{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:07:47Z","timestamp":1785146867664,"version":"3.55.0"},"reference-count":60,"publisher":"Georg Thieme Verlag KG","issue":"01\/02","funder":[{"DOI":"10.13039\/501100005672","name":"Funda\u00e7\u00e3o de Apoio ao Desenvolvimento do Ensino, Ci\u00eancia e Tecnologia do Estado de Mato Grosso do Sul","doi-asserted-by":"crossref","award":["23\/200.540\/2013"],"award-info":[{"award-number":["23\/200.540\/2013"]}],"id":[{"id":"10.13039\/501100005672","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"crossref","award":["E-26\/110.032\/2011"],"award-info":[{"award-number":["E-26\/110.032\/2011"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["PROEPFAR II Proc 440018\/2022-6"],"award-info":[{"award-number":["PROEPFAR II Proc 440018\/2022-6"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Planta Med"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic myeloid leukemia (CML) is a myeloproliferative disease, characterized by the presence of the oncogene BCR-ABL. Imatinib mesylate (IMA) is the first-line treatment for CML, and some treatment resistance has been reported. Natural products are rich sources of bioactive compounds with biological effects, opening a possibility to alter cell susceptibility to drugs such as imatinib. Herein, we evaluated the interference of betulinic acid and ursolic acid in glycoprotein P (P-gp) activity and the possible synergistic effect when associated with IMA by the Chou-Talalay method. Ursolic acid presented an IC50 of 14.0\u2009\u00b5M and 19.6\u2009\u00b5M for K562 and Lucena 1, respectively, whilst betulinic acid presented an IC50 of 8.6\u2009\u00b5M and 12.5\u2009\u00b5M for these cell lines. Evaluation of the combination of terpenoids and imatinib mesylate revealed that ursolic acid or betulinic acid acts in synergism with IMA, as indicated by the combination indexes (CI&lt;1). Analysis of\n          annexin V labeling demonstrated that a combination of IMA with betulinic acid enhances the inhibition on cell proliferation via the apoptosis pathway, with caspases 3\/7 activation after 24 hours of treatment and inhibition of the STAT5\/survivin pathway, decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant leukemia cell line is a promising strategy for CML treatment.<\/jats:p>","DOI":"10.1055\/a-2440-4847","type":"journal-article","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T22:30:17Z","timestamp":1728772217000},"page":"19-28","source":"Crossref","is-referenced-by-count":2,"title":["Betulinic Acid Acts in Synergism with Imatinib Mesylate, Triggering Apoptosis in MDR Leukemia Cells"],"prefix":"10.1055","volume":"91","author":[{"given":"Claudia","family":"Stutz","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Eus\u00e9bio, CE, Brasil"},{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Campo Grande, MS, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula Greg\u00f3rio Alves","family":"Font\u00e3o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Molecular, Instituto de Tecnologia em F\u00e1rmacos; Fiocruz, Rio de Janeiro, RJ, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Werneck de Souza e","family":"Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Molecular, Instituto de Tecnologia em F\u00e1rmacos; Fiocruz, Rio de Janeiro, RJ, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Noboru","family":"Seito","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Aplicada, Instituto de Tecnologia em F\u00e1rmacos; Fiocruz, Rio de Janeiro, RJ, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2747-7039","authenticated-orcid":false,"given":"Renata Trentin","family":"Perdomo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Molecular e Culturas Celulares, Faculdade de Ci\u00eancias Farmac\u00eauticas, Alimentos e Nutri\u00e7\u00e3o; UFMS, Campo Grande, MS, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5596-6174","authenticated-orcid":false,"given":"Andr\u00e9 Luiz Franco","family":"Sampaio","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Molecular, Instituto de Tecnologia em F\u00e1rmacos; Fiocruz, Rio de Janeiro, RJ, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1111\/jcmm.13436","article-title":"Combination of arsenic trioxide and Dasatinib: A new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia","volume":"22","author":"T Wang","year":"2018","journal-title":"J Cell Mol Med"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40880-016-0108-0","article-title":"The Philadelphia chromosome in leukemogenesis","volume":"35","author":"Z J Kang","year":"2016","journal-title":"Chin J Cancer"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2015.07.010","article-title":"A historical overview of protein kinases and their targeted small molecule inhibitors","volume":"100","author":"R J Roskoski","year":"2015","journal-title":"Pharmacol