{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T05:47:24Z","timestamp":1762062444619,"version":"build-2065373602"},"reference-count":76,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia, I.P.","doi-asserted-by":"publisher","award":["SFRH\/BD\/129431\/2017","CEEC-IND\/00201\/2017"],"award-info":[{"award-number":["SFRH\/BD\/129431\/2017","CEEC-IND\/00201\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Norte Portugal Regional Operational Programme (NORTE 2020)","award":["SFRH\/BD\/129431\/2017","CEEC-IND\/00201\/2017"],"award-info":[{"award-number":["SFRH\/BD\/129431\/2017","CEEC-IND\/00201\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic \u03b2 cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of \u03b2 cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.<\/jats:p>","DOI":"10.3390\/cancers14163865","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T01:58:30Z","timestamp":1660183110000},"page":"3865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Characterisation of an Atrx Conditional Knockout Mouse Model: Atrx Loss Causes Endocrine Dysfunction Rather Than Pancreatic Neuroendocrine Tumour"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7410-7869","authenticated-orcid":false,"given":"Tiago Bordeira","family":"Gaspar","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7752-998X","authenticated-orcid":false,"given":"Sofia","family":"Macedo","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"}]},{"given":"Ana","family":"S\u00e1","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3279-6050","authenticated-orcid":false,"given":"Mariana Alves","family":"Soares","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Laborat\u00f3rio de Endocrinologia Experimental (LEEx), Instituto de Ci\u00eancias Biom\u00e9dicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-912, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-905, Brazil"}]},{"given":"Daniela Ferreira","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute for Molecular and Cell Biology (IBMC), University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2238-1070","authenticated-orcid":false,"given":"Mafalda","family":"Sousa","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute for Molecular and Cell Biology (IBMC), University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0570-2277","authenticated-orcid":false,"given":"Nuno","family":"Mendes","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1349-3281","authenticated-orcid":false,"given":"Rui Sousa","family":"Martins","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Faculty of Sciences of the University of Porto (FCUP), 4169-007 Porto, Portugal"}]},{"given":"Lu\u00eds","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"In\u00eas","family":"Borges","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico Veterin\u00e1rio (Cedivet), 4200-071 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3736-1323","authenticated-orcid":false,"given":"Sule","family":"Canberk","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5302-0086","authenticated-orcid":false,"given":"F\u00e1tima","family":"G\u00e4rtner","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7832-8717","authenticated-orcid":false,"given":"Leandro","family":"Miranda-Alves","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Endocrinologia Experimental (LEEx), Instituto de Ci\u00eancias Biom\u00e9dicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-912, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-905, Brazil"}]},{"given":"Manuel","family":"Sobrinho-Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"},{"name":"Department of Pathology, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o (CHUSJ), 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8597-3474","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Lopes","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"},{"name":"Department of Pathology, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o (CHUSJ), 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9607-6998","authenticated-orcid":false,"given":"Paula","family":"Soares","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-1427","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Vinagre","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/0092-8674(95)90287-2","article-title":"Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome)","volume":"80","author":"Gibbons","year":"1995","journal-title":"Cell"},{"key":"ref_2","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., and Wallace, S.E. (1993\u20132021). Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. GeneReviews, University of Washington. GeneReviews\u00ae [Internet]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a011759","DOI":"10.1101\/cshperspect.a011759","article-title":"alpha-Thalassemia, mental retardation, and myelodysplastic syndrome","volume":"2","author":"Gibbons","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1080\/14728222.2018.1487953","article-title":"Mutant ATRX: Uncovering a new therapeutic target for glioma","volume":"22","author":"Haase","year":"2018","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1002\/humu.20734","article-title":"Mutations in the chromatin-associated protein ATRX","volume":"29","author":"Gibbons","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"a026567","DOI":"10.1101\/cshperspect.a026567","article-title":"ATRX and DAXX: Mechanisms and Mutations","volume":"7","author":"Dyer","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.cell.2010.01.003","article-title":"Distinct factors control histone variant H3.3 localization at specific genomic regions","volume":"140","author":"Goldberg","year":"2010","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10635","DOI":"10.1073\/pnas.1937626100","article-title":"The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies","volume":"100","author":"Xue","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Amorim, J.P., Santos, G., Vinagre, J., and Soares, P. (2016). The Role of ATRX in the Alternative Lengthening of Telomeres (ALT) Phenotype. Genes, 7.","DOI":"10.3390\/genes7090066"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1093\/nar\/gkp582","article-title":"Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway","volume":"37","author":"Rizzo","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.cell.2010.09.023","article-title":"ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner","volume":"143","author":"Law","year":"2010","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sanchez-Martin, V., Soriano, M., and Garcia-Salcedo, J.A. (2021). Quadruplex Ligands in Cancer Therapy. Cancers, 13.","DOI":"10.3390\/cancers13133156"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1126\/science.1207313","article-title":"Altered telomeres in tumors with ATRX and DAXX mutations","volume":"333","author":"Heaphy","year":"2011","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.18632\/oncotarget.689","article-title":"Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma","volume":"3","author":"Kannan","year":"2012","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.1239947","article-title":"Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma","volume":"343","author":"Johnson","year":"2014","journal-title":"Science"},{"key":"ref_16","unstructured":"(2022, January 01). cBioPortal for Cancer Genomics. Gene Query, 7255 Samples, ATRX & DAXX Mutations. Available online: https:\/\/bit.ly\/3pLSNqD."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1126\/science.1200609","article-title":"DAXX\/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors","volume":"331","author":"Jiao","year":"2011","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1038\/ncomms3810","article-title":"Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1","volume":"4","author":"Cao","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nature21063","article-title":"Whole-genome landscape of pancreatic neuroendocrine tumours","volume":"543","author":"Scarpa","year":"2017","journal-title":"Nature"},{"key":"ref_20","unstructured":"(2022, January 01). cBioPortal for Cancer Genomics. Gene Query, 118 Samples, 2 Genes. Available online: https:\/\/bit.ly\/3eKEkoi."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lovejoy, C.A., Li, W., Reisenweber, S., Thongthip, S., Bruno, J., de Lange, T., De, S., Petrini, J.H., Sung, P.A., and Jasin, M. (2012). Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002772"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7538","DOI":"10.1038\/ncomms8538","article-title":"Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX","volume":"6","author":"Clynes","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1053\/j.gastro.2013.10.020","article-title":"Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors","volume":"146","author":"Marinoni","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1158\/1078-0432.CCR-16-1113","article-title":"Alternative Lengthening of Telomeres and Loss of DAXX\/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors","volume":"23","author":"Singhi","year":"2017","journal-title":"Clin. Cancer. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1158\/1078-0432.CCR-16-1147","article-title":"Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival","volume":"23","author":"Kim","year":"2017","journal-title":"Clin. Cancer. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gaspar, T.B., Sa, A., Lopes, J.M., Sobrinho-Simoes, M., Soares, P., and Vinagre, J. (2018). Telomere Maintenance Mechanisms in Cancer. Genes, 9.","DOI":"10.3390\/genes9050241"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.humpath.2018.07.032","article-title":"ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors","volume":"82","author":"Chou","year":"2018","journal-title":"Hum. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1053\/j.gastro.2018.02.026","article-title":"Loss of Chromatin-Remodeling Proteins and\/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times","volume":"154","author":"Roy","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.mce.2015.08.004","article-title":"Animal models of spontaneous pancreatic neuroendocrine tumors","volume":"421","author":"Yu","year":"2016","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Marini, F., Giusti, F., Tonelli, F., and Brandi, M.L. (2021). Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084041"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jcmgh.2018.09.004","article-title":"The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice","volume":"7","author":"Young","year":"2019","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1172\/JCI200522329","article-title":"The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis","volume":"115","author":"Mangelsdorf","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Garrick, D., Sharpe, J.A., Arkell, R., Dobbie, L., Smith, A.J., Wood, W.G., Higgs, D.R., and Gibbons, R.J. (2006). Loss of Atrx affects trophoblast development and the pattern of X-inactivation in extraembryonic tissues. PLoS Genet., 2.","DOI":"10.1371\/journal.pgen.0020058"},{"key":"ref_34","unstructured":"(2022, January 01). Mouse Genome Informatics. Atrxtm1Rjg. Available online: http:\/\/www.informatics.jax.org\/allele\/MGI:3528480."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1093\/nar\/24.19.3685","article-title":"Functional analysis of the DNA-stimulated ATPase domain of yeast SWI2\/SNF2","volume":"24","author":"Richmond","year":"1996","journal-title":"Nucleic Acids Res."},{"key":"ref_36","unstructured":"(2022, January 01). Mouse Genome Informatics. Tg(Ins2-cre)25Mgn. Available online: http:\/\/www.informatics.jax.org\/allele\/MGI:2176227."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., Dirnagl, U., and Emerson, M. (2020). Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000411"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1293\/tox.2016-0016","article-title":"A comparison of the anatomical structure of the pancreas in experimental animals","volume":"29","author":"Tsuchitani","year":"2016","journal-title":"J. Toxicol. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Liang, W., Menke, A.L., Driessen, A., Koek, G.H., Lindeman, J.H., Stoop, R., Havekes, L.M., Kleemann, R., and van den Hoek, A.M. (2014). Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115922"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"154704","DOI":"10.1016\/j.metabol.2021.154704","article-title":"Maternal high-fat high-sucrose diet and gestational exercise modulate hepatic fat accumulation and liver mitochondrial respiratory capacity in mothers and male offspring","volume":"116","author":"Beleza","year":"2021","journal-title":"Metabolism"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"439","DOI":"10.2147\/DMSO.S234665","article-title":"Guidelines and Considerations for Metabolic Tolerance Tests in Mice","volume":"13","author":"Ramadori","year":"2020","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1158\/0008-5472.CAN-04-2910","article-title":"The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function","volume":"65","author":"Burger","year":"2005","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s42003-019-0692-z","article-title":"Telomere analysis using 3D fluorescence microscopy suggests mammalian telomere clustering in hTERT-immortalized Hs68 fibroblasts","volume":"2","author":"Adam","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1213\/ANE.0000000000002864","article-title":"Correlation Coefficients: Appropriate Use and Interpretation","volume":"126","author":"Schober","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_46","first-page":"2349","article-title":"Orange: Data Mining Toolbox in Python","volume":"14","author":"Demsar","year":"2013","journal-title":"J. Mach. Learn. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"R315","DOI":"10.1530\/ERC-17-0012","article-title":"Genetic and epigenetic drivers of neuroendocrine tumours (NET)","volume":"24","author":"Wiedmer","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1530\/ERC-16-0554","article-title":"Hypo-methylation mediates chromosomal instability in pancreatic NET","volume":"24","author":"Marinoni","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s13148-011-0032-8","article-title":"Long interspersed nuclear element-1 hypomethylation in cancer: Biology and clinical applications","volume":"2","author":"Kitkumthorn","year":"2011","journal-title":"Clin. Epigenetics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eaba8415","DOI":"10.1126\/sciadv.aba8415","article-title":"Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo","volume":"6","author":"Wasylishen","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Fernandez-Ortiz, M., Sayed, R.K.A., Roman-Montoya, Y., de Lama, M.A.R., Fernandez-Martinez, J., Ramirez-Casas, Y., Florido-Ruiz, J., Rusanova, I., Escames, G., and Acuna-Castroviejo, D. (2022). Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126846"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40168-022-01243-w","article-title":"Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain","volume":"10","author":"Parker","year":"2022","journal-title":"Microbiome"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.2337\/diabetes.53.suppl_3.S215","article-title":"The high-fat diet-fed mouse: A model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes","volume":"53","author":"Winzell","year":"2004","journal-title":"Diabetes"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nrendo.2017.161","article-title":"Animal models of obesity and diabetes mellitus","volume":"14","author":"Kleinert","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1002\/oby.20811","article-title":"Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL\/6J mice","volume":"22","author":"Yang","year":"2014","journal-title":"Obesity (Silver Spring)"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1242\/dmm.006239","article-title":"Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice","volume":"3","author":"Ayala","year":"2010","journal-title":"Dis. Model. Mech."},{"key":"ref_58","unstructured":"The Jackson Laboratory (2022, February 01). Body Weight Information for C57BL\/6J (000664). Available online: https:\/\/www.jax.org\/jax-mice-and-services\/strain-data-sheet-pages\/body-weight-chart-000664."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Oh, Y.S., Seo, E.H., Lee, Y.S., Cho, S.C., Jung, H.S., Park, S.C., and Jun, H.S. (2016). Increase of Calcium Sensing Receptor Expression Is Related to Compensatory Insulin Secretion during Aging in Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159689"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2337\/dc12-0421","article-title":"beta-cell mass and turnover in humans: Effects of obesity and aging","volume":"36","author":"Saisho","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.molmet.2017.06.019","article-title":"Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis","volume":"6","author":"Chen","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.molmet.2017.04.010","article-title":"The dynamic plasticity of insulin production in beta-cells","volume":"6","author":"Boland","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.redox.2017.12.015","article-title":"Age-related oxidative changes in pancreatic islets are predominantly located in the vascular system","volume":"15","author":"Kehm","year":"2018","journal-title":"Redox. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.diabres.2009.06.021","article-title":"No mantle formation in rodent islets\u2014the prototype of islet revisited","volume":"85","author":"Kharouta","year":"2009","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev.physiol.68.040104.124723","article-title":"From mice to men: Insights into the insulin resistance syndromes","volume":"68","author":"Biddinger","year":"2006","journal-title":"Annu. Rev. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"27407","DOI":"10.1074\/jbc.M112.350736","article-title":"Pancreatic beta cells in very old mice retain capacity for compensatory proliferation","volume":"287","author":"Hija","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_67","unstructured":"Treutin, P.M., Dintzis, S.M., and Montine, K.S. (2018). Pancreas. Comparative Anatomy and Histology. A Mouse, Rat, and Human Atlas, Elsevier. [2nd ed.]."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e1024405","DOI":"10.1080\/19382014.2015.1024405","article-title":"Structural similarities and differences between the human and the mouse pancreas","volume":"7","author":"Rupnik","year":"2015","journal-title":"Islets"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.4067\/S0717-95022019000401331","article-title":"Pancreatic Islet Stereology: Estimation of Beta Cells Mass","volume":"37","author":"Marinho","year":"2019","journal-title":"Int. J. Morphol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.devcel.2013.06.013","article-title":"The plastic pancreas","volume":"26","author":"Ziv","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.diabres.2014.04.006","article-title":"Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes","volume":"105","author":"Esser","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1210\/er.2019-00034","article-title":"The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance","volume":"40","author":"Watt","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.1038\/emm.2016.6","article-title":"Pancreatic regulation of glucose homeostasis","volume":"48","author":"Roder","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.1073\/pnas.0609367104","article-title":"High-throughput telomere length quantification by FISH and its application to human population studies","volume":"104","author":"Canela","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/s41591-019-0493-4","article-title":"Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors","volume":"25","author":"Cejas","year":"2019","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s42003-020-01479-y","article-title":"Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression","volume":"3","author":"Pipinikas","year":"2020","journal-title":"Commun. Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/16\/3865\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:06:58Z","timestamp":1760141218000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/16\/3865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":76,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cancers14163865"],"URL":"https:\/\/doi.org\/10.3390\/cancers14163865","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2022,8,10]]}}}