CD36 maintains the gastric mucosa and associates with gastric disease

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd3

Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation

Alternative (M2) macrophage activation driven through interleukin 4 receptor α (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth, and blocked protective responses against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation

CD36 maintains the gastric mucosa and associates with gastric disease.

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy

Assessing allele frequencies of single nucleotide polymorphisms in DNA pools by pyrosequencing technology

Single nucleotide polymorphism (SNP) association studies searching for differences in allele frequencies between cases and controls have been widely used for genetic analysis. Individual genotyping is prohibitively expensive in large sample sizes. Pooling of samples provides the obvious advantage of higher throughput and lower cost. Here we report our results with the analysis of SNP allele frequencies in DNA pools using Pyrosequencing technology. For seven different SNPs, we observed a mean difference of 1.1 +/- 0.6% between allele frequencies determined in two different DNA pools (n = 150 cases and 150 controls) compared to individually genotyped samples

Identification of challenges and a framework for implementation of the AMP/ASCO/CAP classification guidelines for reporting somatic variants

OBJECTIVES: In 2017, AMP, ASCO and CAP jointly published the first formalized classification system for the interpretation and reporting of sequence variants in cancer. The challenges of incorporating new variant interpretation guidelines into existing, validated workflows have likely hampered adoption and implementation in labs with classification methods in place. Ambiguity in assigning clinical significance across guidelines is grounded in differential weighting of evidence used in variant assessment. Therefore, we undertook an internal process-improvement exercise to correlate the two classification schemes using historical laboratory data. DESIGN AND METHODS: Existing clinical variant assignments from 40 consecutive oncology cases comprising 150 somatic variants were re-assessed according to the 2017 AMP/ASCO/CAP scheme. Approximately 50% of these were cancers of the gynecologic tract. RESULTS: Our laboratory-developed (GPS) classifications for \u27actionable\u27 variants and variants of uncertain clinical significance mapped consistently with the AMP/ASCO/CAP Tiers I-III. The majority of Level 1 variants were reclassified to Tier I (21/25; 84%) while all Level 2 and Level 4 variants were assigned to Tier II (9/9; 100%) and Tier III (17/17; 100%), respectively. The greatest variability was seen for GPS Level 3 variants, which was strongly influenced by CONCLUSIONS: Our internally developed 5-level classifications mapped consistently with the proposed AMP/ASCO/CAP 4-Tiered system. As a result of this analysis, we can provide a framework for other labs considering a similar transition to the 2017 AMP/ASCO/CAP guidelines and a rationale for explaining specific discrepancies

A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4 � Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population

Variants in hepatocyte nuclear factor-4 � (HNF4�), a transcription factor that influences the expression of glucose metabolic genes, have been correlated with maturityonset diabetes of the young, a monogenic form of diabetes. Previously, in a genome scan of Ashkenazi Jewish type 2 diabetic families, we observed linkage to the chromosome 20q region encompassing HNF4�. Here, haplotype-tag single nucleotide polymorphisms (htSNPs) were identified across a 78-kb region around HNF4 � and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetic (n � 275) and control (n � 342) subjects. We found that two of nine htSNPs were associated with type 2 diabetes: a3 � intronic SNP, rs3818247 (29.2 % case subjects vs. 21.7 % control subjects; P � 0.0028, odds ratio [OR] 1.49) anda5 � htSNP located �3.9 kb upstream of P2, rs188461