty","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"78","doi-asserted-by":"publisher","first-page":"2200","DOI":"10.1158\/1535-7163.MCT-11-0306","article-title":"A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.","volume":"1","author":"McCann","year":"2011","journal-title":"Mol Cancer Ther"},{"key":"79","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1158\/2159-8290.CD-14-1029","article-title":"First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway.","volume":"5","author":"Lengauer","year":"2015","journal-title":"Cancer Discov"},{"key":"80","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1158\/2159-8290.CD-19-0555","article-title":"First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma.","volume":"9","author":"Zhu","year":"2019","journal-title":"Cancer Discov"},{"key":"81","doi-asserted-by":"publisher","first-page":"6999","DOI":"10.1158\/0008-5472.CAN-17-1865","article-title":"H3B-6527 Is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma.","volume":"7","author":"Subramanian","year":"2017","journal-title":"Cancer Res"},{"key":"82","doi-asserted-by":"publisher","first-page":"954","DOI":"10.18632\/oncotarget.652","article-title":"Mutations and deregulation of Ras\/Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR cascades which alter therapy response.","volume":"3","author":"B\u00e4secke","year":"2012","journal-title":"Oncotarget"},{"key":"83","doi-asserted-by":"publisher","first-page":"192","DOI":"10.18632\/aging.100296","article-title":"Roles of the Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging.","volume":"3","author":"Malaponte","year":"2011","journal-title":"Aging (Albany NY)"},{"key":"84","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.18632\/oncotarget.659","article-title":"Ras\/Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.","volume":"3","author":"Nicoletti","year":"2012","journal-title":"Oncotarget"},{"key":"85","doi-asserted-by":"publisher","first-page":"2762","DOI":"10.1002\/jcp.22647","article-title":"Therapeutic resistance resulting from mutations in Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR signaling pathways.","volume":"22","author":"Montalto","year":"2011","journal-title":"J Cell Physiol"},{"key":"86","first-page":"757","article-title":"BAY-43-9006 Bayer\/Onyx.","volume":"4","author":"McCubrey","year":"2003","journal-title":"Curr Opin Investig Drugs"},{"key":"87","doi-asserted-by":"publisher","first-page":"e1568","DOI":"10.1200\/JCO.2017.35.15_suppl.e15682","article-title":"A multicenter phase II study of donafenib in patients with advanced hepatocellular carcinoma.","volume":"3","author":"Li","year":"2017","journal-title":"J Clin Oncol"},{"key":"88","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.jhep.2011.01.032","article-title":"Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur\/uracil.","volume":"5","author":"Shih","year":"2011","journal-title":"J Hepatol"},{"key":"89","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1093\/annonc\/mdw415","article-title":"A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC).","volume":"2","author":"Lim","year":"2016","journal-title":"Ann Oncol"},{"key":"90","doi-asserted-by":"publisher","first-page":"2368","DOI":"10.1158\/1078-0432.CCR-15-1681","article-title":"A phase I study of the safety, pharmacokinetic, and pharmodyamics of combination therapy with rfametinb plus sorafenib in patients with advanced cancer.","volume":"2","author":"Shen","year":"2016","journal-title":"Clin Cancer Res"},{"key":"91","doi-asserted-by":"publisher","first-page":"5976","DOI":"10.1158\/1078-0432.CCR-13-3445","article-title":"A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma.","volume":"2","author":"Kappeler","year":"2014","journal-title":"Clin Cancer Res"},{"key":"92","doi-asserted-by":"publisher","first-page":"43013","DOI":"10.1038\/srep43013","article-title":"PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.","volume":"7","author":"Cesta Incani","year":"2017","journal-title":"Sci Rep"},{"key":"93","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1080\/15384101.2016.1138183","article-title":"A PTEN inhibitor displays preclinical activity against hepatocarcinoma cells.","volume":"1","author":"Cervello","year":"2016","journal-title":"Cell Cycle"},{"key":"94","doi-asserted-by":"publisher","first-page":"17147","DOI":"10.18632\/oncotarget.3940","article-title":"The novel dual PI3K\/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells.","volume":"6","author":"Neri","year":"2015","journal-title":"Oncotarget"},{"key":"95","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.tips.2014.11.004","article-title":"Current treatment strategies for inhibiting mTOR in cancer.","volume":"3","author":"Martelli","year":"2015","journal-title":"Trends Pharmacol Sci"},{"key":"96","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1111\/apt.12132","article-title":"Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma.","volume":"3","author":"Chen","year":"2013","journal-title":"Aliment Pharmacol Ther"},{"key":"97","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1001\/jama.2014.7189","article-title":"Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.","volume":"31","author":"Santoro","year":"2014","journal-title":"JAMA"},{"key":"98","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1093\/annonc\/mdw054","article-title":"Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77\/08 and SASL 29).","volume":"2","author":"Lakatos","year":"2016","journal-title":"Ann Oncol"},{"key":"99","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/s10637-014-0169-3","article-title":"A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma.","volume":"3","author":"Erlichman","year":"2015","journal-title":"Invest New Drugs"},{"key":"100","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.ejca.2012.11.008","article-title":"A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.","volume":"4","author":"Toh","year":"2013","journal-title":"Eur J Cancer"},{"key":"101","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1097\/TP.0000000000000965","article-title":"Sirolimus use in liver transplant recipients with hepatocellular carcinoma: A Randomized, multicenter, open-label phase 3 trial.","volume":"10","author":"Heise","year":"2016","journal-title":"Transplantation"},{"key":"102","doi-asserted-by":"publisher","first-page":"3699","DOI":"10.1242\/dev.030338","article-title":"The