{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:39:40Z","timestamp":1782315580042,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Ministry of Health &amp; Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["HI21C187101"],"award-info":[{"award-number":["HI21C187101"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Ministry of Health &amp; Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["RS-2023-00260968"],"award-info":[{"award-number":["RS-2023-00260968"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MSIT)","doi-asserted-by":"publisher","award":["HI21C187101"],"award-info":[{"award-number":["HI21C187101"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MSIT)","doi-asserted-by":"publisher","award":["RS-2023-00260968"],"award-info":[{"award-number":["RS-2023-00260968"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Our prior findings showed that BCL2A1 in neutrophils is highly expressed in the extra-placental membranes (EPMs) of both the human spontaneous preterm-birth (PTB) (i.e., PTL or preterm PROM) and nonhuman-primate PTB model. However, no data exist on whether the intensity of BCL2A1 expression quantitatively increases according to the stage progression of acute histologic chorioamnionitis (acute HCA) in EPM. The objective is to investigate whether the intensity of BCL2A1 expression quantitatively increases according to the stage progression of acute HCA in EPM among spontaneous PTB cases, as measured using QuPath. The study population included 121 singleton PTBs (gestational age [GA] at delivery &lt; 34 weeks) due to either preterm labor or preterm PROM. With digital image analysis, we calculated the percentage of BCL2A1-positive cells in immunohistochemistry according to the stage progression of acute HCA in EPMs as the primary outcome and examined the relationship between the percentage of BCL2A1-positive cells and either the GA at delivery or the amniotic-fluid (AF) WBC count as the secondary outcome. The median percentage of BCL2A1-positive cells progressively increases with the stage progression of acute HCA in EPM (group-1 vs. group-2 vs. group-3 vs. group-4 vs. group-5; 7.62 vs. 5.15 vs. 43.57 vs. 71.07; \u03b3 = 0.552, p &lt; 0.000001). The percentage of BCL2A1-positive cells in EPMs and the AFWBC count shows a positive correlation (\u03b3 = 0.492, p = 0.000385). Moreover, the percentage of BCL2A1-positive cells in EPMs continuously decreased with increasing GA at delivery (\u03b3 = \u22120.253, p = 0.005148). In conclusion, the intensity of BCL2A1 expression increases according to the stage progression of acute HCA in EPMs and the elevation of AFWBC among spontaneous PTB cases. This finding suggests BCL2A1 in EPMs may be a promising marker and target for acute HCA.<\/jats:p>","DOI":"10.3390\/life14121535","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T12:07:32Z","timestamp":1732277252000},"page":"1535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Intensity of BCL2A1 Expression Increases According to the Stage Progression of Acute Histologic Chorioamnionitis in the Extra-Placental Membranes of Spontaneous Preterm Birth"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1290-6438","authenticated-orcid":false,"given":"Chan-Wook","family":"Park","sequence":"first","affiliation":[{"name":"The Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7928-1524","authenticated-orcid":false,"given":"Eun-Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1469-589X","authenticated-orcid":false,"given":"Seung-Han","family":"Shin","sequence":"additional","affiliation":[{"name":"The Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul","family":"Lee","sequence":"additional","affiliation":[{"name":"The Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1459-8093","authenticated-orcid":false,"given":"Jae-Kyung","family":"Won","sequence":"additional","affiliation":[{"name":"The Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1056\/NEJM200005183422007","article-title":"Intrauterine infection and preterm delivery","volume":"342","author":"Goldenberg","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1097\/00003081-198809000-00006","article-title":"Infection and preterm labor","volume":"31","author":"Romero","year":"1988","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/mrdd.10008","article-title":"Intrauterine infection and prematurity","volume":"8","author":"Goncalves","year":"2002","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/j.ajog.2015.08.040","article-title":"Acute chorioamnionitis and funisitis: Definition, pathologic features, and clinical significance","volume":"213","author":"Kim","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_5","first-page":"639","article-title":"Acute chorioamnionitis and intra-amniotic inflammation are more severe according to outside-in neutrophil migration within the same chorio-decidua. Taiwan","volume":"60","author":"Oh","year":"2021","journal-title":"J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.placenta.2017.07.200","article-title":"Amniotic necrosis is associated with severe and advanced acute histologic chorioamnionitis","volume":"57","author":"Park","year":"2017","journal-title":"Placenta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1067\/mob.2001.117680","article-title":"Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes","volume":"185","author":"Yoon","year":"2001","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.ajog.2004.06.085","article-title":"Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes","volume":"191","author":"Shim","year":"2004","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sohn, J.W., Choi, E.S., Park, C.