{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:12:51Z","timestamp":1790374371001,"version":"4.1.0"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,8,5]],"date-time":"2023-08-05T00:00:00Z","timestamp":1691193600000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2019-12370334"],"award-info":[{"award-number":["RF-2019-12370334"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009882","name":"Regione Lombardia","doi-asserted-by":"publisher","award":["TRANS-ALS"],"award-info":[{"award-number":["TRANS-ALS"]}],"id":[{"id":"10.13039\/501100009882","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell. Mol. Life Sci."],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the<jats:italic>SMN1<\/jats:italic>gene resulting in reduced levels of the SMN protein. Nusinersen, the first antisense oligonucleotide (ASO) approved for SMA treatment, binds to the<jats:italic>SMN2<\/jats:italic>gene, paralogue to<jats:italic>SMN1<\/jats:italic>, and mediates the translation of a functional SMN protein. Here, we used longitudinal high-resolution mass spectrometry (MS) to assess both global proteome and metabolome in cerebrospinal fluid (CSF) from ten SMA type 3 patients, with the aim of identifying novel readouts of pharmacodynamic\/response to treatment and predictive markers of treatment response. Patients had a median age of 33.5 [29.5; 38.25] years, and 80% of them were ambulant at time of the enrolment, with a median HFMSE score of 37.5 [25.75; 50.75]. Untargeted CSF proteome and metabolome were measured using high-resolution MS (nLC-HRMS) on CSF samples obtained before treatment (T0) and after 2\u00a0years of follow-up (T22). A total of 26 proteins were found to be differentially expressed between T0 and T22 upon VSN normalization and LIMMA differential analysis, accounting for paired replica. Notably, key markers of the insulin-growth factor signaling pathway were upregulated after treatment together with selective modulation of key transcription regulators. Using CombiROC multimarker signature analysis, we suggest that detecting a reduction of SEMA6A and an increase of COL1A2 and GRIA4 might reflect therapeutic efficacy of nusinersen. Longitudinal metabolome profiling, analyzed with paired<jats:italic>t<\/jats:italic>-Test, showed a significant shift for some aminoacid utilization induced by treatment, whereas other metabolites were largely unchanged. Together, these data suggest perturbation upon nusinersen treatment still sustained after 22\u00a0months of follow-up and confirm the utility of CSF multi-omic profiling as pharmacodynamic biomarker for SMA type 3. Nonetheless, validation studies are needed to confirm this evidence in a larger sample size and to further dissect combined markers of response to treatment.<\/jats:p>","DOI":"10.1007\/s00018-023-04885-7","type":"journal-article","created":{"date-parts":[[2023,8,5]],"date-time":"2023-08-05T17:01:22Z","timestamp":1691254882000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Multi-omics profiling of CSF from spinal muscular atrophy type 3 patients after nusinersen treatment: a 2-year follow-up multicenter retrospective study"],"prefix":"10.1007","volume":"80","author":[{"given":"Irene","family":"Faravelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Gagliardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Abati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megi","family":"Meneri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Ongaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Magri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Parente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Petrozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ricci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorenza","family":"Far\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Garrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Fontana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Caruso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Siciliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Govoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-969X","authenticated-orcid":false,"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Ottoboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,5]]},"reference":[{"key":"4885_CR1","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1002\/ana.25101","volume":"82","author":"SJ Kolb","year":"2017","unstructured":"Kolb SJ, Coffey CS, Yankey JW et al (2017) Natural history of infantile-onset spinal muscular atrophy. Ann