{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:05:10Z","timestamp":1789758310147,"version":"4.0.1"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL156866"],"award-info":[{"award-number":["HL156866"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp;amp; Cancer"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly associated with a somatic activating\n                      <jats:italic>NRAS p.Q61R<\/jats:italic>\n                      (\n                      <jats:italic>\n                        NRAS\n                        <jats:sup>Q61R<\/jats:sup>\n                      <\/jats:italic>\n                      ) mutation. KLA is characterized by malformed lymphatic vessels that can lead to effusions and coagulopathy. The goal of this study was to generate an in vivo mouse model to determine if prenatal expression of the Nras\n                      <jats:sup>Q61R<\/jats:sup>\n                      mutation in lymphatic endothelial cells induces disease characteristics found in KLA patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Procedure<\/jats:title>\n                    <jats:p>\n                      A Cre\u2010loxP system was used to conditionally express Nras\n                      <jats:sup>Q61R<\/jats:sup>\n                      in cells expressing lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), a marker of lymphatic and other types of endothelial cells that starts being expressed at embryonic day (E) 7.5. Because pups did not survive birth, embryos were collected at E14.5, E15.5, and E18.5 for gross analysis, histology and immunostaining, and organ whole\u2010mounts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Staining for NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      demonstrated robust recombination in the\n                      <jats:italic>\n                        Nras\n                        <jats:sup>Q61R<\/jats:sup>\n                      <\/jats:italic>\n                      mutant embryos and localization of Nras\n                      <jats:sup>Q61R<\/jats:sup>\n                      at sites of vascular abnormalities.\n                      <jats:italic>\n                        Nras\n                        <jats:sup>Q61R<\/jats:sup>\n                      <\/jats:italic>\n                      mutant embryos had significant edema and dysmorphic jugular lymph sacs with abnormal Lyve1\u2010positive cellular masses. The lymphatic vessel network in the back skin of the\n                      <jats:italic>\n                        Nras\n                        <jats:sup>Q61R<\/jats:sup>\n                      <\/jats:italic>\n                      mutant embryos had fewer branch points and increased vessel diameter.\n                      <jats:italic>\n                        Nras\n                        <jats:sup>Q61R<\/jats:sup>\n                      <\/jats:italic>\n                      mutant embryos had severe hepatic defects characterized by disordered and enlarged vessels. By E18.5,\n                      <jats:italic>\n                        Nras\n                        <jats:sup>Q61R<\/jats:sup>\n                      <\/jats:italic>\n                      mutant embryos were dead.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Conditional expression of Nras\n                      <jats:sup>Q61R<\/jats:sup>\n                      in Lyve1\u2010positive cells caused edema, abnormal lymphatic development, and hepatic vascular defects in mouse embryos. These findings further support the role of NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      as a driver of the lymphatic overgrowth, vessel enlargement, and dysfunction in the pathophysiology of KLA.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pbc.31492","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T09:09:57Z","timestamp":1735204197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Lyve1\u2010Driven Nras\n                    <sup>Q61R<\/sup>\n                    Causes Edema, Enlarged Lymphatic Vessels, and Hepatic Vascular Defects in Embryonic Mice"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-0956","authenticated-orcid":false,"given":"C. Griffin","family":"McDaniel","sequence":"first","affiliation":[{"name":"Division of Pulmonary Biology Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dermot","family":"Fox","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Pastura","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4477-9592","authenticated-orcid":false,"given":"Sara","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey S.","family":"Huppert","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Hepatology and Nutrition Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-2703","authenticated-orcid":false,"given":"Timothy D.","family":"Le Cras","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/stke.2502004re13"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.033287"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-2612"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23042358"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.28036"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2013.10.013"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.30219"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1147-9"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0390-0"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202012324"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.044"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-022-09836-7"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.31032"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-018-9595-8"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0729"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091619"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8712-2_2"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21605"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71609"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sempedsurg.2020.150967"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0289187"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddae080"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-1010fje"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1588407"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.10.080"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1276333"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20192205"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00247-016-3611-1"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-022-02800-x"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31492","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pbc.31492","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31492","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:02:53Z","timestamp":1787760173000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.31492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,26]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/pbc.31492"],"URL":"https:\/\/doi.org\/10.1002\/pbc.31492","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"value":"1545-5009","type":"print"},{"value":"1545-5017","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,26]]},"assertion":[{"value":"2024-08-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e31492"}}