{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:30Z","timestamp":1785410550305,"version":"3.56.0"},"reference-count":58,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Surgery, Cooper University Health Care"},{"id":[{"id":"https:\/\/ror.org\/056nm0533","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001774","name":"New Jersey Health Foundation","doi-asserted-by":"crossref","award":["PC52-25"],"award-info":[{"award-number":["PC52-25"]}],"id":[{"id":"10.13039\/100001774","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PC52-25"],"award-info":[{"award-number":["PC52-25"]}],"id":[{"id":"https:\/\/ror.org\/040may582","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal peritoneal metastases relies primarily on DNA-damaging agents whose efficacy depends on sustained cytotoxic exposure. Whether brief treatment can induce durable transcriptional remodeling remains unclear. Mithramycin A (MA) is a GC-rich DNA-binding agent with transcriptional regulatory activity involving chromatin-associated pathways. Here, we investigated the molecular and functional consequences of a single 90-min HIPEC-mimetic MA exposure in colorectal cancer models. RNA sequencing revealed extensive and coordinated transcriptional remodeling, affecting a substantial fraction of expressed genes and producing a response qualitatively distinct from mitomycin C. MA selectively suppressed key chromatin-associated regulatory factors, including DNMT1, JARID2, and HDAC4, while coordinately activating canonical cyclin-dependent kinase inhibitors CDKN1A, CDKN1C, and CDKN2C. Gene set enrichment analysis demonstrated enrichment of G2\/M checkpoint pathways and suppression of oncogenic gene networks. These molecular changes translated into sustained inhibition of clonogenic growth and activation of caspase-dependent apoptosis following drug washout, with hyperthermia potentiating apoptotic signaling. Collectively, these findings indicate that brief MA exposure induces selective modulation of chromatin regulators and durable transcriptional reorganization, supporting modulation of chromatin regulatory networks as a potential therapeutic strategy for HIPEC-based colorectal cancer therapy.<\/jats:p>","DOI":"10.3390\/ijms27083580","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:11:04Z","timestamp":1776420664000},"page":"3580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Short-Duration HIPEC-Mimetic Mithramycin A Exposure Induces Durable Transcriptional Remodeling Involving Chromatin Regulatory Networks in Colorectal Cancer Models"],"prefix":"10.3390","volume":"27","author":[{"given":"Olivia","family":"Coburn-Flynn","sequence":"first","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Virginia","family":"Butchy","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0113-9632","authenticated-orcid":false,"given":"Yazid","family":"Ghanem","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Emery","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Verchio","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Knapp","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4093-4567","authenticated-orcid":false,"given":"Jessica","family":"Collier","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7899-4408","authenticated-orcid":false,"given":"Sahil","family":"Jethi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cooper Medical School, Rowan University, Camden, NJ 08103, USA"},{"name":"Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis R.","family":"Spitz","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"},{"name":"Department of Surgery, Cooper Medical School, Rowan University, Camden, NJ 08103, USA"},{"name":"Camden Cancer Research Center, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"},{"name":"Department of Surgery, Cooper Medical School, Rowan University, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weam Othman","family":"Elbezanti","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"},{"name":"Department of Surgery, Cooper Medical School, Rowan University, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Ki","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"},{"name":"Department of Surgery, Cooper Medical School, Rowan University, Camden, NJ 08103, USA"},{"name":"Camden Cancer Research Center, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s12029-025-01176-1","article-title":"Trends in Colorectal Cancer Peritoneal Metastases Research: A Comprehensive Bibliometric Analysis","volume":"56","author":"Zhang","year":"2025","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1097\/00000658-199501000-00004","article-title":"Peritonectomy procedures","volume":"221","author":"Sugarbaker","year":"1995","journal-title":"Ann. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1200\/JCO.2003.04.187","article-title":"Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer","volume":"21","author":"Verwaal","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S1470-2045(20)30599-4","article-title":"Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): A multicentre, randomised, open-label, phase 3 trial","volume":"22","author":"Elias","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/1074-5521(95)90120-5","article-title":"Mitomycin C: Small, fast and deadly (but very selective)","volume":"2","author":"Tomasz","year":"1995","journal-title":"Chem. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrc2167","article-title":"The resurgence of platinum-based cancer chemotherapy","volume":"7","author":"Kelland","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1038\/onc.2011.384","article-title":"Molecular mechanisms of cisplatin resistance","volume":"31","author":"Galluzzi","year":"2012","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.2478\/raon-2019-0018","article-title":"Cisplatin and beyond: Molecular mechanisms of action and drug resistance development in cancer chemotherapy","volume":"53","author":"Makovec","year":"2019","journal-title":"Radiol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nrg.2016.13","article-title":"Epigenetic modulators, modifiers and mediators in cancer aetiology and progression","volume":"17","author":"Feinberg","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/nrg.2016.93","article-title":"Targeting the cancer epigenome for therapy","volume":"17","author":"Jones","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1053\/j.gastro.2008.07.076","article-title":"Genomic and epigenetic instability in colorectal cancer pathogenesis","volume":"135","author":"Grady","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/nrc1507","article-title":"CpG island methylator phenotype in cancer","volume":"4","author":"Issa","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/carcin\/bgp220","article-title":"Epigenetics in cancer","volume":"31","author":"Sharma","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cell.2012.06.013","article-title":"Cancer epigenetics: From mechanism to therapy","volume":"150","author":"Dawson","year":"2012","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.trecan.2017.08.003","article-title":"Aberrant DNA Methylation in Colorectal Cancer: What Should We Target?","volume":"3","author":"Tse","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.2174\/0929867328666210915105929","article-title":"Histone Deacetylases and their Inhibitors in Colorectal Cancer Therapy: Current Evidence and Future Considerations","volume":"29","author":"Garmpis","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nature08788","article-title":"JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells","volume":"464","author":"Pasini","year":"2010","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11606","DOI":"10.1073\/pnas.1933744100","article-title":"EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells","volume":"100","author":"Kleer","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"147584","DOI":"10.1016\/j.gene.2023.147584","article-title":"JARID2 and EZH2, the eminent epigenetic drivers in human cancer","volume":"879","author":"Sreeshma","year":"2023","journal-title":"Gene"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tange, S., Oktyabri, D., Terashima, M., Ishimura, A., and Suzuki, T. (2014). JARID2 is involved in transforming growth factor-beta-induced epithelial-mesenchymal transition of lung and colon cancer cell lines. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115684"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3892\/mmr.2024.13278","article-title":"Research progress of DNA methylation in colorectal cancer (Review)","volume":"30","author":"Wang","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s12929-014-0073-3","article-title":"Promoter methylation analysis of WNT\/\u03b2-catenin pathway regulators and its association with expression of DNMT1 enzyme in colorectal cancer","volume":"21","author":"Samaei","year":"2014","journal-title":"J. Biomed. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4062","DOI":"10.1091\/mbc.e08-02-0139","article-title":"HDAC4 promotes growth of colon cancer cells via repression of p21","volume":"19","author":"Wilson","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Stypula-Cyrus, Y., Damania, D., Kunte, D.P., Cruz, M.D., Subramanian, H., Roy, H.K., and Backman, V. (2013). HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064600"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1097\/00000441-198711000-00015","article-title":"Mithramycin selectively inhibits transcription of G-C containing DNA","volume":"294","author":"Miller","year":"1987","journal-title":"Am. J. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108672","DOI":"10.1016\/j.pharmthera.2024.108672","article-title":"Mithramycin and its analogs: Molecular features and antitumor action","volume":"260","author":"Portugal","year":"2024","journal-title":"Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7701","DOI":"10.1007\/s00253-020-10782-x","article-title":"The antitumor antibiotic mithramycin: New advanced approaches in modification and production","volume":"104","author":"Kormanec","year":"2020","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ygyno.2010.03.020","article-title":"Inhibition of Sp1-dependent transcription and antitumor activity of the new aureolic acid analogues mithramycin SDK and SK in human ovarian cancer xenografts","volume":"118","author":"Previdi","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.fob.2014.10.007","article-title":"Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder","volume":"4","author":"Banerjee","year":"2014","journal-title":"FEBS Open