{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:15:21Z","timestamp":1793826921601,"version":"4.6.1"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Projekt DEAL"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with dismal prognosis. Platinum-based chemotherapy is regularly used as part of multimodality therapy. The expression of metallothioneins (MT) has been identified as a reason for cisplatin resistance, which often leads to early therapy failure or relapse. Thus, knockdown of MT expression may improve response to cisplatin treatment. The MT gene- and protein expression of the MPM-cell lines MSTO-211H, NCI-H2052 and NCI-H2452 and the human fibroblast cell line MRC-5, as well as their sensitivity to cisplatin treatment have been evaluated. Knockdown of MT1A, 1B and 2A expression was induced by RNA interference. MT expression was measured using quantitative real-time PCR. An in vitro Assay based on enzyme activity was used to detect cell viability, necrosis and apoptosis before and after incubation with cisplatin. MT2A gene expression could be detected in all MPM cell lines, showing the highest expression in NCI-H2452 and NCI-H2052, whereas gene expression levels of MT1A and MT1B were low or absent. The immunohistochemically protein expression of MT-I\/II reflect MT2A gene expression levels. Especially for MSTO-211H cell presenting low initial MT2A levels, a strong induction of MT2A expression could be observed during cisplatin treatment, indicating a cell line-specific and platin-dependent adaption mechanism. Additionally, a MT2A-dependent cellular evasion of apoptosis during cisplatin could be observed, leading to three different MT based phenotypes. MSTO-211H cells showed lower apoptosis rates at an increased expression level of MT2A after cisplatin treatment (from sixfold to fourfold). NCI-H2052 cells showed no changes in MT2A expression, while apoptosis rate is the highest (8\u201312-fold). NCI-H2452 cells showed neither changes in alteration rate of MT2A expression nor changes in apoptosis rates, indicating an MT2A-independent resistance mechanism. Knockdown of MT2A expression levels resulted in significantly induced apoptotic rates during cisplatin treatment with strongest induction of apoptosis in each of the MPM cell lines, but in different markedness. A therapeutic meaningful effect of MT2A knockdown and subsequent cisplatin treatment could be observed in MSTO-211H cells. The present study showed MT2A to be part of the underlying mechanism of cisplatin resistance in MPM. Especially in MSTO-211H cells we could demonstrate major effects by knockdown of MT2A expression, verifying our hypothesis of an MT driven resistance mechanism. We could prove the inhibition of MT2A as a powerful tool to boost response rates to cisplatin-based therapy in vitro. These data carry the potential to enhance the clinical outcome and management of MPM in the future.<\/jats:p>","DOI":"10.1038\/s41598-020-75807-x","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T07:02:57Z","timestamp":1603954977000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0447-3206","authenticated-orcid":false,"given":"Sabrina","family":"Borchert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia-Maria","family":"Suckrau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3725-7064","authenticated-orcid":false,"given":"Robert F. H.","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4399-8646","authenticated-orcid":false,"given":"Michael","family":"Wessolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8523-1849","authenticated-orcid":false,"given":"Elena","family":"Mairinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Steinborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-4153","authenticated-orcid":false,"given":"Balazs","family":"Hegedus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfried E. E.","family":"Eberhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-2489","authenticated-orcid":false,"given":"Jeremias","family":"Wohlschlaeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-991X","authenticated-orcid":false,"given":"Clemens","family":"Aigner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0632-077X","authenticated-orcid":false,"given":"Agnes","family":"Bankfalvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0241-0420","authenticated-orcid":false,"given":"Kurt Werner","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1067-0051","authenticated-orcid":false,"given":"Fabian D.","family":"Mairinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"75807_CR1","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s00428-017-2133-z","volume":"470","author":"FD Mairinger","year":"2017","unstructured":"Mairinger, F. D. et al. miRNA regulation is important for DNA damage repair and recognition in malignant pleural mesothelioma. Virchows Arch. 470, 627\u2013637. https:\/\/doi.org\/10.1007\/s00428-017-2133-z (2017).","journal-title":"Virchows Arch."