Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis

Background: Prostate-specific antigen (PSA) screening has low specificity. Assessment of methylation status in body fluids may complement PSA screening if the test has high specificity. Method: The purpose of this study was to conduct a meta-analysis of the sensitivity and specificity for prostate cancer detection of glutathione-s-transferase–π (GSTP1) methylation in body fluids (plasma, serum, whole blood, urine, ejaculate, and prostatic secretions). We conducted a comprehensive literature search on Medline (Pubmed). We included studies if they met all four of the following criteria: (1) measurement of DNA methylation in body fluids; (2) a case-control or case-only design; (3) publication in an English journal; and (4) adult subjects. Reviewers conducted data extraction independently using a standardised protocol. Twenty-two studies were finally included in this paper. Primer sequences and methylation method in each study were summarised and evaluated using meta-analyses. This paper represents a unique cross-disciplinary approach to molecular epidemiology. Results: The pooled specificity of GSTP1 promoter methylation measured in plasma, serum, and urine samples from negative-biopsy controls was 0.89 (95% CI, 0.80–0.95). Stratified analyses consistently showed a high specificity across different sample types and methylation methods (include both primer sequences and location). The pooled sensitivity was 0.52 (95% CI, 0.40–0.64). Conclusions: The pooled specificity of GSTP1 promoter methylation measures in plasma, serum, and urine was excellent and much higher than the specificity of PSA. The sensitivity of GSTP1 was modest, no higher than that of PSA. These results suggest that measurement of GSTP1 promoter methylation in plasma, serum, or urine samples may complement PSA screening for prostate cancer diagnosis

Five Glutathione S-Transferase Gene Variants in 23,452 Cases of Lung Cancer and 30,397 Controls: Meta-Analysis of 130 Studies

BACKGROUND: Glutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results. METHODS AND FINDINGS: Literature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms ( GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14–1.23) and 1.09 (95% CI: 1.02–1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95–1.14) and 0.99 (95% CI: 0.86–1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99–1.09), 1.15 (95% CI: 0.95–1.39), and 1.05 (95% CI: 0.89–1.23), respectively. CONCLUSIONS: The risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies

Causes of decoupling between larval supply and settlement and consequences for understanding recruitment and population connectivity

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Experimental Marine Biology and Ecology 392 (2010): 9-21, doi:10.1016/j.jembe.2010.04.008.Marine broadcast spawners have two-phase life cycles, with pelagic larvae and benthic adults. Larval supply and settlement link these two phases and are crucial for the persistence of marine populations. Mainly due to the complexity in sampling larval supply accurately, many researchers use settlement as a proxy for larval supply. Larval supply is a constraining variable for settlement because, without larval supply, there is no settlement. Larval supply and settlement may not be well correlated, however, and settlement may not consistently estimate larval supply. This paper explores the argument that larval supply (i.e., larval abundance near settlement sites) may not relate linearly to settlement. We review the relationship between larval supply and settlement, from estimates and biases in larval supply sampling, to non-behavioral and behavioral components, including small-scale hydrodynamics, competency, gregarious behavior, intensification of settlement, lunar periodicity, predation and cannibalism. Physical and structural processes coupled with behavior, such as small-scale hydrodynamics and intensification of settlement, sometimes result in under- or overestimation of larval supply, where it is predicted from a linear relationship with settlement. Although settlement is a function of larval supply, spatial and temporal processes interact with larval behavior to distort the relationship between larval supply and settlement, and when these distortions act consistently in time and space, they cause biased estimates of larval supply from settlement data. Most of the examples discussed here suggest that behavior is the main source of the decoupling between larval supply and settlement because larval behavior affects the vertical distribution of larvae, the response of larvae to hydrodynamics, intensification of settlement, gregariousness, predation and cannibalism. Thus, larval behavior seems to limit broad generalizations on the regulation of settlement by larval supply. Knowledge of the relationship is further hindered by the lack of a well founded theoretical relationship between the two variables. The larval supply- settlement transition may have strong general consequences for population connectivity, since larval supply is a result of larval transport, and settlement constrains recruitment. Thus, measuring larval supply and settlement effectively allows more accurate quantification and understanding of larval transport, recruitment and population connectivity.JP would like to thank WHOI Ocean Life Institute for partial funding. FP’s contribution is based upon research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation

