{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:10:38Z","timestamp":1790691038322,"version":"4.1.0"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,9,15]],"date-time":"2016-09-15T00:00:00Z","timestamp":1473897600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,9,15]],"date-time":"2016-09-15T00:00:00Z","timestamp":1473897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour or determine the efficacy of chemotherapy in the adjuvant (micrometastatic) setting. Here we delineate the natural history of metastasis in an autochthonous model of pancreatic ductal adenocarcinoma (PDAC), using lineage tracing to examine the evolution of disseminated cancer cells and their associated microenvironment. With increasing size, lesions shift from mesenchymal to epithelial histology, become hypovascular and accumulate a desmoplastic stroma, ultimately recapitulating the primary tumours from which they arose. Moreover, treatment with gemcitabine and nab-paclitaxel significantly reduces the overall number of metastases by inducing cell death in lesions of all sizes, challenging the paradigm that PDAC stroma imposes a critical barrier to drug delivery. These results illuminate the cellular dynamics of metastatic progression and suggest that adjuvant chemotherapy affords a survival benefit by directly targeting micrometastases.<\/jats:p>","DOI":"10.1038\/ncomms12819","type":"journal-article","created":{"date-parts":[[2016,9,15]],"date-time":"2016-09-15T09:10:11Z","timestamp":1473930611000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":124,"title":["Metastatic progression is associated with dynamic changes in the local microenvironment"],"prefix":"10.1038","volume":"7","author":[{"given":"Nicole M.","family":"Aiello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Bajor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Norgard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amine","family":"Sahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Bhagwat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh N.","family":"Pham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1902-2109","authenticated-orcid":false,"given":"Toby C.","family":"Cornish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4672-3023","authenticated-orcid":false,"given":"Christine A.","family":"Iacobuzio-Donahue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Vonderheide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben Z.","family":"Stanger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,15]]},"reference":[{"key":"BFncomms12819_CR1","unstructured":"Howlader, N. et al. Cancer Statistics Review 1975\u20132013 SEER (2014)."},{"key":"BFncomms12819_CR2","first-page":"9","volume":"64","author":"R Siegal","year":"2014","unstructured":"Siegal, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA 64, 9\u201329 (2014).","journal-title":"CA"},{"key":"BFncomms12819_CR3","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1200\/JCO.2008.17.7188","volume":"27","author":"CA Iacobuzio-Donahue","year":"2009","unstructured":"Iacobuzio-Donahue, C. A. et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 27, 1806\u20131813 (2009).","journal-title":"J. Clin. Oncol."},{"key":"BFncomms12819_CR4","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1056\/NEJMra1404198","volume":"371","author":"DP Ryan","year":"2014","unstructured":"Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039\u20131049 (2014).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12819_CR5","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.cell.2011.09.024","volume":"147","author":"S Valastyan","year":"2011","unstructured":"Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275\u2013292 (2011).","journal-title":"Cell"},{"key":"BFncomms12819_CR6","doi-asserted-by":"publisher","first-page":"3471","DOI":"10.1242\/dev.071209","volume":"139","author":"J Lim","year":"2012","unstructured":"Lim, J. & Thiery, J. P. Epithelial-mesenchymal transitions: insights from development. Development 139, 3471\u20133486 (2012).","journal-title":"Development"},{"key":"BFncomms12819_CR7","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1002\/(SICI)1097-0142(19980501)82:9<1649::AID-CNCR9>3.0.CO;2-5","volume":"82","author":"N Gunji","year":"1998","unstructured":"Gunji, N. et al. Pancreatic carcinoma\u2014correlation between E-cadherin and alpha-catenin expression status and liver metastasis. Cancer 82, 1649\u20131656 (1998).","journal-title":"Cancer"},{"key":"BFncomms12819_CR8","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/j.humpath.2004.09.014","volume":"35","author":"T Imai","year":"2004","unstructured":"Imai, T. et al. Elevated expression of E-cadherin and alpha-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas. Hum. Pathol. 