{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T19:14:06Z","timestamp":1784747646706,"version":"3.55.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"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":["Br J Cancer"],"published-print":{"date-parts":[[2023,2,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Small RNAs (sRNAs), a heterogenous group of non-coding RNAs, are emerging as promising molecules for cancer patient risk stratification and as players in tumour pathogenesis. Here, we have studied microRNAs (miRNAs) and other sRNAs in relation to survival and disease severity in multiple myeloma.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We comprehensively characterised sRNA expression in multiple myeloma patients by performing sRNA-sequencing on myeloma cells isolated from bone marrow aspirates of 86 myeloma patients. The sRNA expression profiles were correlated with the patients\u2019 clinical data to investigate associations with survival and disease subgroups, by using cox proportional hazards (coxph) -models and <jats:italic>limma-voom<\/jats:italic>, respectively. A publicly available sRNA dataset was used as external validation (<jats:italic>n<\/jats:italic>\u2009=\u2009151).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We show that multiple miRNAs are differentially expressed between ISS Stage I and III. Interestingly, we observed the downregulation of seven different U2 spliceosomal RNAs, a type of small nuclear RNAs in severe disease stages. Further, by a discovery-based approach, we identified miRNA miR-105-5p as a predictor of poor overall survival (OS) in multiple myeloma. Multivariate analysis showed that miR-105-5p predict OS independently of established disease markers.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Overexpression of miR-105-5p in myeloma cells correlates with reduced OS, potentially improving prognostic risk stratification in multiple myeloma.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/s41416-022-02065-1","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T21:51:54Z","timestamp":1669758714000},"page":"656-664","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Comprehensive small RNA-sequencing of primary myeloma cells identifies miR-105-5p as a predictor of patient survival"],"prefix":"10.1038","volume":"128","author":[{"given":"Kristin","family":"Roseth Aass","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonje Marie Vikene","family":"Nedal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siri","family":"Anshushaug Bouma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Synne Stokke","family":"Tryggestad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar","family":"Hauk\u00e5s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7488-4863","authenticated-orcid":false,"given":"Tobias Schmidt","family":"Sl\u00f8rdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9072-1220","authenticated-orcid":false,"given":"Anders","family":"Waage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-8522","authenticated-orcid":false,"given":"Therese","family":"Standal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3509-4134","authenticated-orcid":false,"given":"Robin","family":"Mjelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"2065_CR1","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1002\/ajh.26590","volume":"97","author":"SV Rajkumar","year":"2022","unstructured":"Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97:1086\u2013107.","journal-title":"Am J Hematol"},{"key":"2065_CR2","doi-asserted-by":"publisher","first-page":"2516","DOI":"10.1182\/blood-2007-10-116129","volume":"111","author":"SK Kumar","year":"2008","unstructured":"Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516\u201320.","journal-title":"Blood"},{"key":"2065_CR3","doi-asserted-by":"publisher","first-page":"3574","DOI":"10.1002\/cncr.32357","volume":"125","author":"RW Hsieh","year":"2019","unstructured":"Hsieh RW, Go RS, Abeykoon JP, Kapoor P, Kumar SK, Gertz MA, et al. Characteristics of long-term survivors with multiple myeloma: a National Cancer Data Base analysis. Cancer. 2019;125:3574\u201381.","journal-title":"Cancer"},{"key":"2065_CR4","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1038\/leu.2017.331","volume":"32","author":"SK Kumar","year":"2018","unstructured":"Kumar SK, Dispenzieri A, Fraser R, Mingwei F, Akpek G, Cornell R, et al. Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time. Leukemia. 