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Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.−27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.−27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To elucidate the mechanism of the unique beneficial effect of intravitreal steroid therapy on diabetic macular edema, we investigated the effect of locally administered triamcinolone acetonide (TA) on the expression of vascular endothelial growth factor (VEGF)-A and its receptors in retinas of rats with streptozotocin (STZ)-induced diabetes. We then correlated the expression of these proteins with breakdown of the blood-retinal barrier (BRB). RESEARCH DESIGN AND METHODS--Thirty-two eyes of 16 diabetic and nondiabetic rats were divided into four groups. TA was injected into the vitreous of the right eye, and saline was injected into the left eye (control) 3.5 weeks after induction of diabetes. Retinas were harvested 48 h following treatment. mRNA and protein expression of VEGF-A, VEGF-A receptor 1 (fms-like tyrosine kinase [FLT]-1), and VEGF-A receptor 2 (fetal liver kinase [FLK]-1) were determined by real-time RT-PCR and immunohistochemistry. BRB permeability was quantitated by measuring extravasated endogenous albumin and retinal thickness. RESULTS--Diabetes-induced retinal thickness and albumin extravasation were significantly reduced in TA-treated diabetic retinas to a level similar to that in sham-treated nondiabetic eyes. A close correlation between albumin leakage and increased expression of both Vegf-a and Flk-1 was noted in the diabetic retinas. TA downregulated the expression of Vegf-a and Flk-1 but upregulated the expression of Flt-1. TA did not alter the expression of these genes in nondiabetic retinas. CONCLUSIONS--Intravitreal injection of TA stabilizes the BRB in association with regulation of Vegf-a, Flk-1, and Flt-1 expression in retinas in the early stages of diabetes. [ABSTRACT FROM AUTHOR]

Background: Knowledge of genetic markers that are correlated to stress tolerance may improve spatial mapping of reef vulnerability and can inform restoration efforts, including the choice of genotypes for breeding and reseeding. In this manuscript we present two methods for screening transcriptome data for candidate genetic markers in two reef building corals, Acropora millepora and Pocillopora damicornis (types a and ß). In A. millepora, Single Nucleotide Polymorphisms (SNPs) were pre-selected by targeting genes believed to be involved in the coral thermal stress responses. In P. damicornis (type a and ß), SNPs showing varying allele frequencies between two populations from distinct environments were pre-selected. Allele frequencies at nine, five and eight of the pre-selected SNP loci were correlated against gradients of water clarity and temperature in a large number of populations along the Great Barrier Reef. Results: A significant correlation between environmental category and SNP allele frequency was detected in up to 55% of the tested loci, which is an exceptional success rate for these types of tests. In P. damicornis, SNP allele frequencies of ß-hexosaminidase and Elongation factor 1-a were significantly correlated to temperature in type a and to temperature and/or water clarity respectively in type ß. Type a also showed a correlation between water clarity and SNP allele frequency in a gene of unknown function. In A. millepora, allele frequencies at five (ß-gamma crystallin, Galaxin, Ubiquitin, Ligand of Numb X2 and Thioredoxin) SNP loci showed significant correlations. Conclusions: After validation of these candidate loci through laboratory or field assessment of relative stress tolerance of colonies harbouring different alleles, it is anticipated that a proportion of these markers may represent the first coral candidate Quantitative Trait Loci for environmental stress tolerance and provide an important genetic tool that can be incorporated into spatial management decisions and restoration efforts of coral reefs. One pertinent example would be to combine spatial data of tolerant populations with genetic connectivity and thus identify high priority conservation reefs and implement targeted coral husbandry and active restoration efforts that use locally- and stress-adapted genotypes. [ABSTRACT FROM AUTHOR]