{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T15:26:43Z","timestamp":1793978803442,"version":"4.8.0"},"reference-count":35,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Cerebral cavernous malformations (CCMs) are low-flow vascular malformations commonly found in the central nervous system with the potential to cause neurological deficits, seizures, and headache through bleeding and growth. CCMs are typically assessed with imaging such as MRI or CT. However, there is a clinical need to reduce the cost, risk (with sedation\/anesthesia in children), and travel associated with these imaging studies. Prior work from the authors\u2019 group and others have highlighted the potential utility of noninvasive biomarkers as tools to potentially complement the use of imaging. Here, the authors present YES1, a member of the Src family kinases, as a potential plasma-based biomarker associated with the presence of CCM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Plasma samples from symptomatic patients with pathology-confirmed CCM (n = 16) (aged 1\u201322 years) and healthy matched control subjects (n = 24) (aged 1\u201319 years) were obtained and compared after institutional review board approval. Protein levels of CCM and control plasma were analyzed using the Olink Proximity Extension Assay (PEA), and ELISA was used to confirm findings. Patient-derived primary cells and CCM tissues were stained for YES1. CCM tissues were sequenced to evaluate the mutational profile of YES1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Compared to healthy controls, patients with CCM showed significantly higher levels of plasma YES1 (approximately 4.5-fold higher, p = 0.002). Analysis confirmed the presence of YES1 in the source CCM tissue, linking pathology with putative biomarker expression. Whole exome sequencing (WES) revealed functional mutations in the gene encoding for YES1, providing an avenue of investigation to explore and to explain the overexpression of YES1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Here, for the first time, the authors present a putative diagnostic biomarker for CCM, YES1, that was demonstrated to be significantly elevated in the plasma of affected patients, with high correlative expression in the source tissue. Together, these data further support the development of CCM-related noninvasive biomarkers and may add insight into their pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3171\/2026.4.peds2681","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:01:28Z","timestamp":1788307288000},"page":"633-641","source":"Crossref","is-referenced-by-count":0,"title":["YES1, a plasma-based biomarker for cavernous malformations"],"prefix":"10.3171","volume":"38","author":[{"given":"Yousef","family":"Hattar","sequence":"first","affiliation":[{"name":"Vascular Biology Program, Boston Children\u2019s Hospital, Harvard Medical School, Boston;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Sesen","sequence":"additional","affiliation":[{"name":"Vascular Biology Program, Boston Children\u2019s Hospital, Harvard Medical School, Boston;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyra","family":"Martinez","sequence":"additional","affiliation":[{"name":"Vascular Biology Program, Boston Children\u2019s Hospital, Harvard Medical School, Boston;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Lupieri","sequence":"additional","affiliation":[{"name":"Cardiovascular Division Brigham and Women\u2019s Hospital, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Shan","family":"Lang","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery Children\u2019s Hospital of Philadelphia, Philadelphia;"},{"name":"Department of Neurosurgery Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory G.","family":"Heuer","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery Children\u2019s Hospital of Philadelphia, Philadelphia;"},{"name":"Department of Neurosurgery Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery Children\u2019s Hospital of Philadelphia, Philadelphia;"},{"name":"Department of Neurosurgery Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Vascular Biology Program, Boston Children\u2019s Hospital, Harvard Medical School, Boston;"},{"name":"Department of Surgery Boston Children\u2019s Hospital, Harvard Medical School, Boston; and"},{"name":"Department of Neurosurgery Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aram","family":"Ghalali","sequence":"additional","affiliation":[{"name":"Vascular Biology Program, Boston Children\u2019s Hospital, Harvard Medical School, Boston;"},{"name":"Department of Surgery Boston Children\u2019s Hospital, Harvard Medical School, Boston; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"11","key":"b1","series-title":"N