2018;32:986\u201395.","journal-title":"Leukemia"},{"key":"2065_CR5","doi-asserted-by":"publisher","first-page":"3412","DOI":"10.1200\/JCO.2005.04.242","volume":"23","author":"PR Greipp","year":"2005","unstructured":"Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blad\u00e9 J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412\u201320.","journal-title":"J Clin Oncol"},{"key":"2065_CR6","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1200\/JCO.2015.61.2267","volume":"33","author":"A Palumbo","year":"2015","unstructured":"Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33:2863\u20139.","journal-title":"J Clin Oncol"},{"key":"2065_CR7","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1182\/blood-2018-09-825331","volume":"133","author":"C Pawlyn","year":"2019","unstructured":"Pawlyn C, Davies FE. Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood. 2019;133:660\u201375.","journal-title":"Blood"},{"key":"2065_CR8","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1038\/s41388-020-01630-3","volume":"40","author":"Z Zhang","year":"2021","unstructured":"Zhang Z, Zhang J, Diao L, Han L. Small non-coding RNAs in human cancer: function, clinical utility, and characterization. Oncogene. 2021;40:1570\u20137.","journal-title":"Oncogene"},{"key":"2065_CR9","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","volume":"116","author":"DP Bartel","year":"2004","unstructured":"Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281\u201397.","journal-title":"Cell"},{"key":"2065_CR10","doi-asserted-by":"publisher","first-page":"15004","DOI":"10.1038\/sigtrans.2015.4","volume":"1","author":"Y Peng","year":"2016","unstructured":"Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016;1:15004.","journal-title":"Signal Transduct Target Ther"},{"key":"2065_CR11","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.3390\/cancers11111738","volume":"11","author":"H Handa","year":"2019","unstructured":"Handa H, Murakami Y, Ishihara R, Kimura-Masuda K, Masuda Y. The role and function of microRNA in the pathogenesis of multiple myeloma. Cancers. 2019;11:1738.","journal-title":"Cancers"},{"key":"2065_CR12","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3390\/ncrna5020037","volume":"5","author":"C Federico","year":"2019","unstructured":"Federico C, Sacco A, Belotti A, Ribolla R, Cancelli V, Giacomini A, et al. Circulating microRNAs and their role in multiple myeloma. Noncoding RNA. 2019;5:37.","journal-title":"Noncoding RNA"},{"key":"2065_CR13","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1182\/blood-2016-09-742296","volume":"129","author":"S Manier","year":"2017","unstructured":"Manier S, Liu CJ, Avet-Loiseau H, Park J, Shi J, Campigotto F, et al. Prognostic role of circulating exosomal miRNAs in multiple myeloma. Blood. 2017;129:2429\u201336.","journal-title":"Blood"},{"key":"2065_CR14","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.leukres.2015.04.010","volume":"39","author":"F Li","year":"2015","unstructured":"Li F, Hao M, Feng X, Zang M, Qin Y, Yi S, et al. Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma. Leuk Res. 2015;39:793\u20139.","journal-title":"Leuk Res"},{"key":"2065_CR15","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1111\/bjh.12394","volume":"162","author":"P Wu","year":"2013","unstructured":"Wu P, Agnelli L, Walker BA, Todoerti K, Lionetti M, Johnson DC, et al. Improved risk stratification in myeloma using a microRNA-based classifier. Br J Haematol. 2013;162:348\u201359.","journal-title":"Br J Haematol"},{"key":"2065_CR16","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s41416-021-01602-8","volume":"126","author":"M-A Papadimitriou","year":"2022","unstructured":"Papadimitriou M-A, Papanota A-M, Adamopoulos PG, Pilala K-M, Liacos C-I, Malandrakis P, et al. miRNA-seq and clinical evaluation in multiple myeloma: miR-181a overexpression predicts short-term disease progression and poor post-treatment outcome. Br J Cancer. 