},{"key":"75807_CR2","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1016\/j.jtho.2018.06.011","volume":"13","author":"L Mutti","year":"2018","unstructured":"Mutti, L. et al. Scientific advances and new frontiers in mesothelioma therapeutics. J. Thorac. Oncol. 13, 1269\u20131283. https:\/\/doi.org\/10.1016\/j.jtho.2018.06.011 (2018).","journal-title":"J. Thorac. Oncol."},{"key":"75807_CR3","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1097\/CCO.0000000000000053","volume":"26","author":"DC Christoph","year":"2014","unstructured":"Christoph, D. C. & Eberhardt, W. E. Systemic treatment of malignant pleural mesothelioma: New agents in clinical trials raise hope of relevant improvements. Curr. Opin. Oncol. 26, 171\u2013181. https:\/\/doi.org\/10.1097\/CCO.0000000000000053 (2014).","journal-title":"Curr. Opin. Oncol."},{"key":"75807_CR4","first-page":"3553","volume":"33","author":"CC Boons","year":"2013","unstructured":"Boons, C. C. et al. The value of pemetrexed for the treatment of malignant pleural mesothelioma: A comprehensive review. Anticancer Res. 33, 3553\u20133561 (2013).","journal-title":"Anticancer Res."},{"key":"75807_CR5","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1111\/1759-7714.13063","volume":"10","author":"M Zhuo","year":"2019","unstructured":"Zhuo, M. et al. Survival analysis via nomogram of surgical patients with malignant pleural mesothelioma in the Surveillance, Epidemiology, and End Results database. Thorac. Cancer 10, 1193\u20131202. https:\/\/doi.org\/10.1111\/1759-7714.13063 (2019).","journal-title":"Thorac. Cancer"},{"issue":"Suppl 1","key":"75807_CR6","doi-asserted-by":"publisher","first-page":"S103","DOI":"10.1016\/j.lungcan.2004.04.020","volume":"45","author":"S Tomek","year":"2004","unstructured":"Tomek, S. & Manegold, C. Chemotherapy for malignant pleural mesothelioma: Past results and recent developments. Lung Cancer 45(Suppl 1), S103-119. https:\/\/doi.org\/10.1016\/j.lungcan.2004.04.020 (2004).","journal-title":"Lung Cancer"},{"key":"75807_CR7","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1001\/jamaoncol.2016.1056","volume":"2","author":"D Liu","year":"2016","unstructured":"Liu, D. et al. Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol. 2, 1094\u20131096. https:\/\/doi.org\/10.1001\/jamaoncol.2016.1056 (2016).","journal-title":"JAMA Oncol."},{"key":"75807_CR8","doi-asserted-by":"publisher","first-page":"4117","DOI":"10.7314\/APJCP.2014.15.10.4117","volume":"15","author":"YB Cihan","year":"2014","unstructured":"Cihan, Y. B. et al. ERCC1 as a biological marker guiding management in malignant pleural mesothelioma. Asian Pac. J. Cancer Prev. 15, 4117\u20134123 (2014).","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"75807_CR9","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1093\/annonc\/mdr324","volume":"23","author":"N Erculj","year":"2012","unstructured":"Erculj, N., Kovac, V., Hmeljak, J. & Dolzan, V. The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma. Ann. Oncol. 23, 961\u2013967. https:\/\/doi.org\/10.1093\/annonc\/mdr324 (2012).","journal-title":"Ann. Oncol."},{"key":"75807_CR10","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s00280-017-3401-y","volume":"80","author":"G Srinivasan","year":"2017","unstructured":"Srinivasan, G. et al. Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition. Cancer Chemother. Pharmacol. 80, 861\u2013867. https:\/\/doi.org\/10.1007\/s00280-017-3401-y (2017).","journal-title":"Cancer Chemother. Pharmacol."},{"key":"75807_CR11","first-page":"12","volume":"110","author":"V Ascoli","year":"2018","unstructured":"Ascoli, V. et al. What\u2019s new in mesothelioma. Pathologica 110, 12\u201328 (2018).","journal-title":"Pathologica"},{"key":"75807_CR12","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10060203","author":"C Ledda","year":"2018","unstructured":"Ledda, C., Senia, P. & Rapisarda, V. Biomarkers for early diagnosis and prognosis of malignant pleural mesothelioma: The quest goes on. Cancers https:\/\/doi.org\/10.3390\/cancers10060203 (2018).","journal-title":"Cancers"},{"key":"75807_CR13","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1016\/j.humpath.2009.01.026","volume":"40","author":"KJ Schmitz","year":"2009","unstructured":"Schmitz, K. J. et al. Metallothionein overexpression and its prognostic relevance in intrahepatic cholangiocarcinoma and extrahepatic hilar cholangiocarcinoma (Klatskin tumors). Hum. Pathol. 