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  • Title: Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy.
    Author: Fissolo N, Pignolet B, Matute-Blanch C, Triviño JC, Miró B, Mota M, Perez-Hoyos S, Sanchez A, Vermersch P, Ruet A, de Sèze J, Labauge P, Vukusic S, Papeix C, Almoyna L, Tourbah A, Clavelou P, Moreau T, Pelletier J, Lebrun-Frenay C, Montalban X, Brassat D, Comabella M, Biomarkers and Response to Natalizumab for Multiple Sclerosis Treatment (BIONAT), Best EScalation Treatment in Multiple Sclerosis (BEST-MS), and the Société Francophone de la Sclérose En Plaques (SFSEP) Network.
    Journal: Ann Neurol; 2017 Aug; 82(2):186-195. PubMed ID: 28681388.
    Abstract:
    OBJECTIVE: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). METHODS: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively. RESULTS: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment. INTERPRETATION: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195.
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