134 research outputs found
Glutathione-S-transferases in lung and sputum specimens, effects of smoking and COPD severity
<p>Abstract</p> <p>Background</p> <p>Oxidative stress plays a potential role in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Glutathione S-transferases (GSTs) detoxify toxic compounds in tobacco smoke via glutathione-dependent mechanisms. Little is known about the regulation and expression of GSTs in COPD lung and their presence in airway secretions.</p> <p>Methods</p> <p>GST alpha, pi and mu were investigated by immunohistochemistry in 72 lung tissue specimens and by Western analysis in total lung homogenates and induced sputum supernatants from non-smokers, smokers and patients with variable stages of COPD severity.</p> <p>Results</p> <p>GST alpha was expressed mainly in the airway epithelium. The percentage of GST alpha positive epithelial cells was lower in the central airways of patients with very severe (Stage IV) COPD compared to mild/moderate COPD (p = 0.02). GST alpha by Western analysis was higher in the total lung homogenates in mild/moderate COPD compared to cases of very severe disease (p < 0.001). GST pi was present in airway and alveolar epithelium as well as in alveolar macrophages. GST mu was expressed mainly in the epithelium. Both GST alpha and pi were detectable in sputum supernatants especially in patients with COPD.</p> <p>Conclusion</p> <p>This study indicates the presence of GST alpha and pi especially in the epithelium and sputum supernatants in mild/moderate COPD and low expression of GST alpha in the epithelium in cases of very severe COPD. The presence of GSTs in the airway secretions points to their potential protective role both as intracellular and extracellular mediators in human lung.</p
Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1C in pancreatic endocrine tumors
<p>Abstract</p> <p>Background</p> <p><it>RASSF1A </it>gene silencing by DNA methylation has been suggested as a major event in pancreatic endocrine tumor (PET) but <it>RASSF1A </it>expression has never been studied. The <it>RASSF1 </it>locus contains two CpG islands (<it>A </it>and <it>C</it>) and generates seven transcripts (<it>RASSF1A</it>-<it>RASSF1G</it>) by differential promoter usage and alternative splicing.</p> <p>Methods</p> <p>We studied 20 primary PETs, their matched normal pancreas and three PET cell lines for the (i) methylation status of the <it>RASSF1 </it>CpG islands using methylation-specific PCR and pyrosequencing and (ii) expression of <it>RASSF1 </it>isoforms by quantitative RT-PCR in 13 cases. CpG island A methylation was evaluated by methylation-specific PCR (MSP) and by quantitative methylation-specific PCR (qMSP); pyrosequencing was applied to quantify the methylation of 51 CpGs also encompassing those explored by MSP and qMSP approaches.</p> <p>Results</p> <p>MSP detected methylation in 16/20 (80%) PETs and 13/20 (65%) normal pancreas. At qMSP, 11/20 PETs (55%) and 9/20 (45%) normals were methylated in at least 20% of <it>RASSF1A </it>alleles.</p> <p>Pyrosequencing showed variable distribution and levels of methylation within and among samples, with PETs having average methylation higher than normals in 15/20 (75%) cases (<it>P </it>= 0.01). The evaluation of mRNA expression of <it>RASSF1 </it>variants showed that: i) <it>RASSF1A </it>was always expressed in PET and normal tissues, but it was, on average, expressed 6.8 times less in PET (<it>P </it>= 0.003); ii) <it>RASSF1A </it>methylation inversely correlated with its expression; iii) <it>RASSF1 </it>isoforms were rarely found, except for <it>RASSF1B </it>that was always expressed and <it>RASSF1C </it>whose expression was 11.4 times higher in PET than in normal tissue (<it>P </it>= 0.001). A correlation between <it>RASSF1A </it>expression and gene methylation was found in two of the three PET cell lines, which also showed a significant increase in <it>RASSF1A </it>expression upon demethylating treatment.</p> <p>Conclusions</p> <p><it>RASSF1A </it>gene methylation in PET is higher than normal pancreas in no more than 75% of cases and as such it cannot be considered a marker for this neoplasm. <it>RASSF1A </it>is always expressed in PET and normal pancreas and its levels are inversely correlated with gene methylation. Isoform <it>RASSF1C </it>is overexpressed in PET and the recent demonstration of its involvement in the regulation of the Wnt pathway points to a potential pathogenetic role in tumor development.</p
Predicting environmental chemical factors associated with disease-related gene expression data
<p>Abstract</p> <p>Background</p> <p>Many common diseases arise from an interaction between environmental and genetic factors. Our knowledge regarding environment and gene interactions is growing, but frameworks to build an association between gene-environment interactions and disease using preexisting, publicly available data has been lacking. Integrating freely-available environment-gene interaction and disease phenotype data would allow hypothesis generation for potential environmental associations to disease.</p> <p>Methods</p> <p>We integrated publicly available disease-specific gene expression microarray data and curated chemical-gene interaction data to systematically predict environmental chemicals associated with disease. We derived chemical-gene signatures for 1,338 chemical/environmental chemicals from the Comparative Toxicogenomics Database (CTD). We associated these chemical-gene signatures with differentially expressed genes from datasets found in the Gene Expression Omnibus (GEO) through an enrichment test.</p> <p>Results</p> <p>We were able to verify our analytic method by accurately identifying chemicals applied to samples and cell lines. Furthermore, we were able to predict known and novel environmental associations with prostate, lung, and breast cancers, such as estradiol and bisphenol A.</p> <p>Conclusions</p> <p>We have developed a scalable and statistical method to identify possible environmental associations with disease using publicly available data and have validated some of the associations in the literature.</p
Intracranial tumors of the central nervous system and air pollution - A nationwide case-control study from Denmark
Background: Inconclusive evidence has suggested a possible link between air pollution and central nervous
system (CNS) tumors. We investigated a range of air pollutants in relation to types of CNS tumors.
