Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation.

Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation

The Paranormal is (Still) Normal: The Sociological Implications of a Survey of Paranormal Experiences in Great Britain

Historically, there has been limited sociological interest in the paranormal and no systematic study of reported paranormal experiences. There are also few medium-to-large-scale survey results with nationally representative populations focusing on paranormal experiences. This paper provides details of an exploratory survey conducted in 2009 with a nationally representative sample of 4,096 adults aged 16 years and over across Great Britain. Our findings show that 37% of British adults report at least one paranormal experience and that women, those who are middle-aged or individuals resident in the South West are more likely to report such experiences. These results establish incidence levels of reported paranormal experiences in contemporary Britain. We argue also that they merit a more sustained sociological consideration of the paranormal. In this respect we renew and update the robust justification and call for serious research positioning the paranormal as a social phenomenon, originally proposed well over thirty years ago by Greeley (1975)

Retrospectively Estimating Energy Intake and Misreporting From a Qualitative Food Frequency Questionnaire: An Example Using Australian Cohort and National Survey Data

Qualitative food frequency questionnaires (Q-FFQ) omit portion size information from dietary assessment. This restricts researchers to consumption frequency data, limiting investigations of dietary composition (i.e., energy-adjusted intakes) and misreporting. To support such researchers, we provide an instructive example of Q-FFQ energy intake estimation that derives typical portion size information from a reference survey population and evaluates misreporting. A sample of 1,919 Childhood Determinants of Adult Health Study (CDAH) participants aged 26-36 years completed a 127-item Q-FFQ. We assumed sex-specific portion sizes for Q-FFQ items using 24-h dietary recall data from the 2011-2012 Australian National Nutrition and Physical Activity Survey (NNPAS) and compiled energy density values primarily using the Australian Food Composition Database. Total energy intake estimation was daily equivalent frequency x portion size (g) x energy density (kJ/g) for each Q-FFQ item, summed. We benchmarked energy intake estimates against a weighted sample of age-matched NNPAS respondents (n = 1,383). Median (interquartile range) energy intake was 9,400 (7,580-11,969) kJ/day in CDAH and 9,055 (6,916-11,825) kJ/day in weighted NNPAS. Median energy intake to basal metabolic rate ratios were 1.43 (1.15-1.78) in CDAH and 1.35 (1.03-1.74) in weighted NNPAS, indicating notable underreporting in both samples, with increased levels of underreporting among the overweight and obese. Using the Goldberg and predicted total energy expenditure methods for classifying misreporting, 65 and 41% of CDAH participants had acceptable/plausible energy intake estimates, respectively. Excluding suspected CDAH misreporters improved the plausibility of energy intake estimates, concordant with expected body weight associations. This process can assist researchers wanting an estimate of energy intake from a Q-FFQ and to evaluate misreporting, broadening the scope of diet-disease investigations that depend on consumption frequency data

Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD

Period and Cohort Changes in Americans’ Support for Marijuana Legalization: Convergence and Divergence across Social Groups

We cast fresh light on how and why Americans’ views on marijuana legalization shifted between 1973 and 2014. Results from age-period-cohort models show a strong negative effect of age and relatively high levels of support for legalization among baby boom cohorts. Despite the baby boom effect, the large increase in support for marijuana legalization is predominantly a broad, period-based change in the population. Additional analyses demonstrate that differences in support for legalization by education, region, and religion decline, that differences by political party increase, and that differences between whites and African Americans reverse direction. We conclude by discussing the implications of these findings and by identifying promising directions for future research on this topic

Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality

High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort

Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0×10(-3)), and earlier cancer onset (33 vs 48 years, P = 1.19×10(-3)). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.Gillian Mitchell, Mandy L. Ballinger, Stephen Wong, Chelsee Hewitt, Paul James, Mary- Anne Young, Arcadi Cipponi, Tiffany Pang, David L. Goode, Alex Dobrovic, David M. Thomas, on behalf of the International Sarcoma Kindred Stud

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Bayesian Modeling of the Yeast SH3 Domain Interactome Predicts Spatiotemporal Dynamics of Endocytosis Proteins

A genome-scale specificity and interaction map for yeast SH3 domain-containing proteins reveal how family members show selective binding to target proteins and predicts the dynamic localization of new candidate endocytosis proteins