regulation of TGFbeta signal transduction.","volume":"13","author":"Heldin","year":"2009","journal-title":"Development"},{"key":"103","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/nrc3603","article-title":"The roles of TGF\u03b2 in the tumour microenvironment.","volume":"1","author":"Moses","year":"2013","journal-title":"Nat Rev Cancer"},{"key":"104","doi-asserted-by":"publisher","first-page":"a021873","DOI":"10.1101\/cshperspect.a021873","article-title":"TGF-\u03b2 and the TGF-\u03b2 family: context-dependent roles in cell and tissue physiology.","volume":"8","author":"Miyazono","year":"2016","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"105","doi-asserted-by":"publisher","first-page":"a022103","DOI":"10.1101\/cshperspect.a022103","article-title":"Structural biology and evolution of the TGF-\u03b2 family.","volume":"8","author":"Springer","year":"2016","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"106","doi-asserted-by":"publisher","first-page":"djt369","DOI":"10.1093\/jnci\/djt369","article-title":"TGF-\u03b2: duality of function between tumor prevention and carcinogenesis.","volume":"10","author":"Grippo","year":"2014","journal-title":"J Natl Cancer Inst"},{"key":"107","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s10555-006-9006-2","article-title":"Transforming growth factor-beta in cancer and metastasis.","volume":"2","author":"Jakowlew","year":"2006","journal-title":"Cancer Metastasis Rev"},{"key":"108","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/j.cellsig.2010.10.015","article-title":"Transforming growth factor-\u03b2 and the hallmarks of cancer.","volume":"2","author":"Schiemann","year":"2011","journal-title":"Cell Signal"},{"key":"109","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s10555-012-9375-7","article-title":"TGF-\u03b2 signalling and its role in cancer progression and metastasis.","volume":"3","author":"ten Dijke","year":"2012","journal-title":"Cancer Metastasis Rev"},{"key":"110","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s00441-011-1199-1","article-title":"Deconstructing the mechanisms and consequences of TGF-\u03b2-induced EMT during cancer progression.","volume":"34","author":"Schiemann","year":"2012","journal-title":"Cell Tissue Res"},{"key":"111","doi-asserted-by":"publisher","first-page":"5353","DOI":"10.1093\/emboj\/16.17.5353","article-title":"TGF-\u03b2 receptor-mediated signalling through Smad2, Smad3 and Smad4.","volume":"1","author":"ten Dijke","year":"1997","journal-title":"EMBO J"},{"key":"112","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.tcb.2017.04.005","article-title":"Transforming growth factor-\u03b2 receptors and Smads: regulatory complexity and functional versatility.","volume":"2","author":"Derynck","year":"2017","journal-title":"Trends Cell Biol"},{"key":"113","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-\u03b2 family signalling.","volume":"42","author":"Zhang","year":"2003","journal-title":"Nature"},{"key":"114","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.ceb.2009.01.021","article-title":"Mechanism of TGF-\u03b2 signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition.","volume":"2","author":"Moustakas","year":"2009","journal-title":"Curr Opin Cell Biol"},{"key":"115","doi-asserted-by":"publisher","first-page":"a022129","DOI":"10.1101\/cshperspect.a022129","article-title":"Non-Smad signaling pathways of the TGF- \u03b2 family.","volume":"9","author":"Zhang","year":"2017","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"116","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1159\/000335605","article-title":"Transforming growth factor beta 1 overexpression is closely related to invasiveness of hepatocellular carcinoma.","volume":"8","author":"Lee","year":"2012","journal-title":"Oncology"},{"key":"117","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1478-3231.2004.00882.x","article-title":"Possible contribution of circulating transforming growth factor-beta1 to immunity and prognosis in unresectable hepatocellular carcinoma.","volume":"2","author":"Kawata","year":"2004","journal-title":"Liver Int"},{"key":"118","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.canlet.2014.07.029","article-title":"Circulating TGF-\u03b21-related biomarkers in patients with hepatocellular carcinoma and their association with HCC staging scores.","volume":"35","author":"Giannelli","year":"2014","journal-title":"Cancer Lett"},{"key":"119","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.jhep.2016.05.007","article-title":"Role of epithelial to mesenchymal transition in hepatocellular carcinoma.","volume":"6","author":"Mikulits","year":"2016","journal-title":"J Hepatol"},{"key":"120","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","article-title":"TGF-\u03b2 in progression of liver disease.","volume":"34","author":"ten Dijke","year":"2012","journal-title":"Cell Tissue Res"},{"key":"121","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1002\/hep.23285","article-title":"Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma.","volume":"5","author":"Giannelli","year":"2010","journal-title":"Hepatology"},{"key":"122","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1053\/j.gastro.2005.09.055","article-title":"Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma.","volume":"12","author":"Antonaci","year":"2005","journal-title":"Gastroenterology"},{"key":"123","doi-asserted-by":"publisher","first-page":"4022","DOI":"10.1038\/onc.2009.253","article-title":"Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge.","volume":"2","author":"Mikulits","year":"2009","journal-title":"Oncogene"},{"key":"124","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3892\/ol.2012.954","article-title":"Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: clinical significance of transforming growth factor-\u03b2 signaling.","volume":"5","author":"Baba","year":"2013","journal-title":"Oncol