{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:34:46Z","timestamp":1782088486674,"version":"3.54.5"},"reference-count":44,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CBM"],"published-print":{"date-parts":[[2023,2,16]]},"abstract":"<jats:p>BACKGROUND: Acute myeloid leukemia (AML) is a significantly heterogeneous malignancy of the blood. Cytogenetic abnormalities are crucial for the prognosis of AML. However, since more than half of patients with AML are cytogenetically normal AML (CN-AML), predictive prognostic indicators need to be further refined. In recent years, gene abnormalities are considered to be strong prognostic factors of CN-AML, already having clinical significance for treatment. In addition, the relationship of methylation in some genes and AML prognosis predicting has been discovered. RASGEF1A is a guanine nucleotide exchange factors of Ras and widely expressed in brain tissue, bone marrow and 17 other tissues. RASGEF1A has been reported to be associated with a variety of malignant tumors, examples include Hirschsprung disease, renal cell carcinoma, breast cancer, diffuse large B cell lymphoma, intrahepatic cholangiocarcinoma and so on [1, 2]. However, the relationship between the RASGEF1A gene and CN-AML has not been reported. METHODS: By integrating the Cancer Genome Atlas (TCGA) database 75 patients with CN-AML and 240 Gene Expression Omnibus (GEO) database CN-AML samples, we examined the association between RASGEF1A\u2019s RNA expression level and DNA methylation of and AML patients\u2019 prognosis. Then, we investigated the RASGEF1A RNA expression and DNA methylation\u2019s prognostic value in 77 patients with AML after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) as well as 101 AML patients after chemotherapy respectively. We investigated the association between sensitivity to Crenolanib and expression level of RASGED1A in patients by integrating 191 CN-AML patients from BeatAML dadataset. We integrated the expression and methylation of RASGEF1A to predict the CN-AML patients\u2019 prognosis and investigated the relationship between prognostic of AML patients with different risk classification and expression levels or methylation levels of RASGEF1A. RESULTS: We found that RASGEF1A gene high expression group predicted poorer event-free survival (EFS) (P&lt; 0.0001) as well as overall survival (OS) (P&lt; 0.0001) in CN-AML samples, and the identical results were found in AML patients receiving chemotherapy (P&lt; 0.0001) and Allo-HSCT (P&lt; 0.0001). RASGEF1A RNA expression level is an CN-AML patients\u2019 independent prognostic factor (EFS: HR = 5.5534, 95% CI: 1.2982\u201323.756, P= 0.0208; OS: HR = 5.3615, 95% CI: 1.1014\u201326.099, P= 0.0376). The IC50 (half maximal inhibitory concentration) of Crenolanib of CN-AML samples with RASGEF1A high expression level is lower. In addition, patients with high RASGEF1A methylation level had significant favorable prognosis (EPS: P&lt; 0.0001, OS: P&lt; 0.0001). Furthermore, the integrative analysis of expression and methylation of RASGEF1A could classify CN-AML patients into subgroups with different prognosis (EFS: P= 0.034, OS: P= 0.0024). Expression levels or methylation levels of RASGEF1A help to improve risk classification of 2010 European Leukemia Net. CONCLUSION: Higher RASGEF1A RNA expression and lower DNA methylation predicts CN-AML patients\u2019 poorer prognosis. The RASGEF1A high expression level from patients with CN-AML have better sensitivity to Crenolanib. The integrative analysis of RASGEF1A RNA expression and DNA methylation can provide a more accurate classification for prognosis. Lower RASGEF1A expression is a favorable prognostic factor for AML patients receiving chemotherapy or Allo-HSCT. 2010 European Leukemia Net\u2019s risk classification can be improved by RASGEF1A expression levels or methylation levels.<\/jats:p>","DOI":"10.3233\/cbm-210407","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T11:38:09Z","timestamp":1668512289000},"page":"103-116","source":"Crossref","is-referenced-by-count":1,"title":["The prognostic value of RASGEF1A RNA expression and DNA methylation in cytogenetically normal acute myeloid leukemia"],"prefix":"10.1177","volume":"36","author":[{"given":"Xue","family":"He","sequence":"first","affiliation":[{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"Department of Pathology, Capital Medical University, Beijing, China"},{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China"},{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China"},{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoni","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"Department