Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival

The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.     

Alcohol metabolism, alcohol intake, and breast cancer risk: a sister-set analysis using the Breast Cancer Family Registry

Moderate alcohol intake has been consistently associated with a modest (30–50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.     

Is correction for protein concentration appropriate for protein adduct dosimetry? Hypothesis and clues from an aflatoxin B1‐exposed population

Protein adducts are useful biomarkers for assessing exposure, metabolism and risk of carcinogens. Aflatoxin B1-albumin adducts (AAA) and protein carbonyl content (PCC) have long been used for assessing aflatoxin exposure and oxidative stress to proteins, and the quantitative data are almost exclusively expressed per mg protein. Given the large variation in protein concentrations in plasma among populations, this may not be the most appropriate method. The objective was to test the hypothesis that AAA and PCC should be expressed per mL plasma in population studies. AAA and PCC were analyzed among 402 subjects from three regions of China with a gradient in hepatocellular carcinoma (HCC) mortality ranging from 21 to 97 per 100,000. When biomarker values were expressed per mL plasma, the AAA level was significantly associated with plasma PCC (r = 0.262, P < 0.001), and adjusted levels of AAA and PCC paralleled HCC mortalities in the three regions, suggesting a role for aflatoxin-related oxidative stress in hepatocarcinogenesis in this population. In addition, there were statistically significant associations between both protein biomarkers, expressed per mL plasma, and the levels of alanine aminotransferase and aspartate aminotransferase in hepatitis B virus-infected subjects, suggesting roles for aflatoxin exposure, oxidative stress and hepatitis B virus infection in the development of HCC. The present data suggest that interindividual variation in plasma protein concentration may influence the dosimetry and relevant interpretation of protein biomarkers.     

Changing Epidemiology of Extended-Spectrum β-Lactamases in Argentina: Emergence of CTX-M-15

A multicenter survey, carried out in 2010 in Argentina, showed an increased prevalence of extended-spectrum β-lactamase (ESBL)-producing enterobacteria, with some changes in the molecular epidemiology of circulating ESBLs. While enzymes of the CTX-M-2 group remain endemic, the emergence of CTX-M-15 and of enzymes of the CTX-M-8 and CTX-M-9 groups was observed. The CTX-M-15-positive isolates represented 40% of CTX-M producers and included representatives of Escherichia coli ST131 and Klebsiella pneumoniae ST11.     

Quantitation of plasma levels of 8-methoxypsoralen by competitive enzyme-linked immunosorbent assay.

An immunologic method for the quantitation of 8-methoxypsoralen (8-MOP) levels in human plasma has been developed. A monoclonal antibody recognizing 8-MOP was prepared by immunizing mice with an 8-MOP derivative conjugated to bovine serum albumin with 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide-HCl. The antibody was characterized by competitive enzyme-linked immunosorbent assay (ELISA) and recognizes 8-MOP (50% inhibition at 2 pmol) as well as structurally related psoralen derivatives including 4'-aminomethyl-4,5',8-trimethylpsoralen (50% inhibition at 50 pmol), 5-methoxypsoralen (50% inhibition at 150 pmole), and 6,4,4'-trimethylangelicin (50% inhibition at 360 pmol). The assay has a limit of sensitivity of 1 ng/ml plasma. For analysis of 8-MOP levels in plasma, samples were first extracted using SepPak C18 cartridges. The extracts were analyzed for 8-MOP levels both by ELISA and high-pressure liquid chromatography. There was a good correlation between the values determined by both methods (r = 0.92, p less than 0.0005). The development of immunologic methods should greatly facilitate the quantitation of 8-MOP levels in patient plasma.     

Polymorphisms in XRCC1 modify the association between polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, dietary antioxidants, and breast cancer risk.

