{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:30:19Z","timestamp":1740148219325,"version":"3.37.3"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Transl Oncol"],"published-print":{"date-parts":[[2022,1]]},"DOI":"10.1007\/s12094-021-02663-0","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T13:02:54Z","timestamp":1624280574000},"page":"13-23","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The inverse paradigm and the ancestral cell of IDH-wildtype glioblastoma"],"prefix":"10.1007","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-6041","authenticated-orcid":false,"given":"Enrico","family":"Brognaro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"2663_CR1","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1056\/NEJMoa043330","volume":"352","author":"M Stupp","year":"2005","unstructured":"Stupp M, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:997\u20131003.","journal-title":"N Engl J Med"},{"issue":"61","key":"2663_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3897\/folmed.61.e34900","volume":"1","author":"E Brognaro","year":"2019","unstructured":"Brognaro E. Glioblastoma unique features drive the ways for innovative therapies in the trunk-branch era. Folia Med. 2019;1(61):7\u201325.","journal-title":"Folia Med"},{"key":"2663_CR3","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1101\/gr.180612.114","volume":"25","author":"H Kim","year":"2015","unstructured":"Kim H, Zheng S, Amini SS, et al. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res. 2015;25:316\u201327.","journal-title":"Genome Res"},{"issue":"3","key":"2663_CR4","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.ccell.2015.07.013","volume":"28","author":"J Kim","year":"2015","unstructured":"Kim J, Lee IH, Cho HJ, et al. Spatiotemporal evolution of the primary glioblastoma genome. Cancer Cell. 2015;28(3):318\u201328.","journal-title":"Cancer Cell"},{"issue":"4","key":"2663_CR5","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1093\/neuonc\/now231","volume":"19","author":"K Abou-El-Ardat","year":"2017","unstructured":"Abou-El-Ardat K, Seifert M, Becker K, et al. Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas. Neuro Oncol. 2017;19(4):546\u201357.","journal-title":"Neuro Oncol"},{"key":"2663_CR6","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1093\/annonc\/mdy506","volume":"30","author":"I Spiteri","year":"2019","unstructured":"Spiteri I, Caravagna G, Cresswell GD, et al. Evolutionary dynamics of residual disease in human glioblastoma. Ann of Oncol. 2019;30:456\u201363.","journal-title":"Ann of Oncol"},{"issue":"1","key":"2663_CR7","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1158\/0008-5472.CAN-13-3131","volume":"75","author":"SGM Piccirillo","year":"2015","unstructured":"Piccirillo SGM, Spiteri I, Sottoriva A, et al. Contributions to drug resistance in glioblastoma derived from malignant cells in the sub-ependymal zone. Cancer Res. 2015;75(1):194\u2013202.","journal-title":"Cancer Res"},{"issue":"Suppl3","key":"2663_CR8","doi-asserted-by":"publisher","first-page":"iii70","DOI":"10.1093\/neuonc\/nox036.262","volume":"19","author":"E Brognaro","year":"2017","unstructured":"Brognaro E. Glioblastoma unique aspects dictate the ways to overcome the two causes of resistance to current therapy and find future effective treatments in the trunk-branch era. Neuro Oncol. 2017;19(Suppl3):iii70-71.","journal-title":"Neuro Oncol"},{"issue":"suppl3","key":"2663_CR9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1093\/neuonc\/noy139.051","volume":"20","author":"E Brognaro","year":"2018","unstructured":"Brognaro E. Micro-infiltration before growth: the inverse paradigm of primary glioblastoma is crucial to overcome resistance and develop effective therapies. Neuro Oncol. 2018;20(suppl3):229\u201330.","journal-title":"Neuro Oncol"},{"issue":"suppl3","key":"2663_CR10","doi-asserted-by":"publisher","first-page":"iii70","DOI":"10.1093\/neuonc\/noz126.254","volume":"21","author":"E Brognaro","year":"2019","unstructured":"Brognaro E. The inverse paradigm of IDH-wildtype glioblastoma is fundamental to overcome the two causes of resistance and develop novel effective therapies. Neuro Oncol. 2019;21(suppl3):iii70.","journal-title":"Neuro Oncol"},{"issue":"7","key":"2663_CR11","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41583-018-0014-3","volume":"19","author":"D Laug","year":"2018","unstructured":"Laug D, Glasgow SM, Deneen B. A glial blueprint for gliomagenesis. Nat Rev Neurosci. 