{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T19:50:43Z","timestamp":1775591443441,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,5,31]],"date-time":"2019-05-31T00:00:00Z","timestamp":1559260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The R132H mutation in isocitrate dehydrogenase 1 (IDH1R132H) is commonly observed and associated with better survival in glioblastoma multiforme (GBM), a malignant brain tumor. However, the functional role of IDH1R132H as a molecular target for GBM treatment is not completely understood. In this study, we found that the overexpression of IDH1R132H suppresses cell growth, cell cycle progression and motility in U87MG glioblastoma cells. Based on cell viability and apoptosis assays, we found that IDH1R132H-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Octyl-(R)-2-hydroxyglutarate (Octyl-2HG), which is a membrane-permeable precursor form of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1-mutant tumor cells, significantly increased HDACi resistance in glioblastoma cells. Mechanistically, IDH1R132H and Octyl-2HG enhanced the promoter activation of NANOG via increased H3K4-3Me, consequently increasing NANOG mRNA and protein expression. Indeed, HDACi resistance was attenuated in IDH1R132H-expressing glioblastoma cells by the suppression of NANOG using small interfering RNAs. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1R132H, significantly attenuates HDACi resistance and NANOG expression IDH1R132H-expressing glioblastoma cells. These results suggested that IDH1R132H is a potential molecular target for HDACi-based therapy for GBM.<\/jats:p>","DOI":"10.3390\/ijms20112679","type":"journal-article","created":{"date-parts":[[2019,5,31]],"date-time":"2019-05-31T11:59:56Z","timestamp":1559303996000},"page":"2679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["IDH1R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells"],"prefix":"10.3390","volume":"20","author":[{"given":"Geon-Hee","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Applied Life Science, Graduate School of Konkuk University, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"So Young","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taek-In","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science, Graduate School of Konkuk University, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang-Yeon","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science, Graduate School of Konkuk University, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyeji","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science, Graduate School of Konkuk University, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sujin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science, Graduate School of Konkuk University, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taerim","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Myung","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Life Science, College of Science and Technology, Woosuk University, 66 Daehak-ro, Jincheon-eup, Chungcheongbuk-do 27841, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Hong","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science, Graduate School of Konkuk University, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea"},{"name":"Department of Biomedical Chemistry, College of Biomedical &amp; Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ccr.2010.01.020","article-title":"The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate","volume":"17","author":"Ward","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1084\/jem.20092506","article-title":"Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations","volume":"207","author":"Gross","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nature08617","article-title":"Cancer-associated IDH1 mutations produce 2-hydroxyglutarate","volume":"462","author":"Dang","year":"2009","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJMoa0903840","article-title":"Recurring mutations found by sequencing an acute myeloid leukemia genome","volume":"361","author":"Mardis","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1056\/NEJMoa0808710","article-title":"IDH1 and IDH2 mutations in gliomas","volume":"360","author":"Yan","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1126\/science.1164382","article-title":"An integrated genomic analysis of human glioblastoma multiforme","volume":"321","author":"Parsons","year":"2008","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ccell.2018.04.011","article-title":"Biological Role and Therapeutic Potential of IDH Mutations in Cancer","volume":"34","author":"Waitkus","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_8","first-page":"270","article-title":"IDH1 mutation diminishes aggressive phenotype in glioma stem cells","volume":"52","author":"Yao","year":"2018","journal-title":"Int J. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.celrep.2017.03.053","article-title":"IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation","volume":"19","author":"Jiang","year":"2017","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.ccell.2016.08.017","article-title":"Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis","volume":"30","author":"Bardella","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.biocel.2016.02.007","article-title":"R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt\/\u03b2-catenin signaling","volume":"73","author":"Cui","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6695","DOI":"10.3892\/mmr.2015.4241","article-title":"IDH1R132H decreases the proliferation of U87 glioma cells through upregulation of microRNA-128a","volume":"12","author":"Yang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.radonc.2015.08.007","article-title":"IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status","volume":"116","author":"Kessler","year":"2015","journal-title":"Radiother. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1093\/neuonc\/not087","article-title":"IDH1\/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma","volume":"15","author":"Zhang","year":"2013","journal-title":"Neuro-Oncology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature11323","article-title":"IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics","volume":"488","author":"Sasaki","year":"2012","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ccr.2010.12.014","article-title":"Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of \u03b1-ketoglutarate-dependent dioxygenases","volume":"19","author":"Xu","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/nature10860","article-title":"IDH mutation impairs histone demethylation and results in a block to cell differentiation","volume":"483","author":"Lu","year":"2012","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nature13981","article-title":"Intracellular \u03b1-ketoglutarate maintains the pluripotency of embryonic stem cells","volume":"518","author":"Carey","year":"2015","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nature10898","article-title":"Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation","volume":"483","author":"Koivunen","year":"2012","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36289","DOI":"10.1038\/srep36289","article-title":"Oncometabolite D-2-Hydroxyglutarate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer","volume":"6","author":"Colvin","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"32428","DOI":"10.1038\/srep32428","article-title":"The