Neurol 82:883\u2013891. https:\/\/doi.org\/10.1002\/ana.25101","journal-title":"Ann Neurol"},{"key":"4885_CR2","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1002\/nbm.3369","volume":"28","author":"C Calcagno","year":"2015","unstructured":"Calcagno C, Lobatto ME, Dyvorne H et al (2015) Three-dimensional dynamic contrast-enhanced MRI for the accurate, extensive quantification of microvascular permeability in atherosclerotic plaques. NMR Biomed 28:1304\u20131314. https:\/\/doi.org\/10.1002\/nbm.3369","journal-title":"NMR Biomed"},{"key":"4885_CR3","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","volume":"80","author":"S Lefebvre","year":"1995","unstructured":"Lefebvre S, B\u00fcrglen L, Reboullet S et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155\u2013165. https:\/\/doi.org\/10.1016\/0092-8674(95)90460-3","journal-title":"Cell"},{"key":"4885_CR4","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/nrneurol.2015.77","volume":"11","author":"I Faravelli","year":"2015","unstructured":"Faravelli I, Nizzardo M, Comi GP, Corti S (2015) Spinal muscular atrophy\u2013recent therapeutic advances for an old challenge. Nat Rev Neurol 11:351\u2013359. https:\/\/doi.org\/10.1038\/nrneurol.2015.77","journal-title":"Nat Rev Neurol"},{"key":"4885_CR5","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1007\/s00018-015-2106-9","volume":"73","author":"C Simone","year":"2016","unstructured":"Simone C, Ramirez A, Bucchia M et al (2016) Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications? Cell Mol Life Sci 73:1003\u20131020. https:\/\/doi.org\/10.1007\/s00018-015-2106-9","journal-title":"Cell Mol Life Sci"},{"key":"4885_CR6","doi-asserted-by":"publisher","first-page":"104870","DOI":"10.1016\/j.nbd.2020.104870","volume":"140","author":"E Abati","year":"2020","unstructured":"Abati E, Citterio G, Bresolin N et al (2020) Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease? Neurobiol Dis 140:104870. https:\/\/doi.org\/10.1016\/j.nbd.2020.104870","journal-title":"Neurobiol Dis"},{"key":"4885_CR7","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/s0959-437x(02)00301-5","volume":"12","author":"T Frugier","year":"2002","unstructured":"Frugier T, Nicole S, Cifuentes-Diaz C, Melki J (2002) The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev 12:294\u2013298. https:\/\/doi.org\/10.1016\/s0959-437x(02)00301-5","journal-title":"Curr Opin Genet Dev"},{"key":"4885_CR8","doi-asserted-by":"publisher","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","volume":"96","author":"CL Lorson","year":"1999","unstructured":"Lorson CL, Hahnen E, Androphy EJ, Wirth B (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 96:6307\u20136311. https:\/\/doi.org\/10.1073\/pnas.96.11.6307","journal-title":"Proc Natl Acad Sci USA"},{"key":"4885_CR9","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/1750-1172-6-71","volume":"6","author":"A D\u2019Amico","year":"2011","unstructured":"D\u2019Amico A, Mercuri E, Tiziano FD, Bertini E (2011) Spinal muscular atrophy. Orphanet J Rare Dis 6:71. https:\/\/doi.org\/10.1186\/1750-1172-6-71","journal-title":"Orphanet J Rare Dis"},{"key":"4885_CR10","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1086\/338627","volume":"70","author":"M Feldk\u00f6tter","year":"2002","unstructured":"Feldk\u00f6tter M, Schwarzer V, Wirth R et al (2002) Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 70:358\u2013368. https:\/\/doi.org\/10.1086\/338627","journal-title":"Am J Hum Genet"},{"key":"4885_CR11","doi-asserted-by":"publisher","first-page":"175628561875450","DOI":"10.1177\/1756285618754501","volume":"11","author":"V Parente","year":"2018","unstructured":"Parente V, Corti S (2018) Advances in spinal muscular atrophy therapeutics. Ther Adv Neurol Disord 11:1756285618754501. https:\/\/doi.org\/10.1177\/1756285618754501","journal-title":"Ther Adv Neurol Disord"},{"key":"4885_CR12","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/s40265-017-0711-7","volume":"77","author":"SM Hoy","year":"2017","unstructured":"Hoy SM (2017) Nusinersen: first global approval. Drugs 77:473\u2013479. https:\/\/doi.org\/10.1007\/s40265-017-0711-7","journal-title":"Drugs"},{"key":"4885_CR13","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","volume":"377","author":"RS Finkel","year":"2017","unstructured":"Finkel RS, Mercuri E, Darras BT et al (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377:1723\u20131732. https:\/\/doi.org\/10.1056\/NEJMoa1702752","journal-title":"N Engl J Med"},{"key":"4885_CR14","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/S1474-4422(20)30037-5","volume":"19","author":"T