Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.     

Inhibition of Neu-Induced Mammary Carcinogenesis in Transgenic Mice Expressing ERΔ3, a Dominant Negative Estrogen Receptor α Variant

The estrogen receptor ?? (ER??) splicing variant with an in-frame deletion of exon 3 (ER??3) is frequently expressed in the normal breast, but its influence on tumorigenesis has not been explored. In vitro, ER??3 has dominant negative activity, suggesting it may suppress estrogen stimulation in the breast. ER??3 may inhibit classical signaling on estrogen response element (ERE)-regulated genes as well as activate non-classical pathways at Sp1 and AP-1 sites. Transgenic mice were developed that express mouse ER??3 in all tissues examined, including the mammary gland. To investigate if ER??3 expression affects tumorigenesis, ER??3 mice were crossbred with MMTV-Neu mice. Mammary tumor onset was significantly delayed in ER??3/Neu versus MMTV-Neu females and metastatic incidence and burden was significantly reduced. Consequently, ER??3 expression suppressed tumor development and metastasis in this aggressive model of HER2/Neu-positive breast cancer. To determine if ER ligands with anticancer activity may augment ER??3 protection, the bitransgenic mice were treated with tamoxifen and soy isoflavones starting at age 2?months. Soy protein with isoflavones (181?mg/1,800?kcal) did not affect tumor development in MMTV-Neu or ER??3/Neu mice; however, metastatic progression was not inhibited in soy-treated ER??3/Neu mice, as it was in untreated ER??3/Neu mice. In contrast, tamoxifen (20?mg/1,800?kcal) significantly enhanced tumor prevention in ER??3/Neu versus MMTV-Neu mice (98?% vs. 81?% tumor free). The results in ER??3/Neu mice demonstrate that ER??3 influences estrogen-dependent mammary carcinogenesis and, thus, may be protective in women expressing ER??3 in the breast. However, exposure to different estrogens may augment or block its beneficial effects.     

Chemical emissions from residential dryer vents during use of fragranced laundry products

Common laundry products, used in washing and drying machines, can contribute to outdoor emissions through dryer vents. However, the types and amounts of chemicals emitted are largely unknown. To investigate these emissions, we analyzed the volatile organic compounds (VOCs) both in the headspace of fragranced laundry products and in the air emitted from dryer vents during use of these products. In a controlled study of washing and drying laundry, we sampled emissions from two residential dryer vents during the use of no products, fragranced detergent, and fragranced detergent plus fragranced dryer sheet. Our analyses found more than 25 VOCs emitted from dryer vents, with the highest concentrations of acetaldehyde, acetone, and ethanol. Seven of these VOCs are classified as hazardous air pollutants (HAPs) and two as carcinogenic HAPs (acetaldehyde and benzene) with no safe exposure level, according to the US Environmental Protection Agency. As context for significance, the acetaldehyde emissions during use of one brand of laundry detergent would represent 3% of total acetaldehyde emissions from automobiles in the study area. Our study points to the need for additional research on this source of emissions and the potential impacts on human and environmental health.     

Effect of intestinal microflora on the urinary metabolic profile of rats: a 1 H-nuclear magnetic resonance spectroscopy study

1. Analysis of urine by 1 H-nuclear magnetic resonance (NMR) spectroscopy is used to detect biochemical disturbances predictive of toxicological changes. Recent studies, using 1 H-NMR spectroscopy have suggested that Alderley Park rats can be classified as hippuric acid (HA) or m -(hydroxyphenyl)propionic acid (m -HPPA) excretors. Evidence exists for the role of intestinal microflora in the excretion of aromatic phenolic compounds including HA and m -HPPA. 2. We sought to investigate whether intestinal microflora contribute to the difference in excretion. Urinary HA and m -HPPA levels were monitored to characterize excretion over time. The effect of intestinal microflora on the 1 H-NMR spectrum was also investigated using antibiotics to sterilize the intestine. Finally, the levels of m -HPPA and phenylpropionic acid (a precursor for HA) were analysed in the caecum and colon (entire tissue, including contents). 3. Characterization confirmed the presence of HA and m -HPPA excretors; enquiries revealed that the rats were obtained from two floors within a barriered breeding unit. Housing the rats from the two floors together for 21 days resulted in comparable levels of HA and m -HPPA excretion demonstrating that the profiles are not stable. 4. Following antibiotic treatment, HA and m -HPPA excretion decreased, indicating that intestinal microflora contribute to the excretion of these compounds. Finally, m -HPPA levels were higher in the colon of rats that excreted m -HPPA whilst PPA was increased in the caecum and colon of rats that excreted HA. 5. These results demonstrate that the observed difference in HA/ m -HPPA excretion is due to differences in the intestinal microflora.