Res"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1182\/blood.V110.11.463.463","article-title":"DCC-2036: A novel switch pocket inhibitor of ABL tyrosine kinase with therapeutic efficacy against BCR-ABL T315I in vitro and in a CML mouse model","volume":"110","author":"R A Van Etten","year":"2007","journal-title":"Blood"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.3892\/or.2013.2293","article-title":"Identification of plant extracts sensitizing breast cancer cells to TRAIL","volume":"29","author":"S Abdelhamed","year":"2013","journal-title":"Oncol Rep"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0254-6272(14)60062-5","article-title":"Research progress on synergistic anti-tumor mechanisms of compounds in traditional Chinese medicine","volume":"34","author":"J Zhou","year":"2014","journal-title":"J Tradit Chin Med"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.7314\/APJCP.2015.16.7.2939","article-title":"Aloe vera inhibits proliferation of human breast and cervical cancer cells and acts synergistically with cisplatin","volume":"16","author":"A Hussain","year":"2015","journal-title":"Asian Pac J Cancer Prev"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"T C Chou","year":"2010","journal-title":"Cancer Res"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.addr.2015.10.022","article-title":"Recent advances of cocktail chemotherapy by combination drug delivery systems","volume":"98","author":"Q Hu","year":"2016","journal-title":"Adv Drug Deliv Rev"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4236\/pp.2012.32018","article-title":"Biological activity of betulinic acid: A review","volume":"3","author":"M G Moghaddam","year":"2012","journal-title":"Pharm Pharmacol"},{"key":"ref11","first-page":"401","article-title":"Phytotoxic terpenes produced by phytopathogenic fungi and allelopathic plants","volume":"9","author":"A Cimmino","year":"2014","journal-title":"Nat Prod Commun"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/bcpt.12221","article-title":"Structure\u2013activity relationship of terpenes with anti-inflammatory profile \u2013 A systematic review","volume":"115","author":"M T Souza","year":"2014","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"14","DOI":"10.4103\/0973-1482.139746","article-title":"Review on anti-tumor effect of triterpene acid compounds","volume":"10","author":"W Zhang","year":"2014","journal-title":"J Cancer Res Ther"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"3502","DOI":"10.2174\/0929867322666150821101047","article-title":"Sesterterpenoids with anticancer activity","volume":"22","author":"A Evidente","year":"2015","journal-title":"Curr Med Chem"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"616","DOI":"10.3109\/14756366.2010.546793","article-title":"Clinically useful anticancer, antitumor, and antiwrinkle agent, ursolic acid and related derivatives as medicinally important natural product","volume":"26","author":"N Sultana","year":"2011","journal-title":"J Enzyme Inhib Med Chem"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"20614","DOI":"10.3390\/molecules201119721","article-title":"Ursolic acid\u2013A pentacyclic triterpenoid with a wide spectrum of pharmacological activities","volume":"20","author":"\u0141 Wo\u017aniak","year":"2015","journal-title":"Molecules"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/med.10053","article-title":"Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection","volume":"24","author":"R H Cichewicz","year":"2004","journal-title":"Med Res Rev"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1002\/med.21353","article-title":"Betulinic acid and its derivatives as potential antitumor agents","volume":"35","author":"D M Zhang","year":"2015","journal-title":"Med Res Rev"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1111\/cbdd.12682","article-title":"Betulinic acid: Recent advances in chemical modifications, effective delivery, and molecular mechanisms of a promising anticancer therapy","volume":"87","author":"M Ali-Seyed","year":"2016","journal-title":"Chem Biol Drug Des"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"5920","DOI":"10.3390\/ijms21165920","article-title":"Ursolic acid-based derivatives as potential anti-cancer agents: An update","volume":"21","author":"V Khwaza","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/j.biopha.2016.10.018","article-title":"Multiple molecular targets in breast cancer therapy by betulinic acid","volume":"84","author":"R Luo","year":"2016","journal-title":"Biomed Pharmacother"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s11655-011-0815-y","article-title":"Proliferation-inhibiting and apoptosis-inducing effects of ursolic acid and oleanolic acid on multi-drug resistance cancer cells in vitro","volume":"17","author":"J Z Shan","year":"2011","journal-title":"Chin J Integr Med"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/CMR.0000000000000137","article-title":"Ursolic