molecules-20-11154-v4(1)
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Molecules 2015, 20, 11154-11172; doi:10.3390/molecules200611154 molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Non-Invasive Biomarkers for Duchenne Muscular Dystrophy and Carrier Detection Mónica Alejandra Anaya-Segura 1,† , Froylan Arturo García-Martínez 2 , Luis Ángel Montes-Almanza 2 , Benjamín-Gómez Díaz 3 , Guillermina Ávila-Ramírez 4 , Ikuri Alvarez-Maya 1 , Ramón Mauricio Coral-Vázquez 5 , Paul Mondragón-Terán 2 , Rosa Elena Escobar-Cedillo 3 , Noemí García-Calderón 6,7 , Norma Alejandra Vázquez-Cardenas 8 , Silvia García 2 and Luz Berenice López-Hernández 2,†, * 1 Research Center in Technology and Design Assistance of Jalisco State (CIATEJ, AC), National Council of Science and Technology (CONACYT), Guadalajara 44270, Mexico; E-Mails: [email protected] (M.A.A.-S.); [email protected] (I.A.-M.) 2 National Medical Centre “20 de Noviembre”, Institute for Social Security of State Workers, Mexico City 03100, Mexico; E-Mails: [email protected] (F.A.G.-M.); [email protected] (L.A.M.-A.); [email protected] (P.M.-T.); [email protected] (S.G.) 3 National Institute of Rehabilitation, Mexico City 14389, Mexico; E-Mails: [email protected] (B.G.-D.); [email protected] (R.E.E.-C.) 4 Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico; E-Mail: [email protected] 5 Studies Section of Postgraduate and Research, School of Medicine, National Polytechnic Institute, Mexico City 11340, Mexico; E-Mail: [email protected] 6 Asociación de Distrofia Muscular de Occidente A.C., Guadalajara 44380, Mexico; E-Mail: [email protected] 7 Mexican Institute of Social Security-CMNO, Guadalajara 44340, Mexico 8 Faculty of Medicine, Autonomous University of Guadalajara, Guadalajara 45129, Mexico; E-Mail: [email protected] † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +52-55-5200-5003; Fax: +52-33-3632-6200. Academic Editor: Leonidas A. Phylactou OPEN ACCESS
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Transcript of molecules-20-11154-v4(1)
Molecules 2015, 20, 11154-11172; doi:10.3390/molecules200611154 molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Non-Invasive Biomarkers for Duchenne Muscular Dystrophy and Carrier Detection Mnica Alejandra Anaya-Segura 1,, Froylan Arturo Garca-Martnez 2,Luis ngel Montes-Almanza 2, Benjamn-Gmez Daz 3, Guillermina vila-Ramrez 4,Ikuri Alvarez-Maya 1, Ramn Mauricio Coral-Vzquez 5, Paul Mondragn-Tern 2,Rosa Elena Escobar-Cedillo 3, Noem Garca-Caldern 6,7, Norma Alejandra Vzquez-Cardenas 8, Silvia Garca 2 and Luz Berenice Lpez-Hernndez 2,,* 1Research Center in Technology and Design Assistance of Jalisco State (CIATEJ, AC),National Council of Science and Technology (CONACYT), Guadalajara 44270, Mexico;E-Mails: [email protected] (M.A.A.-S.); [email protected] (I.A.-M.) 2National Medical Centre 20 de Noviembre, Institute for Social Security of State Workers,Mexico City 03100, Mexico; E-Mails: [email protected] (F.A.G.-M.); [email protected] (L.A.M.-A.); [email protected] (P.M.-T.);[email protected] (S.G.) 3National Institute of Rehabilitation, Mexico City 14389, Mexico;E-Mails: [email protected] (B.G.-D.); [email protected] (R.E.E.-C.) 4Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico;E-Mail: [email protected] 5Studies Section of Postgraduate and Research, School of Medicine, National Polytechnic Institute, Mexico City 11340, Mexico; E-Mail: [email protected] 6Asociacin de Distrofia Muscular de Occidente A.C., Guadalajara 44380, Mexico;E-Mail: [email protected] 7Mexican Institute of Social Security-CMNO, Guadalajara 44340, Mexico 8Faculty of Medicine, Autonomous University of Guadalajara, Guadalajara 45129, Mexico;E-Mail: [email protected] These authors contributed equally to this work. *Author to whom correspondence should be addressed; E-Mail: [email protected];Tel.: +52-55-5200-5003; Fax: +52-33-3632-6200. Academic Editor: Leonidas A. Phylactou OPEN ACCESSMolecules 2015, 2011155 Received: 28 February 2015 / Accepted: 8 June 2015 / Published: 17 June 2015 Abstract:Non-invasivebiologicalindicatorsoftheabsence/presenceorprogressofthediseasethatcouldbeusedtosupportdiagnosisandtoevaluatetheeffectivenessof treatmentareofutmostimportanceinDuchenneMuscularDystrophy(DMD).This neuromusculardisorderaffectsmalechildren,causingweaknessanddisability,whereas femalerelativesareatriskofbeingcarriersofthedisease.Abiomarkerwithbothhigh sensitivityandspecificityforaccuratepredictionispreferred.Untilnowcreatinekinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 (MMP-9) and matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1),myostatin(GDF-8)andfollistatin(FSTN)asnon-invasivebiomarkersto distinguishbetweenDMDsteroidnavepatientsandhealthycontrolsofsimilarageand also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN areusefultodiscriminateDMDfromcontrols(p289.8 ng/mL, a value that represents the best fitting point for sensitivity and specificity, corresponding to a sensitivity of 78.95 and 61.9 for specificity. ForGDF-8theAUCwas0.915(p 1.0922 ng/mL, sensitivity and specificity were 84.21 and 76.19, respectively. A non-parametric paired comparison among ROC curves for MMP-9, GDF-8, FSTN, and the ratio ofGDF-8/FSTNwasperformed.TherewasnodifferenceinthecomparisonoftheseAUCs.MMP-9 vs.GDF-8(p=0.084),vs.FSTN(p=0.936),vs.GDF-8/FSTNratio(p=0.095).GDF-8vs.FSTN(p = 0.113), vs. GDF-8/FSTN ratio (p = 0.275). FSTN vs. GDF-8/FSTN ratio (p = 0.054) (Figure 2f). ForthefemalegrouptheROCcurveanalysiswasalsoperformedforGDF-8andFSTN(Figure3e). WheretheAUCforGDF-8was0.706,p=0.028,withanassociationcriterionforbeingacarrieras 2.2477ng/mL;sensitivityandspecificitywere70.59and70.59,respectively.TheAUCofFSTNwas0.877,p
