{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T18:48:10Z","timestamp":1788979690359,"version":"build-2803163510"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["F31CA275334"],"award-info":[{"award-number":["F31CA275334"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R00ES034053"],"award-info":[{"award-number":["R00ES034053"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R00CA226363"],"award-info":[{"award-number":["R00CA226363"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA240963"],"award-info":[{"award-number":["R01CA240963"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01CA244327"],"award-info":[{"award-number":["1R01CA244327"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01CA281801"],"award-info":[{"award-number":["1R01CA281801"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AI175417"],"award-info":[{"award-number":["1R01AI175417"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Nucl Med Mol Imaging"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Cadherin-17 (CDH17) is a calcium-dependent cell adhesion protein that is overexpressed in several adenocarcinomas, including gastric, colorectal, and pancreatic adenocarcinoma. High levels of CDH17 have been linked to metastatic disease and poor prognoses in patients with these malignancies, fueling interest in the protein as a target for diagnostics and therapeutics. Herein, we report the synthesis, <jats:italic>in vitro<\/jats:italic> validation, and <jats:italic>in vivo<\/jats:italic> evaluation of a CDH17-targeted <jats:sup>89<\/jats:sup>Zr-labeled immunoPET probe.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The CDH17-targeting mAb D2101 was modified with an isothiocyanate-bearing derivative of desferrioxamine (DFO) to produce a chelator-bearing immunoconjugate \u2014 DFO-D2101 \u2014 and flow cytometry and surface plasmon resonance (SPR) were used to interrogate its antigen-binding properties. The immunoconjugate was then radiolabeled with zirconium-89 (<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub> ~ 3.3 days), and the serum stability and immunoreactive fraction of [<jats:sup>89<\/jats:sup>Zr]Zr-DFO-D2101 were determined. Finally, [<jats:sup>89<\/jats:sup>Zr]Zr-DFO-D2101\u2019s performance was evaluated in a trio of murine models of pancreatic ductal adenocarcinoma (PDAC): subcutaneous, orthotopic, and patient-derived xenografts (PDX). PET images were acquired over the course of 5 days, and terminal biodistribution data were collected after the final imaging time point.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>DFO-D2101 was produced with a degree of labeling of ~ 1.1 DFO\/mAb. Flow cytometry with CDH17-expressing AsPC-1 cells demonstrated that the immunoconjugate binds to its target in a manner similar to its parent mAb, while SPR with recombinant CDH17 revealed that D2101 and DFO-D2101 exhibit nearly identical <jats:italic>K<\/jats:italic><jats:sub>D<\/jats:sub> values: 8.2 \u00d7 10<jats:sup>\u22129<\/jats:sup> and 6.7 \u00d7 10<jats:sup>\u22129<\/jats:sup> M, respectively. [<jats:sup>89<\/jats:sup>Zr]Zr-DFO-D2101 was produced with a specific activity of 185 MBq\/mg (5.0 mCi\/mg), remained &gt;80% stable in human serum over the course of 5 days, and boasted an immunoreactive fraction of &gt;0.85. In all three murine models of PDAC, the radioimmunoconjugate yielded high contrast images, with high activity concentrations in tumor tissue and low uptake in non-target organs. Tumoral activity concentrations reached as high as &gt;60 %ID\/g in two of the cohorts bearing PDXs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Taken together, these data underscore that [<jats:sup>89<\/jats:sup>Zr]Zr-DFO-D2101 is a highly promising probe for the non-invasive visualization of CDH17 expression in PDAC. We contend that this radioimmunoconjugate could have a significant impact on the clinical management of patients with both PDAC and gastrointestinal adenocarcinoma, most likely as a theranostic imaging tool in support of CDH17-targeted therapies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-024-06709-7","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T09:01:56Z","timestamp":1713258116000},"page":"2547-2557","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cadherin-17 