of Pathology, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"Department of Pathology, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"Department of Pathology, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehong","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"Department of Pathology, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjian","family":"Yan","sequence":"additional","affiliation":[{"name":"Gannan Medical University, Ganzhou, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhao","sequence":"additional","affiliation":[{"name":"General Practice Medicine, The First People\u2019s Hospital of Huzhou, Huzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Zeng","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/CBM-210407_ref1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/gcc.22833","article-title":"Characterization of renal cell carcinoma-associated constitutional chromosome abnormalities by genome sequencing","volume":"59","author":"Smith","year":"2020","journal-title":"Genes, Chromosomes & Cancer"},{"key":"10.3233\/CBM-210407_ref2","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1101\/gr.264473.120","article-title":"Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease","volume":"30","author":"Fu","year":"2020","journal-title":"Genome Research"},{"key":"10.3233\/CBM-210407_ref3","doi-asserted-by":"crossref","first-page":"926","DOI":"10.6004\/jnccn.2017.0116","article-title":"Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology","volume":"15","author":"O\u2019Donnell","year":"2017","journal-title":"Journal of the National Comprehensive Cancer Network: JNCCN"},{"key":"10.3233\/CBM-210407_ref4","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1200\/JCO.2010.30.1820","article-title":"Therapeutic advances in acute myeloid leukemia","volume":"29","author":"Burnett","year":"2011","journal-title":"Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology"},{"key":"10.3233\/CBM-210407_ref5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.clml.2014.08.006","article-title":"Progress in acute myeloid leukemia","volume":"15","author":"Kadia","year":"2015","journal-title":"Clinical Lymphoma, Myeloma & Leukemia"},{"key":"10.3233\/CBM-210407_ref6","doi-asserted-by":"crossref","first-page":"e303","DOI":"10.1016\/j.clml.2018.05.003","article-title":"Effectiveness and Safety of Therapeutic Regimens for Elderly Patients With Acute Myeloid Leukemia: A Systematic Literature Review","volume":"18","author":"Bell","year":"2018","journal-title":"Clinical Lymphoma, Myeloma & Leukemia"},{"key":"10.3233\/CBM-210407_ref7","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1002\/ajh.23834","article-title":"Acute myeloid leukemia: 2014 update on risk-stratification and management","volume":"89","author":"Estey","year":"2014","journal-title":"American Journal of Hematology"},{"key":"10.3233\/CBM-210407_ref8","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1182\/blood.V98.5.1302","article-title":"Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial","volume":"98","author":"Goldstone","year":"2001","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref9","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1111\/j.1365-2141.2009.07663.x","article-title":"Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials","volume":"145","author":"Wheatley","year":"2009","journal-title":"British Journal of Haematology"},{"key":"10.3233\/CBM-210407_ref10","doi-asserted-by":"crossref","first-page":"4325","DOI":"10.1182\/blood-2002-03-0772","article-title":"Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)","volume":"100","author":"Byrd","year":"2002","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref11","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1182\/blood.V92.7.2322","article-title":"The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children\u2019s Leukaemia Working Parties","volume":"92","author":"Grimwade","year":"1998","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref12","doi-asserted-by":"crossref","DOI":"10.1177\/15330338211052152","article-title":"Higher Expression of WT1 With Lower CD58 Expression may be Biomarkers for Risk Stratification of Patients With Cytogenetically Normal Acute Myeloid Leukemia","volume":"20","author":"Chen","year":"2021","journal-title":"Technology in Cancer Research & Treatment"},{"key":"10.3233\/CBM-210407_ref13","doi-asserted-by":"crossref","first-page":"5593","DOI":"10.1182\/blood-2011-03-343988","article-title":"Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia","volume":"118","author":"Shen","year":"2011","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref14","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1182\/blood-2009-03-209262","article-title":"The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes","volume":"114","author":"Vardiman","year":"2009","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref15","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1182\/blood-2006-06-001149","article-title":"Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification?","volume":"109","author":"Mrozek","year":"2007","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.3324\/haematol.2016.151910","article-title":"CEBPA-double-mutated acute myeloid leukemia displays a unique phenotypic profile: a reliable screening method and insight into biological features","volume":"102","author":"Mannelli","year":"2017","journal-title":"Haematologica"},{"key":"10.3233\/CBM-210407_ref17","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/ajh.24648","article-title":"Diagnostic work-up of acute myeloid leukemia","volume":"92","author":"Weinberg","year":"2017","journal-title":"American Journal of Hematology"},{"key":"10.3233\/CBM-210407_ref18","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1182\/blood-2016-01-693879","article-title":"Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia","volume":"128","author":"Metzeler","year":"2016","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref19","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13045-014-0074-4","article-title":"Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations","volume":"7","author":"Loghavi","year":"2014","journal-title":"Journal of Hematology & Oncology"},{"key":"10.3233\/CBM-210407_ref20","first-page":"773","article-title":"14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia","volume":"138","author":"Di Giacomo","year":"2021","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology"},{"key":"10.3233\/CBM-210407_ref22","doi-asserted-by":"crossref","first-page":"8503","DOI":"10.1093\/nar\/gkt652","article-title":"Integrative analysis of tissue-specific methylation and alternative splicing identifies conserved transcription factor binding motifs","volume":"41","author":"Wan","year":"2013","journal-title":"Nucleic Acids Research"},{"key":"10.3233\/CBM-210407_ref23","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1038\/onc.2011.354","article-title":"DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer","volume":"31","author":"Lopez-Serra","year":"2012","journal-title":"Oncogene"},{"key":"10.3233\/CBM-210407_ref24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2217\/epi.09.33","article-title":"DNA hypomethylation in cancer cells","volume":"1","author":"Ehrlich","year":"2009","journal-title":"Epigenomics"},{"key":"10.3233\/CBM-210407_ref25","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1038\/leu.2012.346","article-title":"GADD45A methylation predicts poor overall survival in acute myeloid leukemia and is associated with IDH1\/2 and DNMT3A mutations","volume":"27","author":"Perugini","year":"2013","journal-title":"Leukemia"},{"key":"10.3233\/CBM-210407_ref26","first-page":"469","article-title":"Level of HOXA5 hypermethylation in acute myeloid leukemia is associated with short-term outcome","volume":"30","author":"Kim","year":"2010","journal-title":"The Korean Journal of Laboratory Medicine"},{"key":"10.3233\/CBM-210407_ref27","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/mc.22794","article-title":"Decreased SCIN expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia","volume":"57","author":"Zhang","year":"2018","journal-title":"Molecular Carcinogenesis"},{"key":"10.3233\/CBM-210407_ref28","doi-asserted-by":"crossref","first-page":"4607","DOI":"10.1111\/j.1742-4658.2009.07166.x","article-title":"RasGEF1A and RasGEF1B are guanine nucleotide exchange factors that discriminate between Rap GTP-binding proteins and mediate Rap2-specific nucleotide exchange","volume":"276","author":"Yaman","year":"2009","journal-title":"The FEBS Journal"},{"key":"10.3233\/CBM-210407_ref29","doi-asserted-by":"crossref","first-page":"6623","DOI":"10.1038\/s41598-017-06162-7","article-title":"Rap2a serves as a potential prognostic indicator of renal cell carcinoma and promotes its migration and invasion through up-regulating p-Akt","volume":"7","author":"Wu","year":"2017","journal-title":"Scientific Reports"},{"key":"10.3233\/CBM-210407_ref30","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.cellsig.2015.02.026","article-title":"Rap2a is