Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade <8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.     

The effect of controlled growth factor delivery on embryonic stem cell differentiation inside fibrin scaffolds

The goal of this project was to develop 3-D biomaterial scaffolds that present cues to direct the differentiation of embryonic stem (ES) cell-derived neural progenitor cells, seeded inside the scaffolds, into mature neural phenotypes, specifically neurons and oligodendrocytes. Release studies were performed to determine the appropriate conditions for retention of neurotrophin-3 (NT-3), sonic hedgehog, and platelet-derived growth factor (PDGF) by an affinity-based delivery system incorporated into fibrin scaffolds. Embryoid bodies containing neural progenitors were formed from mouse ES cells, using a 4−/4+ retinoic acid treatment protocol, and then seeded inside fibrin scaffolds containing the drug delivery system. This delivery system was used to deliver various growth factor doses and combinations to the cells seeded inside the scaffolds. Controlled delivery of NT-3 and PDGF simultaneously increased the fraction of neural progenitors, neurons, and oligodendrocytes while decreasing the fraction of astrocytes obtained compared to control cultures seeded inside unmodified fibrin scaffolds with no growth factors present in the medium. These results demonstrate that such a strategy can be used to generate an engineered tissue for the potential treatment of spinal cord injury and could be extended to the study of differentiation in other tissues.     

Extremely high Tp53 mutation load in esophageal squamous cell carcinoma in Golestan Province, Iran

Background

Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC.

Methodology/Principal Findings

Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 “hotspots” but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence.

Conclusion/Significance

ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.     

The application of GIS and spatiotemporal analyses to investigations of unusual marine mammal strandings and mortality events

In 2006–2007, an unusually high number of harbor porpoises (Phocoena phocoena) stranded along the Washington and Oregon coastlines. Spatiotemporal analyses were used to examine their ability to detect clusters of porpoise strandings during an unusual mortality event (UME) in the Pacific Northwest using stranding location data. Strandings were evaluated as two separate populations, outer coast and inland waters. The presence of global clustering was evaluated using the Knox spatiotemporal test, and the presence of local clusters was investigated using a spatiotemporal scan statistic (space–time permutation). There was evidence of global clustering, but no local clustering, supporting the hypothesis that strandings were due to more varied etiologies instead of localized causes. Further analyses at subregional levels, and concurrently assessing environmental factors, might reveal additional geographic distribution patterns. This article describes the spatial analytical tools applied in this study and how they can help elucidate the spatiotemporal epidemiology of other UMEs and assist in determining their causes. More than one spatial analytical technique should be used if the study objective is to detect and describe clustering in time and space and to generate hypotheses regarding causation of marine mammal disease and stranding events.     

DOES VARIATION IN SELECTION IMPOSED BY BEARS DRIVE DIVERGENCE AMONG POPULATIONS IN THE SIZE AND SHAPE OF SOCKEYE SALMON?

Few studies have determined whether formal estimates of selection explain patterns of trait divergence among populations, yet this is one approach for evaluating whether the populations are in equilibria. If adaptive divergence is complete, directional selection should be absent and stabilizing selection should prevail. We estimated natural selection, due to bear predation, acting on the body size and shape of male salmon in three breeding populations that experience differing predation regimes. Our approach was to (1) estimate selection acting within each population on each trait based on an empirical estimate of reproductive activity, (2) test for trait divergence among populations, and (3) test whether selection coefficients were correlated with trait divergence among populations. Stabilizing selection was never significant, indicating that these populations have yet to attain equilibria. Directional selection varied among populations in a manner consistent with trait divergence, indicating ongoing population differentiation. Specifically, the rank order of the creeks in terms of patterns of selection paralleled the rank order in terms of size and shape. The shortest and least deep-bodied males had the highest reproductive activity in the creek with the most intense predation and longer and deeper-bodied males were favored in the creeks with lower predation risk.     

Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind,Cross-Over Study

The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration ‘wait-time’ prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups.     

Raccoon Social Networks and the Potential for Disease Transmission

Raccoons are an important vector of rabies and other pathogens. The degree to which these pathogens can spread through a raccoon population should be closely linked to association rates between individual raccoons. Most studies of raccoon sociality have found patterns consistent with low levels of social connectivity within populations, thus the likelihood of direct pathogen transmission between raccoons is theoretically low. We used proximity detecting collars and social network metrics to calculate the degree of social connectivity in an urban raccoon population for purposes of estimating potential pathogen spread. In contrast to previous assumptions, raccoon social association networks were highly connected, and all individuals were connected to one large social network during 15 out of 18 months of study. However, these metrics may overestimate the potential for a pathogen to spread through a population, as many of the social connections were based on relatively short contact periods. To more closely reflect varying probabilities of pathogen spread, we censored the raccoon social networks based on the total amount of time spent in close proximity between two individuals per month. As this time criteria for censoring the social networks increased from one to thirty minutes, corresponding measures of network connectivity declined. These findings demonstrate that raccoon populations are much more tightly connected than would have been predicted based on previous studies, but also point out that additional research is needed to calculate more precise transmission probabilities by infected individuals, and determine how disease infection changes normal social behaviors.