30 research outputs found
A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
BACKGROUND: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. METHODS: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. RESULTS: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 Ă 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. CONCLUSIONS: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study
PercepçÔes de pacientes sobre alimentação no seu processo de adoecimento crĂŽnico por sĂndrome metabĂłlica: um estudo qualitativo
Relevance of the Diversity among Members of the Trypanosoma Cruzi Trans-Sialidase Family Analyzed with Camelids Single-Domain Antibodies
The sialic acid present in the protective surface mucin coat of
Trypanosoma cruzi is added by a membrane anchored
trans-sialidase (TcTS), a modified sialidase that is expressed from a large gene
family. In this work, we analyzed single domain camelid antibodies produced
against trans-sialidase. Llamas were immunized with a recombinant
trans-sialidase and inhibitory single-domain antibody fragments were obtained by
phage display selection, taking advantage of a screening strategy using an
inhibition test instead of the classic binding assay. Four single domain
antibodies displaying strong trans-sialidase inhibition activity against the
recombinant enzyme were identified. They share the same
complementarity-determining region 3 length (17 residues) and have very similar
sequences. This result indicates that they likely derived from a unique clone.
Probably there is only one structural solution for tight binding inhibitory
antibodies against the TcTS used for immunization. To our surprise, this single
domain antibody that inhibits the recombinant TcTS, failed to inhibit the
enzymatic activity present in parasite extracts. Analysis of individual
recombinant trans-sialidases showed that enzymes expressed from different genes
were inhibited to different extents (from 8 to 98%) by the llama
antibodies. Amino acid changes at key positions are likely to be responsible for
the differences in inhibition found among the recombinant enzymes. These results
suggest that the presence of a large and diverse trans-sialidase family might be
required to prevent the inhibitory response against this essential enzyme and
might thus constitute a novel strategy of T. cruzi to evade the
host immune system
Compatibility of Biosimilar Filgrastim with Cytotoxic Chemotherapy during the Treatment of Malignant Diseases (VENICE): A Prospective, Multicenter, Non-Interventional, Longitudinal Study
Meanings attributed to breastfeeding in the first two years of life: a study with women from two municipalities in the RecĂŽncavo Baiano region of Bahia, Brazil
Vaccination with Trypanosoma rangeli modulates the profiles of immunoglobulins and IL-6 at local and systemic levels in the early phase of Trypanosoma cruzi experimental infection
The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry
Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes
Immunization with an engineered mutant trans-sialidase highly protects mice from experimental Tryponosoma cruzi infection: A vaccine candidate
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