40, 1706\u20131714. https:\/\/doi.org\/10.1016\/j.humpath.2009.01.026 (2009).","journal-title":"Hum. Pathol."},{"key":"75807_CR14","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1039\/c8mt00165k","volume":"10","author":"A Ziller","year":"2018","unstructured":"Ziller, A. & Fraissinet-Tachet, L. Metallothionein diversity and distribution in the tree of life: A multifunctional protein. Metallomics 10, 1549\u20131559. https:\/\/doi.org\/10.1039\/c8mt00165k (2018).","journal-title":"Metallomics"},{"key":"75807_CR15","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1007\/s12011-017-1119-7","volume":"183","author":"AK Baltaci","year":"2018","unstructured":"Baltaci, A. K., Yuce, K. & Mogulkoc, R. Zinc metabolism and metallothioneins. Biol. Trace Elem. Res. 183, 22\u201331. https:\/\/doi.org\/10.1007\/s12011-017-1119-7 (2018).","journal-title":"Biol. Trace Elem. Res."},{"key":"75807_CR16","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s13045-018-0645-x","volume":"11","author":"M Si","year":"2018","unstructured":"Si, M. & Lang, J. The roles of metallothioneins in carcinogenesis. J. Hematol. Oncol. 11, 107. https:\/\/doi.org\/10.1186\/s13045-018-0645-x (2018).","journal-title":"J. Hematol. Oncol."},{"key":"75807_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/nu10121874","author":"S Rodriguez-Menendez","year":"2018","unstructured":"Rodriguez-Menendez, S. et al. The zinc-metallothionein redox system reduces oxidative stress in retinal pigment epithelial cells. Nutrients https:\/\/doi.org\/10.3390\/nu10121874 (2018).","journal-title":"Nutrients"},{"key":"75807_CR18","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/j.1471-4159.2007.05026.x","volume":"104","author":"RS Chung","year":"2008","unstructured":"Chung, R. S., Hidalgo, J. & West, A. K. New insight into the molecular pathways of metallothionein-mediated neuroprotection and regeneration. J. Neurochem. 104, 14\u201320. https:\/\/doi.org\/10.1111\/j.1471-4159.2007.05026.x (2008).","journal-title":"J. Neurochem."},{"key":"75807_CR19","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1039\/C7MT00332C","volume":"10","author":"A Drozd","year":"2018","unstructured":"Drozd, A., Wojewska, D., Peris-Diaz, M. D., Jakimowicz, P. & Krezel, A. Crosstalk of the structural and zinc buffering properties of mammalian metallothionein-2. Metallomics 10, 595\u2013613. https:\/\/doi.org\/10.1039\/C7MT00332C (2018).","journal-title":"Metallomics"},{"key":"75807_CR20","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1038\/onc.2011.384","volume":"31","author":"L Galluzzi","year":"2012","unstructured":"Galluzzi, L. et al. Molecular mechanisms of cisplatin resistance. Oncogene 31, 1869\u20131883. https:\/\/doi.org\/10.1038\/onc.2011.384 (2012).","journal-title":"Oncogene"},{"key":"75807_CR21","doi-asserted-by":"publisher","first-page":"22254","DOI":"10.18632\/oncotarget.24962","volume":"9","author":"FD Mairinger","year":"2018","unstructured":"Mairinger, F. D. et al. Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy. Oncotarget 9, 22254\u201322268. https:\/\/doi.org\/10.18632\/oncotarget.24962 (2018).","journal-title":"Oncotarget"},{"key":"75807_CR22","doi-asserted-by":"publisher","first-page":"248","DOI":"10.21037\/tlcr.2017.04.12","volume":"6","author":"A Singh","year":"2017","unstructured":"Singh, A., Pruett, N. & Hoang, C. D. In vitro experimental models of mesothelioma revisited. Transl. Lung Cancer Res. 6, 248\u2013258. https:\/\/doi.org\/10.21037\/tlcr.2017.04.12 (2017).","journal-title":"Transl. Lung Cancer Res."},{"key":"75807_CR23","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1165\/rcmb.2010-0282OC","volume":"45","author":"A Shukla","year":"2011","unstructured":"Shukla, A. et al. An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury. Am. J. Respir. Cell Mol. Biol. 45, 906\u2013914. https:\/\/doi.org\/10.1165\/rcmb.2010-0282OC (2011).