Methods: We identified all (n = 21,057) intracranial tumors in brain, meninges and cranial nerves diagnosed in
Denmark between 1989 and 2014 and matched controls on age, sex and year of birth. We established personal 10-
year mean residential outdoor exposure to particulate matter < 2.5 ÎŒm (PM2.5), nitrous oxides (NOX), primary emitted
black carbon (BC) and ozone. We used conditional logistic regression to calculate odds ratios (OR) linearly (per
interquartile range (IQR)) and categorically. We accounted for personal income, employment, marital status, use of
medication as well as socio-demographic conditions at area level.
Results: Malignant tumors of the intracranial CNS was associated with BC (OR: 1.034, 95%CI: 1.005â1.065 per IQR.
For NOx the OR per IQR was 1.026 (95%CI: 0.998â1.056). For malignant non-glioma tumors of the brain we found
associations with PM2.5 (OR: 1.267, 95%CI: 1.053â1.524 per IQR), BC (OR: 1.049, 95%CI: 0.996â1.106) and NOx (OR:
1.051, 95% CI: 0.996â1.110).
Conclusion: Our results suggest that air pollution is associated with malignant intracranial CNS tumors and
malignant non-glioma of the brain. However, additional studies are needed
Dietary cadmium and risk of invasive postmenopausal breast cancer in the VITAL cohort.
This study does not support the hypothesis that dietary cadmium intake is a risk factor for breast cancer. However, non-differential measurement error in the estimate of cadmium intake is likely the most important factor that could have obscured an association
Carcinogenicity of cobalt, antimony compounds, and weapons-grade tungsten alloy
The complete evaluation of the carcinogenicity of cobalt, antimony compounds, and weapons-grade tungsten alloy will be published in Volume 131 of the IARC Monographs.[Excerpt] In March, 2022, a Working Group of 31 scientists from 13 countries met remotely at the invitation of the International Agency for Research on Cancer (IARC) to finalise their evaluation of the carcinogenicity of nine agents: cobalt metal (without tungsten carbide or other metal alloys), soluble cobalt(II) salts, cobalt(II) oxide, cobalt(II,III) oxide, cobalt(II) sulfide, other cobalt(II) compounds, trivalent antimony, pentavalent antimony, and weapons-grade tungsten (with nickel and cobalt) alloy. For cobalt metal and the cobalt compounds, particles of all sizes were included in the evaluation. These assessments will be published in Volume 131 of the IARC Monographs.1
Cobalt metal and soluble cobalt(II) salts were classified as âprobably carcinogenic to humansâ (Group 2A) based on âsufficientâ evidence for cancer in experimental animals and âstrongâ mechanistic evidence in human primary cells. Cobalt(II) oxide and weapons-grade tungsten alloy were classified as âpossibly carcinogenic to humansâ (Group 2B) based on âsufficientâ evidence in experimental animals. Trivalent antimony was classified as âprobably carcinogenic to humansâ (Group 2A), based on âlimitedâ evidence for cancer in humans, âsufficientâ evidence for cancer in experimental animals, and âstrongâ mechanistic evidence in human primary cells and in experimental systems. Cobalt(II,III) oxide, cobalt(II) sulfide, other cobalt(II) compounds, and pentavalent antimony were each evaluated as ânot classifiable as to its carcinogenicity to humansâ (Group 3).[...
Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population
Background: The âexposomeâ represents the accumulation of all environmental exposures across a lifetime. Topdown
strategies are required to assess something this comprehensive, and could transform our understanding of
how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an
individualâs metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure,
and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We
investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed
zinc smelter with associated elevated levels of environmental cadmium. Methods: High-resolution 1H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles
from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify
metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were
also measured, using mass spectrometry, as a marker of systemic oxidative stress. Results: Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4-
deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with
cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking
status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels)
was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal
accumulation was causing mitochondrial dysfunction. Conclusions: This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human
population is capable of identifying intermediate biomarkers of response to toxicants at true environmental
concentrations, paving the way for exposome research.
Keywords: metabonomics, cadmium, environmental health, exposome, metabolomics, molecular epidemiolog
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