Genetic polymorphisms in the cyclooxygenase-2 gene, use of nonsteroidal anti-inflammatory drugs, and breast cancer risk

INTRODUCTION: The association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk remains unclear. Inconsistencies in previously reported findings may be partly due to differences in expression of cyclooxygenase (COX)-2. We hypothesized that genetic polymorphisms (COX-2 .926, COX-2 .5209, and COX-2 .8473) may reduce overall breast cancer risk or risk for subtypes of breast cancer by modulating the inflammatory response and may interact with aspirin or any NSAID use. METHODS: We conducted a population-based, case-control study in which we genotyped 1,067 breast cancer cases and 1,110 control individuals included in the Long Island Breast Cancer Study Project. RESULTS: No major effects of the three COX-2 variant alleles on breast cancer risk were found. A total of eight distinct haplotypes and 18 diplotypes were observed in the population. Overall, no significant associations between COX-2 haplotypes/diplotypes and breast cancer risk were observed. Among women who used aspirin or any NSAID there was little evidence for an interaction with the at-risk COX-2 genotypes, with one exception. Among women with hormone receptor positive breast cancer, the reduced risk for any NSAID use was only evident among those who had at least one variant C allele of COX-2 .8473 (odds ratio = 0.7, 95% confidence interval = 0.5 to 1.0; P for the interaction = 0.02). There was no corresponding interaction for aspirin use, possibly because of limited power. CONCLUSION: These data provide modest evidence that the C allele of COX-2 .8473 may interact with NSAIDs to reduce risk for hormone receptor positive breast cancer

Melioidosis Vaccines: A Systematic Review and Appraisal of the Potential to Exploit Biodefense Vaccines for Public Health Purposes

The designation of Burkholderia pseudomallei as a category B select agent has resulted in considerable research funding to develop a protective vaccine. This bacterium also causes a naturally occurring disease (melioidosis), an important cause of death in many countries including Thailand and Australia. In this study, we explored whether a vaccine could be used to provide protection from melioidosis. An economic evaluation based on its use in Thailand indicated that a vaccine could be a cost-effective intervention if used in high-risk populations such as diabetics and those with chronic kidney or lung disease. A literature search of vaccine studies in animal models identified the current candidates, but noted that models failed to take account of the common routes of infection in natural melioidosis and major risk factors for infection, primarily diabetes. This review highlights important areas for future research if biodefence-driven vaccines are to play a role in reducing the global incidence of melioidosis

Mediator Acts Upstream of the Transcriptional Activator Gal4

We show that Mediator, a protein originally isolated on the basis of its ability to respond to transcriptional activators, and thought to be regulated by an activator, can also be the master that controls the activator

Size-scale affects the upper limit of elastic energy storage

Elastically-driven motion has been used as a strategy to achieve high speeds in small organisms and engineered micro-robotic devices. We examine the size-scaling relations determining the limit of elastic energy release from elastomer bands that efficiently cycle mechanical energy with minimal loss. The maximum center-of-mass velocity of the elastomer bands was found to be size-scale independent, while smaller bands demonstrated larger accelerations and shorter durations of elastic energy release. Scaling relationships determined from these measurements are consistent with the performance of small organisms and engineered devices which utilize elastic elements to power motion

PROBIOTICS ENGINEERING FOR THE TREATMENT AND PREVENTION OF GASTROINTESTINAL INFECTIONS

Ph.DDOCTOR OF PHILOSOPHY (NGS

Reprogramming Microbes to Be Pathogen-Seeking Killers

Recent examples of new genetic circuits that enable cells to acquire biosynthetic capabilities, such as specific pathogen killing, present an attractive therapeutic application of synthetic biology. Herein, we demonstrate a novel genetic circuit that reprograms Escherichia coli to specifically recognize, migrate toward, and eradicate both dispersed and biofilm-encased pathogenic Pseudomonas aeruginosa cells. The reprogrammed E. coli degraded the mature biofilm matrix and killed the latent cells encapsulated within by expressing and secreting the antimicrobial peptide microcin S and the nuclease DNaseI upon the detection of quorum sensing molecules naturally secreted by P. aeruginosa. Furthermore, the reprogrammed E. coli exhibited directed motility toward the pathogen through regulated expression of CheZ in response to the quorum sensing molecules. By integrating the pathogen-directed motility with the dual antimicrobial activity in E. coli, we achieved signifincantly improved killing activity against planktonic and mature biofilm cells due to target localization, thus creating an active pathogen seeking killer E. coli

A galactose-stable Gal80 deletion derivative inhibits galactose induction of the <i>GAL1</i> gene.