35, 1469\u20131476 (2004).","journal-title":"Hum. Pathol."},{"key":"BFncomms12819_CR9","doi-asserted-by":"publisher","first-page":"R217","DOI":"10.1186\/bcr651","volume":"5","author":"PJ Kowalski","year":"2003","unstructured":"Kowalski, P. J., Rubin, M. A. & Kleer, C. G. E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res. 5, R217\u2013R222 (2003).","journal-title":"Breast Cancer Res."},{"key":"BFncomms12819_CR10","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/nrc3265","volume":"12","author":"T Brabletz","year":"2012","unstructured":"Brabletz, T. To differentiate or not\u2014routes towards metastasis. Nat. Rev. Cancer 12, 425\u2013436 (2012).","journal-title":"Nat. Rev. Cancer"},{"key":"BFncomms12819_CR11","doi-asserted-by":"publisher","first-page":"11271","DOI":"10.1158\/0008-5472.CAN-06-2044","volume":"66","author":"CL Chaffer","year":"2006","unstructured":"Chaffer, C. L. et al. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 66, 11271\u201311278 (2006).","journal-title":"Cancer Res."},{"key":"BFncomms12819_CR12","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.ccr.2012.09.022","volume":"22","author":"JH Tsai","year":"2012","unstructured":"Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725\u2013736 (2012).","journal-title":"Cancer Cell"},{"key":"BFncomms12819_CR13","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.ccr.2012.10.012","volume":"22","author":"OH Ocana","year":"2012","unstructured":"Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709\u2013724 (2012).","journal-title":"Cancer Cell"},{"key":"BFncomms12819_CR14","unstructured":"Rasheed, Z., Matsui, W. & Maitra, A. in Pancreatic Cancer and Tumor Microenvironment eds Grippo P. J., Munshi H. G. Transworld Research Network, Trivandrum, India (2012)."},{"key":"BFncomms12819_CR15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.cell.2011.11.025","volume":"148","author":"AD Rhim","year":"2012","unstructured":"Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349\u2013361 (2012).","journal-title":"Cell"},{"key":"BFncomms12819_CR16","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/S1535-6108(03)00309-X","volume":"4","author":"SR Hingorani","year":"2003","unstructured":"Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437\u2013450 (2003).","journal-title":"Cancer Cell"},{"key":"BFncomms12819_CR17","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.ccr.2005.04.023","volume":"7","author":"SR Hingorani","year":"2005","unstructured":"Hingorani, S. R. et al. Trp53(R172H) and KraS(G12D) cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469\u2013483 (2005).","journal-title":"Cancer Cell"},{"key":"BFncomms12819_CR18","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/j.ceb.2005.08.001","volume":"17","author":"MA Huber","year":"2005","unstructured":"Huber, M. A., Kraut, N. & Beug, H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol. 17, 548\u2013558 (2005).","journal-title":"Curr. Opin. Cell Biol."},{"key":"BFncomms12819_CR19","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1242\/jcs.00389","volume":"116","author":"J Ikenouchi","year":"2003","unstructured":"Ikenouchi, J., Matsuda, M., Furuse, M. & Tsukita, S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins\/occludin by Snail. J. Cell Sci. 116, 1959\u20131967 (2003).","journal-title":"J. Cell Sci."},{"key":"BFncomms12819_CR20","doi-asserted-by":"publisher","first-page":"6237","DOI":"10.1158\/0008-5472.CAN-04-3545","volume":"65","author":"B De Craene","year":"2005","unstructured":"De Craene, B. et al. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 65, 6237\u20136244 (2005).","journal-title":"Cancer Res."