Lett"},{"key":"125","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1002\/hep.22201","article-title":"Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells.","volume":"4","author":"Giannelli","year":"2008","journal-title":"Hepatology"},{"key":"126","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1002\/hep.22731","article-title":"Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma.","volume":"4","author":"Giannelli","year":"2009","journal-title":"Hepatology"},{"key":"127","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1002\/hep.23118","article-title":"Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation.","volume":"5","author":"Giannelli","year":"2009","journal-title":"Hepatology"},{"key":"128","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s00280-010-1459-x","article-title":"Kinase activation profile associated with TGF-\u03b2-dependent migration of HCC cells: a preclinical study.","volume":"6","author":"Giannelli","year":"2011","journal-title":"Cancer Chemother Pharmacol"},{"key":"129","doi-asserted-by":"publisher","first-page":"e67109","DOI":"10.1371\/journal.pone.0067109","article-title":"Differential inhibition of the TGF-\u03b2 signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-\u03b2 receptor type II.","volume":"8","author":"Giannelli","year":"2013","journal-title":"PLoS One"},{"key":"130","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1016\/j.biocel.2005.02.021","article-title":"Aurora kinases.","volume":"3","author":"Bolanos-Garcia","year":"2005","journal-title":"Int J Biochem Cell Biol"},{"key":"131","doi-asserted-by":"publisher","first-page":"2947","DOI":"10.1111\/febs.14069","article-title":"Switching Aurora-A kinase on and off at an allosteric site.","volume":"28","author":"McIntyre","year":"2017","journal-title":"FEBS J"},{"key":"132","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1002\/cjp2.6","article-title":"Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.","volume":"1","author":"Bodvarsdottir","year":"2014","journal-title":"J Pathol Clin Res"},{"key":"133","doi-asserted-by":"publisher","first-page":"32","DOI":"10.4132\/jptm.2016.10.17","article-title":"Aurora kinase A is a prognostic marker in colorectal adenocarcinoma.","volume":"5","author":"Maeng","year":"2017","journal-title":"J Pathol Transl Med"},{"key":"134","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3892\/or.2011.1250","article-title":"Aurora-A as an independent molecular prognostic marker in gastric cancer.","volume":"2","author":"Shi","year":"2011","journal-title":"Oncol Rep"},{"key":"135","doi-asserted-by":"publisher","first-page":"27953","DOI":"10.18632\/oncotarget.15853","article-title":"Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma.","volume":"8","author":"Yang","year":"2017","journal-title":"Oncotarget"},{"key":"136","doi-asserted-by":"publisher","first-page":"23937","DOI":"10.18632\/oncotarget.14893","article-title":"Aurora kinases: novel therapy targets in cancers.","volume":"8","author":"Zheng","year":"2017","journal-title":"Oncotarget"},{"key":"137","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1038\/nm.4107","article-title":"A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer.","volume":"2","author":"Malek","year":"2016","journal-title":"Nat Med"},{"key":"138","doi-asserted-by":"publisher","first-page":"295","DOI":"10.3389\/fonc.2015.00295","article-title":"Aurora-A kinase as a promising therapeutic target in cancer.","volume":"5","author":"Galanis","year":"2016","journal-title":"Front Oncol"},{"key":"139","doi-asserted-by":"publisher","first-page":"3566","DOI":"10.1128\/MCB.01286-14","article-title":"Aurora B overexpression causes aneuploidy and p21Cip1 repression during tumor development.","volume":"3","author":"Malumbres","year":"2015","journal-title":"Mol Cell Biol"},{"key":"140","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12967-015-0385-4","article-title":"Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy.","volume":"1","author":"Azzariti","year":"2015","journal-title":"J Transl Med"},{"key":"141","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejmech.2017.08.045","article-title":"A comprehensive review on Aurora kinase: small molecule inhibitors and clinical trial studies.","volume":"14","author":"Bhatt","year":"2017","journal-title":"Eur J Med Chem"},{"key":"142","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.bbagrm.2010.09.004","article-title":"Aurora kinase inhibitors as anticancer molecules.","volume":"179","author":"Sen","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"143","doi-asserted-by":"publisher","first-page":"3664","DOI":"10.1242\/jcs.03145","article-title":"Validating Aurora B as an anti-cancer drug target.","volume":"11","author":"Taylor","year":"2006","journal-title":"J Cell Sci"},{"key":"144","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1038\/cdd.2008.47","article-title":"Death through a tragedy: mitotic catastrophe.","volume":"1","author":"Zhivotovsky","year":"2008","journal-title":"Cell Death Differ"},{"key":"145","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1158\/1078-0432.CCR-1057-03","article-title":"Overexpression and amplification of Aurora-A in hepatocellular carcinoma.","volume":"1","author":"Hsu","year":"2004","journal-title":"Clin Cancer Res"},{"key":"146","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1186\/1471-2407-10-461","article-title":"Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC.","volume":"1","author":"Hsu","year":"2010","journal-title":"BMC Cancer"},{"key":"147","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.omtn.2018.08.014","article-title":"A novel aurora-A inhibitor (MLN8237) synergistically enhances the antitumor activity of sorafenib in hepatocellular carcinoma.","volume":"1","author":"Wang","year":"2018","journal-title":"Mol Ther Nucleic Acids"},{"key":"148","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.7150\/jca.20822","article-title":"A quantitative proteomic response of hepatocellular carcinoma Hep3B cells to danusertib, a pan-Aurora kinase inhibitor.","volume":"9","author":"Zhou","year":"2018","journal-title":"J Cancer"},{"key":"149","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.jhep.2008.10.022","article-title":"The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma.","volume":"5","author":"Cheng","year":"2009","journal-title":"J Hepatol"},{"key":"150","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1593\/neo.09664","article-title":"Aurora kinase inhibitor PHA-739358 suppresses growth of hepatocellular carcinoma in vitro and in a xenograft mouse