Bio"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12640","DOI":"10.15252\/emmm.202012640","article-title":"Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor","volume":"13","author":"Chasse","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Safe, S. (2023). Specificity Proteins (Sp) and Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065164"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1038\/s41467-026-69488-9","article-title":"Mithramycin alters EWS::FLI1 DNA binding and RNA polymerase II processivity to inhibit nascent transcription","volume":"17","author":"Kaufman","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.soc.2012.07.013","article-title":"Pharmacology of perioperative intraperitoneal and intravenous chemotherapy in patients with peritoneal surface malignancy","volume":"21","author":"Stuart","year":"2012","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Abdalla, A.N., Malki, W.H., Qattan, A., Shahid, I., Hossain, M.A., and Ahmed, M. (2021). Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer. Molecules, 26.","DOI":"10.3390\/molecules26020334"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15202","DOI":"10.1038\/s41598-019-50917-3","article-title":"Mithramycin A Inhibits Colorectal Cancer Growth by Targeting Cancer Stem Cells","volume":"9","author":"Quarni","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cell.2016.12.013","article-title":"Transcriptional Addiction in Cancer","volume":"168","author":"Bradner","year":"2017","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cell.2010.02.027","article-title":"A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations","volume":"141","author":"Sharma","year":"2010","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eaal2380","DOI":"10.1126\/science.aal2380","article-title":"Epigenetic plasticity and the hallmarks of cancer","volume":"357","author":"Flavahan","year":"2017","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/00000441-199010000-00001","article-title":"Mithramycin Selectively Inhibits the Transcriptional Activity of a Transfected Human C-myc Gene","volume":"300","author":"Ray","year":"1990","journal-title":"Am. J. Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1016\/j.ejca.2005.08.006","article-title":"Sp transcription factor family and its role in cancer","volume":"41","author":"Safe","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.pharmthera.2015.05.008","article-title":"Sp1 transcription factor: A long-standing target in cancer chemotherapy","volume":"152","author":"Mansilla","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nrc2657","article-title":"p21 in cancer: Intricate networks and multiple activities","volume":"9","author":"Abbas","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4131","DOI":"10.1182\/blood-2002-08-2466","article-title":"Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia","volume":"101","author":"Shen","year":"2003","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/(SICI)1096-9896(199902)187:3<302::AID-PATH243>3.0.CO;2-U","article-title":"p21WAF1\/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations","volume":"187","author":"Viale","year":"1999","journal-title":"J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/02656730500532028","article-title":"Cell biological effects of hyperthermia alone or combined with radiation or drugs: A short introduction to newcomers in the field","volume":"22","author":"Kampinga","year":"2006","journal-title":"Int. J. Hyperth."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1158\/0008-5472.CAN-15-0816","article-title":"Hyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53-Dependent Apoptosis","volume":"75","author":"Oei","year":"2015","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.cell.2017.10.022","article-title":"Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer","volume":"171","author":"Topper","year":"2017","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41568-019-0109-9","article-title":"Epigenetic therapy in immune-oncology","volume":"19","author":"Jones","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1002\/imt2.107","article-title":"Ultrafast one-pass FASTQ data preprocessing, quality control, and deduplication using fastp","volume":"2","author":"Chen","year":"2023","journal-title":"iMeta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.2","article-title":"Differential analyses for RNA-seq: Transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2016","journal-title":"F1000Research"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/biostatistics\/kxx028","article-title":"Smooth quantile normalization","volume":"19","author":"Hicks","year":"2018","journal-title":"Biostatistics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/bioinformatics\/btp053","article-title":"Testing significance relative to a fold-change threshold is a TREAT","volume":"25","author":"McCarthy","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"voom: Precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"Law","year":"2014","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3580\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T04:13:28Z","timestamp":1776572008000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083580"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083580","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]}}}