},{"key":"BFncomms12819_CR21","doi-asserted-by":"publisher","first-page":"F563","DOI":"10.1152\/ajprenal.1997.273.4.F563","volume":"273","author":"H Okada","year":"1997","unstructured":"Okada, H., Danoff, T. M., Kalluri, R. & Neilson, E. G. Early role of Fsp1 in epithelial-mesenchymal transformation. Am. J. Physiol.-Renal Physiol. 273, F563\u2013F574 (1997).","journal-title":"Am. J. Physiol.-Renal Physiol."},{"key":"BFncomms12819_CR22","doi-asserted-by":"publisher","first-page":"6979","DOI":"10.1038\/sj.onc.1210508","volume":"26","author":"K Aigner","year":"2007","unstructured":"Aigner, K. et al. The transcription factor ZEB1 (delta EF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26, 6979\u20136988 (2007).","journal-title":"Oncogene"},{"key":"BFncomms12819_CR23","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1097\/MOG.0b013e328363affe","volume":"29","author":"M Waghray","year":"2013","unstructured":"Waghray, M., Yalamanchili, M., di Magliano, M. P. & Simeone, D. M. Deciphering the role of stroma in pancreatic cancer. Curr. Opin. Gastroenterol. 29, 537\u2013543 (2013).","journal-title":"Curr. Opin. Gastroenterol."},{"key":"BFncomms12819_CR24","first-page":"525","volume":"527","author":"X Zheng","year":"2015","unstructured":"Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nat. Med. 527, 525\u2013530 (2015).","journal-title":"Nat. Med."},{"key":"BFncomms12819_CR25","doi-asserted-by":"publisher","first-page":"S44","DOI":"10.1016\/j.cgh.2009.07.039","volume":"7","author":"S Pandol","year":"2009","unstructured":"Pandol, S., Edderkaoui, M., Gukovsky, I., Lugea, A. & Gukovskaya, A. Desmoplasia of pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 7, S44\u2013S47 (2009).","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"BFncomms12819_CR26","doi-asserted-by":"publisher","first-page":"4195","DOI":"10.1242\/jcs.023820","volume":"123","author":"C Frantz","year":"2010","unstructured":"Frantz, C., Stewart, K. M. & Weaver, V. M. The extracellular matrix at a glance. J. Cell Sci. 123, 4195\u20134200 (2010).","journal-title":"J. Cell Sci."},{"key":"BFncomms12819_CR27","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.ccr.2012.04.025","volume":"21","author":"LJ Bayne","year":"2012","unstructured":"Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer cell 21, 822\u2013835 (2012).","journal-title":"Cancer cell"},{"key":"BFncomms12819_CR28","doi-asserted-by":"publisher","first-page":"9518","DOI":"10.1158\/0008-5472.CAN-07-0175","volume":"67","author":"CE Clark","year":"2007","unstructured":"Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518\u20139527 (2007).","journal-title":"Cancer Res."},{"key":"BFncomms12819_CR29","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1126\/science.1171362","volume":"324","author":"KP Olive","year":"2009","unstructured":"Olive, K. P. et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457\u20131461 (2009).","journal-title":"Science"},{"key":"BFncomms12819_CR30","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.ccr.2012.01.007","volume":"21","author":"PP Provenzano","year":"2012","unstructured":"Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418\u2013429 (2012).","journal-title":"Cancer Cell"},{"key":"BFncomms12819_CR31","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nature16064","volume":"527","author":"XF Zheng","year":"2015","unstructured":"Zheng, X. F. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525 (2015).","journal-title":"Nature"},{"key":"BFncomms12819_CR32","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.jss.2006.09.027","volume":"141","author":"T Yin","year":"2007","unstructured":"Yin, T. et al. Expression of snail in pancreatic cancer promotes metastasis and chemoresistance. J. Surg. Res. 141, 196\u2013203 (2007).","journal-title":"J. Surg. Res."},{"key":"BFncomms12819_CR33","doi-asserted-by":"publisher","first-page":"3629","DOI":"10.1245\/s10434-007-9583-5","volume":"14","author":"AN Shah","year":"2007","unstructured":"Shah, A. N. et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann. Surg. Oncol. 14, 3629\u20133637 (2007).","journal-title":"Ann. Surg. Oncol."},{"key":"BFncomms12819_CR34","doi-asserted-by":"crossref","unstructured":"Whatcott, C. J., Watanabe, A., LoBello, J., Von Hoff, D. & Han, H. Y. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Cancer Res. 74, (2014).","DOI":"10.1158\/1538-7445.AM2014-191"},{"key":"BFncomms12819_CR35","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.ccr.2014.04.021","volume":"25","author":"AD Rhim","year":"2014","unstructured":"Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735\u2013747 (2014).","journal-title":"Cancer Cell"},{"key":"BFncomms12819_CR36","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","volume":"369","author":"DD Von Hoff","year":"2013","unstructured":"Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691\u20131703 (2013).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12819_CR37","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","volume":"364","author":"T Conroy","year":"2011","unstructured":"Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817\u20131825 (2011).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12819_CR38","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1136\/gutjnl-2012-302529","volume":"62","author":"MA Jacobetz","year":"2013","unstructured":"Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112\u2013120 (2013).","journal-title":"Gut"},{"key":"BFncomms12819_CR39","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1038\/nm.2344","volume":"17","author":"EA Collisson","year":"2011","unstructured":"Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500\u2013503 (2011).","journal-title":"Nat. Med."},{"key":"BFncomms12819_CR40","doi-asserted-by":"publisher","first-page":"S47","DOI":"10.1016\/S0016-5085(15)30164-5","volume":"148","author":"S Heeg","year":"2015","unstructured":"Heeg, S. et al. The Ets-transcription factor Etv1 regulates stromal expansion and metastasis in pancreatic cancer. Gastroenterology 148, S47\u2013S47 (2015).","journal-title":"Gastroenterology"},{"key":"BFncomms12819_CR41","doi-asserted-by":"crossref","first-page":"4525","DOI":"10.1200\/jco.2009.27.15_suppl.4525","volume":"27","author":"DD Von Hoff","year":"2009","unstructured":"Von Hoff, D. D. et al. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: A phase I\/II study. J. Clin. Oncol. 27, 4525 (2009).","journal-title":"J. Clin. Oncol."},{"key":"BFncomms12819_CR42","doi-asserted-by":"publisher","first-page":"4811","DOI":"10.1158\/1078-0432.CCR-14-3222","volume":"41","author":"M Hidalgo","year":"2015","unstructured":"Hidalgo, M. et al. SPARC expression did not predict efficacy of nab-paclitaxel plus gemcitabine or gemcitabine alone for metastatic pancreatic cancer in an exploratory analysis of the phase III MPACT trial. Clin. Cancer Res. 41, 4811\u20134818 (2015).","journal-title":"Clin. Cancer Res."},{"key":"BFncomms12819_CR43","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1136\/gutjnl-2013-305559","volume":"63","author":"A Neesse","year":"2014","unstructured":"Neesse, A. et al. SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut 63, 974\u2013983 (2014).","journal-title":"Gut"},{"key":"BFncomms12819_CR44","doi-asserted-by":"publisher","first-page":"4548","DOI":"10.1200\/JCO.2011.36.5742","volume":"29","author":"DD Von Hoff","year":"2011","unstructured":"Von Hoff, D. D. et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I\/II trial. J. Clin. Oncol. 29, 4548\u20134554 (2011).","journal-title":"J. Clin. Oncol."},{"key":"BFncomms12819_CR45","first-page":"304","volume":"31","author":"TC Cornish","year":"2009","unstructured":"Cornish, T. C. & Halushka, M. K. Color deconvolution for the analysis of tissue microarrays. Anal. Quant. Cytol. Histol. 31, 304\u2013312 (2009).","journal-title":"Anal. Quant. Cytol. Histol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms12819.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12819","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12819.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T10:07:24Z","timestamp":1672826844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms12819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,15]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,25]]}},"alternative-id":["BFncomms12819"],"URL":"https:\/\/doi.org\/10.1038\/ncomms12819","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,15]]},"assertion":[{"value":"3 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12819"}}