model.","volume":"1","author":"Brummendorf","year":"2009","journal-title":"Neoplasia"},{"key":"151","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jhep.2009.10.013","article-title":"The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma.","volume":"5","author":"Arii","year":"2010","journal-title":"J Hepatol"},{"key":"152","doi-asserted-by":"publisher","first-page":"e65264","DOI":"10.1371\/journal.pone.0065264","article-title":"Small molecule R1498 as a well-tolerated and orally active kinase inhibitor for hepatocellular carcinoma and gastric cancer treatment via targeting angiogenesis and mitosis pathways.","volume":"8","author":"Zhang","year":"2013","journal-title":"PLoS One"},{"key":"153","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1158\/1535-7163.MCT-13-0263","article-title":"Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance.","volume":"1","author":"Mikulits","year":"2013","journal-title":"Mol Cancer Ther"},{"key":"154","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1111\/hepr.13353","article-title":"Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: therapeutic potential of targeting the CDK signaling pathway.","volume":"4","author":"Duan","year":"2019","journal-title":"Hepatol Res"},{"key":"155","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.phrs.2016.03.012","article-title":"Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs.","volume":"10","author":"Roskoski","year":"2016","journal-title":"Pharmacol Res"},{"key":"156","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/nrm2105","article-title":"Multiple levels of cyclin specificity in cell-cycle control.","volume":"8","author":"Cross","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"157","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.phrs.2018.11.035","article-title":"Cyclin-dependent protein serine\/threonine kinase inhibitors as anticancer drugs.","volume":"13","author":"Roskoski","year":"2019","journal-title":"Pharmacol Res"},{"key":"158","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3390\/cancers6010079","article-title":"The complex relationship between liver cancer and the cell cycle: A story of multiple regulations.","volume":"6","author":"Kaldis","year":"2014","journal-title":"Cancers (Basel)"},{"key":"159","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s00795-013-0047-7","article-title":"Clinical significance of cell cycle inhibitors in hepatocellular carcinoma.","volume":"4","author":"Ichida","year":"2013","journal-title":"Med Mol Morphol"},{"key":"160","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.ebiom.2017.04.014","article-title":"Prognostic biomarker identification through integrating the gene signatures of hepatocellular carcinoma properties.","volume":"1","author":"Chen","year":"2017","journal-title":"EBioMedicine"},{"key":"161","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1007\/s00432-015-1990-6","article-title":"Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model.","volume":"14","author":"Kim","year":"2015","journal-title":"J Cancer Res Clin Oncol"},{"key":"162","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/s1386-6346(00)00150-9","article-title":"Overexpression of cyclin E and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas.","volume":"1","author":"Tokuda","year":"2001","journal-title":"Hepatol Res"},{"key":"163","doi-asserted-by":"publisher","first-page":"849","DOI":"10.21037\/tcr.2018.06.04","article-title":"Identification of potential therapeutic targets in hepatocellular carcinoma using an integrated bioinformatics approach.","volume":"7","author":"Ailing","year":"2018","journal-title":"Transl Cancer Res"},{"key":"164","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.yexmp.2011.06.014","article-title":"The role of cyclins and cyclin dependent kinases in development and progression of hepatitis C virus-genotype 4-associated hepatitis and hepatocellular carcinoma.","volume":"9","author":"Al-Zawahry","year":"2011","journal-title":"Exp Mol Pathol"},{"key":"165","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1046\/j.0106-9543.2002.01629.x","article-title":"Activation of cyclin-dependent kinases CDC2 and CDK2 in hepatocellular carcinoma.","volume":"2","author":"Poon","year":"2002","journal-title":"Liver"},{"key":"166","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.canlet.2009.06.011","article-title":"Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo.","volume":"28","author":"Lee","year":"2010","journal-title":"Cancer Lett"},{"key":"167","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1007\/s12032-012-0379-5","article-title":"Clinical implications of deregulated CDK4 and Cyclin D1 expression in patients with human hepatocellular carcinoma.","volume":"3","author":"Hu","year":"2013","journal-title":"Med Oncol"},{"key":"168","doi-asserted-by":"publisher","first-page":"15089","DOI":"10.1073\/pnas.241522398","article-title":"Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver.","volume":"9","author":"Cheng","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"169","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1080\/13543784.2017.1389896","article-title":"CDK4\/6 blockade in breast cancer: current experience and future perspectives.","volume":"2","author":"Tryfonidis","year":"2017","journal-title":"Expert Opin Investig Drugs"},{"key":"170","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1136\/gutjnl-2016-312268","article-title":"Palbociclib (PD-0332991), a selective CDK4\/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma.","volume":"6","author":"Lujambio","year":"2017","journal-title":"Gut"},{"key":"171","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.ejca.2018.07.010","article-title":"Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response.","volume":"10","author":"Chen","year":"2018","journal-title":"Eur J Cancer"},{"key":"172","doi-asserted-by":"publisher","first-page":"2391","DOI":"10.1242\/jcs.147553","article-title":"Cdk5 activity in the brain - multiple paths of regulation.","volume":"12","author":"Lahiri","year":"2014","journal-title":"J Cell Sci"},{"key":"173","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1111\/jnc.12684","article-title":"CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration.","volume":"12","author":"Kermer","year":"2014","journal-title":"J Neurochem"},{"key":"174","doi-asserted-by":"publisher","first-page":"179","DOI":"10.4103\/ijmr.IJMR_1249_14","article-title":"Synaptic roles of cyclin-dependent kinase 