{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:14:14Z","timestamp":1791389654317,"version":"4.3.3"},"reference-count":50,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza University of Rome","doi-asserted-by":"publisher","award":["RP12117A764C1EB2"],"award-info":[{"award-number":["RP12117A764C1EB2"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype\u2013phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A&gt;G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype\u2013phenotype association data is needed to enable the clinical use of sequencing data.<\/jats:p>","DOI":"10.3390\/ijms232213923","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:29:32Z","timestamp":1668392972000},"page":"13923","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity: Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3852-4585","authenticated-orcid":false,"given":"Ottavia","family":"De Luca","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-1452","authenticated-orcid":false,"given":"Gerardo","family":"Salerno","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"},{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"De Bernardini","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Simona","family":"Torre","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Simmaco","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"},{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Lionetto","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8667-3094","authenticated-orcid":false,"given":"Giovanna","family":"Gentile","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"},{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7839-9125","authenticated-orcid":false,"given":"Marina","family":"Borro","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"},{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Via di Grottarossa 1035\/1039, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Meta-Analysis Group In Cancer, L\u00e9vy, E., Piedbois, P., Buyse, M., Pignon, J.P., Rougier, P., Ryan, L., Hansen, R., Zee, B., and Weinerman, B. (1998). Toxicity of fluorouracil in patients with advanced colorectal cancer: Effect of administration schedule and prognostic factors. J. Clin. Oncol., 16, 3537\u20133541.","DOI":"10.1200\/JCO.1998.16.11.3537"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1517\/14740338.2010.511610","article-title":"Safety of capecitabine: A review","volume":"9","author":"Mikhail","year":"2010","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.21037\/pcm-21-17","article-title":"A narrative review of genetic factors affecting fluoropyrimidine toxicity","volume":"4","author":"Gmeiner","year":"2021","journal-title":"Precis. Cancer Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ejca.2019.09.028","article-title":"Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France","volume":"124","author":"Ingrand","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_5","unstructured":"ClinCalc.com (2022, November 03). Evidence-Based Clinical Decision Support Tools and Calculators for Medical Professionals. Available online: https:\/\/clincalc.com\/DrugStats\/Drugs\/Fluorouracil."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1172\/JCI113308","article-title":"Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5- fluorouracil-induced toxicity","volume":"81","author":"Diasio","year":"1988","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/1097-0142(19910801)68:3<499::AID-CNCR2820680309>3.0.CO;2-F","article-title":"Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome","volume":"68","author":"Harris","year":"1991","journal-title":"Cancer"},{"key":"ref_8","first-page":"477","article-title":"Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency","volume":"2","author":"Takimoto","year":"1996","journal-title":"Clin. Cancer Res."},{"key":"ref_9","first-page":"2672","article-title":"Dihydropyrimidine dehydrogenase: Its role in 5-fluorouracil clinical toxicity and tumor resistance","volume":"5","author":"Diasio","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115027","DOI":"10.1016\/j.jpba.2022.115027","article-title":"Quantification of uracil, dihydrouracil, thymine and dihydrothymine for reliable dihydropyrimidine dehydrogenase (DPD) phenotyping critically depend on blood and plasma storage conditions","volume":"221","author":"Streng","year":"2022","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1097\/FTD.0b013e3181ae4516","article-title":"A liquid chromatography-tandem mass spectrometry method for the determination of 5-Fluorouracil degradation rate by intact peripheral blood mononuclear cells","volume":"4","author":"Lostia","year":"2009","journal-title":"Drug Monit."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100125","DOI":"10.1016\/j.esmoop.2021.100125","article-title":"Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature","volume":"6","author":"Hodroj","year":"2021","journal-title":"ESMO Open"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Laures, N., Konecki, C., Brugel, M., Giffard, A.L., Abdelli, N., Botsen, D., Carlier, C., Gozalo, C., Feliu, C., and Slimano, F. (2022). Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102119"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Diasio, R.B., and Offer, S.M. (2022). Testing for Dihydropyrimidine Dehydrogenase Deficiency to Individualize 5-Fluorouracil Therapy. Cancers, 14.","DOI":"10.3390\/cancers14133207"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/BF01799841","article-title":"A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency","volume":"19","author":"Vreken","year":"1996","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1172\/JCI118830","article-title":"Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity","volume":"98","author":"Wei","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_17","first-page":"559","article-title":"Multiple organ failure due to 5-fluorouracil chemotherapy in a patient with a rare dihydropyrimidine dehydrogenase gene variant","volume":"27","author":"Lazar","year":"2004","journal-title":"Onkologie"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/cpt.2667","article-title":"Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping","volume":"112","author":"White","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1002\/onco.13967","article-title":"Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis","volume":"26","author":"Sharma","year":"2021","journal-title":"Oncologist"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41416-022-01779-6","article-title":"A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing","volume":"127","author":"Glewis","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_21","unstructured":"(2022, November 03). Global Variome Shared LOVD DPYD (Dihydropyrimidine Dehydrogenase). Available online: https:\/\/databases.lovd.nl\/shared\/variants\/DPYD?search_var_status=%3D%22Marked%22%7C%3D%22Public%22."