oncometabolite R-2-hydroxyglutarate activates NF-kB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.cmet.2015.06.009","article-title":"2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling","volume":"22","author":"Fu","year":"2015","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.cell.2017.11.031","article-title":"R-2HG Exhibits Anti-tumor Activity by Targeting FTO\/m6A\/MYC\/CEBPA Signaling","volume":"172","author":"Su","year":"2018","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1038\/s41388-017-0077-z","article-title":"Wild-type and mutated IDH1\/2 enzymes and therapy responses","volume":"37","author":"Molenaar","year":"2018","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1126\/science.1236062","article-title":"An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells","volume":"340","author":"Rohle","year":"2013","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13853","DOI":"10.1038\/s41598-017-14065-w","article-title":"A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit","volume":"7","author":"Kopinja","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1158\/0008-5472.CAN-14-3603","article-title":"Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198","volume":"75","author":"Molenaar","year":"2015","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eaal2463","DOI":"10.1126\/scitranslmed.aal2463","article-title":"2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity","volume":"9","author":"Sulkowski","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1158\/1078-0432.CCR-17-2796","article-title":"IDH1\/2Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1\/2-Mutant Inhibitors","volume":"24","author":"Molenaar","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"427","DOI":"10.7314\/APJCP.2014.15.1.427","article-title":"IDH1 Overexpression Induced Chemotherapy Resistance and IDH1 Mutation Enhanced Chemotherapy Sensitivity in Glioma Cells in Vitro and in Vivo","volume":"15","author":"Wang","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1212\/WNL.0b013e3181f96282","article-title":"IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas","volume":"75","author":"Houillier","year":"2010","journal-title":"Neurology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6344","DOI":"10.1096\/fj.201800547R","article-title":"IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity","volume":"32","author":"Khurshed","year":"2018","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12279","DOI":"10.18632\/oncotarget.3733","article-title":"Oncometabolite mutation IDH1 R132H confers a metformin hypersensitive phenotype","volume":"6","author":"Llorens","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/neuonc\/nos261","article-title":"Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation","volume":"15","author":"Li","year":"2013","journal-title":"Neuro-Oncology"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s12032-014-0985-5","article-title":"Histone deacetylase inhibitors in glioblastoma: Pre-clinical and clinical experience","volume":"31","author":"Bezecny","year":"2014","journal-title":"Med. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0092-8674(03)00394-5","article-title":"Nanog: A new recruit to the embryonic stem cell orchestra","volume":"113","author":"Cavaleri","year":"2003","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1002\/ijc.28690","article-title":"Emerging Role of Nanog in Tumorigenesis and Cancer Stem Cells","volume":"135","author":"Xie","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.3892\/ijo.2014.2347","article-title":"Knockdown of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by reducing MDR1 expression","volume":"44","author":"Zhou","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1158\/0008-5472.CAN-17-0072","article-title":"HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells","volume":"77","author":"Song","year":"2017","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1038\/s41598-018-20004-0","article-title":"Depletion of HDAC1, 7 and 8 by Histone Deacetylase Inhibition Confers Elimination of Pancreatic Cancer Stem Cells in Combination with Gemcitabine","volume":"8","author":"Cai","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1172\/JCI69738","article-title":"New and emerging HDAC inhibitors for cancer treatment","volume":"124","author":"West","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Brown, D.V., Filiz, G., Daniel, P.M., Hollande, F., Dworkin, S., Amiridis, S., Kountouri, N., Ng, W., Morokoff, A.P., and Mantamadiotis, T. (2017). Expression of CD133 and CD44 in glioblastoma stem cells correlates with cell proliferation, phenotype stability and intra-tumor heterogeneity. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172791"},{"key":"ref_44","first-page":"222","article-title":"Targeting SOX2 as a Therapeutic Strategy in Glioblastoma","volume":"6","author":"Garcia","year":"2016","journal-title":"Front. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/ng.127","article-title":"An embryonic stem cell\u2013like gene expression signature in poorly differentiated aggressive human tumors","volume":"40","author":"Thomson","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1038\/emboj.2010.137","article-title":"NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53","volume":"29","author":"Zbinden","year":"2010","journal-title":"EMBO J."},{"key":"ref_47","first-page":"1207","article-title":"(Ken) Targeting cancer stem cells: Emerging role of Nanog transcription factor","volume":"6","author":"Wang","year":"2013","journal-title":"OncoTargets Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3389\/fgene.2018.00493","article-title":"IDH1: Linking Metabolism and Epigenetics","volume":"9","author":"Raineri","year":"2018","journal-title":"Front. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41588-017-0001-z","article-title":"Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence","volume":"50","author":"Turcan","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kim, Y.-S., Lee, Y.-M., Oh, T.-I., Shin, D.H., Kim, G.-H., Kan, S.-Y., Kang, H., Kim, J.H., Kim, B.M., and Yim, W.J. (2018). Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103127"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/cr.2011.12","article-title":"Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures","volume":"21","author":"Chou","year":"2011","journal-title":"Cell Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1186\/s13046-018-0945-6","article-title":"Long noncoding RNA LINC00511 contributes to breast cancer tumorigenesis and stemness by inducing the miR-185-3p\/E2F1\/Nanog axis","volume":"37","author":"Lu","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Park, E.-J., Lee, Y.-M., Oh, T.-I., Kim, B.M., Lim, B.-O., Lim, J.-H., and Morikawa, T. (2017). Vanillin Suppresses Cell Motility by Inhibiting STAT3-Mediated HIF-1\u03b1 mRNA Expression in Malignant Melanoma Cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030532"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/11\/2679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:54:57Z","timestamp":1760187297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/11\/2679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,31]]},"references-count":53,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["ijms20112679"],"URL":"https:\/\/doi.org\/10.3390\/ijms20112679","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,31]]}}}