Engl J Med","first-page":"1022","article-title":"Cavernous malformations of the central nervous system","volume":"390","author":"Smith ER","year":"2024","unstructured":"Smith ER. Cavernous malformations of the central nervous system. N Engl J Med. 2024;390(11):1022\u20131028. doi:10.1056\/NEJMra2305116"},{"issue":"2","key":"b2","series-title":"Lancet Neurol","first-page":"166","article-title":"Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data","volume":"15","author":"Horne MA","year":"2016","unstructured":"Horne MA, Flemming KD, Su IC,  Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15(2):166\u2013173. doi:10.1016\/S1474-4422(15)00303-8"},{"key":"b3","series-title":"BMJ","first-page":"b3016","article-title":"Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis","volume":"339","author":"Morris Z","year":"2009","unstructured":"Morris Z, Whiteley WN, Longstreth WT Jr,  Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009;339:b3016. doi:10.1136\/bmj.b3016"},{"issue":"5","key":"b4","series-title":"J Neurosurg","first-page":"1188","article-title":"Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort","volume":"120","author":"Moore SA","year":"2014","unstructured":"Moore SA, Brown RD Jr, Christianson TJ, Flemming KD. Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort. J Neurosurg. 2014;120(5):1188\u20131192. doi:10.3171\/2014.1.JNS131619"},{"issue":"5","key":"b5","series-title":"Neurosurgery","first-page":"665","article-title":"Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel","volume":"80","author":"Akers A","year":"2017","unstructured":"Akers A, Al-Shahi Salman R, A Awad I,  Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery. 2017;80(5):665\u2013680. doi:10.1093\/neuros\/nyx091"},{"issue":"9","key":"b6","series-title":"Radiol Med","first-page":"695","article-title":"Is MRI imaging in pediatric age totally safe? A critical reprisal","volume":"123","author":"Salerno S","year":"2018","unstructured":"Salerno S, Granata C, Trapenese M,  Is MRI imaging in pediatric age totally safe? A critical reprisal. Radiol Med. 2018;123(9):695\u2013702. doi:10.1007\/s11547-018-0896-1"},{"issue":"11","key":"b7","series-title":"Pediatr Radiol","first-page":"1353","article-title":"Paediatric MRI under sedation: is it necessary? What is the evidence for the alternatives?","volume":"41","author":"Edwards AD","year":"2011","unstructured":"Edwards AD, Arthurs OJ. Paediatric MRI under sedation: is it necessary? What is the evidence for the alternatives? Pediatr Radiol. 2011;41(11):1353\u20131364. doi:10.1007\/s00247-011-2147-7"},{"issue":"14","key":"b8","series-title":"Cancer Res","first-page":"3716","article-title":"Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma","volume":"74","author":"Akino T","year":"2014","unstructured":"Akino T, Han X, Nakayama H,  Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma. Cancer Res. 2014;74(14):3716\u20133726. doi:10.1158\/0008-5472.CAN-13-3116"},{"key":"b9","series-title":"Front Neurosci","first-page":"1442110","article-title":"Lectin-type oxidized LDL receptor-1 as a potential therapeutic target for cerebral cavernous malformations treatment","volume":"18","author":"Ashok K","year":"2024","unstructured":"Ashok K, Martinez T, Sesen J,  Lectin-type oxidized LDL receptor-1 as a potential therapeutic target for cerebral cavernous malformations treatment. Front Neurosci. 2024;18:1442110. doi:10.3389\/fnins.2024.1442110"},{"issue":"1","key":"b10","series-title":"Sci Rep","first-page":"19244","article-title":"Disease specific urinary biomarkers in the central nervous system","volume":"13","author":"Duggins-Warf M","year":"2023","unstructured":"Duggins-Warf M, Ghalali A, Sesen J,  Disease specific urinary biomarkers in the central nervous system. Sci Rep. 2023;13(1):19244. doi:10.1038\/s41598-023-46763-z"},{"issue":"4","key":"b11","series-title":"Exp Mol Med","first-page":"658","article-title":"Dysregulation of the EphrinB2-EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients","volume":"52","author":"Fehnel KP","year":"2020","unstructured":"Fehnel KP, Penn DL, Duggins-Warf M,  Dysregulation of the EphrinB2-EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients. Exp Mol Med. 2020;52(4):658\u2013671. doi:10.1038\/s12276-020-0414-0"},{"issue":"4","key":"b12","series-title":"J Neurosurg Pediatr","first-page":"396","article-title":"Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature","volume":"18","author":"Pricola Fehnel K","year":"2016","unstructured":"Pricola Fehnel K, Duggins-Warf M, Zurakowski D,  Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature. J Neurosurg Pediatr. 