Hagenacker","year":"2020","unstructured":"Hagenacker T, Wurster CD, G\u00fcnther R et al (2020) Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Lancet Neurol 19:317\u2013325. https:\/\/doi.org\/10.1016\/S1474-4422(20)30037-5","journal-title":"Lancet Neurol"},{"key":"4885_CR15","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1186\/s13023-021-02065-z","volume":"16","author":"G Coratti","year":"2021","unstructured":"Coratti G, Cutrona C, Pera MC et al (2021) Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis. Orphanet J Rare Dis 16:430. https:\/\/doi.org\/10.1186\/s13023-021-02065-z","journal-title":"Orphanet J Rare Dis"},{"key":"4885_CR16","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1007\/s13311-022-01200-3","volume":"19","author":"M Gavriilaki","year":"2022","unstructured":"Gavriilaki M, Moschou M, Papaliagkas V et al (2022) Nusinersen in adults with 5q spinal muscular atrophy: a systematic review and meta-analysis. Neurotherapeutics 19:464\u2013475. https:\/\/doi.org\/10.1007\/s13311-022-01200-3","journal-title":"Neurotherapeutics"},{"key":"4885_CR17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.nmd.2021.12.005","volume":"32","author":"M Gavriilaki","year":"2022","unstructured":"Gavriilaki M, Moschou M, Papaliagkas V et al (2022) Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis. Neuromuscul Disord 32:185\u2013194. https:\/\/doi.org\/10.1016\/j.nmd.2021.12.005","journal-title":"Neuromuscul Disord"},{"key":"4885_CR18","doi-asserted-by":"publisher","DOI":"10.1007\/s13760-022-02028-6","author":"M Gavriilaki","year":"2022","unstructured":"Gavriilaki M, Papaliagkas V, Stamperna A et al (2022) Biomarkers of therapeutic efficacy in adolescents and adults with 5q spinal muscular atrophy: a systematic review. Acta Neurol Belg. https:\/\/doi.org\/10.1007\/s13760-022-02028-6","journal-title":"Acta Neurol Belg"},{"key":"4885_CR19","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1002\/acn3.51281","volume":"8","author":"M Annoussamy","year":"2021","unstructured":"Annoussamy M, Seferian AM, Daron A et al (2021) Natural history of type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study. Ann Clin Transl Neurol 8:359\u2013373. https:\/\/doi.org\/10.1002\/acn3.51281","journal-title":"Ann Clin Transl Neurol"},{"key":"4885_CR20","doi-asserted-by":"publisher","first-page":"119","DOI":"10.3233\/JND-150081","volume":"2","author":"SR Renusch","year":"2015","unstructured":"Renusch SR, Harshman S, Pi H et al (2015) Spinal muscular atrophy biomarker measurements from blood samples in a clinical trial of valproic acid in ambulatory adults. J Neuromuscul Dis 2:119\u2013130. https:\/\/doi.org\/10.3233\/JND-150081","journal-title":"J Neuromuscul Dis"},{"key":"4885_CR21","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1002\/acn3.406","volume":"4","author":"U Bonati","year":"2017","unstructured":"Bonati U, Holiga \u0160, Hellbach N et al (2017) Longitudinal characterization of biomarkers for spinal muscular atrophy. Ann Clin Transl Neurol 4:292\u2013304. https:\/\/doi.org\/10.1002\/acn3.406","journal-title":"Ann Clin Transl Neurol"},{"key":"4885_CR22","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1111\/ncn3.140","volume":"3","author":"T Saito","year":"2015","unstructured":"Saito T, Nurputra DK, Harahap NIF et al (2015) A Study of valproic acid for patients with spinal muscular atrophy. Neurol Clin Neurosci 3:49\u201357. https:\/\/doi.org\/10.1111\/ncn3.140","journal-title":"Neurol Clin Neurosci"},{"key":"4885_CR23","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1136\/jmedgenet-2018-105482","volume":"56","author":"FD Tiziano","year":"2019","unstructured":"Tiziano FD, Lomastro R, Abiusi E et al (2019) Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol. J Med Genet 56:293\u2013300. https:\/\/doi.org\/10.1136\/jmedgenet-2018-105482","journal-title":"J Med Genet"},{"key":"4885_CR24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139950","volume":"10","author":"C Czech","year":"2015","unstructured":"Czech C, Tang W, Bugawan T et al (2015) Biomarker for spinal muscular atrophy: expression of SMN in peripheral blood of SMA patients and healthy controls. PLoS ONE 10:e0139950. https:\/\/doi.org\/10.1371\/journal.pone.0139950","journal-title":"PLoS ONE"},{"key":"4885_CR25","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3233\/JND-210735","volume":"9","author":"KA Rich","year":"2022","unstructured":"Rich KA, Fox A, Yalvac M et al (2022) Neurofilament levels in CSF and serum in an adult