as a target for the immunoPET of adenocarcinoma"],"prefix":"10.1007","volume":"51","author":[{"given":"Samantha","family":"Delaney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Kein\u00e4nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Hamakubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9091-744X","authenticated-orcid":false,"given":"Brian M.","family":"Zeglis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"6709_CR1","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/0955-0674(95)80102-2","volume":"7","author":"M Takeichi","year":"1995","unstructured":"Takeichi M. Morphogenetic roles of classic cadherins. Curr Opin Cell Biol. 1995;7:619\u201327.","journal-title":"Curr Opin Cell Biol."},{"key":"6709_CR2","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/0955-0674(94)90102-3","volume":"6","author":"B Ranscht","year":"1994","unstructured":"Ranscht B. Cadherins and catenins: interactions and functions in embryonic development. Curr Opin Cell Biol. 1994;6:740\u20136.","journal-title":"Curr Opin Cell Biol."},{"key":"6709_CR3","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1242\/jcs.114.4.629","volume":"114","author":"BD Angst","year":"2001","unstructured":"Angst BD, Marcozzi C, Magee AI. The cadherin superfamily: diversity in form and function. J Cell Sci. 2001;114:629\u201341.","journal-title":"J Cell Sci."},{"key":"6709_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00795-012-0003-y","volume":"46","author":"M Takamura","year":"2013","unstructured":"Takamura M, Yamagiwa S, Matsuda Y, Ichida T, Aoyagi Y. Involvement of liver-intestine cadherin in cancer progression. Med Mol Morphol. 2013;46:1\u20137.","journal-title":"Med Mol Morphol."},{"key":"6709_CR5","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1083\/jcb.136.5.1109","volume":"136","author":"B Kreft","year":"1997","unstructured":"Kreft B, Berndorff D, B\u00f6ttinger A, Finnemann S, Wedlich D, Hortsch M, et al. LI-cadherin-mediated cell-cell adhesion does not require cytoplasmic interactions. J Cell Biol. 1997;136:1109\u201321.","journal-title":"J Cell Biol."},{"key":"6709_CR6","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1136\/gut.49.1.73","volume":"49","author":"C Gr\u00f6tzinger","year":"2001","unstructured":"Gr\u00f6tzinger C, Kneifel J, Patschan D, Schnoy N, Anagnostopoulos I, Faiss S, et al. LI-cadherin: a marker of gastric metaplasia and neoplasia. Gut. 2001;49:73\u201381.","journal-title":"Gut."},{"key":"6709_CR7","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1158\/1078-0432.CCR-17-2823","volume":"24","author":"JF Marshall","year":"2018","unstructured":"Marshall JF. Targeting CDH17 in cancer: when blocking the ligand beats blocking the receptor? Clin Cancer Res. 2018;24:253\u20135.","journal-title":"Clin Cancer Res."},{"key":"6709_CR8","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1111\/his.14420","volume":"79","author":"M Kmeid","year":"2021","unstructured":"Kmeid M, Lukose G, Hodge K, Cho D, Kim KA, Lee H. Aberrant expression of SATB2, CDX2, CDH17 and CK20 in hepatocellular carcinoma: a pathological, clinical and outcome study. Histopathology. 2021;79:768\u201378.","journal-title":"Histopathology."},{"key":"6709_CR9","doi-asserted-by":"publisher","first-page":"262","DOI":"10.4161\/cbt.23299","volume":"14","author":"J Wang","year":"2013","unstructured":"Wang J, Kang WM, Yu JC, Liu YQ, Meng QB, Cao ZJ. Cadherin-17 induces tumorigenesis and lymphatic metastasis in gastric cancer through activation of NFkappaB signaling pathway. Cancer Biol Ther. 2013;14:262\u201370.","journal-title":"Cancer Biol Ther."},{"key":"6709_CR10","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.clon.2008.01.013","volume":"20","author":"J Ge","year":"2008","unstructured":"Ge J, Chen Z, Wu S, Yuan W, Hu B, Chen Z. A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma. Clin Oncol (R Coll Radiol). 2008;20:275\u201383.","journal-title":"Clin Oncol (R Coll Radiol)."},{"key":"6709_CR11","doi-asserted-by":"publisher","first-page":"3941","DOI":"10.1021\/acs.molpharmaceut.0c00700","volume":"17","author":"YL Lum","year":"2020","unstructured":"Lum YL, Luk JM, Staunton DE, Ng DKP, Fong WP. Cadherin-17 targeted near-infrared photoimmunotherapy for treatment of gastrointestinal cancer. Mol Pharm. 