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1.
Nat Commun ; 15(1): 4893, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849340

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.


Subject(s)
Amyotrophic Lateral Sclerosis , Disease Models, Animal , MAP Kinase Signaling System , Mice, Transgenic , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Humans , Female , Animals , Male , Mice , MAP Kinase Signaling System/drug effects , Pyridones/pharmacology , Pyridones/therapeutic use , RNA-Binding Protein FUS/metabolism , RNA-Binding Protein FUS/genetics , Prefrontal Cortex/metabolism , Transcriptome , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Middle Aged , MicroRNAs/genetics , MicroRNAs/metabolism , C9orf72 Protein/genetics , C9orf72 Protein/metabolism , Sex Characteristics , Aged , Sex Factors , Pyrimidinones
2.
Nutrients ; 15(24)2023 Dec 13.
Article in English | MEDLINE | ID: mdl-38140358

ABSTRACT

(1) Background: Previous studies showed an increased prevalence and incidence of coeliac disease (CD) over time. The objective is to ascertain whether the CD prevalence in Catalonia (a region of Southern Europe) among children aged 1-5 is as high as previously found in 2004-2009; (2) Methods: From 2013 to 2019, 3659 subjects aged 1-5 years were recruited following the previously used methodology. Factors with a potential impact on CD prevalence were investigated; (3) Results: In 2013-2019, 43/3659 subjects had positive serology, giving a standardised seroprevalence of 12.55/1000 (95% CI: 8.92; 17.40), compared to 23.62 (13.21; 39.40) in 2004-2007. The biopsy-proven crude prevalence was 7.92/1000 (95% CI: 5.50; 11.30), and the crude prevalence based on ESPGHAN criteria was 8.74/1000 (95% CI: 6.20-12.30). In contrast to 2004-2009, we did not find differences in the seroprevalence rates between 1 and 2 years vs. 3 and 4 years of age (age percentage of change -7.0 (-29.5; 22.8) vs. -45.3 (-67.5; -8.0)). Rotavirus vaccination was the most remarkable potential protective factor (48% vs. 9% in 2004-2009; p < 0.0001), but not the time of gluten introduction. (4) Conclusion: The present study did not confirm a worldwide CD prevalence increase and emphasizes the need to perform prevalence studies over time using the same methodology in the same geographical areas.


Subject(s)
Celiac Disease , Child , Humans , Child, Preschool , Celiac Disease/epidemiology , Cross-Sectional Studies , Prevalence , Seroepidemiologic Studies , Spain/epidemiology
3.
Trials ; 24(1): 432, 2023 Jun 27.
Article in English | MEDLINE | ID: mdl-37365665

ABSTRACT

BACKGROUND: Stenosis is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilation (EBD) is the treatment of choice for a short stenosis adjacent to the anastomosis from previous surgery. Self-expandable metal stents (SEMS) may be a suitable treatment option for longer stenoses. To date, however, there is no scientific evidence as to whether endoscopic (EBD/SEMS) or surgical treatment is the best approach for de novo or primary stenoses that are less than 10 cm in length. METHODS/DESIGN: Exploratory study as "proof-of-concept", multicentre, open-label, randomized trial of the treatment of de novo stenosis in the CD; endoscopic treatment (EBD/SEMS) vs surgical resection (SR). The type of endoscopic treatment will initially be with EDB; if a therapeutic failure occurs, then a SEMS will be placed. We estimate 2 years of recruitment and 1 year of follow-up for the assessment of quality of life, costs, complications, and clinical recurrence. After the end of the study, patients will be followed up for 3 years to re-evaluate the variables over the long term. Forty patients with de novo stenosis in CD will be recruited from 15 hospitals in Spain and will be randomly assigned to the endoscopic or surgical treatment groups. The primary aim will be the evaluation of the patient quality of life at 1 year follow-up (% of patients with an increase of 30 points in the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32). The secondary aim will be evaluation of the clinical recurrence rate, complications, and costs of both treatments at 1-year follow-up. DISCUSSION: The ENDOCIR trial has been designed to determine whether an endoscopic or surgical approach is therapeutically superior in the treatment of de novo stenosis in CD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04330846. Registered on 1 April 1 2020. https://clinicaltrials.gov/ct2/home.


Subject(s)
Crohn Disease , Humans , Crohn Disease/complications , Crohn Disease/diagnosis , Crohn Disease/surgery , Constriction, Pathologic , Dilatation , Quality of Life , Treatment Outcome , Stents/adverse effects
4.
Cell Rep ; 27(13): 3818-3831.e5, 2019 06 25.
Article in English | MEDLINE | ID: mdl-31242416

ABSTRACT

Amyotrophic lateral sclerosis (ALS) has been genetically linked to mutations in RNA-binding proteins (RBPs), including FUS. Here, we report the RNA interactome of wild-type and mutant FUS in human motor neurons (MNs). This analysis identified a number of RNA targets. Whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift toward 3' UTRs. Neural ELAV-like RBPs are among mutant FUS targets. As a result, ELAVL4 protein levels are increased in mutant MNs. ELAVL4 and mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties. Upon oxidative stress, ELAVL4 and mutant FUS are engaged in stress granules. In the spinal cord of FUS ALS patients, ELAVL4 represents a neural-specific component of FUS-positive cytoplasmic aggregates, whereas in sporadic patients it co-localizes with phosphorylated TDP-43-positive inclusions. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Cytoplasm/metabolism , ELAV-Like Protein 4/metabolism , Mutation , RNA-Binding Protein FUS/metabolism , 3' Untranslated Regions , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Cytoplasm/genetics , Cytoplasm/pathology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , ELAV-Like Protein 4/genetics , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Oxidative Stress/genetics , RNA-Binding Protein FUS/genetics
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