SMA cohort treated with Nusinersen. J Neuromuscul Dis 9:111\u2013119. https:\/\/doi.org\/10.3233\/JND-210735","journal-title":"J Neuromuscul Dis"},{"key":"4885_CR26","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1007\/s00415-019-09547-y","volume":"267","author":"CD Wurster","year":"2020","unstructured":"Wurster CD, Steinacker P, G\u00fcnther R et al (2020) Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J Neurol 267:36\u201344. https:\/\/doi.org\/10.1007\/s00415-019-09547-y","journal-title":"J Neurol"},{"key":"4885_CR27","doi-asserted-by":"publisher","first-page":"5397","DOI":"10.3390\/ijms20215397","volume":"20","author":"A Totzeck","year":"2019","unstructured":"Totzeck A, Stolte B, Kizina K et al (2019) Neurofilament heavy chain and tau protein are not elevated in cerebrospinal fluid of adult patients with spinal muscular atrophy during loading with Nusinersen. Int J Mol Sci 20:5397. https:\/\/doi.org\/10.3390\/ijms20215397","journal-title":"Int J Mol Sci"},{"key":"4885_CR28","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1002\/acn3.779","volume":"6","author":"BT Darras","year":"2019","unstructured":"Darras BT, Crawford TO, Finkel RS et al (2019) Neurofilament as a potential biomarker for spinal muscular atrophy. Ann Clin Transl Neurol 6:932\u2013944. https:\/\/doi.org\/10.1002\/acn3.779","journal-title":"Ann Clin Transl Neurol"},{"key":"4885_CR29","doi-asserted-by":"publisher","first-page":"982760","DOI":"10.3389\/fncel.2022.982760","volume":"16","author":"S Bonanno","year":"2022","unstructured":"Bonanno S, Cavalcante P, Salvi E et al (2022) Identification of a cytokine profile in serum and cerebrospinal fluid of pediatric and adult spinal muscular atrophy patients and its modulation upon nusinersen treatment. Front Cell Neurosci 16:982760. https:\/\/doi.org\/10.3389\/fncel.2022.982760","journal-title":"Front Cell Neurosci"},{"key":"4885_CR30","doi-asserted-by":"publisher","first-page":"453","DOI":"10.3233\/JND-190416","volume":"6","author":"MC Walter","year":"2019","unstructured":"Walter MC, Wenninger S, Thiele S et al (2019) Safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3\u2014a prospective observational study. J Neuromuscul Dis 6:453\u2013465. https:\/\/doi.org\/10.3233\/JND-190416","journal-title":"J Neuromuscul Dis"},{"key":"4885_CR31","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1002\/acn3.51340","volume":"8","author":"M Freigang","year":"2021","unstructured":"Freigang M, Wurster CD, Hagenacker T et al (2021) Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment. Ann Clin Transl Neurol 8:1049\u20131063. https:\/\/doi.org\/10.1002\/acn3.51340","journal-title":"Ann Clin Transl Neurol"},{"key":"4885_CR32","doi-asserted-by":"publisher","first-page":"3034","DOI":"10.1111\/jcmm.14939","volume":"24","author":"I Faravelli","year":"2020","unstructured":"Faravelli I, Meneri M, Saccomanno D et al (2020) Nusinersen treatment and cerebrospinal fluid neurofilaments: an explorative study on Spinal Muscular Atrophy type 3 patients. J Cell Mol Med 24:3034\u20133039. https:\/\/doi.org\/10.1111\/jcmm.14939","journal-title":"J Cell Mol Med"},{"key":"4885_CR33","doi-asserted-by":"crossref","unstructured":"Quinn C, Fadda G, McMillan C, et al (2020) Effect of nusinsersen in an adult SMA cohort: CSF biomarkers and RULM (4725). Neurology 94:15","DOI":"10.1212\/WNL.94.15_supplement.4725"},{"key":"4885_CR34","doi-asserted-by":"publisher","first-page":"175628641984605","DOI":"10.1177\/1756286419846058","volume":"12","author":"CD Wurster","year":"2019","unstructured":"Wurster CD, G\u00fcnther R, Steinacker P et al (2019) Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment. Ther Adv Neurol Disord 12:1756286419846058. https:\/\/doi.org\/10.1177\/1756286419846058","journal-title":"Ther Adv Neurol Disord"},{"key":"4885_CR35","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1002\/acn3.51625","volume":"9","author":"B De Wel","year":"2022","unstructured":"De Wel B, De Schaepdryver M, Poesen K, Claeys KG (2022) Biochemical and clinical biomarkers in adult SMA 3\u20134 patients treated with nusinersen for 22 months. Ann Clin Transl Neurol 9:1241\u20131251. https:\/\/doi.org\/10.1002\/acn3.51625","journal-title":"Ann Clin Transl Neurol"},{"key":"4885_CR36","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1002\/mus.27212","volume":"63","author":"A Introna","year":"2021","unstructured":"Introna A, Milella G, D\u2019Errico E et al (2021) Is cerebrospinal fluid amyloid-\u03b242 a promising biomarker of response to nusinersen in adult spinal muscular atrophy