5 & its implications in epilepsy.","volume":"14","author":"Chandra","year":"2017","journal-title":"Indian J Med Res"},{"key":"175","doi-asserted-by":"publisher","first-page":"27108","DOI":"10.18632\/oncotarget.8342","article-title":"Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1\u03b1: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma.","volume":"7","author":"Zahler","year":"2016","journal-title":"Oncotarget"},{"key":"176","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.jhep.2015.01.031","article-title":"Targeting cyclin dependent kinase 5 in hepatocellular carcinoma\u2014A novel therapeutic approach.","volume":"6","author":"Vollmar","year":"2015","journal-title":"J Hepatol"},{"key":"177","doi-asserted-by":"publisher","first-page":"108333","DOI":"10.18632\/oncotarget.22659","article-title":"Clinical role and biological function of CDK5 in hepatocellular carcinoma: A study based on immunohistochemistry, RNA-seq andinvestigation.","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"178","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1002\/hep.30190","article-title":"Inhibition of cyclin-dependent kinase 5: A strategy to improve sorafenib response in hepatocellular carcinoma Therapy.","volume":"6","author":"Arnold","year":"2019","journal-title":"Hepatology"},{"key":"179","doi-asserted-by":"publisher","first-page":"371832","DOI":"10.1155\/2011\/371832","article-title":"Physical and functional HAT\/HDAC interplay regulates protein acetylation balance.","volume":"201","author":"Simone","year":"2011","journal-title":"J Biomed Biotechnol"},{"key":"180","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1615\/CritRevOncog.2015012997","article-title":"Histone deacetylases and mechanisms of regulation of gene expression.","volume":"2","author":"Zhao","year":"2015","journal-title":"Crit Rev Oncog"},{"key":"181","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1615\/CritRevOncog.2014012554","article-title":"Altered expression of histone deacetylases in cancer.","volume":"2","author":"Jer\u00f3nimo","year":"2015","journal-title":"Crit Rev Oncog"},{"key":"182","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.suronc.2018.07.015","article-title":"Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective.","volume":"2","author":"Pawlik","year":"2018","journal-title":"Surg Oncol"},{"key":"183","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1002\/hep.20878","article-title":"Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling.","volume":"4","author":"Liu","year":"2005","journal-title":"Hepatology"},{"key":"184","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1053\/j.gastro.2012.05.033","article-title":"Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells.","volume":"14","author":"Skawran","year":"2012","journal-title":"Gastroenterology"},{"key":"185","doi-asserted-by":"publisher","first-page":"e34265","DOI":"10.1371\/journal.pone.0034265","article-title":"HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer.","volume":"7","author":"Nam","year":"2012","journal-title":"PLoS One"},{"key":"186","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1016\/j.jhep.2012.01.009","article-title":"Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib.","volume":"5","author":"Llovet","year":"2012","journal-title":"J Hepatol"},{"key":"187","doi-asserted-by":"publisher","first-page":"52357","DOI":"10.18632\/oncotarget.14096","article-title":"Prognostic and clinicopathologic significance of SIRT1 expression in hepatocellular carcinoma.","volume":"8","author":"Ma","year":"2016","journal-title":"Oncotarget"},{"key":"188","doi-asserted-by":"publisher","first-page":"2519","DOI":"10.2147\/OTT.S195234","article-title":"SIRT1 inhibits hepatocellular carcinoma metastasis by promoting M1 macrophage polarization via NF-\u03baB pathway.","volume":"1","author":"Li","year":"2019","journal-title":"Onco Targets Ther"},{"key":"189","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1002\/hep.26413","article-title":"Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients.","volume":"5","author":"Strand","year":"2013","journal-title":"Hepatology"},{"key":"190","doi-asserted-by":"publisher","first-page":"3372","DOI":"10.1158\/1078-0432.CCR-15-1638","article-title":"SIRT6 overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway.","volume":"2","author":"Chen","year":"2016","journal-title":"Clin Cancer Res"},{"key":"191","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S0168-8278(01)00257-4","article-title":"The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells.","volume":"3","author":"Schuppan","year":"2002","journal-title":"J Hepatol"},{"key":"192","doi-asserted-by":"publisher","first-page":"638","DOI":"10.3892\/ol.2018.9582","article-title":"Enhanced cytotoxicity of human hepatocellular carcinoma cells following pretreatment with sorafenib combined with trichostatin A.","volume":"1","author":"Hwang","year":"2019","journal-title":"Oncol Lett"},{"key":"193","doi-asserted-by":"publisher","first-page":"349","DOI":"10.21873\/cgp.20045","article-title":"Trichostatin A densitizes hepatocellular carcinoma cells to enhanced NK cell-mediated killing by regulating immune-related genes.","volume":"1","author":"Lee","year":"2017","journal-title":"Cancer Genomics Proteomics"},{"key":"194","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1016\/j.ejca.2009.06.024","article-title":"The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation.","volume":"4","author":"Tesoriere","year":"2009","journal-title":"Eur J Cancer"},{"key":"195","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.4161\/auto.6.8.13365","article-title":"Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma.","volume":"6","author":"Chen","year":"2010","journal-title":"Autophagy"},{"key":"196","doi-asserted-by":"publisher","first-page":"56110","DOI":"10.18632\/oncotarget.18125","article-title":"Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha.","volume":"8","author":"Zhuang","year":"2017","journal-title":"Oncotarget"},{"key":"197","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1007\/s10495-016-1278-6","article-title":"Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma.","volume":"2","author":"Bhadra","year":"2016","journal-title":"Apoptosis"},{"key":"198","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1002\/cam4.1278","article-title":"Vorinostat