{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:44:44Z","timestamp":1785199484536,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bulgarian National Science Fund","award":["DN 11\/16\/18 December 2017"],"award-info":[{"award-number":["DN 11\/16\/18 December 2017"]}]},{"name":"Bulgarian National Science Fund","award":["D01-217\/30 November 2018"],"award-info":[{"award-number":["D01-217\/30 November 2018"]}]},{"name":"Ministry of Education and Science of the Republic of Bulgaria","award":["DN 11\/16\/18 December 2017"],"award-info":[{"award-number":["DN 11\/16\/18 December 2017"]}]},{"name":"Ministry of Education and Science of the Republic of Bulgaria","award":["D01-217\/30 November 2018"],"award-info":[{"award-number":["D01-217\/30 November 2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>The successful design of antitumour drugs often combines in one molecule different biologically active subunits that can affect various regulatory pathways in the cell and thus achieve higher efficacy. Two ferrocene derivatives, DK-164 and CC-78, with different residues were tested for cytotoxic potential on non-small lung cancer cell lines, A549 and H1299, and non-cancerous MRC5. DK-164 demonstrated remarkable selectivity toward cancer cells and more pronounced cytotoxicity against A549. The cytotoxicity of CC-78 toward H1299 was even higher than that of the well-established anticancer drugs cisplatin and tamoxifen, but it did not reveal any noticeable selective effect. DK-164 showed predominantly pro-apoptotic activity in non-small cell lung carcinoma (NSCLC) cells, while CC-78 caused accidental cell death with features characteristic of necrosis. The level of induced autophagy was similar for both substances in cancer cells. DK-164 treatment of A549, H1299, and MRC5 cells for 48 h significantly increased the fluorescence signal of the NFkB (nuclear factor \u2018kappa-light-chain-enhancer\u2019 of activated B-cells) protein in the nucleus in all three cell lines, while CC-78 did not provoke NFkB translocation in any of the tested cell lines. Both compounds caused a significant transfer of the p53 protein in the nucleus of A549 cells but not in non-cancerous MRC5 cells. In A549, DK-164 generated oxidative stress close to the positive control after 48 h, while CC-78 had a moderate effect on the cellular redox status. In the non-cancerous cells, MRC5, both compounds produced ROS similar to the positive control for the same incubation period. The different results related to the cytotoxic potential of DK-164 and CC-78 associated with the examined cellular mechanisms induced in lung cancer cells might be used to conclude the specific functions of the various functional groups in the ferrocene compounds, which can offer new perspectives for the design of antitumour drugs.<\/jats:p>","DOI":"10.3390\/biomedicines10061353","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T10:49:14Z","timestamp":1654771754000},"page":"1353","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In Vitro Anticancer Activity of Two Ferrocene-Containing Camphor Sulfonamides as Promising Agents against Lung Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9528-6248","authenticated-orcid":false,"given":"Maria","family":"Schr\u00f6der","sequence":"first","affiliation":[{"name":"Institute of Molecular Biology \u201cAkad. Roumen Tsanev\u201d, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 21, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0766-3934","authenticated-orcid":false,"given":"Maria","family":"Petrova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology \u201cAkad. Roumen Tsanev\u201d, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 21, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zlatina","family":"Vlahova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology \u201cAkad. Roumen Tsanev\u201d, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 21, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0437-2162","authenticated-orcid":false,"given":"Georgi M.","family":"Dobrikov","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 9, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivaylo","family":"Slavchev","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 9, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evdokia","family":"Pasheva","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology \u201cAkad. Roumen Tsanev\u201d, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 21, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0116-0079","authenticated-orcid":false,"given":"Iva","family":"Ugrinova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology \u201cAkad. Roumen Tsanev\u201d, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 21, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Verband Forschender Arzneimittelherstellere e.V. (2020). Neue Chancen f\u00fcr Krebspatienten. Perspektive 2023. Neue Medikamente in Entwicklung, Verband Forschender Arzneimittelhersteller e.V.","DOI":"10.24945\/MVF.04.23.1866-0533.2530"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8743","DOI":"10.1002\/anie.201004437","article-title":"Combining Independent Drug Classes into Superior, Synergistically Acting Hybrid Molecules","volume":"49","author":"Andreyeva","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"961","DOI":"10.3332\/ecancer.2019.961","article-title":"Innovative approaches for cancer treatment: Current perspectives and new challenges","volume":"13","author":"Pucci","year":"2019","journal-title":"Ecancermedicalscience"},{"key":"ref_4","first-page":"1","article-title":"Cisplatin and Oxaliplatin: Our Current Understanding of Their Actions","volume":"18","author":"Riddell","year":"2018","journal-title":"Metal. Ions Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/1476-4598-9-147","article-title":"The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin","volume":"9","author":"Kvardova","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1039\/B707077M","article-title":"Bioorganometallic chemistry\u2014from teaching paradigms to medicinal applications","volume":"38","author":"Hartinger","year":"2009","journal-title":"Chem. Soc. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.cbpa.2012.01.013","article-title":"The potential of organometallic complexes in medicinal chemistry","volume":"16","author":"Gasser","year":"2012","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.2174\/0929867003374066","article-title":"Antitumour Metallocenes: Structure-Activity Studies and Interactions with Biomolecules","volume":"7","author":"Harding","year":"2001","journal-title":"Curr. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/1681039b0","article-title":"A New Type of Organo-Iron Compound","volume":"168","author":"Kealy","year":"1951","journal-title":"Nature"},{"key":"ref_10","first-page":"S479","article-title":"Molecular biology of lung cancer","volume":"5","author":"Cooper","year":"2013","journal-title":"J. Thorac. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Shaw","year":"2018","journal-title":"Nat. Reviews. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.2174\/1871520619666190724094334","article-title":"The Effect of a Ferrocene Containing Camphor Sulfonamide DK-164 on Breast Cancer Cell Lines","volume":"19","author":"Petrova","year":"2019","journal-title":"Anti Cancer Agents Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9103","DOI":"10.1039\/C7NJ00619E","article-title":"Synthesis of ferrocenylmethylidene and arylidene substituted camphane based compounds as potential anticancer agents","volume":"41","author":"Pasheva","year":"2017","journal-title":"New J. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.biopha.2018.05.007","article-title":"Autophagy in health and disease: A comprehensive review","volume":"104","author":"Saha","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yun, C.W., Jeon, J., Go, G., Lee, J.H., and Lee, S.H. (2020). The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010179"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.coph.2011.03.009","article-title":"The dual role of autophagy in cancer","volume":"11","author":"Eskelinen","year":"2011","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nature14587","article-title":"Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism","volume":"524","author":"Perera","year":"2015","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pfeffer, C.M., and Singh, A.T.K. (2018). Apoptosis: A Target for Anticancer Therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020448"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1038\/onc.2010.566","article-title":"NF-\u03baB addiction and its role in cancer: \u2018one size does not fit all\u2019","volume":"30","author":"Chaturvedi","year":"2011","journal-title":"Oncogene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s12276-020-0384-2","article-title":"ROS in cancer therapy: The bright side of the moon","volume":"52","author":"Perillo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e3128","DOI":"10.21769\/BioProtoc.3128","article-title":"Analysis of the Mitochondrial Membrane Potential Using the Cationic JC-1 Dye as a Sensitive Fluorescent Probe","volume":"9","author":"Sivandzade","year":"2019","journal-title":"Bio Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1016\/j.bmc.2017.05.029","article-title":"Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases","volume":"25","author":"Akdemir","year":"2017","journal-title":"Bioorganic Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s10555-019-09799-0","article-title":"The role of carbonic anhydrase IX in cancer development: Links to hypoxia, acidosis, and beyond","volume":"38","author":"Pastorekova","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1016\/j.jinorgbio.2008.07.014","article-title":"Evaluation of cytotoxic properties of organometallic ferrocifens on melanocytes, primary and metastatic melanoma cell lines","volume":"102","author":"Michard","year":"2008","journal-title":"J. Inorg. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1002\/cmdc.201402016","article-title":"Quantitative analyses of ROS and RNS production in breast cancer cell lines incubated with ferrocifens","volume":"9","author":"Lu","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8802","DOI":"10.1039\/C5CS00486A","article-title":"Ferrocifen type anti cancer drugs","volume":"44","author":"Jaouen","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jinorgbio.2009.12.020","article-title":"A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines","volume":"104","author":"Corbet","year":"2010","journal-title":"J. Inorg. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jinorgbio.2014.08.015","article-title":"Ferrocifen derivatives that induce senescence in cancer cells: Selected examples","volume":"141","author":"Mathieu","year":"2014","journal-title":"J. Inorg. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1002\/cmdc.201402219","article-title":"Molecular mechanism of action of 2-ferrocenyl-1,1-diphenylbut-1-ene on HL-60 leukemia cells","volume":"9","author":"Rocha","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1038\/onc.2011.168","article-title":"Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study","volume":"30","author":"Shen","year":"2011","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejps.2019.04.011","article-title":"Autophagy as a molecular target for cancer treatment","volume":"134","author":"Kocaturk","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/s41388-017-0046-6","article-title":"Dual role of autophagy in hallmarks of cancer","volume":"37","author":"Singh","year":"2018","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/cdd.2014.137","article-title":"Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015","volume":"22","author":"Galluzzi","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/sj.cdd.4401359","article-title":"Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells","volume":"11","author":"Kanzawa","year":"2004","journal-title":"Cell Death Differ."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Knizhnik, A.V., Roos, W.P., Nikolova, T., Quiros, S., Tomaszowski, K.H., Christmann, M., and Kaina, B. (2013). Survival and death strategies in glioma cells: Autophagy, senescence and apoptosis triggered by a single type of temozolomide-induced DNA damage. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055665"},{"key":"ref_37","first-page":"151","article-title":"Modulation of Autophagy by Sorafenib: Effects on Treatment Response","volume":"7","author":"Mauriz","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3892\/ol.2017.6107","article-title":"Temozolomide induces autophagy in primary and established glioblastoma cells in an EGFR independent manner","volume":"14","author":"Schneider","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1086\/BBLv193n2p228","article-title":"Effect of Gossypol on the Ultrastructure of Spisula Sperm","volume":"193","author":"Burgos","year":"1997","journal-title":"Biol. Bull."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1158\/1541-7786.MCR-09-0562","article-title":"The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma","volume":"8","author":"Voss","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/cdd.2010.74","article-title":"A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum","volume":"18","author":"Lian","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1593\/neo.05691","article-title":"(-)-gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo","volume":"8","author":"Wolter","year":"2006","journal-title":"Neoplasia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1158\/1535-7163.MCT-08-0333","article-title":"Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa","volume":"7","author":"Meng","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/cdd.2011.32","article-title":"Anti-tumoral action of cannabinoids on hepatocellular carcinoma: Role of AMPK-dependent activation of autophagy","volume":"18","author":"Vara","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1172\/JCI37948","article-title":"Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells","volume":"119","author":"Salazar","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nrc1588","article-title":"Nuclear factor-\u03baB inhibitors as sensitizers to anticancer drugs","volume":"5","author":"Nakanishi","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"25530","DOI":"10.1074\/jbc.M112.356279","article-title":"NF-\u03baB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression","volume":"287","author":"Liu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.bcp.2003.08.039","article-title":"Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues","volume":"67","author":"Ashikawa","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bcp.2014.12.007","article-title":"Transcription factor NF-\u03baB associates with microtubules and stimulates apoptosis in response to suppression of microtubule dynamics in MCF-7 cells","volume":"93","author":"Rai","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3828","DOI":"10.1046\/j.1432-1327.2000.01421.x","article-title":"The pro- or anti-apoptotic function of NF-kappaB is determined by the nature of the apoptotic stimulus","volume":"267","author":"Kaltschmidt","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.bmc.2014.12.023","article-title":"Ferrocenes as potential chemotherapeutic drugs: Synthesis, cytotoxic activity, reactive oxygen species production and micronucleus assay","volume":"23","author":"Soto","year":"2015","journal-title":"Bioorganic Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"37832","DOI":"10.1074\/jbc.M301546200","article-title":"Inhibition of mitochondrial respiration: A novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism","volume":"278","author":"Pelicano","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1158\/1535-7163.MCT-08-0298","article-title":"Elesclomol induces cancer cell apoptosis through oxidative stress","volume":"7","author":"Kirshner","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.jep.2012.07.005","article-title":"Life or death: Neuroprotective and anticancer effects of quercetin","volume":"143","author":"Dajas","year":"2012","journal-title":"J. Ethnopharmacol."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1353\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:26:05Z","timestamp":1760138765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1353"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,8]]},"references-count":54,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biomedicines10061353"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines10061353","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,8]]}}}