Concentration of submicrometre particles from vehicle emissions near a major road.

As part of a program of study to assess the exposure risks related to particulate matter in the outdoor environment, number concentrations of particles from vehicle emissions were measured at increasing distances from a major road. Particles in the size range from 0.015 – 0.697 µm were measured with the Scanning Mobility Particle Sizer (SMPS) and in the size range from 0.5 – 20 µm, with the Aerodynamic Particle Sizer (APS). In addition to number concentration measurements, an approximation of PM2.5 fraction was obtained using a DustTrak (simple photometer). The measurements conducted at distances from the road ranging from 15 to 375 m showed, that for conditions where the wind is blowing directly from the road, the concentration of fine and ultrafine particles decays to around half of the maximum (measured at the closest point to the road) at a distance of approximately 100 - 150 m from the road. For the wind blowing parallel to the road, the reduction to half of the concentration occurs at 50 – 100 m. There is no effect on total particle number concentration at a distance greater than 15 m from the road when the wind is blowing towards the road and away from the sampling points. Total number concentrations of larger particles measured were not significantly higher than the average values for the urban environment, and decrease with distance from the road, reaching about 60% at 150 m from the road for wind from the road. PM2.5 levels also decrease with distance to around 75% for wind from the road and to 65% for wind parallel to the road, at a distance of 375 m

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesLynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.Ohio State University (OSU) Comprehensive Cancer Center OSU Colorectal Cancer Research fund Obrine-Weaver Fund Pelotonia Fellowship Award deCODE genetic

Correlation of Global and Gene-Specific DNA Methylation in Maternal-Infant Pairs

The inheritance of DNA methylation patterns is a popular theory to explain the influence of parental genetic and environmental factors on the phenotype of their offspring but few studies have examined this relationship in humans. Using 120 paired maternal-umbilical cord blood samples randomly selected from a prospective birth cohort in Bangladesh, we quantified DNA methylation by pyrosequencing seven CpG positions in the promoter region of p16, four CpG positions in the promoter region of p53, LINE-1 and Alu. Positive correlations were observed between maternal and umbilical cord blood at p16, LINE-1, and Alu but not p53. Multiple linear regression models observed a significant association between maternal and umbilical cord blood at LINE-1 and Alu (LINE-1: β = 0.63, p<0.0001; Alu: β = 0.28, p = 0.009). After adjusting for multiple comparisons, maternal methylation of p16 at position 4 significantly predicted methylation at the same position in umbilical cord blood (β = 0.43, p = <0.0001). These models explained 48%, 5% and 16% of the observed variability in umbilical cord %5mC for LINE-1, Alu and p16 at position 4, respectively. These results suggest that DNA methylation in maternal blood was correlated with her offspring at LINE-1, Alu, and p16 but not p53. Additional studies are needed to confirm whether these observed associations were due to the inheritance of epigenetic events or the shared environment between mother and fetus. Future studies should also use a multi-generational family-based design that would quantify both maternal and paternal contributions to DNA methylation in offspring across more than one generation

Detection of SARS-CoV-2 infection by saliva and nasopharyngeal sampling in frontline healthcare workers: An observational cohort study

Background The SARS-CoV-2 pandemic has caused an unprecedented strain on healthcare systems worldwide, including the United Kingdom National Health Service (NHS). We conducted an observational cohort study of SARS-CoV-2 infection in frontline healthcare workers (HCW) working in an acute NHS Trust during the first wave of the pandemic, to answer emerging questions surrounding SARS-CoV-2 infection, diagnosis, transmission and control. Methods Using self-collected weekly saliva and twice weekly combined oropharyngeal/nasopharyngeal (OP/NP) samples, in addition to self-assessed symptom profiles and isolation behaviours, we retrospectively compared SARS-CoV-2 detection by RT-qPCR of saliva and OP/NP samples. We report the association with contemporaneous symptoms and isolation behaviour. Results Over a 12-week period from 30th March 2020, 40∙0% (n = 34/85, 95% confidence interval 31∙3-51∙8%) HCW had evidence of SARS-CoV-2 infection by surveillance OP/NP swab and/or saliva sample. Symptoms were reported by 47∙1% (n = 40) and self-isolation by 25∙9% (n = 22) participants. Only 44.1% (n = 15/34) participants with SARS-CoV-2 infection reported any symptoms within 14 days of a positive result and only 29∙4% (n = 10/34) reported self-isolation periods. Overall agreement between paired saliva and OP/NP swabs was 93∙4% (n = 211/226 pairs) but rates of positive concordance were low. In paired samples with at least one positive result, 35∙0% (n = 7/20) were positive exclusively by OP/NP swab, 40∙0% (n = 8/20) exclusively by saliva and in only 25∙0% (n = 5/20) were the OP/NP and saliva result both positive. Conclusions HCW are a potential source of SARS-CoV-2 transmission in hospitals and symptom screening will identify the minority of infections. Without routine asymptomatic SARS-CoV-2 screening, it is likely that HCW with SARS-CoV-2 infection would continue to attend work. Saliva, in addition to OP/NP swab testing, facilitated ascertainment of symptomatic and asymptomatic SARS-CoV-2 infections. Combined saliva and OP/NP swab sampling would improve detection of SARS-CoV-2 for surveillance and is recommended for a high sensitivity strategy

DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma

The significance of chromosome 3p gene alterations in lung cancer is poorly understood. This study set out to investigate promoter methylation in the deleted in lung and oesophageal cancer 1 (DLEC1), MLH1 and other 3p genes in 239 non-small cell lung carcinomas (NSCLC). DLEC1 was methylated in 38.7%, MLH1 in 35.7%, RARβ in 51.7%, RASSF1A in 32.4% and BLU in 35.3% of tumours. Any two of the gene alterations were associated with each other except RARβ. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P=0.025) and in squamous cell carcinoma (P=0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P=0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P=0.009). However, microsatellite instability and loss of MLH1 expression was rare, suggesting that MLH1 promoter methylation does not usually lead to gene silencing in lung cancer. This is the first study describing the prognostic value of DLEC1 and MLH1 methylation in NSCLC. The concordant methylation is possibly a consequence of a long-range epigenetic effect in this region of chromosome 3p, which has recently been described in other cancers