2022;126:79\u201390.","journal-title":"Br J Cancer"},{"key":"2065_CR17","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.canlet.2012.11.058","volume":"340","author":"ES Martens-Uzunova","year":"2013","unstructured":"Martens-Uzunova ES, Olvedy M, Jenster G. Beyond microRNA-novel RNAs derived from small non-coding RNA and their implication in cancer. Cancer Lett. 2013;340:201\u201311.","journal-title":"Cancer Lett"},{"key":"2065_CR18","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s13238-021-00856-5","volume":"13","author":"H Yang","year":"2022","unstructured":"Yang H, Beutler B, Zhang D. Emerging roles of spliceosome in cancer and immunity. Protein Cell. 2022;13:559\u201379.","journal-title":"Protein Cell"},{"key":"2065_CR19","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/j.bbagrm.2014.12.005","volume":"1849","author":"SS Grewal","year":"2015","unstructured":"Grewal SS. Why should cancer biologists care about tRNAs? tRNA synthesis, mRNA translation and the control of growth. Biochimica et Biophysica Acta. 2015;1849:898\u2013907.","journal-title":"Biochimica et Biophysica Acta"},{"key":"2065_CR20","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3389\/fonc.2019.00587","volume":"9","author":"J Liang","year":"2019","unstructured":"Liang J, Wen J, Huang Z, Chen XP, Zhang BX, Chu L. Small nucleolar RNAs: insight into their function in cancer. Front Oncol. 2019;9:587.","journal-title":"Front Oncol"},{"key":"2065_CR21","doi-asserted-by":"publisher","first-page":"e3","DOI":"10.1093\/nar\/gkv808","volume":"44","author":"A Chu","year":"2016","unstructured":"Chu A, Robertson G, Brooks D, Mungall AJ, Birol I, Coope R, et al. Large-scale profiling of microRNAs for The Cancer Genome Atlas. Nucleic Acids Res. 2016;44:e3.","journal-title":"Nucleic Acids Res"},{"key":"2065_CR22","doi-asserted-by":"crossref","unstructured":"Dvinge H, Guenthoer J, Porter PL, Bradley RK. RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing. Genome Res. 2019;29:1591\u2013604.","DOI":"10.1101\/gr.246678.118"},{"key":"2065_CR23","doi-asserted-by":"publisher","first-page":"2656","DOI":"10.1182\/bloodadvances.2017010801","volume":"1","author":"M Zahoor","year":"2017","unstructured":"Zahoor M, Westhrin M, Aass KR, Moen SH, Misund K, Psonka-Antonczyk KM, et al. Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss. Blood Adv. 2017;1:2656\u201366.","journal-title":"Blood Adv"},{"key":"2065_CR24","doi-asserted-by":"publisher","first-page":"90077","DOI":"10.18632\/oncotarget.21412","volume":"8","author":"R Mjelle","year":"2017","unstructured":"Mjelle R, Sell\u00e6g K, S\u00e6trom P, Thommesen L, Sjursen W, Hofsli E. Identification of metastasis-associated microRNAs in serum from rectal cancer patients. Oncotarget. 2017;8:90077\u201389.","journal-title":"Oncotarget"},{"key":"2065_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-16448-0","volume":"12","author":"KR Aass","year":"2022","unstructured":"Aass KR, Nedal TMV, Tryggestad SS, Hauk\u00e5s E, Sl\u00f8rdahl TS, Waage A, et al. Paired miRNA- and messenger RNA-sequencing identifies novel miRNA-mRNA interactions in multiple myeloma. Sci Rep. 2022;12:12147.","journal-title":"Sci Rep."},{"key":"2065_CR26","unstructured":"Andrews S. A quality control tool for high throughput sequence data. 2019. https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"2065_CR27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.14806\/ej.17.1.200","volume":"17","author":"M MARTIN","year":"2011","unstructured":"MARTIN M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011;17:10\u201312.","journal-title":"EMBnet J"},{"key":"2065_CR28","unstructured":"Hannon GJ. FASTX-Toolkit. 2010. http:\/\/hannonlab.cshl.edu\/fastx_toolkit."},{"key":"2065_CR29","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","volume":"9","author":"B Langmead","year":"2012","unstructured":"Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357\u20139.","journal-title":"Nat Methods"},{"key":"2065_CR30","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166\u20139.","journal-title":"Bioinformatics"},{"key":"2065_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2014-15-2-r29","volume":"15","author":"CW Law","year":"2014","unstructured":"Law CW, Chen Y, Shi W, Smyth G. K. voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014;15:R29.","journal-title":"Genome Biol"},{"key":"2065_CR32","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-016-0906-9","volume":"14","author":"F Kryukov","year":"2016","unstructured":"Kryukov F, Nemec P, Radova L, Kryukova E, Okubote S, Minarik J, et al. Centrosome associated genes pattern for risk sub-stratification in multiple myeloma. J Transl Med. 2016;14:150.","journal-title":"J Transl Med"},{"key":"2065_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5330-0","volume":"19","author":"R Mjelle","year":"2019","unstructured":"Mjelle R, Sjursen W, Thommesen L, Saetrom P, Hofsli E. Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location. BMC Cancer. 