patients? Muscle Nerve 63:905\u2013909. https:\/\/doi.org\/10.1002\/mus.27212","journal-title":"Muscle Nerve"},{"key":"4885_CR37","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14051","author":"G \u0160imi\u0107","year":"2022","unstructured":"\u0160imi\u0107 G, Vuki\u0107 V, Babi\u0107 M et al (2022) Total tau in cerebrospinal fluid detects treatment responders among spinal muscular atrophy types 1\u20133 patients treated with nusinersen. CNS Neurosci Ther. https:\/\/doi.org\/10.1111\/cns.14051","journal-title":"CNS Neurosci Ther"},{"key":"4885_CR38","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.3390\/biomedicines11051254","volume":"11","author":"M Meneri","year":"2023","unstructured":"Meneri M, Abati E, Gagliardi D et al (2023) Identification of novel biomarkers of spinal muscular atrophy and therapeutic response by proteomic and metabolomic profiling of human biological fluid samples. Biomedicines 11:1254. https:\/\/doi.org\/10.3390\/biomedicines11051254","journal-title":"Biomedicines"},{"key":"4885_CR39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035462","volume":"7","author":"RS Finkel","year":"2012","unstructured":"Finkel RS, Crawford TO, Swoboda KJ et al (2012) Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLoS ONE 7:e35462. https:\/\/doi.org\/10.1371\/journal.pone.0035462","journal-title":"PLoS ONE"},{"key":"4885_CR40","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/jnc.14953","volume":"153","author":"T Kessler","year":"2020","unstructured":"Kessler T, Latzer P, Schmid D et al (2020) Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy. J Neurochem 153:650\u2013661. https:\/\/doi.org\/10.1111\/jnc.14953","journal-title":"J Neurochem"},{"key":"4885_CR41","doi-asserted-by":"publisher","first-page":"4329","DOI":"10.3390\/ijms22094329","volume":"22","author":"L Bianchi","year":"2021","unstructured":"Bianchi L, Sframeli M, Vantaggiato L et al (2021) Nusinersen modulates proteomics profiles of cerebrospinal fluid in spinal muscular atrophy type 1 patients. Int J Mol Sci 22:4329. https:\/\/doi.org\/10.3390\/ijms22094329","journal-title":"Int J Mol Sci"},{"key":"4885_CR42","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1111\/ene.15331","volume":"29","author":"DC Schorling","year":"2022","unstructured":"Schorling DC, K\u00f6lbel H, Hentschel A et al (2022) Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy. Eur J Neurol 29:2084\u20132096. https:\/\/doi.org\/10.1111\/ene.15331","journal-title":"Eur J Neurol"},{"key":"4885_CR43","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3390\/metabo11040206","volume":"11","author":"L Deutsch","year":"2021","unstructured":"Deutsch L, Osredkar D, Plavec J, Stres B (2021) Spinal muscular atrophy after nusinersen therapy: improved physiology in pediatric patients with no significant change in urine, serum, and liquor 1H-NMR metabolomes in comparison to an age-Matched. Healthy Cohort Metab 11:206. https:\/\/doi.org\/10.3390\/metabo11040206","journal-title":"Healthy Cohort Metab"},{"key":"4885_CR44","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.3390\/biom12101431","volume":"12","author":"F Errico","year":"2022","unstructured":"Errico F, Marino C, Grimaldi M et al (2022) Nusinersen induces disease-severity-specific neurometabolic effects in spinal muscular atrophy. Biomolecules 12:1431. https:\/\/doi.org\/10.3390\/biom12101431","journal-title":"Biomolecules"},{"key":"4885_CR45","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1002\/mus.26419","volume":"59","author":"MC Pera","year":"2019","unstructured":"Pera MC, Coratti G, Mazzone ES et al (2019) Revised upper limb module for spinal muscular atrophy: 12 month changes. Muscle Nerve 59:426\u2013430. https:\/\/doi.org\/10.1002\/mus.26419","journal-title":"Muscle Nerve"},{"key":"4885_CR46","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s12883-017-0790-9","volume":"17","author":"MC Pera","year":"2017","unstructured":"Pera MC, Coratti G, Forcina N et al (2017) Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol 17:39. https:\/\/doi.org\/10.1186\/s12883-017-0790-9","journal-title":"BMC Neurol"},{"key":"4885_CR47","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.molcel.2014.10.027","volume":"57","author":"SY Lunt","year":"2015","unstructured":"Lunt SY, Muralidhar V, Hosios AM et al (2015) Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol Cell 57:95\u2013107. https:\/\/doi.org\/10.1016\/j.molcel.2014.10.027","journal-title":"Mol Cell"},{"key":"4885_CR48","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1002\/ana.25533","volume":"86","author":"M