enhances the anticancer effect of oxaliplatin on hepatocellular carcinoma cells.","volume":"7","author":"Jiang","year":"2018","journal-title":"Cancer Med"},{"key":"199","doi-asserted-by":"publisher","first-page":"285","DOI":"10.3233\/CLO-2010-0511","article-title":"The pan-deacetylase inhibitor panobinostat inhibits growth of hepatocellular carcinoma models by alternative pathways of apoptosis.","volume":"3","author":"Ocker","year":"2010","journal-title":"Cell Oncol"},{"key":"200","doi-asserted-by":"publisher","first-page":"963","DOI":"10.3892\/ijo.2015.3087","article-title":"The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression.","volume":"4","author":"Quint","year":"2015","journal-title":"Int J Oncol"},{"key":"201","doi-asserted-by":"publisher","first-page":"110367","DOI":"10.18632\/oncotarget.22775","article-title":"Resminostat induces changes in epithelial plasticity of hepatocellular carcinoma cells and sensitizes them to sorafenib-induced apoptosis.","volume":"8","author":"Fabregat","year":"2017","journal-title":"Oncotarget"},{"key":"202","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jhep.2016.02.043","article-title":"Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study.","volume":"6","author":"Trevisani","year":"2016","journal-title":"J Hepatol"},{"key":"203","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s10637-009-9219-7","article-title":"The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines.","volume":"2","author":"Chan","year":"2010","journal-title":"Invest New Drugs"},{"key":"204","first-page":"1093","article-title":"Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines.","volume":"3","author":"Eckhardt","year":"2011","journal-title":"Anticancer Res"},{"key":"205","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1007\/s00262-018-2283-0","article-title":"Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model.","volume":"6","author":"Sarobe","year":"2019","journal-title":"Cancer Immunol Immunother"},{"key":"206","doi-asserted-by":"publisher","first-page":"3361","DOI":"10.1200\/JCO.2011.41.2395","article-title":"Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I\/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group.","volume":"3","author":"Roh","year":"2012","journal-title":"J Clin Oncol"},{"key":"207","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1158\/1078-0432.CCR-17-0289","article-title":"Immunotherapy of hepatocellular carcinoma: facts and hopes.","volume":"2","author":"Sangro","year":"2018","journal-title":"Clin Cancer Res"},{"key":"208","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.","volume":"1","author":"Honjo","year":"1992","journal-title":"EMBO J"},{"key":"209","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1084\/jem.182.2.459","article-title":"CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.","volume":"18","author":"Allison","year":"1995","journal-title":"J Exp Med"},{"key":"210","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1111\/j.1600-065X.2008.00662.x","article-title":"Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways.","volume":"22","author":"Bluestone","year":"2008","journal-title":"Immunol Rev"},{"key":"211","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1038\/ni.1790","article-title":"Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.","volume":"1","author":"Bluestone","year":"2009","journal-title":"Nat Immunol"},{"key":"212","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13045-018-0582-8","article-title":"Next generation of immune checkpoint therapy in cancer: new developments and challenges.","volume":"1","author":"Lou","year":"2018","journal-title":"J Hematol Oncol"},{"key":"213","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1146\/annurev.immunol.24.021605.090535","article-title":"A molecular perspective of CTLA-4 function.","volume":"2","author":"Madrenas","year":"2006","journal-title":"Annu Rev Immunol"},{"key":"214","unstructured":"Bristol-Myers Squibb Company FDA Approves YERVOY\u2122. (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. Media Release. https:\/\/news.bms.com\/press-release\/rd-news\/fda-approves-yervoy-ipilimumab."},{"key":"215","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma.","volume":"36","author":"Lutzky","year":"2010","journal-title":"N Engl J Med"},{"key":"216","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.jhep.2013.02.022","article-title":"A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.","volume":"5","author":"Prieto","year":"2013","journal-title":"J Hepatol"},{"key":"217","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/S0378-1119(97)00260-6","article-title":"The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors.","volume":"19","author":"Billips","year":"1997","journal-title":"Gene"},{"key":"218","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1016\/j.str.2017.06.011","article-title":"Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1\/PD-L2.","volume":"2","author":"Holak","year":"2017","journal-title":"Structure"},{"key":"219","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1158\/1078-0432.CCR-08-1608","article-title":"Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.","volume":"1","author":"Fan","year":"2009","journal-title":"Clin Cancer Res"},{"key":"220","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1002\/hep.28710","article-title":"Programmed death ligand 1 expression in hepatocellular carcinoma: relationship With clinical and pathological features.","volume":"6","author":"Pawlotsky","year":"2016","journal-title":"Hepatology"},{"key":"221","doi-asserted-by":"publisher","first-page":"246","DOI":"10.4143\/crt.2016.066","article-title":"Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma.","volume":"4","author":"Baek","year":"2017","journal-title":"Cancer Res Treat"},{"key":"222","doi-asserted-by":"publisher","first-page":"5690","DOI":"10.7150\/thno.28742","article-title":"Clinical significance of PD-1\/PD-Ls gene amplification and overexpression in patients with hepatocellular carcinoma.","volume":"8","author":"Cao","year":"2018","journal-title":"Theranostics"},{"key":"223","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1007\/s12094-018-1975-4","article-title":"Programmed cell death protein-1 (PD-1)\/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: prognostic and