{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:52:15Z","timestamp":1761061935832,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["JR\/00050"],"award-info":[{"award-number":["JR\/00050"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union","award":["JR\/00050"],"award-info":[{"award-number":["JR\/00050"]}]},{"name":"GETNE Junior Research Award 2019","award":["JR\/00050"],"award-info":[{"award-number":["JR\/00050"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10\/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse\u2019s condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p &lt; 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.<\/jats:p>","DOI":"10.3390\/ijms25042036","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T08:28:16Z","timestamp":1707294496000},"page":"2036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1437-9878","authenticated-orcid":false,"given":"Aura D.","family":"Herrera-Mart\u00ednez","sequence":"first","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 C\u00f3rdoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2069-4823","authenticated-orcid":false,"given":"Antonio C.","family":"Fuentes-Fayos","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology, and Immunology, University of C\u00f3rdoba, 14004 C\u00f3rdoba, Spain"},{"name":"CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 C\u00f3rdoba, Spain"},{"name":"Reina Sofia University Hospital, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9497-2315","authenticated-orcid":false,"given":"Rafael","family":"Sanchez-Sanchez","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Pathology Service, Reina Sofia University Hospital, 14004 C\u00f3rdoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio J.","family":"Montero","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology, and Immunology, University of C\u00f3rdoba, 14004 C\u00f3rdoba, Spain"},{"name":"CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 C\u00f3rdoba, Spain"},{"name":"Reina Sofia University Hospital, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1204-0371","authenticated-orcid":false,"given":"Andr\u00e9","family":"Sarmento-Cabral","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology, and Immunology, University of C\u00f3rdoba, 14004 C\u00f3rdoba, Spain"},{"name":"CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 C\u00f3rdoba, Spain"},{"name":"Reina Sofia University Hospital, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda A.","family":"G\u00e1lvez-Moreno","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 C\u00f3rdoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4578-2179","authenticated-orcid":false,"given":"Manuel D.","family":"Gahete","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology, and Immunology, University of C\u00f3rdoba, 14004 C\u00f3rdoba, Spain"},{"name":"CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 C\u00f3rdoba, Spain"},{"name":"Reina Sofia University Hospital, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7585-1913","authenticated-orcid":false,"given":"Ra\u00fal M.","family":"Luque","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology, and Immunology, University of C\u00f3rdoba, 14004 C\u00f3rdoba, Spain"},{"name":"CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 C\u00f3rdoba, Spain"},{"name":"Reina Sofia University Hospital, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R157","DOI":"10.1530\/ERC-18-0354","article-title":"Neuroendocrine neoplasms: Current and potential diagnostic, predictive and prognostic markers","volume":"26","author":"Hofland","year":"2019","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S1575-0922(07)71513-9","article-title":"Diagnosis and characteristics of intestinal carcinoid tumors. Carcinoid syndrome","volume":"54","author":"Gaztambide","year":"2007","journal-title":"Endocrinol. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13146","DOI":"10.1111\/jne.13146","article-title":"European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease","volume":"34","author":"Davar","year":"2022","journal-title":"J. Neuroendocr."},{"key":"ref_4","first-page":"21","article-title":"Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives","volume":"79","author":"Hofland","year":"2018","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R145","DOI":"10.1530\/ERC-18-0495","article-title":"Management of carcinoid syndrome: A systematic review and meta-analysis","volume":"26","author":"Hofland","year":"2019","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.14503\/THIJ-17-6562","article-title":"Carcinoid Heart Disease: Review of Current Knowledge","volume":"46","author":"Ram","year":"2019","journal-title":"Tex. Hear. Inst. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1136\/hrt.2004.040329","article-title":"Carcinoid heart disease: Presentation, diagnosis, and management","volume":"90","author":"Fox","year":"2004","journal-title":"Heart"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1161\/01.CIR.87.4.1188","article-title":"Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients","volume":"87","author":"Tajik","year":"1993","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/(SICI)1097-0142(20000215)88:4<770::AID-CNCR6>3.0.CO;2-0","article-title":"Treatment of carcinoid syndrome: A prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance","volume":"88","author":"Ducreux","year":"2000","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1159\/000082875","article-title":"Rapid and Sustained Relief from the Symptoms of Carcinoid Syndrome: Results from an Open 6-Month Study of the 28-Day Prolonged-Release Formulation of Lanreotide","volume":"80","author":"Ruszniewski","year":"2004","journal-title":"Neuroendocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1742-4682-7-34","article-title":"Serotonin synthesis, release and reuptake in terminals: A mathematical model","volume":"7","author":"Best","year":"2010","journal-title":"Theor. Biol. Med Model."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"447","DOI":"10.4155\/cli.15.10","article-title":"Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid sy ndrome","volume":"5","author":"Lapuerta","year":"2015","journal-title":"Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1200\/JCO.2016.69.2780","article-title":"Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome","volume":"35","author":"Kulke","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_14","first-page":"309","article-title":"Telotristat ethyl in carcinoid syndrome: Safety and efficacy in the TELECAST phase 3 trial. Endocr. Relat","volume":"25","author":"Pavel","year":"2018","journal-title":"Cancer"},{"key":"ref_15","first-page":"1419","article-title":"Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center","volume":"36","author":"Eriksson","year":"2011","journal-title":"Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.annonc.2020.03.304","article-title":"Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Pavel","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_17","first-page":"552","article-title":"Toward a Preoperative Classification of Lymph Node Metastases in Patients with Small Intestinal Neuroendocrine Tumors in the Era of Intestinal-Sparing Surgery","volume":"103","author":"Vullierme","year":"2015","journal-title":"Neuroendocrinology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1245\/s10434-015-4620-2","article-title":"Surgical Management of Small Bowel Neuroendocrine Tumors: Specific Requirements and Their Impact on Staging and Prognosis","volume":"22","author":"Pasquer","year":"2015","journal-title":"Ann. Surg. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000461583","article-title":"ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors","volume":"105","author":"Kaltsas","year":"2017","journal-title":"Neuroendocrinology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1016\/j.hrthm.2021.08.021","article-title":"Outcomes and periprocedural management of cardiac implantable electronic devices in patients with carcinoid heart disease","volume":"18","author":"Ward","year":"2021","journal-title":"Hear. Rhythm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1749-6632.1994.tb17289.x","article-title":"The human carcinoid cell line, BON. A model system for the study of carcinoid tumors","volume":"733","author":"Evers","year":"1994","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1210\/endo-128-1-220","article-title":"Regulation of Pancreastatin Release from a Human Pancreatic Carcinoid Cell Line in Vitro*","volume":"128","author":"Jeng","year":"1991","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1159\/000502200","article-title":"Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on Growth and Serotonin Secretion in 2D and 3D Cultured Pancreatic Neuroendocrine Tumor Cells","volume":"110","author":"Feelders","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s12672-019-00361-6","article-title":"Effects of Ketoconazole on ACTH-Producing and Non-ACTH-Producing Neuroendocrine Tumor Cells","volume":"10","author":"Feelders","year":"2019","journal-title":"Horm. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1530\/ERC-19-0086","article-title":"Effects of novel somatostatin-dopamine chimeric drugs in 2D and 3D cell culture models of neuroendocrine tumors","volume":"26","author":"Dungen","year":"2019","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"R73","DOI":"10.1530\/JOE-18-0571","article-title":"Mouse models of endocrine tumors","volume":"240","author":"Gahete","year":"2019","journal-title":"J. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1158\/1078-0432.CCR-08-2346","article-title":"Development and characterization of a novel in vivo model of carcinoid syndrome","volume":"15","author":"Jackson","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0016-5085(91)90004-5","article-title":"Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth","volume":"101","author":"Evers","year":"1991","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.3748\/wjg.v16.i24.2963","article-title":"Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors","volume":"16","author":"Strosberg","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000443168","article-title":"ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms","volume":"103","author":"Sundin","year":"2016","journal-title":"Neuroendocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1159\/000443171","article-title":"ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors","volume":"103","author":"Falconi","year":"2016","journal-title":"Neuroendocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Herrera-Mart\u00ednez, Y., Teomiro, C.A., Idougourram, S.L., Puertas, M.J.M., Continente, A.C., Blanch, R.S., Casta\u00f1o, J.P., Moreno, M.G., Gahete, M.D., and