2018;19(7):393\u2013403.","journal-title":"Nat Rev Neurosci"},{"key":"2663_CR12","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1101\/gad.188326.112","volume":"26","author":"AV Molofsky","year":"2012","unstructured":"Molofsky AV, Krenick R, Ullian E, et al. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 2012;26:891\u2013907.","journal-title":"Genes Dev"},{"key":"2663_CR13","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1159\/000072269","volume":"25","author":"CT Jacobsen","year":"2003","unstructured":"Jacobsen CT, Miller RH. Control of astrocyte migration in the developing cerebral cortex. Dev Neurosci. 2003;25:207\u201316.","journal-title":"Dev Neurosci"},{"key":"2663_CR14","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1002\/cne.902920213","volume":"292","author":"HF Zhou","year":"1990","unstructured":"Zhou HF, Lee LH, Lund RD. Timing and patterns of astrocyte migration from xenogenic transplants of the cortex and corpus callosum. J Comp Neurol. 1990;292:320\u201330.","journal-title":"J Comp Neurol"},{"issue":"10","key":"2663_CR15","doi-asserted-by":"publisher","first-page":"4009","DOI":"10.1073\/pnas.1219747110","volume":"110","author":"A Sottoriva","year":"2013","unstructured":"Sottoriva A, Spiteri I, Piccirillo SGM, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. PNAS. 2013;110(10):4009\u201314.","journal-title":"PNAS"},{"key":"2663_CR16","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s11060-014-1695-8","volume":"122","author":"J-M Lem\u00e9e","year":"2015","unstructured":"Lem\u00e9e J-M, Clavreul A, Aubry M, et al. Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis. J Neurooncol. 2015;122:53\u201361.","journal-title":"J Neurooncol"},{"key":"2663_CR17","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1002\/stem.1349","volume":"31","author":"P Ruiz-Onta\u0148on","year":"2013","unstructured":"Ruiz-Onta\u0148on P, Orgaz JL, Aldaz B, et al. Cellular plasticity confers migratory and invasive advantages to a population of glioblastoma-initiating cells that infiltrate peritumoral tissue. Stem Cells. 2013;31:1075\u201385.","journal-title":"Stem Cells"},{"issue":"7717","key":"2663_CR18","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/s41586-018-0389-3","volume":"560","author":"JH Lee","year":"2018","unstructured":"Lee JH, Lee JE, Khnag JY, et al. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature. 2018;560(7717):243\u20137.","journal-title":"Nature"},{"issue":"4","key":"2663_CR19","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.ccell.2019.02.007","volume":"35","author":"V K\u00f6rber","year":"2019","unstructured":"K\u00f6rber V, Yang J, Barah P, et al. Evolutionary trajectories of IDHwt glioblastomas reveal a common path of early tumorigenesis instigated years ahead of initial diagnosis. Cancer Cell. 2019;35(4):692\u2013704.","journal-title":"Cancer Cell"},{"issue":"3","key":"2663_CR20","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s00401-015-1454-8","volume":"130","author":"DE Reuss","year":"2015","unstructured":"Reuss DE, Kratz A, Sahm F, et al. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neurophatol. 2015;130(3):407\u201317.","journal-title":"Acta Neurophatol"},{"issue":"6","key":"2663_CR21","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1093\/jnen\/nly012","volume":"77","author":"M Hasselblatt","year":"2018","unstructured":"Hasselblatt M, Jaber M, Reuss D, et al. Diffuse astrocytoma, IDH-wildtype: a dissolving diagnosis. J Neuropathol Exp Neurol. 2018;77(6):422\u20135.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"60","key":"2663_CR22","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1515\/folmed-2017-0069","volume":"1","author":"GS Stoyanov","year":"2018","unstructured":"Stoyanov GS, Dzhenkov DL. On the concepts and history of glioblastoma multiforme \u2013 morphology, genetics and epigenetics. Folia Med. 2018;1(60):48\u201366.","journal-title":"Folia Med"},{"issue":"11","key":"2663_CR23","first-page":"e61482","volume":"11","author":"GS Stoyanov","year":"2019","unstructured":"Stoyanov GS, Petkova L, Dzhenkov DL, et al. Hans Joachim Sherer and his impact on the diagnostic, clinical, and modern reasearch aspects of glial tumors. Cureus. 