therapeutic perspectives.","volume":"2","author":"Leucuta","year":"2019","journal-title":"Clin Transl Oncol"},{"key":"224","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1126\/science.aaf1292","article-title":"T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.","volume":"35","author":"Vale","year":"2017","journal-title":"Science"},{"key":"225","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection.","volume":"43","author":"Ahmed","year":"2006","journal-title":"Nature"},{"key":"226","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase \u00bd dose escalation and expansion trial.","volume":"38","author":"Yeo","year":"2017","journal-title":"Lancet"},{"key":"227","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1016\/S1470-2045(18)30351-6","article-title":"Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.","volume":"1","author":"Chan","year":"2018","journal-title":"Lancet Oncol"},{"key":"228","unstructured":"https:\/\/investors.merck.com\/news\/press-release-details\/2019\/Merck-Provides-Update-on-KEYNOTE-240-a-Phase-3-Study-of-KEYTRUDA-pembrolizumab-in-Previously-Treated-Patients-with-Advanced-Hepatocellular-Carcinoma\/default.aspx."},{"key":"229","doi-asserted-by":"publisher","first-page":"4071","DOI":"10.1200\/JCO.2017.35.15_suppl.4071","article-title":"Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC).","volume":"3","author":"Antal","year":"2017","journal-title":"J Clin Oncol"},{"key":"230","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.35.15_suppl.4073","article-title":"Phase I\/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma(HCC): phase I safety and efficacy analyses.","volume":"3","author":"Sangro","year":"2017","journal-title":"J Clin Oncolol"},{"key":"231","unstructured":"https:\/\/oncologypro.esmo.org\/Meeting-Resources\/ESMO-2018-Congress\/Updated-safety-and-clinical-activity-results-from-a-Phase-Ib-study-of-atezolizumab-bevacizumab-in-hepatocellular-carcinoma-HCC."},{"key":"232","unstructured":"World Health Organization. Proposed working definition of an older person in Africa for the MDS Project. WHO. 2002. http:\/\/www.who.int\/healthinfo\/survey\/ageingdefnolder\/en\/."},{"key":"233","unstructured":"World Health Organization. What is Healthy Ageing? WHO. http:\/\/www.who.int\/ageing\/healthy-ageing\/en\/."},{"key":"234","doi-asserted-by":"publisher","first-page":"663","DOI":"10.4254\/wjh.v11.i9.678","article-title":"Cirrhotic patients and older people.","volume":"1","author":"Loustaud-Ratti","year":"2019","journal-title":"World J Hepatol"},{"key":"235","unstructured":"World Health Organization. Healt situation in the European Region. 2018. http:\/\/www.euro.who.int\/en\/data-and-evidence\/european-health-report\/european-health-report-2018\/report-by-chapters\/chapter-2-health-situation-in-the-european-region."},{"key":"236","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1016\/j.ejca.2010.02.022","article-title":"EORTC elderly task force position paper: approach to the older cancer patient.","volume":"4","author":"Wildiers","year":"2010","journal-title":"Eur J Cancer"},{"key":"237","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1055\/s-2007-1007122","article-title":"Prognosis of hepatocellular carcinoma: the BCLC staging classification.","volume":"1","author":"Bruix","year":"1999","journal-title":"Semin Liver Dis"},{"key":"238","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","article-title":"Electronic address: easloffice@easloffice.eu, and European Association for the Study of the Liver. Management of hepatocellular carcinoma.","volume":"6","author":"Vilgrain","year":"2018","journal-title":"J Hepatol"},{"key":"239","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1634\/theoncologist.2010-0223","article-title":"A multicenter retrospective study on clinical characteristics, treatment patterns, and outcome in elderly patients with hepatocellular carcinoma.","volume":"1","author":"Zhu","year":"2011","journal-title":"Oncologist"},{"key":"240","doi-asserted-by":"publisher","first-page":"15028","DOI":"10.3748\/wjg.v20.i41.15028","article-title":"Safety of hepatectomy for elderly patients with hepatocellular carcinoma.","volume":"2","author":"Kitamoto","year":"2014","journal-title":"World J Gastroenterol"},{"key":"241","unstructured":"Life expectancy and Healthy life expectancy Data by country. http:\/\/apps.who.int\/gho\/data\/view.main.SDG2016LEXv?lang=en."},{"key":"242","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.surg.2009.10.054","article-title":"Outcome of repeat hepatectomy in patients with hepatocellular carcinoma aged 75 years and older.","volume":"14","author":"Ishida","year":"2010","journal-title":"Surgery"},{"key":"243","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1159\/000494733","article-title":"The short- and long-term outcomes in elderly patients with hepatocellular carcinoma after curative surgery: A case-controlled study with propensity score matching.","volume":"5","author":"Uesaka","year":"2018","journal-title":"Eur Surg Res"},{"key":"244","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1111\/j.1872-034X.2011.00952.x","article-title":"Outcome of hepatectomy in super-elderly patients with hepatocellular carcinoma.","volume":"4","author":"Saito","year":"2012","journal-title":"Hepatol Res"},{"key":"245","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1097\/MEG.0b013e32835fa668","article-title":"Surgical resection for hepatocellular carcinoma: clinical outcomes and safety in elderly patients.","volume":"2","author":"Osaki","year":"2013","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"246","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1007\/s00595-013-0739-6","article-title":"Recent trends in hepatectomy for elderly patients with hepatocellular carcinoma.","volume":"4","author":"Yamaue","year":"2014","journal-title":"Surg Today"},{"key":"247","doi-asserted-by":"publisher","first-page":"3094","DOI":"10.1245\/s10434-014-4350-x","article-title":"Validation of hepatectomy for elderly patients with hepatocellular carcinoma.","volume":"2","author":"Kitagawa","year":"2015","journal-title":"Ann Surg Oncol"},{"key":"248","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1007\/s11605-016-3354-1","article-title":"Effect of age (over 75 years) on postoperative complications and survival in patients undergoing hepatic resection