{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T10:46:58Z","timestamp":1768906018159,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/01219"],"award-info":[{"award-number":["PI18\/01219"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CB16\/012\/00481"],"award-info":[{"award-number":["CB16\/012\/00481"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Center Portuguese Oncology Institute of Porto","award":["74-CBEG-CI-IPOP-19-2015"],"award-info":[{"award-number":["74-CBEG-CI-IPOP-19-2015"]}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["ACIF\/2016\/030"],"award-info":[{"award-number":["ACIF\/2016\/030"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Liga Portuguesa Contra o Cancro\/Funda\u00e7\u00e3o","award":["predoctoral"],"award-info":[{"award-number":["predoctoral"]}]},{"DOI":"10.13039\/501100008963","name":"Sociedad Espa\u00f1ola de Oncolog\u00eda M\u00e9dica","doi-asserted-by":"publisher","award":["R\u00edo Hortega-SEOM"],"award-info":[{"award-number":["R\u00edo Hortega-SEOM"]}],"id":[{"id":"10.13039\/501100008963","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MicroRNAs have emerged as new diagnostic and therapeutic biomarkers for breast cancer. Herein, we analysed miR-99a-5p expression levels in primary tumours and plasma of breast cancer patients to evaluate its usefulness as a minimally invasive diagnostic biomarker. MiR-99a-5p expression levels were determined by quantitative real-time PCR in three independent cohorts of patients: (I) Discovery cohort: breast cancer tissues (n = 103) and healthy breast tissues (n = 26); (II) Testing cohort: plasma samples from 105 patients and 98 healthy donors; (III) Validation cohort: plasma samples from 89 patients and 85 healthy donors. Our results demonstrated that miR-99a-5p was significantly downregulated in breast cancer tissues compared to healthy breast tissues. Conversely, miR-99a-5p levels were significantly higher in breast cancer patients than in healthy controls in plasma samples from both testing and validation cohorts, and ROC curve analysis revealed that miR-99a-5p has good diagnostic potential even to detect early breast cancer. In conclusion, miR-99a-5p\u2019s deregulated expression distinguished healthy patients from breast cancer patients in two different types of samples (tissues and plasma). Interestingly, expression levels in plasma were significantly lower in healthy controls than in early-stage breast cancer patients. Our findings suggest circulating miR-99a-5p as a novel promising non-invasive biomarker for breast cancer detection.<\/jats:p>","DOI":"10.3390\/ijms21197427","type":"journal-article","created":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T10:19:23Z","timestamp":1602238763000},"page":"7427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Circulating miR-99a-5p Expression in Plasma: A Potential Biomarker for Early Diagnosis of Breast Cancer"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1211-473X","authenticated-orcid":false,"given":"Iris","family":"Garrido-Cano","sequence":"first","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Cancer Biology and Epigenetics Group\u2013Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3151-0367","authenticated-orcid":false,"given":"Vera","family":"Const\u00e2ncio","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group\u2013Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"}]},{"given":"Anna","family":"Adam-Artigues","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0441-6356","authenticated-orcid":false,"given":"Ana","family":"Lameirinhas","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"}]},{"given":"Soraya","family":"Sim\u00f3n","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"}]},{"given":"Belen","family":"Ortega","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"}]},{"given":"Mar\u00eda Teresa","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"}]},{"given":"Cristina","family":"Hernando","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"}]},{"given":"Bego\u00f1a","family":"Bermejo","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2766-407X","authenticated-orcid":false,"given":"Ana","family":"Lluch","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"},{"name":"Department of Medicine, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"}]},{"given":"Paula","family":"Lopes","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group\u2013Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal"}]},{"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group\u2013Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar-University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group\u2013Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar-University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"given":"Juan Miguel","family":"Cejalvo","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Clinical Oncology Department, Hospital Cl\u00ednico Universitario de Valencia, 46010 Valencia, Spain"}]},{"given":"Pilar","family":"Eroles","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute INCLIVA, 46010 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"},{"name":"COST Action CA15204, 1210 Brussels, Belgium"},{"name":"Department of Physiology, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3322\/caac.21565","article-title":"Cancer treatment and survivorship statistics, 2019","volume":"69","author":"Miller","year":"2019","journal-title":"CA A Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5200","DOI":"10.1002\/jcp.26379","article-title":"Breast cancer diagnosis: Imaging techniques and biochemical markers","volume":"233","author":"Jafari","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"117417","DOI":"10.1016\/j.lfs.2020.117417","article-title":"Cell-free miRNAs as non-invasive biomarkers in breast cancer: Significance in early diagnosis and metastasis prediction","volume":"246","author":"Kashyap","year":"2020","journal-title":"Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ng, E.K.O., Li, R., Shin, V.Y., Jin, H.C., Leung, C.P.H., Ma, E.S.K., Pang, R., Chua, D., Chu, K.M., and Law, W.L. (2013). Circulating microRNAs as Specific Biomarkers for Breast Cancer Detection. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053141"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e3045","DOI":"10.1038\/cddis.2017.440","article-title":"Circulating microRNAs in breast cancer: Novel diagnostic and prognostic biomarkers","volume":"8","author":"Hamam","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bottani, M., Banfi, G., and Lombardi, G. (2019). Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Common Solid Tumors: Focus on Lung, Breast, Prostate Cancers, and Osteosarcoma. J. Clin. Med., 8.","DOI":"10.3390\/jcm8101661"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Loh, H.Y., Norman, B.P., Lai, K.S., Rahman, N.M.A.N.A., Alitheen, N.B.M., and Osman, M.A. (2019). The regulatory role of microRNAs in breast cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194940"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/978-3-642-28160-0_13","article-title":"Circulating MicroRNAs as Noninvasive Biomarkers in Breast Cancer","volume":"195","author":"Cortez","year":"2012","journal-title":"Recent Results Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: Genomics, Biogenesis, Mechanism, and Function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrg1379","article-title":"MicroRNAs: Small RNAs with a big role in gene regulation","volume":"5","author":"He","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tormo, E., Adam-Artigues, A., Ballester, S., Pineda, B., Zazo, S., Gonz\u00e1lez-Alonso, P., Albanell, J., Rovira, A., Rojo, F., and Lluch, A. (2017). The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene. Sci. Rep., 7.","DOI":"10.1038\/srep41309"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tormo, E., Ballester, S., Adam-Artigues, A., Burgu\u00e9s, O., Alonso, E., Bermejo, B., Men\u00e9ndez, S., Zazo, S., Madoz-G\u00farpide, J., and Rovira, A. (2019). The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-41472-y"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7065","DOI":"10.1158\/0008-5472.CAN-05-1783","article-title":"MicroRNA gene expression deregulation in human breast cancer","volume":"65","author":"Iorio","year":"2005","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10513","DOI":"10.1073\/pnas.0804549105","article-title":"Circulating microRNAs as stable blood-based markers for cancer detection","volume":"105","author":"Mitchell","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1136\/gut.2008.167817","article-title":"Differential expression of microRNAs in plasma of patients with colorectal cancer: A potential marker for colorectal cancer screening","volume":"58","author":"Ng","year":"2009","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fonc.2019.00900","article-title":"Circulating MicroRNAs as Biomarkers for Prostate Cancer Detection and Metastasis Development Prediction","volume":"9","author":"Bidarra","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Estev\u00e3o-Pereira, H., Lobo, J., Salta, S., Amorim, M., Lopes, P., Cantante, M., Reis, B., Antunes, L., Castro, F., and Palma De Sousa, S. (2019). Overexpression of circulating MiR-30b-5p identifies advanced breast cancer. J. Transl. Med., 17.","DOI":"10.1186\/s12967-019-02193-y"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R34","DOI":"10.1186\/bcr3127","article-title":"Expression profiling of cancerous and normal breast tissues identifies microRNAs that are differentially expressed in serum from patients with (metastatic) breast cancer and healthy volunteers","volume":"14","author":"Wouters","year":"2012","journal-title":"Breast Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1373\/clinchem.2015.238691","article-title":"Tumor MicroRNA expression profiling identifies circulating MicroRNAs for early breast cancer detection","volume":"61","author":"Matamala","year":"2015","journal-title":"Clin. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Feng, Y., Kang, Y., He, Y., Liu, J., Liang, B., Yang, P., and Yu, Z. (2014). MicroRNA-99a acts as a tumor suppressor and is down-regulated in bladder cancer. BMC Urol.","DOI":"10.1186\/1471-2490-14-50"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1080\/15384047.2015.1045692","article-title":"Circulating microRNAs as novel prognosis biomarkers for head and neck squamous cell carcinoma","volume":"16","author":"Hou","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hu, Y., Zhu, Q., and Tang, L. (2014). MiR-99a Antitumor Activity in Human Breast Cancer Cells through Targeting of mTOR Expression. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092099"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32737","DOI":"10.18632\/oncotarget.5355","article-title":"MicroRNA-99a inhibits tumor aggressive phenotypes through regulating HOXA1 in breast cancer cells","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Qin, H., and Liu, W. (2018). MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. J. Cell. Physiol., 1\u201312.","DOI":"10.1002\/jcp.26906"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/1878-0261.12602","article-title":"RNA-sequence-based microRNA expression signature in breast cancer: Tumor-suppressive miR-101-5p regulates molecular pathogenesis","volume":"14","author":"Toda","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_27","first-page":"1755","article-title":"MiR-99a suppress proliferation, migration and invasion through regulating insulin-like growth factor 1 receptor in breast cancer","volume":"20","author":"Xia","year":"2016","journal-title":"Eur. Rev. Med Pharmacol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Turcatel, G., Rubin, N., El-Hashash, A., and Warburton, D. (2012). MIR-99a and MIR-99b Modulate TGF-\u03b2 Induced Epithelial to Mesenchymal Plasticity in Normal Murine Mammary Gland Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031032"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Long, X., Shi, Y., Ye, P., Guo, J., Zhou, Q., and Tang, Y. (2020). MicroRNA-99a Suppresses Breast Cancer Progression by Targeting FGFR3. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01473"},{"key":"ref_30","first-page":"3381","article-title":"MiR-155, miR-96 and miR-99a as potential diagnostic and prognostic tools for the clinical management of hepatocellular carcinoma","volume":"18","author":"Ning","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.3892\/ijo.2015.3135","article-title":"miRNA-99b-3p functions as a potential tumor suppressor by targeting glycogen synthase kinase-3\u03b2 in oral squamous cell carcinoma Tca-8113 cells","volume":"47","author":"He","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Torres, A., Torres, K., Pesci, A., Ceccaroni, M., Paszkowski, T., Cassandrini, P., Zamboni, G., and Maciejewski, R. (2012). Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-369"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/jcb.24965","article-title":"miR-99a suppresses the metastasis of human non-small cell lung cancer cells by targeting AKT1 signaling pathway","volume":"116","author":"Yu","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.7314\/APJCP.2015.16.12.4937","article-title":"MiR-99a inhibits cell proliferation and tumorigenesis through targeting mTOR in human anaplastic thyroid cancer","volume":"16","author":"Huang","year":"2015","journal-title":"Asian Pac. J. Cancer Prev. APJCP"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"36677","DOI":"10.1074\/jbc.M111.270561","article-title":"MicroRNA-99a Inhibits Hepatocellular Carcinoma Growth and Correlates with Prognosis of Patients with Hepatocellular Carcinoma","volume":"286","author":"Li","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tanaka, M., Oikawa, K., Takanashi, M., Kudo, M., Ohyashiki, J., Ohyashiki, K., and Kuroda, M. (2009). Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005532"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1002\/ijc.27799","article-title":"Circulating microRNAs in plasma as early detection markers for breast cancer","volume":"132","author":"Cuk","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4477","DOI":"10.1158\/1078-0432.CCR-12-3401","article-title":"Identification of circulating microRNA signatures for breast cancer detection","volume":"19","author":"Chan","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pigati, L., Yaddanapudi, S.C.S., Iyengar, R., Kim, D.J., Hearn, S.A., Danforth, D., Hastings, M.L., and Duelli, D.M. (2010). Selective release of MicroRNA species from normal and malignant mammary epithelial cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013515"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7223","DOI":"10.1093\/nar\/gkr254","article-title":"Characterization of extracellular circulating microRNA","volume":"39","author":"Turchinovich","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Li, J., Song, Z.J.J., Wang, Y.Y.Y., Yin, Y., Liu, Y., and Nan, X. (2016). Low levels of serum miR-99a is a predictor of poor prognosis in breast cancer. Genet. Mol. Res., 15.","DOI":"10.4238\/gmr.15038338"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"363","DOI":"10.4048\/jbc.2018.21.e56","article-title":"Identification and validation of circulating microRNA signatures for breascancer early detection based on large scale tissue-derived data","volume":"21","author":"Yu","year":"2018","journal-title":"J. Breast Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/ijc.26153","article-title":"Circulating microRNA expression profiles in early stage non- small cell lung cancer","volume":"130","author":"Heegaard","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s10549-018-4757-3","article-title":"Circulating microRNAs from the miR-106a\u2013363 cluster on chromosome X as novel diagnostic biomarkers for breast cancer","volume":"170","author":"Li","year":"2018","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/1097-0142(1950)3:1<32::AID-CNCR2820030106>3.0.CO;2-3","article-title":"Index for rating diagnostic tests","volume":"3","author":"Youden","year":"1950","journal-title":"Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/01.ede.0000147512.81966.ba","article-title":"Optimal cut-point and its corresponding Youden index to discriminate individuals using pooled blood samples","volume":"16","author":"Schisterman","year":"2005","journal-title":"Epidemiology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:17:38Z","timestamp":1760177858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,8]]},"references-count":46,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21197427"],"URL":"https:\/\/doi.org\/10.3390\/ijms21197427","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,8]]}}}