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"75807_CR24","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0304-3835(00)00534-6","volume":"160","author":"A Nguyen","year":"2000","unstructured":"Nguyen, A. et al. In vivo gene expression profile analysis of metallothionein in renal cell carcinoma. Cancer Lett. 160, 133\u2013140 (2000).","journal-title":"Cancer Lett."},{"key":"75807_CR25","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19020590","author":"MA Skowron","year":"2018","unstructured":"Skowron, M. A. et al. Multifaceted mechanisms of cisplatin resistance in long-term treated urothelial carcinoma cell lines. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms19020590 (2018).","journal-title":"Int. J. Mol. Sci."},{"key":"75807_CR26","doi-asserted-by":"publisher","first-page":"e0189076","DOI":"10.1371\/journal.pone.0189076","volume":"12","author":"P de Francisco","year":"2017","unstructured":"de Francisco, P., Martin-Gonzalez, A., Turkewitz, A. P. & Gutierrez, J. C. Extreme metal adapted, knockout and knockdown strains reveal a coordinated gene expression among different Tetrahymena thermophila metallothionein isoforms. PLoS ONE 12, e0189076. https:\/\/doi.org\/10.1371\/journal.pone.0189076 (2017).","journal-title":"PLoS ONE"},{"key":"75807_CR27","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1159\/000095539","volume":"104","author":"I Sabolic","year":"2006","unstructured":"Sabolic, I. Common mechanisms in nephropathy induced by toxic metals. Nephron Physiol. 104, 107\u2013114. https:\/\/doi.org\/10.1159\/000095539 (2006).","journal-title":"Nephron Physiol."},{"key":"75807_CR28","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1007\/s10534-010-9351-z","volume":"23","author":"I Sabolic","year":"2010","unstructured":"Sabolic, I., Breljak, D., Skarica, M. & Herak-Kramberger, C. M. Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23, 897\u2013926. https:\/\/doi.org\/10.1007\/s10534-010-9351-z (2010).","journal-title":"Biometals"},{"key":"75807_CR29","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.bbrc.2017.08.137","volume":"493","author":"DP Jayawardena","year":"2017","unstructured":"Jayawardena, D. P., Heinemann, I. U. & Stillman, M. J. Zinc binds non-cooperatively to human liver metallothionein 2a at physiological pH. Biochem. Biophys. Res. Commun. 493, 650\u2013653. https:\/\/doi.org\/10.1016\/j.bbrc.2017.08.137 (2017).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"75807_CR30","doi-asserted-by":"publisher","first-page":"e874","DOI":"10.1038\/cddis.2013.405","volume":"4","author":"N Habel","year":"2013","unstructured":"Habel, N. et al. Zinc chelation: A metallothionein 2A\u2019s mechanism of action involved in osteosarcoma cell death and chemotherapy resistance. Cell Death Dis. 4, e874. https:\/\/doi.org\/10.1038\/cddis.2013.405 (2013).","journal-title":"Cell Death Dis."},{"key":"75807_CR31","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s12885-019-5314-0","volume":"19","author":"S Borchert","year":"2019","unstructured":"Borchert, S. et al. Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro. BMC Cancer 19, 108. https:\/\/doi.org\/10.1186\/s12885-019-5314-0 (2019).","journal-title":"BMC Cancer"},{"key":"75807_CR32","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.jconrel.2015.07.015","volume":"215","author":"JH Lee","year":"2015","unstructured":"Lee, J. H. et al. Inhibition of cisplatin-resistance by RNA interference targeting metallothionein using reducible oligo-peptoplex. J. Control Release 215, 82\u201390. https:\/\/doi.org\/10.1016\/j.jconrel.2015.07.015 (2015).","journal-title":"J. Control Release"},{"key":"75807_CR33","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.jdermsci.2017.07.009","volume":"88","author":"Y Nobeyama","year":"2017","unstructured":"Nobeyama, Y. & Nakagawa, H. Silencing of metallothionein 1A gene in melanoma. J. Dermatol. Sci. 88, 232\u2013237. https:\/\/doi.org\/10.1016\/j.jdermsci.2017.07.009 (2017).","journal-title":"J. Dermatol. Sci."},{"key":"75807_CR34","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1158\/1078-0432.CCR-16-1754","volume":"23","author":"JM Flanagan","year":"2017","unstructured":"Flanagan, J. M. et al. Platinum-based chemotherapy induces methylation changes in blood DNA associated with overall survival in patients with ovarian cancer. Clin. Cancer Res. 23, 2213\u20132222. https:\/\/doi.org\/10.1158\/1078-0432.CCR-16-1754 (2017).","journal-title":"Clin. Cancer Res."},{"key":"75807_CR35","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.omtn.2017.07.001","volume":"8","author":"HL Moody","year":"2017","unstructured":"Moody, H. L., Lind, M. J. & Maher, S. G. MicroRNA-31 regulates chemosensitivity in malignant pleural mesothelioma. Mol. Ther. Nucleic Acids 8, 317\u2013329. https:\/\/doi.org\/10.1016\/j.omtn.2017.07.001 (2017).