Pane","year":"2019","unstructured":"Pane M, Coratti G, Sansone VA et al (2019) Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data. Ann Neurol 86:443\u2013451. https:\/\/doi.org\/10.1002\/ana.25533","journal-title":"Ann Neurol"},{"key":"4885_CR49","doi-asserted-by":"publisher","first-page":"e2492","DOI":"10.1212\/WNL.0000000000007527","volume":"92","author":"BT Darras","year":"2019","unstructured":"Darras BT, Chiriboga CA, Iannaccone ST et al (2019) Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1\/2 studies. Neurology 92:e2492\u2013e2506. https:\/\/doi.org\/10.1212\/WNL.0000000000007527","journal-title":"Neurology"},{"key":"4885_CR50","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1136\/jnnp-2020-323822","volume":"91","author":"L Maggi","year":"2020","unstructured":"Maggi L, Bello L, Bonanno S et al (2020) Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3. J Neurol Neurosurg Psychiatry 91:1166\u20131174. https:\/\/doi.org\/10.1136\/jnnp-2020-323822","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"4885_CR51","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1091\/mbc.e03-09-0667","volume":"15","author":"Y Wu","year":"2004","unstructured":"Wu Y, Sheng W, Chen L et al (2004) Versican V1 isoform induces neuronal differentiation and promotes neurite outgrowth. Mol Biol Cell 15:2093\u20132104. https:\/\/doi.org\/10.1091\/mbc.e03-09-0667","journal-title":"Mol Biol Cell"},{"key":"4885_CR52","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1002\/acn3.50855","volume":"6","author":"M-O Deguise","year":"2019","unstructured":"Deguise M-O, Baranello G, Mastella C et al (2019) Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Ann Clin Transl Neurol 6:1519\u20131532. https:\/\/doi.org\/10.1002\/acn3.50855","journal-title":"Ann Clin Transl Neurol"},{"key":"4885_CR53","doi-asserted-by":"publisher","first-page":"144874","DOI":"10.1016\/j.gene.2020.144874","volume":"756","author":"E Rassart","year":"2020","unstructured":"Rassart E, Desmarais F, Najyb O et al (2020) Apolipoprotein D. Gene 756:144874. https:\/\/doi.org\/10.1016\/j.gene.2020.144874","journal-title":"Gene"},{"key":"4885_CR54","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1002\/glia.21010","volume":"58","author":"MD Ganfornina","year":"2010","unstructured":"Ganfornina MD, Do Carmo S, Mart\u00ednez E et al (2010) ApoD, a glia-derived apolipoprotein, is required for peripheral nerve functional integrity and a timely response to injury. Glia 58:1320\u20131334. https:\/\/doi.org\/10.1002\/glia.21010","journal-title":"Glia"},{"key":"4885_CR55","doi-asserted-by":"publisher","first-page":"e5","DOI":"10.1042\/BJ20050149","volume":"386","author":"DR Richardson","year":"2005","unstructured":"Richardson DR (2005) More roles for selenoprotein P: local selenium storage and recycling protein in the brain. Biochem J 386:e5-7. https:\/\/doi.org\/10.1042\/BJ20050149","journal-title":"Biochem J"},{"key":"4885_CR56","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.neuro.2013.05.016","volume":"38","author":"M Vinceti","year":"2013","unstructured":"Vinceti M, Solovyev N, Mandrioli J et al (2013) Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite. Neurotoxicology 38:25\u201332. https:\/\/doi.org\/10.1016\/j.neuro.2013.05.016","journal-title":"Neurotoxicology"},{"key":"4885_CR57","doi-asserted-by":"publisher","first-page":"9865","DOI":"10.3390\/ijms23179865","volume":"23","author":"T Urbano","year":"2022","unstructured":"Urbano T, Vinceti M, Mandrioli J et al (2022) Selenoprotein P concentrations in the cerebrospinal fluid and serum of individuals affected by amyotrophic lateral sclerosis, mild cognitive impairment and Alzheimer\u2019s dementia. Int J Mol Sci 23:9865. https:\/\/doi.org\/10.3390\/ijms23179865","journal-title":"Int J Mol Sci"},{"key":"4885_CR58","doi-asserted-by":"publisher","first-page":"341","DOI":"10.3390\/ph13110341","volume":"13","author":"M Gavriilaki","year":"2020","unstructured":"Gavriilaki M, Kimiskidis VK, Gavriilaki E (2020) Precision medicine in neurology: the inspirational paradigm of complement therapeutics. Pharmaceuticals (Basel) 13:341. https:\/\/doi.org\/10.3390\/ph13110341","journal-title":"Pharmaceuticals (Basel)"},{"key":"4885_CR59","doi-asserted-by":"publisher","first-page":"672891","DOI":"10.3389\/fnsyn.2021.672891","volume":"13","author":"D Carulli","year":"2021","unstructured":"Carulli D, de Winter F, Verhaagen J (2021) Semaphorins in Adult Nervous System Plasticity and Disease. Front Synaptic Neurosci 