for hepatocellular carcinoma.","volume":"2","author":"Opocher","year":"2017","journal-title":"J Gastrointest Surg"},{"key":"249","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12957-018-1541-0","article-title":"Liver resection for hepatocellular carcinoma in oldest old patients.","volume":"1","author":"P\u2019eng","year":"2019","journal-title":"World J Surg Oncol"},{"key":"250","doi-asserted-by":"publisher","first-page":"6325","DOI":"10.21873\/anticanres.13843","article-title":"Assessment of Outcome of Hepatic Resection for Extremely Elderly Patients With a Hepatic Malignancy.","volume":"3","author":"Yanaga","year":"2019","journal-title":"Anticancer Res"},{"key":"251","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1097\/SLA.0000000000002751","article-title":"Treatment Optimization for Hepatocellular Carcinoma in Elderly Patients in a Japanese Nationwide Cohort.","volume":"27","author":"Matsuyama","year":"2019","journal-title":"Ann Surg"},{"key":"252","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.18632\/aging.101854","article-title":"Hepatic resection for hepatocellular carcinoma in the octogenarian: is it justified?","volume":"1","author":"Yu","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"253","first-page":"1490","article-title":"Minor hepatic resection for hepatocellular carcinoma in cirrhotic patients: kelly clamp crushing resection versus heat coagulative necrosis with bipolar radiofrequency device.","volume":"7","author":"Latteri","year":"2011","journal-title":"Am Surg"},{"key":"254","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1111\/j.1872-034X.2010.00713.x","article-title":"Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients.","volume":"4","author":"Fujimoto","year":"2010","journal-title":"Hepatol Res"},{"key":"255","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1111\/j.1440-1746.2009.06037.x","article-title":"Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients.","volume":"2","author":"Koizumi","year":"2010","journal-title":"J Gastroenterol Hepatol"},{"key":"256","first-page":"397","article-title":"Percutaneous radiofrequency ablation for hepatocellular carcinoma: clinical outcome and safety in elderly patients.","volume":"2","author":"Kimura","year":"2012","journal-title":"J Gastrointestin Liver Dis"},{"key":"257","doi-asserted-by":"publisher","first-page":"929","DOI":"10.3389\/fonc.2019.00929","article-title":"Stereotactic Radiofrequency Ablation of Liver Tumors in Octogenarians.","volume":"9","author":"Bale","year":"2019","journal-title":"Front Oncol"},{"key":"258","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1002\/cncr.10735","article-title":"Hepatocellular carcinoma in elderly patients: beneficial therapeutic efficacy using percutaneous ethanol injection therapy.","volume":"9","author":"Omata","year":"2002","journal-title":"Cancer"},{"key":"259","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1002\/hep.1840190508","article-title":"Transarterial oily chemoembolization for the treatment of hepatocellular carcinoma: a multivariate analysis of prognostic factors.","volume":"1","author":"Id\u00e8o","year":"1994","journal-title":"Hepatology"},{"key":"260","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.3748\/wjg.v19.i16.2521","article-title":"Trans-arterial chemo-embolization is safe and effective for very elderly patients with hepatocellular carcinoma.","volume":"1","author":"Shibolet","year":"2013","journal-title":"World J Gastroenterol"},{"key":"261","doi-asserted-by":"publisher","first-page":"590","DOI":"10.7150\/jca.9413","article-title":"Transcatheter arterial chemoembolization for intermediate-stage hepatocellular carcinoma: clinical outcome and safety in elderly patients.","volume":"5","author":"Osaki","year":"2014","journal-title":"J Cancer"},{"key":"262","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1007\/s00270-019-02290-x","article-title":"Safety and Prognosis of Transarterial Chemoembolization for Octogenarians with Hepatocellular Carcinoma.","volume":"4","author":"Kichikawa","year":"2019","journal-title":"Cardiovasc Intervent Radiol"},{"key":"263","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma.","volume":"35","author":"Zeuzem","year":"2008","journal-title":"N Engl J Med"},{"key":"264","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S1470-2045(08)70285-7","article-title":"Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.","volume":"1","author":"Liang","year":"2009","journal-title":"Lancet Oncol"},{"key":"265","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1111\/ijcp.12352","article-title":"GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis.","volume":"6","author":"Nakajima","year":"2014","journal-title":"Int J Clin Pract"},{"key":"266","doi-asserted-by":"publisher","first-page":"vi90","DOI":"10.1093\/annonc\/mdv344.11","article-title":"Hepatocellular Carcinoma in Elderly Patients: final results of the Italian Cohort Of GIDEON (Global Investigation of therapeutic Decision and Of its treatment with sorafeNib) Study.","volume":"2","author":"Cillo","year":"2015","journal-title":"Ann Oncol"},{"key":"267","doi-asserted-by":"publisher","first-page":"302","DOI":"10.6004\/jnccn.2019.0019","article-title":"Guidelines insights: hepatobiliary cancers, version 2.2019.","volume":"1","author":"Hawkins","year":"2019","journal-title":"J Natl Compr Canc Netw"},{"key":"268","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.13427","article-title":"Safety and efficacy of lenvatinib in elderly patients with unresectable hepatocellular carcinoma: A multicenter analysis with propensity score matching.","author":"Shimada","year":"2019","journal-title":"Hepatol Res"}],"container-title":["Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.aging-us.com\/lookup\/doi\/10.18632\/aging.102777","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T20:03:19Z","timestamp":1599076999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.aging-us.com\/lookup\/doi\/10.18632\/aging.102777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,4]]},"references-count":268,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,2,15]]}},"alternative-id":["102777","32018226"],"URL":"https:\/\/doi.org\/10.18632\/aging.102777","relation":{},"ISSN":["1945-4589"],"issn-type":[{"value":"1945-4589","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,4]]}}}