2019;11(11):e61482.","journal-title":"Cureus"},{"issue":"5","key":"2663_CR24","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00401-018-1913-0","volume":"136","author":"DJ Brat","year":"2018","unstructured":"Brat DJ, Aldape K, Colman H, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for \u201cDiffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.\u201d Acta Neuropathol. 2018;136(5):805\u201310.","journal-title":"Acta Neuropathol"},{"issue":"6979","key":"2663_CR25","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/nature02301","volume":"426","author":"N Sanai","year":"2004","unstructured":"Sanai N, Tramontin AD, Hinojosa Q, et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;426(6979):740\u20134.","journal-title":"Nature"},{"issue":"3","key":"2663_CR26","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1002\/cne.20798","volume":"494","author":"A Quinones-Hinojosa","year":"2006","unstructured":"Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells. J Comp Neurol. 2006;494(3):415\u201334.","journal-title":"J Comp Neurol"},{"issue":"6","key":"2663_CR27","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","volume":"131","author":"DN Louis","year":"2016","unstructured":"Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803\u201320.","journal-title":"Acta Neuropathol"},{"issue":"19","key":"2663_CR28","doi-asserted-by":"publisher","first-page":"7011","DOI":"10.1158\/0008-5472.CAN-04-1364","volume":"64","author":"R Galli","year":"2004","unstructured":"Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011\u201321.","journal-title":"Cancer Res"},{"key":"2663_CR29","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1158\/0008-5472.CAN-07-6867","volume":"68","author":"C-H Kwon","year":"2008","unstructured":"Kwon C-H, Zhao D, Chen J, et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res. 2008;68:3286\u201394.","journal-title":"Cancer Res"},{"key":"2663_CR30","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ccr.2008.12.006","volume":"15","author":"RS Alcantara Llaguno","year":"2009","unstructured":"Alcantara Llaguno RS, Chen J, Kwon C-H, et al. Malignant astrocytomas originate from neural stem\/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell. 2009;15:45\u201356.","journal-title":"Cancer Cell"},{"key":"2663_CR31","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.ccell.2015.09.007","volume":"28","author":"RS Alcantara Llaguno","year":"2015","unstructured":"Alcantara Llaguno RS, Wang Z, Sun D, et al. Adult lineage-restricted progenitors specify distinct glioblastoma subtypes. Cancer Cell. 2015;28:429\u201340.","journal-title":"Cancer Cell"},{"issue":"6","key":"2663_CR32","doi-asserted-by":"publisher","first-page":"386","DOI":"10.2183\/pjab.93.024","volume":"93","author":"BJ Takouda","year":"2017","unstructured":"Takouda BJ, Katada S, Nakashima K. Emerging mechanisms underlying astrogenesis in the developing mammalian brain. Proc Jpn Acad. 2017;93(6):386\u201398.","journal-title":"Proc Jpn Acad"},{"issue":"1","key":"2663_CR33","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/s40478-019-0801-8","volume":"7","author":"A Reinhardt","year":"2019","unstructured":"Reinhardt A, Stichel D, Schrimpf D, et al. Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities. Acta Neuropathol Comm. 2019;7(1):163.","journal-title":"Acta Neuropathol Comm"},{"key":"2663_CR34","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1093\/neuonc\/noy123","volume":"21","author":"HJ Cho","year":"2019","unstructured":"Cho HJ, Zhao J, Jung SW, et al. Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma. Neuro Oncol. 2019;21:47\u201358.","journal-title":"Neuro Oncol"},{"issue":"Suppl6","key":"2663_CR35","doi-asserted-by":"publisher","first-page":"S553","DOI":"10.21037\/tcr.2019.08.24","volume":"8","author":"MS Tora","year":"2019","unstructured":"Tora MS, Adamson DC. Discernable differences in the genetic and molecular profile of cerebellar glioblastoma. Transl Cancer Res. 2019;8(Suppl6):S553\u20138.","journal-title":"Transl Cancer Res"},{"key":"2663_CR36","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1007\/s00401-017-1771-1","volume":"134","author":"M Nomura","year":"2017","unstructured":"Nomura M, Mukasa A, Nagae G, et al. Distinct molecular profile of diffuse cerebellar gliomas. Acta Neuropathol. 