13:672891. https:\/\/doi.org\/10.3389\/fnsyn.2021.672891","journal-title":"Front Synaptic Neurosci"},{"key":"4885_CR60","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1016\/0092-8674(93)90625-z","volume":"75","author":"AL Kolodkin","year":"1993","unstructured":"Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:1389\u20131399. https:\/\/doi.org\/10.1016\/0092-8674(93)90625-z","journal-title":"Cell"},{"key":"4885_CR61","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1749-8104-2-28","volume":"2","author":"O Mauti","year":"2007","unstructured":"Mauti O, Domanitskaya E, Andermatt I et al (2007) Semaphorin6A acts as a gate keeper between the central and the peripheral nervous system. Neural Dev 2:28. https:\/\/doi.org\/10.1186\/1749-8104-2-28","journal-title":"Neural Dev"},{"key":"4885_CR62","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s00401-008-0411-1","volume":"116","author":"G Simic","year":"2008","unstructured":"Simic G (2008) Pathogenesis of proximal autosomal recessive spinal muscular atrophy. Acta Neuropathol 116:223\u2013234. https:\/\/doi.org\/10.1007\/s00401-008-0411-1","journal-title":"Acta Neuropathol"},{"key":"4885_CR63","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/s00401-007-0327-1","volume":"115","author":"G Simic","year":"2008","unstructured":"Simic G, Mladinov M, Seso Simic D et al (2008) Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy. Acta Neuropathol 115:313\u2013326. https:\/\/doi.org\/10.1007\/s00401-007-0327-1","journal-title":"Acta Neuropathol"},{"key":"4885_CR64","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1002\/glia.22378","volume":"60","author":"F Bernard","year":"2012","unstructured":"Bernard F, Moreau-Fauvarque C, Heitz-Marchaland C et al (2012) Role of transmembrane semaphorin Sema6A in oligodendrocyte differentiation and myelination. Glia 60:1590\u20131604. https:\/\/doi.org\/10.1002\/glia.22378","journal-title":"Glia"},{"key":"4885_CR65","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.1093\/hmg\/ddw141","volume":"25","author":"G Hunter","year":"2016","unstructured":"Hunter G, Powis RA, Jones RA et al (2016) Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy. Hum Mol Genet 25:2853\u20132861. https:\/\/doi.org\/10.1093\/hmg\/ddw141","journal-title":"Hum Mol Genet"},{"key":"4885_CR66","doi-asserted-by":"publisher","first-page":"15356","DOI":"10.1073\/pnas.0907213106","volume":"106","author":"J Zhang","year":"2009","unstructured":"Zhang J, Rubio V, Lieberman MW, Shi Z-Z (2009) OLA1, an Obg-like ATPase, suppresses antioxidant response via nontranscriptional mechanisms. Proc Natl Acad Sci U S A 106:15356\u201315361. https:\/\/doi.org\/10.1073\/pnas.0907213106","journal-title":"Proc Natl Acad Sci U S A"},{"key":"4885_CR67","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1002\/mus.27715","volume":"66","author":"AY Kaymaz","year":"2022","unstructured":"Kaymaz AY, Bal SK, Bora G et al (2022) Alterations in insulin-like growth factor system in spinal muscular atrophy. Muscle Nerve 66:631\u2013638. https:\/\/doi.org\/10.1002\/mus.27715","journal-title":"Muscle Nerve"},{"key":"4885_CR68","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1093\/hmg\/ddr067","volume":"20","author":"M Bosch-Marc\u00e9","year":"2011","unstructured":"Bosch-Marc\u00e9 M, Wee CD, Martinez TL et al (2011) Increased IGF-1 in muscle modulates the phenotype of severe SMA mice. Hum Mol Genet 20:1844\u20131853. https:\/\/doi.org\/10.1093\/hmg\/ddr067","journal-title":"Hum Mol Genet"},{"key":"4885_CR69","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1046\/j.1471-4159.1998.70031304.x","volume":"70","author":"K Kanamori","year":"1998","unstructured":"Kanamori K, Ross BD, Kondrat RW (1998) Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15N NMR. J Neurochem 70:1304\u20131315. https:\/\/doi.org\/10.1046\/j.1471-4159.1998.70031304.x","journal-title":"J Neurochem"},{"key":"4885_CR70","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1007\/s11064-016-2159-7","volume":"42","author":"N Westergaard","year":"2017","unstructured":"Westergaard N, Waagepetersen HS, Belhage B, Schousboe A (2017) Citrate, a ubiquitous key metabolite with regulatory function in the CNS. Neurochem Res 42:1583\u20131588. https:\/\/doi.org\/10.1007\/s11064-016-2159-7","journal-title":"Neurochem Res"},{"key":"4885_CR71","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1021\/acs.jproteome.8b00523","volume":"18","author":"J Willforss","year":"2019","unstructured":"Willforss J, Chawade A, Levander F (2019) NormalyzerDE: online tool for improved normalization of omics