5 research outputs found
Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)
Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries
BackgroundUncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype-phenotype correlations and factors that potentially impact disease progression.MethodsThis is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta.ResultsOut of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival.InterpretationWithin the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Abstract In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS
Castel di Sangro-Scontrone field camp – structural and applied geomorphology
<p>The Geomorphological Field Camp 2014 in the Castel di Sangro-Scontrone area is the result of geological and geomorphological teaching field work activities carried out in Central Italy by a group of 23 students attending the Structural Geomorphology and Applied Geomorphology courses (Master's Degree in Geological Science and Technology of the Università degli Studi ‘G. d'Annunzio’ Chieti-Pescara, Italy, Department of Engineering and Geology). The Field Camp 2014 was organized in May 2014, following regular classes held during the fall term. General activities for the field camp were developed over four main stages: (1) preliminary analysis of the regional geological and geomorphological setting of the area; (2) preliminary activities for the analysis of the local area (orography, hydrography and photogeology investigations, and geographical information system processing); (3) field work, focused on the analysis of a specific issue concerning structural geomorphology or applied geomorphology (e.g. landscape evolution, river channel change, landslide distribution, and flood hazard); and (4) post-field work production of the map. Finally, the fundamental role of field work in the analysis of landscape and in land management was outlined: indeed, the overall field camp enhanced the crucial role of field-based learning for young geomorphologists in order to acquire a strong sensitivity to geomorphological processes and landscape evolution.</p