The variability in DNA repair capacity of the general population may depend in part upon common variants in DNA repair genes. X-ray repair cross complementing group 1 (XRCC1) is an important DNA base excision repair gene and exhibits polymorphic variation. Using the Long Island Breast Cancer Study Project, a population-based case-control study, we evaluated the hypothesis that two common single nucleotide polymorphisms of XRCC1 (codon 194 Arg-->Trp and 399 Arg-->Gln) influence breast cancer susceptibility and interact with polycyclic aromatic hydrocarbon (PAH)-DNA adducts, cigarette smoking, and intake of fruits and vegetables and antioxidants. The available sample for genotyping included 1,067 cases and 1,110 controls. Genotyping was done by a high-throughput single-nucleotide extension assay with fluorescence polarization detection of the incorporated nucleotide. We observed no significant increases in risk among all subjects who were carriers of XRCC1 194Trp or 399Gln alleles. Among never smokers, we observed an increased risk of breast cancer in 399Gln carriers [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7). Further analysis indicated a suggestive weak additive interaction between the 399Gln allele and detectable PAH-DNA adducts (OR for exposure with mutant genotype, 1.9; 95% CI, 1.2-3.1). The estimated age-adjusted interaction contrast ratio (ICR) and 95% CI (ICR, 0.38; 95% CI, -0.32 to 1.10) indicated that the departure from additivity was not statistically significant, but that there was some suggestion of a relative excess risk due to the interaction. In subjects with at least one copy of XRCC1 194Trp allele, there was a moderate interaction with high intake of fruits and vegetables (>/=35 half-cup servings per week of any fruits, fruit juices, and vegetables, OR, 0.58; 95% CI, 0.38-0.89; ICR, -0.49; 95% CI, -0.03 to -0.95), and dietary plus supplement antioxidant intake with 33% to 42% decreases in breast cancer risk compared with those with the Arg194Arg genotype and low-intake individuals. These results do not show that the two genetic polymorphisms of XRCC1 independently influence breast cancer risk. However, there is evidence for interactions between the two XRCC1 single nucleotide polymorphisms and PAH-DNA adducts or fruit and vegetable and antioxidant intake on breast cancer risk. Further understanding of the biological function of XRCC1 variants and their interactions with PAH-DNA adducts, antioxidants, and other genes in the pathway are needed.     

An unusual pneumomediastinum case in a child caused by spontaneous bronchial rupture

We report a case of spontaneous pneumomediastinum (SPM) in a 3 year-old child, admitted to the emergency department because he presented dyspnea for a few hours, after a paroxysm of cough. The SPM is rare in children; the term "spontaneous" is reserved for cases of pneumomediastinum that haven't a traumatic cause. SPM is seen most commonly in asthmatics and in any patient who induces a Valsalva maneuver. The clinical diagnosis is confirmed by chest radiograph. When the diagnosis is uncertain, the chest CT scan is considered the gold standard of imaging tests, capable of detecting pneumomediastinum even in patients with small amounts of mediastinal air. In this case CT images showed the cause: spontaneous bronchial rupture. The direct sign of bronchial injury is the contiguity of the luminal air with that in the mediastinum. In the literature SPM cases are very rare, at least in health patients without tracheobronchial anomalies. The SPM is generally a benign entity that requires supportive care, and resolution occurs spontaneously, such as in our patient. In this article we want to explain the main clinical, diagnostic and therapeutic aspects of SPM, because, even if it's rare in children, it must be considered in the differential diagnosis of dyspnea; then we want to demonstrate as, in this case, a TC scan was important to identifying the SPM cause: a bronchial rupture.     

Polycyclic aromatic hydrocarbon-DNA adducts in smokers and their relationship to micronutrient levels and the glutathione-S-transferase M1 genotype

Sixty-three male cigarette smokers were entered into a cross-sectionalstudy to determine whether inverse associations existed betweenpolycydlic aromatic hydrocarbon (PAH)—DNA adduct levelsand intake/serum levels of vitamin A, vitamin C and vitaminE. Associations between PAH–DNA adducts and intakes ofcarotene, as well as serum levels of ß-carotene, werealso determined. Fasting blood samples were collected for assaysof PAH—DNA adducts in circulating mononuclear cells, plasmacotinine and serum levels of vitamin A, ß-carotene,vitamin C and vitamin E. Since genetic deficiency in the detoxifyingenzyme glutathione S-traasferase M1 (GSTM1) has been associatedwith increased risk of lung cancer, GSTM1 genotype was alsodetermined. Analysis of PAH—DNA adducts by competitiveenzyme-linked immunosorbent assay (ELISA) indicated that 70%of the subjects had detectable adducts, with a mean of 4.38adducts/10⁸ nucleotides (range 1.00–24.1/10⁸ Pearson'smethod was utilized to determine whether any associations existedbetween the various host variables and PAH—DNA adducts.Previously, no significant associations were found between PAH—DNAadducts and cigarettes smoked/day, pack-years, daily/life timetar exposures or plasma cotinine levels (Santella et al., Carcinogenesis,13, 2041–2045, 1992). PAH—DNA adducts were inverselyassociated with serum cholesterol-adjusted vitamin E levels(r = –0.25, P