expression data and high-sensitivity differential expression analysis. J Proteome Res 18:732\u2013740. https:\/\/doi.org\/10.1021\/acs.jproteome.8b00523","journal-title":"J Proteome Res"},{"key":"4885_CR72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/bib\/bbw095","volume":"19","author":"T V\u00e4likangas","year":"2018","unstructured":"V\u00e4likangas T, Suomi T, Elo LL (2018) A systematic evaluation of normalization methods in quantitative label-free proteomics. Brief Bioinform 19:1\u201311. https:\/\/doi.org\/10.1093\/bib\/bbw095","journal-title":"Brief Bioinform"},{"key":"4885_CR73","doi-asserted-by":"publisher","first-page":"38881","DOI":"10.1038\/srep38881","volume":"6","author":"B Li","year":"2016","unstructured":"Li B, Tang J, Yang Q et al (2016) Performance evaluation and online realization of data-driven normalization methods used in LC\/MS based untargeted metabolomics analysis. Sci Rep 6:38881. https:\/\/doi.org\/10.1038\/srep38881","journal-title":"Sci Rep"},{"key":"4885_CR74","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1093\/bib\/bbx031","volume":"19","author":"MP van Ooijen","year":"2018","unstructured":"van Ooijen MP, Jong VL, Eijkemans MJC et al (2018) Identification of differentially expressed peptides in high-throughput proteomics data. Brief Bioinform 19:971\u2013981. https:\/\/doi.org\/10.1093\/bib\/bbx031","journal-title":"Brief Bioinform"},{"key":"4885_CR75","unstructured":"GENE-E. https:\/\/software.broadinstitute.org\/GENE-E\/. Accessed 11 Jun 2023"},{"key":"4885_CR76","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou Y, Zhou B, Pache L et al (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10:1523. https:\/\/doi.org\/10.1038\/s41467-019-09234-6","journal-title":"Nat Commun"},{"key":"4885_CR77","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1101\/gr.092759.109","volume":"19","author":"M Krzywinski","year":"2009","unstructured":"Krzywinski M, Schein J, Birol I et al (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19:1639\u20131645. https:\/\/doi.org\/10.1101\/gr.092759.109","journal-title":"Genome Res"},{"key":"4885_CR78","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498\u20132504. https:\/\/doi.org\/10.1101\/gr.1239303","journal-title":"Genome Res"},{"key":"4885_CR79","doi-asserted-by":"publisher","first-page":"D380","DOI":"10.1093\/nar\/gkx1013","volume":"46","author":"H Han","year":"2018","unstructured":"Han H, Cho J-W, Lee S et al (2018) TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res 46:D380\u2013D386. https:\/\/doi.org\/10.1093\/nar\/gkx1013","journal-title":"Nucleic Acids Res"},{"key":"4885_CR80","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/1471-2105-4-2","volume":"4","author":"GD Bader","year":"2003","unstructured":"Bader GD, Hogue CWV (2003) An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform 4:2. https:\/\/doi.org\/10.1186\/1471-2105-4-2","journal-title":"BMC Bioinform"},{"key":"4885_CR81","doi-asserted-by":"publisher","first-page":"45477","DOI":"10.1038\/srep45477","volume":"7","author":"S Mazzara","year":"2017","unstructured":"Mazzara S, Rossi RL, Grifantini R et al (2017) CombiROC: an interactive web tool for selecting accurate marker combinations of omics data. Sci Rep 7:45477. https:\/\/doi.org\/10.1038\/srep45477","journal-title":"Sci Rep"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-023-04885-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-023-04885-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-023-04885-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T14:46:46Z","timestamp":1702910806000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-023-04885-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8]]},"references-count":81,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["4885"],"URL":"https:\/\/doi.org\/10.1007\/s00018-023-04885-7","relation":{},"ISSN":["1420-682X","1420-9071"],"issn-type":[{"value":"1420-682X","type":"print"},{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8]]},"assertion":[{"value":"2 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors confirm that there are no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki and followed ICH GCP guidelines. All subjects and the parents of minors provided written informed consent for the collection, storage and analysis of biological materials according to the disposition of the local ethics committees.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors give consent for the publication of the manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"241"}}