Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Promoting microstructural homogeneity during flash sintering of ceramics through thermal management

International audienceFlash sintering (FS) is a novel field-assisted sintering technology, where the ceramic is heated internally by the Joule effect. While FS promises a tremendous reduction of ceramic firing time and furnace temperature, it has been applied only at the laboratory scale to date. The key limitation of scaling up the technique to the industrial manufacturing level is the intrinsic difficulty managing the heat generation and obtaining homogenous microstructures in components of industrial interest. Heterogeneous regions primarily originate from the different types of thermal gradients that develop during FS; therefore, the management of heat generation is crucial to achieve uniformity. In this article, we discuss the advantages of controlling the microstructural homogeneity of ceramics during FS, and the technical routes to achieve this. The origin and formation mechanisms of thermal gradients upon flash sintering are outlined. Possible approaches to reduce thermal and microstructural gradients are identified. The opportunities and challenges in scale-up of FS are discussed from both industrial and scientific perspectives

Promoting microstructural homogeneity during flash sintering of ceramics through thermal management

International audienceFlash sintering (FS) is a novel field-assisted sintering technology, where the ceramic is heated internally by the Joule effect. While FS promises a tremendous reduction of ceramic firing time and furnace temperature, it has been applied only at the laboratory scale to date. The key limitation of scaling up the technique to the industrial manufacturing level is the intrinsic difficulty managing the heat generation and obtaining homogenous microstructures in components of industrial interest. Heterogeneous regions primarily originate from the different types of thermal gradients that develop during FS; therefore, the management of heat generation is crucial to achieve uniformity. In this article, we discuss the advantages of controlling the microstructural homogeneity of ceramics during FS, and the technical routes to achieve this. The origin and formation mechanisms of thermal gradients upon flash sintering are outlined. Possible approaches to reduce thermal and microstructural gradients are identified. The opportunities and challenges in scale-up of FS are discussed from both industrial and scientific perspectives