Comparisons of resistance of CF and Non-CF pathogens to Hydrogen Peroxide and Hypochlorous Acid Oxidants In Vitro

<p>Abstract</p> <p>Background</p> <p>Cystic fibrosis (CF) lung disease has a unique profile of pathogens predominated by <it>Pseudomonas aeruginosa </it>(PsA) and <it>Staphylococcus aureus </it>(SA). These microorganisms must overcome host immune defense to colonize the CF lungs. Polymorphonuclear neutrophils are a major component of the host defense against bacterial infection. A crucial microbicidal mechanism is the production of oxidants including hydrogen peroxide (H₂O₂) and hypochlorous acid (HOCl) by neutrophils to achieve efficient bacterial killing. To determine to what degrees various CF pathogens resist the oxidants relative to non-CF pathogens, we compared the susceptibility of PsA, SA, <it>Burkholderia cepacia </it>(BC), <it>Klebsiella pneumoniae </it>(KP), and <it>Escherichia coli </it>(EC) to various concentrations of H₂O₂or HOCl, <it>in vitro</it>. The comparative oxidant-resistant profiles were established. Oxidant-induced damage to ATP production and cell membrane integrity of the microbes were quantitatively assessed. Correlation of membrane permeability and ATP levels with bacterial viability was statistically evaluated.</p> <p>Results</p> <p>PsA was relatively resistant to both H₂O₂(LD₅₀= 1.5 mM) and HOCl (LD₅₀= 0.035 mM). SA was susceptible to H₂O₂(LD₅₀= 0.1 mM) but resistant to HOCl (LD₅₀= 0.035 mM). Interestingly, KP was extremely resistant to high doses of H₂O₂(LD₅₀= 2.5-5.0 mM) but was very sensitive to low doses of HOCl (LD₅₀= 0.015 mM). BC was intermediate to resist both oxidants: H₂O₂(LD₅₀= 0.3-0.4 mM) and HOCl (LD₅₀= 0.025 mM). EC displayed the least resistance to H₂O₂(LD₅₀= 0.2-0.3 mM) and HOCl (LD₅₀= 0.015 mM). The identified profile of H₂O₂-resistance was KP > PsA > BC > EC > SA and the profile of HOCl-resistance PsA > SA > BC > EC > KP. Moreover, both oxidants affected ATP production and membrane integrity of the cells. However, the effects varied among the tested organisms and, the oxidant-mediated damage correlated differentially with the bacterial viability.</p> <p>Conclusions</p> <p>The order of HOCl-resistance identified herein best fits the clinical profile of CF infections. Even though oxidants are able to disrupt ATP production and cell membrane integrity, the degrees of damage vary among the organisms and correlate differentially with their viability.</p

HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6%), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51%) than those without (42 of 137, 30%), P=9.9×10−8 [odds ratio 4.42 (95% confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P=6.5×10−6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95% of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5% of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-012-1229-4) contains supplementary material, which is available to authorized users