Luque, R.M. (2021). Sarcopenia and Ghrelin System in the Clinical Outcome and Prognosis of Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers, 14.","DOI":"10.3390\/cancers14010111"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000442983","article-title":"Malnutrition Predicts Clinical Outcome in Patients with Neuroendocrine Neoplasia","volume":"104","author":"Maasberg","year":"2015","journal-title":"Neuroendocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e010765","DOI":"10.1136\/bmjopen-2015-010765","article-title":"Screening for malnutrition in patients with gastro-entero-pancreatic neuroendocrine tumours: A cross-sectional study","volume":"6","author":"Burch","year":"2016","journal-title":"BMJ Open"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41430-021-00915-4","article-title":"Computed tomography (CT)-defined sarcopenia and myosteatosis are prevalent in patients with neuroendocrine neoplasms (NENs) treated with peptide receptor radionuclide therapy (PRRT)","volume":"76","author":"Chan","year":"2021","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1016\/j.clnu.2021.02.005","article-title":"ESPEN practical guideline: Clinical Nutrition in cancer","volume":"40","author":"Muscaritoli","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1172\/JCI105329","article-title":"Evidence for the release of bradykinin in carcinoid syndrome","volume":"45","author":"Doctor","year":"1966","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/S0140-6736(64)92907-1","article-title":"Release of a kinin peptide in the carcinoid syndrome","volume":"1","author":"Oates","year":"1964","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/jso.20179","article-title":"Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract","volume":"89","author":"Rorstad","year":"2005","journal-title":"J. Surg. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"78","DOI":"10.6004\/jnccn.2015.0011","article-title":"Neuroendocrine tumors, version 1.2015","volume":"13","author":"Kulke","year":"2015","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1590\/S0004-27302005000500028","article-title":"Carcinoid syndrome: Diagnosis and medical management","volume":"49","year":"2005","journal-title":"Arq. Bras. Endocrinol. Metabol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1530\/EJE-16-0392","article-title":"Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours","volume":"175","author":"Zandee","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.cca.2018.03.030","article-title":"Comparison of serum serotonin and serum 5-HIAA LC-MS\/MS assays in the diagnosis of serotonin producing neuroendocrine neoplasms: A pilot study","volume":"482","author":"Tohmola","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.amjcard.2008.05.047","article-title":"Usefulness of N-terminal Pro\u2013Brain Natriuretic Peptide as a Biomarker of the Presence of Carcinoid Heart Disease","volume":"102","author":"Bhattacharyya","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Dobson, R., Burgess, M.I., Banks, M., Pritchard, D.M., Vora, J., Valle, J.W., Wong, C., Chadwick, C., George, K., and Keevil, B. (2013). The Association of a Panel of Biomarkers with the Presence and Severity of Carcinoid Heart Disease: A Cross-Sectional Study. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073679"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.jacc.2016.12.030","article-title":"Diagnosing and Managing Carcinoid Heart Disease in Patients with Neuroendocrine Tumors: An Expert Statement","volume":"69","author":"Davar","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/oncolo\/oyad126","article-title":"Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration","volume":"28","author":"Das","year":"2023","journal-title":"Oncologist"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"102021","DOI":"10.1016\/j.xpro.2022.102021","article-title":"An intrasplenic injection model of pancreatic cancer metastasis to the liver in mice","volume":"4","author":"Ernst","year":"2023","journal-title":"STAR Protoc."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1097\/00006676-199401000-00013","article-title":"Characterization of a human pancreatic carcinoid in vitro: Morphology, amine and peptide storage, and secretion","volume":"9","author":"Parekh","year":"1994","journal-title":"Pancreas"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Puri, S., Garc\u00eda-N\u00fa\u00f1ez, A., Hebrok, M., and Cano, D.A. (2013). Elimination of Von Hippel-Lindau Function Perturbs Pancreas Endocrine Homeostasis in Mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072213"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2036\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:56:36Z","timestamp":1760104596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2036"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,7]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25042036"],"URL":"https:\/\/doi.org\/10.3390\/ijms25042036","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,2,7]]}}}