2020;17:3941\u201351.","journal-title":"Mol Pharm."},{"key":"6709_CR12","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s40824-022-00312-3","volume":"26","author":"J Ma","year":"2022","unstructured":"Ma J, Xu X, Fu C, Xia P, Tian M, Zheng L, et al. CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin. Biomater Res. 2022;26:64.","journal-title":"Biomater Res."},{"key":"6709_CR13","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1080\/14712598.2017.1322577","volume":"17","author":"M Bourgeois","year":"2017","unstructured":"Bourgeois M, Bailly C, Frindel M, Guerard F, Ch\u00e9rel M, Faivre-Chauvet A, et al. Radioimmunoconjugates for treating cancer: recent advances and current opportunities. Expert Opin Biol Ther. 2017;17:813\u20139.","journal-title":"Expert Opin Biol Ther."},{"key":"6709_CR14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2967\/jnumed.108.056887","volume":"50","author":"AM Wu","year":"2009","unstructured":"Wu AM. Antibodies and antimatter: the resurgence of immuno-PET. J Nucl Med. 2009;50:2\u20135.","journal-title":"J Nucl Med."},{"key":"6709_CR15","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1002\/jlcr.3612","volume":"61","author":"LM Carter","year":"2018","unstructured":"Carter LM, Poty S, Sharma SK, Lewis JS. Preclinical optimization of antibody-based radiopharmaceuticals for cancer imaging and radionuclide therapy-model, vector, and radionuclide selection. J Labelled Comp Radiopharm. 2018;61:611\u201335.","journal-title":"J Labelled Comp Radiopharm."},{"key":"6709_CR16","doi-asserted-by":"publisher","first-page":"20180440","DOI":"10.1259\/bjr.20180440","volume":"91","author":"JH Turner","year":"2018","unstructured":"Turner JH. An introduction to the clinical practice of theranostics in oncology. Br J Radiol. 2018;91:20180440.","journal-title":"Br J Radiol."},{"key":"6709_CR17","doi-asserted-by":"publisher","first-page":"97S","DOI":"10.2967\/jnumed.116.186841","volume":"58","author":"U Eberlein","year":"2017","unstructured":"Eberlein U, Cremonesi M, Lassmann M. Individualized dosimetry for theranostics: necessary, nice to have, or counterproductive? J Nucl Med. 2017;58:97S-103S.","journal-title":"J Nucl Med."},{"key":"6709_CR18","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17\u201348.","journal-title":"CA Cancer J Clin."},{"key":"6709_CR19","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s12149-019-01408-y","volume":"34","author":"K Fujiwara","year":"2020","unstructured":"Fujiwara K, Tsuji AB, Sudo H, Sugyo A, Akiba H, Iwanari H, et al. In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis. Ann Nucl Med. 2020;34:13\u201323.","journal-title":"Ann Nucl Med."},{"key":"6709_CR20","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1097\/MNM.0000000000001203","volume":"41","author":"K Fujiwara","year":"2020","unstructured":"Fujiwara K, Akiba H, Tsuji AB, Sudo H, Sugyo A, Nagatsu K, et al. 64Cu-labeled minibody D2101 visualizes CDH17-positive gastric cancer xenografts with short waiting time. Nucl Med Commun. 2020;41:688\u201395.","journal-title":"Nucl Med Commun."},{"key":"6709_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/mab.2017.0043","volume":"37","author":"O Kusano-Arai","year":"2018","unstructured":"Kusano-Arai O, Iwanari H, Kudo S, Kikuchi C, Yui A, Akiba H, et al. Synergistic cytotoxic effect on gastric cancer cells of an immunotoxin cocktail in which antibodies recognize different epitopes on CDH17. Monoclon Antib Immunodiagn Immunother. 2018;37:1\u201311.","journal-title":"Monoclon Antib Immunodiagn Immunother."},{"key":"6709_CR22","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.nucmedbio.2019.04.005","volume":"71","author":"SK Sharma","year":"2019","unstructured":"Sharma SK, Lyashchenko SK, Park HA, Pillarsetty N, Roux Y, Wu J, et al. A rapid bead-based radioligand binding assay for the determination of target-binding fraction and quality control of radiopharmaceuticals. Nucl Med Biol. 2019;71:32\u20138.","journal-title":"Nucl Med Biol."