<p>(A) <i>BY4742ΔW</i> cells over-expressing the indicated HA-Gal80 deletion derivatives from <i>RS316</i> under the control of the <i>ACT1</i> promoter were 10-fold serially diluted, titrated onto the indicated plates, and incubated for 3 d (Glucose) and 6 d (Galactose+AA = 1 mg/l Antimycin A), respectively. (B) Cells of part A, lines 1, 2 and 6, were grown in glucose liquid media to OD_{600 nm} = 1 and induced with galactose liquid media for the indicated number of hours. Total RNA was isolated and <i>GAL1</i> mRNA was determined relative to <i>ACT1</i> mRNA by quantitative real-time PCR. The value determined for <i>BY4742ΔW</i> cells containing <i>RS316</i> grown with glucose liquid media was set as 1 and the error bars indicate the standard deviations between three replicates. (C) <i>BY4742ΔW</i> cells expressing HA-tagged wild-type Gal80 or Gal80ΔN12 from <i>RS317</i> under the control of the <i>ACT1</i> promoter were grown in glucose liquid media to OD_{600 nm} = 1 and induced with galactose liquid media for 1 h. Cycloheximide was added at time = 0 and the amount of HA-Gal80 and HA-Gal80ΔN12 proteins remaining in the cells after the indicated number of minutes was determined by Western blot with the help of an anti-HA antibody (upper panels). The membranes were stripped and reprobed with an anti-CPY antibody (middle panels), followed by a second stripping and staining with Coomassie Blue as loading controls (lower panels). (D) The ratio of the amount of HA-Gal80 protein to CPY protein (white bars) and of HA-Gal80ΔN12 protein to CPY protein (black bars) in <i>BY4742ΔW</i> cells for each time point in part C was determined with Image J. The ratio of the band intensities before the addition of cycloheximide (time = 0) was set as 1 and the error bars indicate the deviations between duplicates.</p

The protein kinase Snf1 is required for galactose-induced protein degradation of Gal80.

<p>(A) <i>BY4742ΔW</i> (lanes 1 to 12), <i>BY4742ΔWΔSNF1</i> (lanes 13 to 24), and <i>BY4741ΔWΔSNF4</i> (lanes 25 to 36) cells expressing HA-tagged Gal80 under the control of the <i>ACT1</i> promoter were grown in glucose liquid media to OD_{600 nm} = 1 and induced with galactose liquid media for 1 h. Cycloheximide was added at time = 0 and the amount of Gal80 protein remaining in the cells after the indicated number of minutes was determined by Western blot with the help of an anti-HA antibody (upper panels). The membranes were stripped and reprobed with an anti-CPY antibody (middle panels), followed by a second stripping and staining with Coomassie Blue as loading controls (lower panels). (B) The ratio of the amount of HA-Gal80 protein to CPY protein in <i>BY4742ΔW</i> cells (white bars), <i>BY4742ΔWΔSNF1</i> cells (black bars), and <i>BY4741ΔWΔSNF4</i> cells (grey bars) for each time point in part A was determined with Image J. The ratio of the band intensities before the addition of cycloheximide (time = 0) was set as 1 and the error bars indicate the deviations between duplicates. (C) <i>BY4742ΔW</i> cells (lines 1 to 3) and <i>BY4741ΔW</i> cells (lines 4 to 6) of the indicated genotype were 10-fold serially diluted, dropped onto the depicted plates, and incubated for 6 d at 28°C. The galactose plate contained 1 mg/l Antimycin A. (D) Cells of part C, lines 1 to 3, were grown in glucose liquid media to OD_{600 nm} = 1 and induced with galactose liquid media for the indicated number of hours. Total RNA was isolated and <i>GAL1</i> mRNA was determined relative to <i>ACT1</i> mRNA by quantitative real-time PCR. The value determined for <i>BY4742ΔW</i> cells grown with glucose liquid media was set as 1 and the error bars indicate the standard deviations between three replicates.</p