ABSTRACT
We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10-9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: -2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: -1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
Subject(s)
Acyltransferases/adverse effects , Amyotrophic Lateral Sclerosis/complications , Genome-Wide Association Study/methods , Polymorphism, Single Nucleotide/genetics , Weight Loss/genetics , Amyotrophic Lateral Sclerosis/genetics , Genetic Predisposition to Disease , HumansABSTRACT
Gastric cancer (GC) is the fifth most common cancer worldwide, and mortality rates are still high. Primary preventive strategies, aimed to reduce risk factors and promote protective ones, will lead to a decrease in GC incidence. Helicobacter pylori infection is a well-established carcinogen for GC, and its eradication is recommended as the best strategy for the primary prevention. However, the role of other factors such as lifestyle, diet, and drug use is still under debate in GC carcinogenesis. Unfortunately, most patients with GC are diagnosed at late stages when treatment is often ineffective. Neoplastic transformation of the gastric mucosa is a multistep process, and appropriate diagnosis and management of preneoplastic conditions can reduce GC-related mortality. Several screening strategies in relation to GC incidence have been proposed in order to detect neoplastic lesions at early stages. The efficacy of screening strategies in reducing GC mortality needs to be confirmed. This review provides an overview of current international guidelines and recent literature on primary and secondary prevention strategies for GC.
Subject(s)
Primary Prevention , Stomach Neoplasms/etiology , Stomach Neoplasms/prevention & control , Acyltransferases/adverse effects , Biomarkers, Tumor , Diet , Endoscopy , Exercise , Gastritis/complications , Gastritis/drug therapy , Gastritis/microbiology , Helicobacter Infections , Humans , Life Style , Mass Screening , Neoplasms, Second Primary/prevention & control , Precancerous Conditions/diagnosis , Proton Pump Inhibitors/adverse effects , Risk Factors , Smoking/adverse effects , Stomach Neoplasms/diagnosis , Stomach Neoplasms/epidemiologyABSTRACT
BACKGROUND: Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. METHODS: BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150µg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. RESULTS: H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50µg of H4 in combination with the 500nmol IC31 adjuvant dose. CONCLUSIONS: The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50µg of H4 and 500nmol of IC31. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02066428 and NCT02074956.