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"75807_CR36","doi-asserted-by":"publisher","first-page":"e252","DOI":"10.1038\/mtna.2015.23","volume":"4","author":"JK Lam","year":"2015","unstructured":"Lam, J. K., Chow, M. Y., Zhang, Y. & Leung, S. W. siRNA versus miRNA as therapeutics for gene silencing. Mol. Ther. Nucleic Acids 4, e252. https:\/\/doi.org\/10.1038\/mtna.2015.23 (2015).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"75807_CR37","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/S1470-2045(17)30621-6","volume":"18","author":"N van Zandwijk","year":"2017","unstructured":"van Zandwijk, N. et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: A first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 18, 1386\u20131396. https:\/\/doi.org\/10.1016\/S1470-2045(17)30621-6 (2017).","journal-title":"Lancet Oncol."},{"key":"75807_CR38","doi-asserted-by":"publisher","first-page":"3128","DOI":"10.1093\/annonc\/mdt412","volume":"24","author":"G Reid","year":"2013","unstructured":"Reid, G. et al. Restoring expression of miR-16: A novel approach to therapy for malignant pleural mesothelioma. Ann. Oncol. 24, 3128\u20133135. https:\/\/doi.org\/10.1093\/annonc\/mdt412 (2013).","journal-title":"Ann. Oncol."},{"key":"75807_CR39","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.msec.2017.07.023","volume":"81","author":"S Matsuda","year":"2017","unstructured":"Matsuda, S. et al. Effective induction of death in mesothelioma cells with magnetite nanoparticles under an alternating magnetic field. Mater. Sci. Eng. C Mater. Biol. Appl. 81, 90\u201396. https:\/\/doi.org\/10.1016\/j.msec.2017.07.023 (2017).","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"75807_CR40","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3892\/or.2012.1799","volume":"28","author":"M Kitazono-Saitoh","year":"2012","unstructured":"Kitazono-Saitoh, M. et al. Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines. Oncol. Rep. 28, 33\u201340. https:\/\/doi.org\/10.3892\/or.2012.1799 (2012).","journal-title":"Oncol. Rep."},{"key":"75807_CR41","doi-asserted-by":"publisher","first-page":"762","DOI":"10.2353\/ajpath.2009.080721","volume":"174","author":"S Romagnoli","year":"2009","unstructured":"Romagnoli, S. et al. Identification of potential therapeutic targets in malignant mesothelioma using cell-cycle gene expression analysis. Am. J. Pathol. 174, 762\u2013770. https:\/\/doi.org\/10.2353\/ajpath.2009.080721 (2009).","journal-title":"Am. J. Pathol."},{"key":"75807_CR42","doi-asserted-by":"publisher","first-page":"2818","DOI":"10.1158\/1078-0432.CCR-08-1579","volume":"15","author":"F Vandermeers","year":"2009","unstructured":"Vandermeers, F. et al. Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma. Clin. Cancer Res. 15, 2818\u20132828. https:\/\/doi.org\/10.1158\/1078-0432.CCR-08-1579 (2009).","journal-title":"Clin. Cancer Res."},{"key":"75807_CR43","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.prp.2018.12.027","volume":"215","author":"J Schmeller","year":"2019","unstructured":"Schmeller, J. et al. Setting out the frame conditions for feasible use of FFPE derived RNA. Pathol. Res. Pract. 215, 381\u2013386. https:\/\/doi.org\/10.1016\/j.prp.2018.12.027 (2019).","journal-title":"Pathol. Res. Pract."},{"key":"75807_CR44","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","volume":"55","author":"SA Bustin","year":"2009","unstructured":"Bustin, S. A. et al. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55, 611\u2013622. https:\/\/doi.org\/10.1373\/clinchem.2008.112797 (2009).","journal-title":"Clin. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75807-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75807-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75807-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T17:40:21Z","timestamp":1670348421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75807-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,29]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["75807"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-75807-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,29]]},"assertion":[{"value":"27 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2020","order":3,"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"}}],"article-number":"18677"}}