-W., Moon, K.C., Park, J.S., and Jun, J.K. (2022). Preterm Labor and Preterm-PROM at a Lower Gestational Age Are Associated with a Longer Latency-to-Delivery Even in Patients with the Same Intensity of Intra-Amniotic Inflammation: \u201cCarroll-Model\u201d Revisited. Life, 12.","DOI":"10.3390\/life12091329"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"98","DOI":"10.3109\/14767058.2013.806898","article-title":"Fetal, amniotic and maternal inflammatory responses in early stage of ascending intrauterine infection, inflammation restricted to chorio-decidua, in preterm gestation","volume":"27","author":"Park","year":"2014","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.placenta.2008.09.017","article-title":"The involvement of human amnion in histologic chorioamnionitis is an indicator that a fetal and an intra-amniotic inflammatory response is more likely and severe: Clinical implications","volume":"30","author":"Park","year":"2009","journal-title":"Placenta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"227","DOI":"10.5468\/ogs.2013.56.4.227","article-title":"Which is more important for the intensity of intra-amniotic in-flammation between total grade or involved anatomical region in preterm gestations with acute histologic chorioam-nionitis?","volume":"56","author":"Park","year":"2013","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Park, C.-W., Moon, K.C., Park, J.S., and Jun, J.K. (2021). The Inflammatory Milieu of Amniotic Fluid Increases with Cho-rio-Deciduitis Grade in Inflammation-Restricted to Choriodecidua, but Not Amnionitis, of Extra-Placental Membranes. J. Clin. Med., 10.","DOI":"10.3390\/jcm10143041"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/ajh.21078","article-title":"Constitutive neutrophil apoptosis: Mechanisms and regulation","volume":"83","author":"Luo","year":"2008","journal-title":"Am. J. Hematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/cdd.2011.158","article-title":"BCL2A1: The underdog in the BCL2 family","volume":"19","author":"Vogler","year":"2012","journal-title":"Cell. Death. Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2103","DOI":"10.1038\/cddis.2016.23","article-title":"The anti-apoptotic Bcl-2 family protein A1\/Bfl-1 regulates neutrophil survival and homeostasis and is controlled via PI3K and JAK\/STAT signaling","volume":"7","author":"Vier","year":"2016","journal-title":"Cell. Death. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e98306","DOI":"10.1172\/jci.insight.98306","article-title":"IL-1 signaling mediates intra-uterine inflammation and chorio-decidua neutrophil recruitment and activation","volume":"3","author":"Presicce","year":"2018","journal-title":"JCI Insight."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bankhead, P., Loughrey, M.B., Fern\u00e1ndez, J.A., Dombrowski, Y., McArt, D.G., Dunne, P.D., McQuaid, S., Gray, R.T., Murray, L.J., and Coleman, H.G. (2017). QuPath: Open source software for digital pathology image analysis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17204-5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/0002-9378(95)90028-4","article-title":"Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity","volume":"172","author":"Yoon","year":"1995","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.4103\/jpi.jpi_11_21","article-title":"QuPath Digital Immunohistochemical Analysis of Placental Tissue","volume":"12","author":"Hein","year":"2021","journal-title":"J. Pathol. Inform."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Porter, R.J., Din, S., Bankhead, P., Oniscu, A., and Arends, M.J. (2023). QuPath Algorithm Accurately Identifies MLH1-Deficient Inflammatory Bowel Disease-Associated Colorectal Cancers in a Tissue Microarray. Diagnostics, 13.","DOI":"10.3390\/diagnostics13111890"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0029-7844(95)00380-0","article-title":"Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: A comparison with amniotic fluid white blood cell count","volume":"87","author":"Yoon","year":"1996","journal-title":"Obstet. Gynecol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/S0029-7844(96)00339-0","article-title":"Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes","volume":"88","author":"Yoon","year":"1996","journal-title":"Obstet. Gynecol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"698","DOI":"10.5858\/arpa.2015-0225-CC","article-title":"Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement","volume":"140","author":"Khong","year":"2016","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_25","first-page":"243A","article-title":"A more frequent advanced-stage, but not early-stage, ascending intra-uterine infection is associated with preterm birth due to preterm labor and preterm-PROM at lower gestational age","volume":"Volume 23","author":"Park","year":"2016","journal-title":"Reproductive Sciences"},{"key":"ref_26","first-page":"127","article-title":"Inflammatory lesions of the human placenta: Clinical significance of acute chorioamnionitis","volume":"2","author":"Russell","year":"1979","journal-title":"Am. J. Diagn. Gynecol. Obstet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.placenta.2015.09.010","article-title":"The inflammatory milieu of amniotic fluid in acute-chorioamnionitis de-creases with increasing gestational age","volume":"36","author":"Park","year":"2015","journal-title":"Placenta"},{"key":"ref_28","unstructured":"The Human Protein Atlas (2024, September 18). BCL2A1. Available online: https:\/\/www.proteinatlas.org\/ENSG00000140379-BCL2A1."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.3390\/ph5111160","article-title":"Cyclooxygenase (COX) Inhibitors and the Newborn Kidney","volume":"5","author":"Smith","year":"2012","journal-title":"Pharmaceuticals"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Park, C.-W., Moon, K.C., Park, J.S., and Jun, J.K. (2021). Neutrophil to Lymphocyte Ratio in Maternal Blood: A Clue to Suspect Amnionitis. J. Clin. Med., 10.","DOI":"10.3390\/jcm10122673"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bezemer, R.E., Schoots, M.H., Timmer, A., Scherjon, S.A., Erwich, J.J.H.M., van Goor, H., Gordijn, S.J., and Prins, J.R. (2020). Altered Levels of Decidual Immune Cell Subsets in Fetal Growth Restriction, Stillbirth, and Placental Pathology. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01898"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/12\/1535\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:37:53Z","timestamp":1760114273000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/12\/1535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,22]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["life14121535"],"URL":"https:\/\/doi.org\/10.3390\/life14121535","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,22]]}}}