acid and resveratrol synergize with chloroquine to reduce melanoma cell viability","volume":"25","author":"J J Junco","year":"2015","journal-title":"Melanoma Res"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s13238-016-0295-0","article-title":"Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer","volume":"7","author":"J Shan","year":"2016","journal-title":"Protein Cell"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"e23206","DOI":"10.1002\/jbt.23206","article-title":"Betulinic acid: A natural promising anticancer drug, current situation, and future perspectives","volume":"36","author":"M Aswathy","year":"2022","journal-title":"J Biochem Mol Toxicol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1593\/neo.04442","article-title":"Sensitization for anticancer drug-induced apoptosis by betulinic Acid","volume":"7","author":"S Fulda","year":"2005","journal-title":"Neoplasia"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.toxlet.2004.06.015","article-title":"Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl","volume":"155","author":"D V Raghuvar Gopal","year":"2005","journal-title":"Toxicol Lett"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nrc3599","article-title":"Cancer drug resistance: An evolving paradigm","volume":"13","author":"C Holohan","year":"2013","journal-title":"Nat Rev Cancer"},{"key":"ref29","first-page":"2738","article-title":"A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia","volume":"141","author":"V Krishnan","year":"2023","journal-title":"Blood"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"7715","DOI":"10.3390\/ijms23147715","article-title":"Ketoconazole reverses imatinib resistance in human chronic myelogenous leukemia K562 cells","volume":"23","author":"O Prado-Carrillo","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"jcs223826","DOI":"10.1242\/jcs.223826","article-title":"Survivin at a glance","volume":"132","author":"S P Wheatley","year":"2019","journal-title":"J Cell Sci"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1002\/ptr.5347","article-title":"Korean red ginseng extract enhances the anticancer effects of imatinib mesylate through abrogation p\u200a38 and STAT5 activation in KBM-5 cells","volume":"29","author":"S Y Jung","year":"2015","journal-title":"Phytother Res"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1002\/ptr.5272","article-title":"The hydrolysed products of iridoid glycosides can enhance imatinib mesylate-induced apoptosis in human myeloid leukaemia cells","volume":"29","author":"M B Kim","year":"2015","journal-title":"Phytother Res"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2015.07.010","article-title":"A historical overview of protein kinases and their targeted small molecule inhibitors","volume":"100","author":"R J Roskoski","year":"2015","journal-title":"Pharmacol Res"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.phrs.2015.10.021","article-title":"Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes","volume":"103","author":"R J Roskoski","year":"2016","journal-title":"Pharmacol Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"90","DOI":"10.3389\/fonc.2018.00090","article-title":"Metabolic reprogramming during multidrug resistance in leukemias","volume":"8","author":"R S Vidal","year":"2018","journal-title":"Front Oncol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11010-013-1761-0","article-title":"Characterization of a multidrug-resistant chronic myeloid leukemia cell line presenting multiple resistance mechanisms","volume":"383","author":"N Daflon-Yunes","year":"2013","journal-title":"Mol Cell Biochem"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"e00081","DOI":"10.1042\/BSR20130067","article-title":"Multidrug resistance in chronic myeloid leukaemia: How much can we learn from MDR-CML cell lines?","volume":"33","author":"V M Rumjanek","year":"2013","journal-title":"Biosci Rep"},{"key":"ref39","first-page":"5773","article-title":"Natural products that target cancer stem cells","volume":"35","author":"J Moselhy","year":"2015","journal-title":"Anticancer Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.3390\/ijms19061578","article-title":"Natural products for drug discovery in the 21st century: Innovations for novel drug discovery","volume":"19","author":"N E Thomford","year":"2018","journal-title":"Int J Mol Sci"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.drudis.2018.01.021","article-title":"Administration of antioxidants in cancer: Debate of the decade","volume":"23","author":"R K Khurana","year":"2018","journal-title":"Drug Discov Today"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1517\/13543784.2012.727395","article-title":"Terpenoids: natural products for cancer therapy","volume":"21","author":"M Huang","year":"2012","journal-title":"Expert Opin Investig Drugs"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/ijc.25044","article-title":"Enhancement