2017;134:941\u201356.","journal-title":"Acta Neuropathol"},{"key":"2663_CR37","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1111\/eva.12017","volume":"6","author":"M Greaves","year":"2013","unstructured":"Greaves M. Cancer stem cells as \u201cunits of selection.\u201d Evol Appl. 2013;6:102\u20138.","journal-title":"Evol Appl"},{"issue":"3","key":"2663_CR38","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.ccr.2006.02.019","volume":"9","author":"HS Phillips","year":"2006","unstructured":"Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157\u201373.","journal-title":"Cancer Cell"},{"issue":"1","key":"2663_CR39","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","volume":"17","author":"RGW Verhaak","year":"2010","unstructured":"Verhaak RGW, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98\u2013110.","journal-title":"Cancer Cell"},{"issue":"1","key":"2663_CR40","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.ccell.2017.06.003","volume":"32","author":"Q Wang","year":"2017","unstructured":"Wang Q, Hu B, Hu X, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2017;32(1):42\u201356.","journal-title":"Cancer Cell"},{"issue":"4","key":"2663_CR41","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","volume":"178","author":"C Neftel","year":"2019","unstructured":"Neftel C, Laffy J, Filbin MG, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178(4):835-49e21.","journal-title":"Cell"},{"issue":"2","key":"2663_CR42","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/j.celrep.2018.03.107","volume":"23","author":"CF de Souza","year":"2018","unstructured":"de Souza CF, Sabedot TS, Malta TM, et al. A distinct DNA methylation shift in a subset of glioma CpG island methylator phenotypes during tumor recurrence. Cell Rep. 2018;23(2):637\u201351.","journal-title":"Cell Rep"},{"key":"2663_CR43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.stemcr.2014.10.016","volume":"4","author":"SGM Piccirillo","year":"2015","unstructured":"Piccirillo SGM, Colman S, Potter NE, et al. Genetic and functional diversity of propagating cells in glioblastoma. Stem Cells Reports. 2015;4:1\u20139.","journal-title":"Stem Cells Reports"},{"issue":"1","key":"2663_CR44","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1200\/JCO.19.00367","volume":"38","author":"K Draaisma","year":"2020","unstructured":"Draaisma K, Chatzipli A, Taphoom M, et al. Molecular evolution of IDH wild-type glioblastomas treated with standard of care affects survival and design precision medicine trials: a report from the EORTC 1542 study. J Clin Oncol. 2020;38(1):81\u201399.","journal-title":"J Clin Oncol"},{"key":"2663_CR45","first-page":"232561","volume":"2014","author":"A DellaPuppa","year":"2014","unstructured":"DellaPuppa A, Ciccarino P, Lombardi G, et al. 5-aminolevulinic acid fluorescence in high grade glioma surgery: surgical outcome, intraoperative findings, and fluorescence patterns. Biomed Res Int. 2014;2014:232561.","journal-title":"Biomed Res Int"},{"issue":"3","key":"2663_CR46","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1093\/nop\/npu011","volume":"1","author":"SK Kim","year":"2014","unstructured":"Kim SK, Choi SH, Kim YH, et al. Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients. Neuro Oncol Practice. 2014;1(3):81\u20135.","journal-title":"Neuro Oncol Practice"}],"container-title":["Clinical and Translational Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-021-02663-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12094-021-02663-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-021-02663-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T07:23:00Z","timestamp":1675495380000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12094-021-02663-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,21]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["2663"],"URL":"https:\/\/doi.org\/10.1007\/s12094-021-02663-0","relation":{},"ISSN":["1699-048X","1699-3055"],"issn-type":[{"type":"print","value":"1699-048X"},{"type":"electronic","value":"1699-3055"}],"subject":[],"published":{"date-parts":[[2021,6,21]]},"assertion":[{"value":"30 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This article does not contain any studies with human participants or animals performed by the author.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"For this type of study, formal consent is not required.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}