2019;19:161.","journal-title":"BMC Cancer"},{"key":"2065_CR34","doi-asserted-by":"publisher","first-page":"e51862","DOI":"10.1371\/journal.pone.0051862","volume":"7","author":"J Budczies","year":"2012","unstructured":"Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012;7:e51862.","journal-title":"PLoS ONE"},{"key":"2065_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-022-00679-5","volume":"12","author":"P Hagen","year":"2022","unstructured":"Hagen P, Zhang J, Barton K. High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions. Blood Cancer J. 2022;12:83.","journal-title":"Blood Cancer J"},{"key":"2065_CR36","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/s41416-021-01672-8","volume":"126","author":"S Toden","year":"2022","unstructured":"Toden S, Goel A. Non-coding RNAs as liquid biopsy biomarkers in cancer. Br J Cancer. 2022;126:351\u201360.","journal-title":"Br J Cancer"},{"key":"2065_CR37","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1038\/s41417-020-00291-4","volume":"28","author":"D Chen","year":"2021","unstructured":"Chen D, Yang X, Liu M, Zhang Z, Xing E. Roles of miRNA dysregulation in the pathogenesis of multiple myeloma. Cancer Gene Ther. 2021;28:1256\u201368.","journal-title":"Cancer Gene Ther"},{"key":"2065_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-019-0184-x","volume":"9","author":"L Agnelli","year":"2019","unstructured":"Agnelli L, Bisognin A, Todoerti K, Manzoni M, Taiana E, Galletti S, et al. Expanding the repertoire of miRNAs and miRNA-offset RNAs expressed in multiple myeloma by small RNA deep sequencing. Blood Cancer J. 2019;9:21.","journal-title":"Blood Cancer J"},{"key":"2065_CR39","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nsmb.1536","volume":"16","author":"W Shi","year":"2009","unstructured":"Shi W, Hendrix D, Levine M, Haley B. A distinct class of small RNAs arises from pre-miRNA-proximal regions in a simple chordate. Nat Struct Mol Biol. 2009;16:183\u20139.","journal-title":"Nat Struct Mol Biol"},{"key":"2065_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13993-7","volume":"11","author":"JM Oh","year":"2020","unstructured":"Oh JM, Venters CC, Di C, Pinto AM, Wan L, Younis I, et al. U1 snRNP regulates cancer cell migration and invasion in vitro. Nat Commun. 2020;11:1.","journal-title":"Nat Commun"},{"key":"2065_CR41","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41392-021-00486-7","volume":"6","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Qian J, Gu C, Yang Y. Alternative splicing and cancer: a systematic review. Signal Transduct Target Ther. 2021;6:78.","journal-title":"Signal Transduct Target Ther"},{"key":"2065_CR42","doi-asserted-by":"publisher","unstructured":"Bauer MA, Ashby C, Wardell C, Boyle EM, Ortiz M, Flynt E, et al. Differential RNA splicing as a potentially important driver mechanism in multiple myeloma. Haematologica. 2020; https:\/\/doi.org\/10.3324\/haematol.2019.235424.","DOI":"10.3324\/haematol.2019.235424"},{"key":"2065_CR43","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1038\/s41375-020-0750-z","volume":"34","author":"V Shah","year":"2020","unstructured":"Shah V, Sherborne AL, Johnson DC, Ellis S, Price A, Chowdhury F, et al. Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients. Leukemia. 2020;34:3091\u20136.","journal-title":"Leukemia"}],"container-title":["British Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41416-022-02065-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41416-022-02065-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41416-022-02065-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T16:14:06Z","timestamp":1676650446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41416-022-02065-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,29]]},"references-count":43,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,2,16]]}},"alternative-id":["2065"],"URL":"https:\/\/doi.org\/10.1038\/s41416-022-02065-1","relation":{},"ISSN":["0007-0920","1532-1827"],"issn-type":[{"value":"0007-0920","type":"print"},{"value":"1532-1827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,29]]},"assertion":[{"value":"1 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All patient samples were donated after informed consent, and the study was approved by the regional ethics committee (REK2011\/2029 and 2012\/2033). The study was performed in accordance with the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"There is no individual person\u00b4s data.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}]}}