},{"key":"ref_22","first-page":"768","article-title":"Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype","volume":"8","author":"Johnson","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1158\/0008-5472.CAN-12-3858","article-title":"Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity","volume":"73","author":"Offer","year":"2013","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"abstr3510","DOI":"10.1200\/jco.2013.31.15_suppl.3510","article-title":"Validation of DPYD variants DPYD*2A, I560S, and D949V as predictors of 5-fluorouracil (5-FU)-related toxicity in stage III colon cancer (CC) patients from adjuvant trial NCCTG N0147","volume":"31","author":"Lee","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00439-010-0879-3","article-title":"Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity","volume":"128","author":"Meijer","year":"2010","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/S1470-2045(15)00286-7","article-title":"Clinical relevance of DPYD variants c.1679T>G, c.1236G>A\/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: A systematic review and meta-analysis of individual patient data","volume":"16","author":"Meulendijks","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/cpt.911","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update","volume":"103","author":"Amstutz","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41431-019-0540-0","article-title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines","volume":"28","author":"Lunenburg","year":"2020","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_29","unstructured":"European MedicinesAgency EMA (2022, February 24). Press Release: EMA Recommendations on DPD Testing Prior to Treatment with Fluorouracil, Capecitabine, Tegafur and Flucytosine. Available online: https:\/\/www.ema.europa.eu\/en\/news\/ema-recommendations-dpd-testingprior-treatment-luorouracil-capecitabine-tegafur-flucytosine."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"w20375","DOI":"10.4414\/smw.2020.20375","article-title":"Fluoropyrimidine chemotherapy: Recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy","volume":"150","author":"Hamzic","year":"2020","journal-title":"Swiss Med. Wkly."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/00008571-200004000-00002","article-title":"Known variant DPYD alleles do not explain DPD deficiency in cancer patients","volume":"10","author":"Etienne","year":"2000","journal-title":"Pharmacogenetics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14050","DOI":"10.18632\/oncotarget.12571","article-title":"Pre-treatment assay of 5-fluorouracil degradation rate (5-FUDR) to improve prediction of 5-fluorouracil toxicity in gastro-esophageal cancer","volume":"8","author":"Borro","year":"2017","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20612","DOI":"10.18632\/oncotarget.7991","article-title":"Pre-treatment evaluation of 5-fluorouracil degradation rate: Association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort","volume":"7","author":"Mazzuca","year":"2016","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113644","DOI":"10.1016\/j.biopha.2022.113644","article-title":"Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk","volume":"154","author":"Silvestri","year":"2022","journal-title":"Biomed Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Bendl, J., Stourac, J., Salanda, O., Pavelka, A., Wieben, E.D., Zendulka, J., Brezovsky, J., and Damborsky, J. (2014). PredictSNP: Robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput Biol., 10.","DOI":"10.1371\/journal.pcbi.1003440"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1097\/CAD.0000000000000492","article-title":"A nomogram to predict 5-fluorouracil toxicity: When pharmacogenomics meets the patient","volume":"28","author":"Botticelli","year":"2017","journal-title":"Anticancer Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1097\/CAD.0000000000000453","article-title":"5-Fluorouracil degradation rate could predict toxicity in stages II-III colorectal cancer patients undergoing adjuvant FOLFOX","volume":"28","author":"Onesti","year":"2017","journal-title":"Anticancer Drugs"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Botticelli, A., Borro, M., Onesti, C.E., Strigari, L., Gentile, G., Cerbelli, B., Romiti, A., Occhipinti, M., Sebastiani, C., and Lionetto, L. (2016). Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163105"},{"key":"ref_39","first-page":"320","article-title":"Genotype-phenotype correlations in 5-fluorouracil metabolism: A candidate DPYD haplotype to improve toxicity prediction","volume":"16","author":"Gentile","year":"2016","journal-title":"Pharm. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5886","DOI":"10.1158\/1078-0432.CCR-04-1784","article-title":"Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals","volume":"11","author":"Seck","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.bbadis.2016.01.009","article-title":"Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene","volume":"1862","author":"Kuilenburg","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1002\/cpt.1751","article-title":"A New Liver Expression Quantitative Trait Locus Map From 1,183 Individuals Provides Evidence for Novel Expression Quantitative Trait Loci of Drug Response, Metabolic, and Sex-Biased Phenotypes","volume":"107","author":"Etheridge","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/bcp.12821","article-title":"Evaluation of an oral uracil loading test to identify DPD-deficient patients using a limited sampling strategy","volume":"81","author":"Guchelaar","year":"2016","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1007\/s00280-011-1661-5","article-title":"Pharmacokinetics of orally administered uracil in healthy volunteers and in DPD-deficient patients, a possible tool for screening of DPD deficiency","volume":"68","author":"Guchelaar","year":"2011","journal-title":"Cancer Chemother. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1158\/0008-5472.CAN-13-2482","article-title":"Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity","volume":"74","author":"Offer","year":"2014","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1124\/dmd.118.081737","article-title":"Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals","volume":"6","author":"Hishinuma","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_47","unstructured":"(2022, September 09). SNPStats Software. Available online: http:\/\/bioinfo.iconcologia.net\/SNPstats."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1093\/bioinformatics\/btl268","article-title":"SNPStats: A web tool for the analysis of association studies","volume":"22","author":"Valls","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1093\/bioinformatics\/btv402","article-title":"LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants","volume":"31","author":"Machiela","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium, Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini, J.L., McCarthy, S., and McVean, G.A. (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13923\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:16:31Z","timestamp":1760145391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13923"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":50,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213923"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213923","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]}}}