a novel target gene of p53 and regulates cancer cell migration and invasion","volume":"27","author":"Wu","year":"2015","journal-title":"Cellular Signalling"},{"key":"10.3233\/CBM-210407_ref31","first-page":"912","article-title":"The prognostic impact of RAP2A expression in patients with early and locoregionally advanced nasopharyngeal carcinoma in an endemic area","volume":"7","author":"Lee","year":"2015","journal-title":"American Journal of Translational Research"},{"key":"10.3233\/CBM-210407_ref32","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/cbin.10213","article-title":"Over-expression of Rap2a inhibits glioma migration and invasion by down-regulating p-AKT","volume":"38","author":"Wang","year":"2014","journal-title":"Cell Biology International"},{"key":"10.3233\/CBM-210407_ref33","first-page":"350","article-title":"Knockdown of RAP2A gene expression suppresses cisplatin resistance in gastric cancer cells","volume":"19","author":"Zhang","year":"2020","journal-title":"Oncology Letters"},{"key":"10.3233\/CBM-210407_ref34","first-page":"9541","article-title":"Abnormal expression of Rap2A as a prognostic marker for human breast cancer","volume":"24","author":"Liu","year":"2020","journal-title":"European Review for Medical and Pharmacological Sciences"},{"key":"10.3233\/CBM-210407_ref35","doi-asserted-by":"crossref","first-page":"6611","DOI":"10.1158\/1078-0432.CCR-06-0783","article-title":"Enhanced RASGEF1A expression is involved in the growth and migration of intrahepatic cholangiocarcinoma","volume":"12","author":"Ura","year":"2006","journal-title":"Clinical Cancer Research: An Official Journal of the American Association for Cancer Research"},{"key":"10.3233\/CBM-210407_ref36","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Molecular & Cellular Proteomics: MCP"},{"key":"10.3233\/CBM-210407_ref37","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"The New England Journal of Medicine"},{"key":"10.3233\/CBM-210407_ref38","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1182\/blood-2008-02-134411","article-title":"An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia","volume":"112","author":"Metzeler","year":"2008","journal-title":"Blood"},{"key":"10.3233\/CBM-210407_ref39","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41586-018-0623-z","article-title":"Functional genomic landscape of acute myeloid leukaemia","volume":"562","author":"Tyner","year":"2018","journal-title":"Nature"},{"key":"10.3233\/CBM-210407_ref40","doi-asserted-by":"crossref","first-page":"23301","DOI":"10.1038\/s41598-021-02767-1","article-title":"TERT genetic variability and telomere length as factors affecting survival and risk in acute myeloid leukaemia","volume":"11","author":"Dratwa","year":"2021","journal-title":"Scientific Reports"},{"key":"10.3233\/CBM-210407_ref41","doi-asserted-by":"crossref","first-page":"873","DOI":"10.4161\/epi.28571","article-title":"A novel approach to the discovery of survival biomarkers in glioblastoma using a joint analysis of DNA methylation and gene expression","volume":"9","author":"Smith","year":"2014","journal-title":"Epigenetics"},{"key":"10.3233\/CBM-210407_ref42","doi-asserted-by":"crossref","first-page":"R119","DOI":"10.1186\/bcr3588","article-title":"Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties","volume":"15","author":"Lin","year":"2013","journal-title":"Breast Cancer Research: BCR"},{"key":"10.3233\/CBM-210407_ref43","doi-asserted-by":"crossref","first-page":"80664","DOI":"10.18632\/oncotarget.13025","article-title":"Integrative analysis of DNA copy number, DNA methylation and gene expression in multiple myeloma reveals alterations related to relapse","volume":"7","author":"Krzeminski","year":"2016","journal-title":"Oncotarget"},{"key":"10.3233\/CBM-210407_ref44","doi-asserted-by":"crossref","first-page":"r137","DOI":"10.1186\/gb-2013-14-12-r137","article-title":"Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas","volume":"14","author":"Renner","year":"2013","journal-title":"Genome Biology"}],"container-title":["Cancer Biomarkers"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/CBM-210407","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:08:54Z","timestamp":1777385334000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/CBM-210407"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":44,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.3233\/cbm-210407","relation":{},"ISSN":["1875-8592","1574-0153"],"issn-type":[{"value":"1875-8592","type":"electronic"},{"value":"1574-0153","type":"print"}],"subject":[],"published":{"date-parts":[[2023,2,16]]}}}