2016;18(4):396\u2013407. doi:10.3171\/2015.12.PEDS15448"},{"key":"b13","series-title":"Front Neurol","first-page":"661952","article-title":"Non-invasive urinary biomarkers in moyamoya disease","volume":"12","author":"Sesen J","year":"2021","unstructured":"Sesen J, Driscoll J, Moses-Gardner A, Orbach DB, Zurakowski D, Smith ER. Non-invasive urinary biomarkers in moyamoya disease. Front Neurol. 2021;12:661952. doi:10.3389\/fneur.2021.661952"},{"key":"b14","series-title":"Brain Res","first-page":"147348","article-title":"Neogenin is highly expressed in diffuse intrinsic pontine glioma and influences tumor invasion","volume":"1762","author":"Sesen J","year":"2021","unstructured":"Sesen J, Driscoll J, Shah N,  Neogenin is highly expressed in diffuse intrinsic pontine glioma and influences tumor invasion. Brain Res. 2021;1762:147348. doi:10.1016\/j.brainres.2021.147348"},{"issue":"6","key":"b15","series-title":"J Korean Neurosurg Soc","first-page":"415","article-title":"Moyamoya biomarkers","volume":"57","author":"Smith ER","year":"2015","unstructured":"Smith ER. Moyamoya biomarkers. J Korean Neurosurg Soc. 2015;57(6):415\u2013421. doi:10.3340\/jkns.2015.57.6.415"},{"issue":"8","key":"b16","series-title":"Clin Cancer Res","first-page":"2378","article-title":"Urinary biomarkers predict brain tumor presence and response to therapy","volume":"14","author":"Smith ER","year":"2008","unstructured":"Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA. Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res. 2008;14(8):2378\u20132386. doi:10.1158\/1078-0432.CCR-07-1253"},{"key":"b17","series-title":"Front Mol Neurosci","first-page":"1185021","article-title":"Olink proteomics profiling platform reveals non-invasive inflammatory related protein biomarkers in autism spectrum disorder","volume":"16","author":"Bao XH","year":"2023","unstructured":"Bao XH, Chen BF, Liu J,  Olink proteomics profiling platform reveals non-invasive inflammatory related protein biomarkers in autism spectrum disorder. Front Mol Neurosci. 2023;16:1185021. doi:10.3389\/fnmol.2023.1185021"},{"issue":"5","key":"b18","series-title":"Am J Alzheimers Dis Other Demen","first-page":"290","article-title":"Plasma biomarkers: potent screeners of Alzheimer\u2019s disease","volume":"34","author":"Naveed M","year":"2019","unstructured":"Naveed M, Mubeen S, Khan A, Ibrahim S, Meer B. Plasma biomarkers: potent screeners of Alzheimer\u2019s disease. Am J Alzheimers Dis Other Demen. 2019;34(5):290\u2013301. doi:10.1177\/1533317519848239"},{"issue":"1","key":"b19","series-title":"Cardiovasc Diabetol","first-page":"140","article-title":"Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases","volume":"18","author":"Lorenzo-Almor\u00f3s A","year":"2019","unstructured":"Lorenzo-Almor\u00f3s A, Hang T, Peir\u00f3 C,  Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases. Cardiovasc Diabetol. 2019;18(1):140. doi:10.1186\/s12933-019-0935-9"},{"key":"b20","series-title":"Clin Chim Acta","first-page":"117798","article-title":"Urinary biomarkers in kidney disease","volume":"555","author":"Canki E","year":"2024","unstructured":"Canki E, Kho E, Hoenderop JGJ. Urinary biomarkers in kidney disease. Clin Chim Acta. 2024;555:117798. doi:10.1016\/j.cca.2024.117798"},{"issue":"1","key":"b21","series-title":"Cell Mol Neurobiol","first-page":"12","article-title":"Discovery and characterization of Ephrin B2 and EphB4 dysregulation and novel mutations in cerebral cavernous malformations: in vitro and patient-derived evidence of ephrin-mediated endothelial cell pathophysiology","volume":"44","author":"Sesen J","year":"2023","unstructured":"Sesen J, Ghalali A, Driscoll J,  Discovery and characterization of Ephrin B2 and EphB4 dysregulation and novel mutations in cerebral cavernous malformations: in vitro and patient-derived evidence of ephrin-mediated endothelial cell pathophysiology. Cell Mol Neurobiol. 2023;44(1):12. doi:10.1007\/s10571-023-01447-0"},{"issue":"7727","key":"b22","series-title":"Nature","first-page":"367","article-title":"Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris","volume":"562","year":"2018","unstructured":"Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018;562(7727):367\u2013372. doi:10.1038\/s41586-018-0590-4"},{"issue":"Pt 7","key":"b23","series-title":"J Cell Sci","first-page":"965","article-title":"Differential trafficking of Src, Lyn, Yes and Fyn is specified by the state of palmitoylation in the SH4 domain","volume":"122","author":"Sato I","year":"2009","unstructured":"Sato I, Obata Y, Kasahara K,  Differential trafficking of Src, Lyn, Yes and Fyn is specified by the state of palmitoylation in the SH4 domain. J Cell Sci. 2009;122(Pt 7):965\u2013975. doi:10.1242\/jcs.034843"},{"issue":"12","key":"b24","series-title":"Nat Cardiovasc Res","first-page":"1156","article-title":"Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis","volume":"1","author":"Jin