{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T15:23:44Z","timestamp":1775489024473,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL141856"],"award-info":[{"award-number":["R01HL141856"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Down syndrome (DS), also known as trisomy 21 (T21), is the most common human chromosomal anomaly. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests that lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin. The histology of T21 fetal lungs (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200915) was assessed by an experienced pathologist. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC). Comprehensive gene expression in prenatal T21 lungs (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200919), and age\u2010matched controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200919), was performed using high\u2010throughput RNA sequencing (RNAseq) and validated by RT\u2010qPCR. Histopathological abnormalities were observed in approximately half of T21 prenatal lung samples analyzed, which included dilated terminal airways\/acinar tubules, dilated lymphatics, and arterial wall thickening. IHC for Ki67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in tissues displaying pathology. IHC demonstrated that airway smooth muscle was reduced and discontinuous in the proximal airway in conjunction with reduced SOX2. RNAseq identified 118 genes significantly dysregulated (FDR\u2009&lt;\u20090.05) in T21 lung when unadjusted and 316 genes when adjusted for age. Ontology analysis showed that IFN pathway genes were appreciably upregulated, whereas complement and coagulation cascades and extracellular matrix pathway genes were downregulated. RT\u2010qPCR confirmed the changes in genes associated with these pathways in prenatal T21 lungs. Our data demonstrate that specific histological, cellular, and molecular abnormalities occur prenatally in different compartments of human T21 lung, which could be representative of premature stage progression. \u00a9 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.\n                  <\/jats:p>","DOI":"10.1002\/path.5735","type":"journal-article","created":{"date-parts":[[2021,5,29]],"date-time":"2021-05-29T12:36:56Z","timestamp":1622291816000},"page":"41-51","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Prenatal histological, cellular, and molecular anomalies in\n                    <scp>trisomy<\/scp>\n                    21 lung"],"prefix":"10.1002","volume":"255","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-4445","authenticated-orcid":false,"given":"Soula","family":"Danopoulos","sequence":"first","affiliation":[{"name":"Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soumyaroop","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Pediatric Molecular and Personalized Medicine Program and Division of Neonatology University of Rochester  Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Seattle Children's Research Institute  Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina R","family":"Nih","sequence":"additional","affiliation":[{"name":"Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Slaunwhite","sequence":"additional","affiliation":[{"name":"Pediatric Molecular and Personalized Medicine Program and Division of Neonatology University of Rochester  Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas J","family":"Mariani","sequence":"additional","affiliation":[{"name":"Pediatric Molecular and Personalized Medicine Program and Division of Neonatology University of Rochester  Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Al Alam","sequence":"additional","affiliation":[{"name":"Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2007.09.045"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0098-2016"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcl.2008.07.001"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2013-304611"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200004000-00010"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.129.6.642"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.5114\/ceji.2018.80042"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2014.00022"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.7189\/jogh.07.020413"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.1950050405"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2016.08.063"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198211043071902"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/ped.12349"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0046-8177(91)90183-P"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0159005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/35012518"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30098"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv284"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2019.10.014"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101472"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0940-9602(11)80391-2"},{"key":"e_1_2_8_23_1","first-page":"971","article-title":"Thymic extracellular matrix in Down's syndrome","volume":"22","author":"Fonseca EC","year":"1989","journal-title":"Braz J Med Biol Res"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-8-268"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jre.12038"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2009.01214.x"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2009.139816"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00379.2017"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp427"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201203-0406OC"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24234"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0185(199602)244:2<207::AID-AR8>3.0.CO;2-Y"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.104794"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.096560"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22032"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0149OC"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13200"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1674-8301(10)60016-4"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-016-2545-0"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.07.026"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.16220"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.02.035"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2000.279.3.L600"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0216795"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-019-00273-z"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302221"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100019"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5735","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5735","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5735","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T17:57:00Z","timestamp":1761069420000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1002\/path.5735"],"URL":"https:\/\/doi.org\/10.1002\/path.5735","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]},"assertion":[{"value":"2020-12-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}