Clock genes and their genomic distributions in three species of salmonid fishes: Associations with genes regulating sexual maturation and cell cycling

<p>Abstract</p> <p>Background</p> <p>Clock family genes encode transcription factors that regulate clock-controlled genes and thus regulate many physiological mechanisms/processes in a circadian fashion. Clock1 duplicates and copies of Clock3 and NPAS2-like genes were partially characterized (genomic sequencing) and mapped using family-based indels/SNPs in rainbow trout (RT)(<it>Oncorhynchus mykiss</it>), Arctic charr (AC)(<it>Salvelinus alpinus</it>), and Atlantic salmon (AS)(<it>Salmo salar</it>) mapping panels.</p> <p>Results</p> <p>Clock1 duplicates mapped to linkage groups RT-8/-24, AC-16/-13 and AS-2/-18. Clock3/NPAS2-like genes mapped to RT-9/-20, AC-20/-43, and AS-5. Most of these linkage group regions containing the Clock gene duplicates were derived from the most recent 4R whole genome duplication event specific to the salmonids. These linkage groups contain quantitative trait loci (QTL) for life history and growth traits (i.e., reproduction and cell cycling). Comparative synteny analyses with other model teleost species reveal a high degree of conservation for genes in these chromosomal regions suggesting that functionally related or co-regulated genes are clustered in syntenic blocks. For example, anti-müllerian hormone (amh), regulating sexual maturation, and ornithine decarboxylase antizymes (oaz1 and oaz2), regulating cell cycling, are contained within these syntenic blocks.</p> <p>Conclusions</p> <p>Synteny analyses indicate that regions homologous to major life-history QTL regions in salmonids contain many candidate genes that are likely to influence reproduction and cell cycling. The order of these genes is highly conserved across the vertebrate species examined, and as such, these genes may make up a functional cluster of genes that are likely co-regulated. CLOCK, as a transcription factor, is found within this block and therefore has the potential to cis-regulate the processes influenced by these genes. Additionally, clock-controlled genes (CCGs) are located in other life-history QTL regions within salmonids suggesting that at least in part, trans-regulation of these QTL regions may also occur via Clock expression.</p

Ion homeostasis in the Chloroplast

peer reviewedThe chloroplast is an organelle of high demand for macro- and micro-nutrient ions, which are required for the maintenance of the photosynthetic process. To avoid deficiency while preventing excess, homeostasis mechanisms must be tightly regulated. Here, we describe the needs for nutrient ions in the chloroplast and briefly highlight their functions in the chloroplastidial metabolism. We further discuss the impact of nutrient deficiency on chloroplasts and the acclimation mechanisms that evolved to preserve the photosynthetic apparatus. We finally present what is known about import and export mechanisms for these ions. Whenever possible, a comparison between cyanobacteria, algae and plants is provided to add an evolutionary perspective to the description of ion homeostasis mechanisms in photosynthesis

Airflow limitation in a collapsible model of the human pharynx: physical mechanisms studied with fluid‐structure interaction simulations and experiments

Abstract The classical Starling Resistor model has been the paradigm of airway collapse in obstructive sleep apnea (OSA) for the last 30 years. Its theoretical framework is grounded on the wave‐speed flow limitation (WSFL) theory. Recent observations of negative effort dependence in OSA patients violate the predictions of the WSFL theory. Fluid‐structure interaction (FSI) simulations are emerging as a technique to quantify how the biomechanical properties of the upper airway determine the shape of the pressure‐flow curve. This study aimed to test two predictions of the WSFL theory, namely (1) the pressure profile upstream from the choke point becomes independent of downstream pressure during flow limitation and (2) the maximum flowrate in a collapsible tube is VImax=A3/2(ρdA/dP)−1/2, where ρ is air density and A and P are the cross‐sectional area and pressure at the choke point respectively. FSI simulations were performed in a model of the human upper airway with a collapsible pharynx whose wall thickness varied from 2 to 8 mm and modulus of elasticity ranged from 2 to 30 kPa. Experimental measurements in an airway replica with a silicone pharynx validated the numerical methods. Good agreement was found between our FSI simulations and the WSFL theory. Other key findings include: (1) the pressure‐flow curve is independent of breathing effort (downstream pressure vs. time profile); (2) the shape of the pressure‐flow curve reflects the airway biomechanical properties, so that VImax is a surrogate measure of pharyngeal compliance