},{"key":"6709_CR23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.nucmedbio.2012.08.004","volume":"40","author":"MA Deri","year":"2013","unstructured":"Deri MA, Zeglis BM, Francesconi LC, Lewis JS. PET imaging with 89Zr: from radiochemistry to the clinic. Nucl Med Biol. 2013;40:3\u201314. https:\/\/doi.org\/10.1016\/j.nucmedbio.2012.08.004.","journal-title":"Nucl Med Biol."},{"key":"6709_CR24","doi-asserted-by":"publisher","first-page":"6168","DOI":"10.1039\/c0dt01595d","volume":"40","author":"BM Zeglis","year":"2011","unstructured":"Zeglis BM, Lewis JS. A practical guide to the construction of radiometallated bioconjugates for positron emission tomography. Dalton Trans. 2011;40:6168\u201395. https:\/\/doi.org\/10.1039\/c0dt01595d.","journal-title":"Dalton Trans."},{"key":"6709_CR25","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/nprot.2010.13","volume":"5","author":"MJ Vosjan","year":"2010","unstructured":"Vosjan MJ, Perk LR, Visser GW, Budde M, Jurek P, Kiefer GE, van Dongen GA. Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine. Nat Protoc. 2010;5:739\u201343. https:\/\/doi.org\/10.1038\/nprot.2010.13.","journal-title":"Nat Protoc."},{"key":"6709_CR26","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/s43018-022-00344-7","volume":"3","author":"Z Feng","year":"2022","unstructured":"Feng Z, He X, Zhang X, Wu Y, Xing B, Knowles A, et al. Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. Nat Cancer. 2022;3:581\u201394.","journal-title":"Nat Cancer."},{"key":"6709_CR27","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1038\/modpathol.2008.107","volume":"21","author":"MC Su","year":"2008","unstructured":"Su MC, Yuan RH, Lin CY, Jeng YM. Cadherin-17 is a useful diagnostic marker for adenocarcinomas of the digestive system. Mod Pathol. 2008;21:1379\u201386.","journal-title":"Mod Pathol."},{"key":"6709_CR28","doi-asserted-by":"publisher","first-page":"104332","DOI":"10.1016\/j.dib.2019.104332","volume":"25","author":"H Yuan","year":"2019","unstructured":"Yuan H, Stenberg J, Li G. Data on the function of CDH17 in pancreatic cancer growth. Data Brief. 2019;25:104332.","journal-title":"Data Brief."},{"key":"6709_CR29","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1053\/gast.2002.36598","volume":"123","author":"T Hinoi","year":"2002","unstructured":"Hinoi T, Lucas PC, Kuick R, Hanash S, Cho KR, Fearon ER. CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology. 2002;123:1565\u201377.","journal-title":"Gastroenterology."},{"key":"6709_CR30","doi-asserted-by":"publisher","first-page":"3694","DOI":"10.3748\/wjg.v21.i12.3694","volume":"21","author":"ZW Long","year":"2015","unstructured":"Long ZW, Zhou ML, Fu JW, Chu XQ, Wang YN. Association between cadherin-17 expression and pathological characteristics of gastric cancer: a meta-analysis. World J Gastroenterol. 2015;21:3694\u2013705.","journal-title":"World J Gastroenterol."}],"container-title":["European Journal of Nuclear Medicine and Molecular Imaging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-024-06709-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00259-024-06709-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-024-06709-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T15:03:06Z","timestamp":1720105386000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00259-024-06709-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,16]]},"references-count":30,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["6709"],"URL":"https:\/\/doi.org\/10.1007\/s00259-024-06709-7","relation":{},"ISSN":["1619-7070","1619-7089"],"issn-type":[{"value":"1619-7070","type":"print"},{"value":"1619-7089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,16]]},"assertion":[{"value":"29 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments involving laboratory animals were performed in accordance with a protocol that was approved by the Institutional Animal Care and Use Committees of Hunter College of the City University of New York, Weill Cornell Medical College, and Memorial Sloan Kettering Cancer Center and that complied with ARRIVE. No unexpected or unusually high safety hazards were encountered.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"TK is a founder and representative director of PhotoQ3, Inc. The other authors have no relevant financial or non-financial interests to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}