of chemotherapeutic agent-induced apoptosis by inhibition of NF-kappaB using ursolic acid","volume":"127","author":"Y Li","year":"2010","journal-title":"Int J Cancer"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1158\/1541-7786.MCR-13-0237","article-title":"Resveratrol and P-glycoprotein inhibitors enhance the anti-skin cancer effects of ursolic acid","volume":"11","author":"J J Junco","year":"2013","journal-title":"Mol Cancer Res"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"33358","DOI":"10.1038\/srep33358","article-title":"Ursolic acid-mediated apoptosis of K562 cells involves Stat5\/Akt pathway inhibition through the induction of Gfi-1","volume":"6","author":"Z Lin","year":"2016","journal-title":"Sci Rep"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/mc.20638","article-title":"Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells","volume":"49","author":"Y Li","year":"2010","journal-title":"Mol Carcinog"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/sj.leu.2403406","article-title":"Betulinic acid-induced apoptosis in leukemia cells","volume":"18","author":"H Ehrhardt","year":"2004","journal-title":"Leukemia"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s11596-010-0448-y","article-title":"Antitumor effect of betulinic acid on human acute leukemia K562 cells in vitro","volume":"30","author":"Q Wu","year":"2010","journal-title":"J Huazhong Univ Sci Technolog Med Sci"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"T C Chou","year":"2010","journal-title":"Cancer Res"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"T C Chou","year":"2006","journal-title":"Pharmacol Rev"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.drudis.2009.05.015","article-title":"Targeting mitochondrial apoptosis by betulinic acid in human cancers","volume":"14","author":"S Fulda","year":"2009","journal-title":"Drug Discov Today"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/nm1095-1046","article-title":"Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis","volume":"1","author":"E Pisha","year":"1995","journal-title":"Nat Med"},{"key":"ref53","first-page":"4956","article-title":"Betulinic acid triggers CD95 (APO-1\/Fas)- and p\u200a53-independent apoptosis via activation of caspases in neuroectodermal tumors","volume":"57","author":"S Fulda","year":"1997","journal-title":"Cancer Res"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1055\/s-2008-1043808","article-title":"Betulinic acid: A new chemotherapeutic agent in the treatment of neuroectodermal tumors","volume":"211","author":"S Fulda","year":"1999","journal-title":"Klin Padiatr"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"100671","DOI":"10.1016\/j.blre.2020.100671","article-title":"Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications","volume":"43","author":"P S Bernardo","year":"2020","journal-title":"Blood Rev"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1532\/IJH97.A10408","article-title":"Survivin and leukemia","volume":"80","author":"X L Cong","year":"2004","journal-title":"Int J Hematol"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0304-3835(96)04309-1","article-title":"Heparin reverses Rhodamine 123 extrusion by multidrug resistant cells","volume":"106","author":"R C Maia","year":"1996","journal-title":"Cancer Lett"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1590\/S0001-37652001000100007","article-title":"Multidrug resistance in tumour cells: characterization of the multidrug resistant cell line K562-Lucena 1","volume":"73","author":"V M Rumjanek","year":"2001","journal-title":"An Acad Bras Cienc"},{"key":"ref59","first-page":"2993","article-title":"Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells","volume":"29","author":"R B Badisa","year":"2009","journal-title":"Anticancer Res"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1021\/bc5002196","article-title":"Synthesis and characterization of macromolecular rhodamine tethers and their interactions with P-glycoprotein","volume":"25","author":"L Crawford","year":"2014","journal-title":"Bioconjug Chem"}],"container-title":["Planta Medica"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2440-4847.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T23:31:15Z","timestamp":1736379075000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2440-4847"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,12]]},"references-count":60,"journal-issue":{"issue":"01\/02","published-online":{"date-parts":[[2025,1,8]]},"published-print":{"date-parts":[[2025,1]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2440-4847","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0032-0943","1439-0221"],"issn-type":[{"value":"0032-0943","type":"print"},{"value":"1439-0221","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,10,12]]},"published":{"date-parts":[[2024,10,12]]}}}