Y","year":"2022","unstructured":"Jin Y, Ding Y, Richards M,  Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis. Nat Cardiovasc Res. 2022;1(12):1156\u20131173. doi:10.1038\/s44161-022-00172-z"},{"issue":"6","key":"b25","series-title":"Mol Cell","first-page":"915","article-title":"Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability","volume":"4","author":"Eliceiri BP","year":"1999","unstructured":"Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell. 1999;4(6):915\u2013924. doi:10.1016\/s1097-2765(00)80221-x"},{"issue":"4","key":"b26","series-title":"PLoS One","first-page":"e95192","article-title":"Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability","volume":"9","author":"Assarsson E","year":"2014","unstructured":"Assarsson E, Lundberg M, Holmquist G,  Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014;9(4):e95192. doi:10.1371\/journal.pone.0095192"},{"key":"b27","series-title":"GitHub.com","article-title":"Olink R package","unstructured":"Olink R package. GitHub.com. Accessed July 2, 2026. https:\/\/github.com\/Olink-Proteomics\/OlinkRPackage"},{"key":"b28","series-title":"R Project","article-title":"Olink Analyze Vignette","unstructured":"Olink Analyze Vignette. R Project. Accessed July 2, 2026. https:\/\/cran.r-project.org\/web\/packages\/OlinkAnalyze\/vignettes\/OlinkAnalyze-Vignette.html"},{"issue":"1","key":"b29","series-title":"J Exp Clin Cancer Res","first-page":"56","article-title":"AZIN1 level is increased in medulloblastoma and correlates with c-Myc activity and tumor phenotype","volume":"44","author":"Sesen J","year":"2025","unstructured":"Sesen J, Martinez T, Busatto S,  AZIN1 level is increased in medulloblastoma and correlates with c-Myc activity and tumor phenotype. J Exp Clin Cancer Res. 2025;44(1):56. doi:10.1186\/s13046-025-03274-1"},{"issue":"49","key":"b30","series-title":"Oncogene","first-page":"5636","article-title":"Role of Src expression and activation in human cancer","volume":"19","author":"Irby RB","year":"2000","unstructured":"Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000;19(49):5636\u20135642. doi:10.1038\/sj.onc.1203912"},{"key":"b31","series-title":"Annu Rev Cell Dev Biol","first-page":"513","article-title":"Cellular functions regulated by Src family kinases","volume":"13","author":"Thomas SM","year":"1997","unstructured":"Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997;13:513\u2013609. doi:10.1146\/annurev.cellbio.13.1.513"},{"issue":"7537","key":"b32","series-title":"Nature","first-page":"111","article-title":"Optogenetic control of organelle transport and positioning","volume":"518","author":"van Bergeijk P","year":"2015","unstructured":"van Bergeijk P, Adrian M, Hoogenraad CC, Kapitein LC. Optogenetic control of organelle transport and positioning. Nature. 2015;518(7537):111\u2013114. doi:10.1038\/nature14128"},{"issue":"1","key":"b33","series-title":"Int J Oncol","first-page":"302","article-title":"The role of Src family kinases in growth and migration of glioma stem cells","volume":"45","author":"Han X","year":"2014","unstructured":"Han X, Zhang W, Yang X,  The role of Src family kinases in growth and migration of glioma stem cells. Int J Oncol. 2014;45(1):302\u2013310. doi:10.3892\/ijo.2014.2432"},{"issue":"10","key":"b34","series-title":"Oncogene","first-page":"2627","article-title":"Cartwright CA. c-Yes tyrosine kinase activity in human colon carcinoma","volume":"8","author":"Park J","year":"1993","unstructured":"Park J, Meisler AI. Cartwright CA. c-Yes tyrosine kinase activity in human colon carcinoma. Oncogene. 1993;8(10):2627\u20132635."},{"issue":"9","key":"b35","series-title":"Mol Cancer Ther","first-page":"1371","article-title":"YES1: a novel therapeutic target and biomarker in cancer","volume":"21","author":"Garmendia I","year":"2022","unstructured":"Garmendia I, Redin E, Montuenga LM, Calvo A. YES1: a novel therapeutic target and biomarker in cancer. Mol Cancer Ther. 2022;21(9):1371\u20131380. doi:10.1158\/1535-7163.MCT-21-0958"}],"container-title":["Journal of Neurosurgery: Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg-pediatr\/38\/5\/article-p633.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg-pediatr\/38\/5\/article-p633.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg-pediatr\/38\/5\/article-p633.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T14:50:37Z","timestamp":1793976637000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg-pediatr\/38\/5\/article-p633.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":35,"journal-issue":{"issue":"5"},"URL":"https:\/\/doi.org\/10.3171\/2026.4.peds2681","relation":{},"ISSN":["1933-0707","1933-0715"],"issn-type":[{"value":"1933-0707","type":"print"},{"value":"1933-0715","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}