Risk analysis of prostate cancer in PRACTICAL, a multinational consortium, using 25 known prostate cancer susceptibility loci

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS).We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived agespecific absolute risks of developing prostate cancer by PRS stratum and family history. Results The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact:We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.

A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins

BACKGROUND: The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels. METHODS AND RESULTS: Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds \[(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5' untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family. CONCLUSION: Our data provide further evidence for complex inheritance of familial DZ twinning.

Reproductive interference between honey bee species in artificial sympatry

Reproductive isolation between closely related species is often incomplete. The Western honey bee, Apis mellifera, and the Eastern hive bee, A. cerana have been allopatric for millions of years, but are nonetheless similar in morphology and behaviour. During the last century the two species were brought into contact anthropogenically, providing potential opportunities for interspecific matings. Hybrids between A. mellifera and A. cerana are inviable, so natural interspecific matings are of concern because they may reduce the viability of A. cerana and A. mellifera populations – two of the world's most important pollinators. We examined the mating behaviour of A. mellifera and A. cerana queens and drones from Caoba Basin, China and Cairns, Australia. Drone mating flight times overlap in both areas. Analysis of the spermathecal contents of queens with species-specific genetic markers indicated that in Caoba Basin, 14% of A. mellifera queens mated with at least one A. cerana male, but we detected no A. cerana queens that had mated with A. mellifera males. Similarly, in Cairns, no A. cerana queens carried A. mellifera sperm, but one third of A. mellifera queens had mated with at least one A. cerana male. No hybrid embryos were detected in eggs laid by interspecifically-mated A. mellifera queens in either location. However A. mellifera queens artificially inseminated with A. cerana sperm produced inviable hybrid eggs, or unfertilised drones. This suggests that reproductive interference will impact the viability of honey bee populations wherever A. cerana and A. mellifera are in contact. This article is protected by copyright. All rights reserved.

Genome-wide association study of prostate cancer-specific survival

BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS: We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.

Prediction of individual genetic risk to prostate cancer using a polygenic score

BACKGROUND Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction. Prostate 75:1467–1474, 2015. © 2015 Wiley Periodicals, Inc.

The effects of height and BMI on prostate cancer incidence and mortality: A Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Background Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. Methods We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. Results The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). Conclusions We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

New Catalytic Methods for the Preparation of Tryptophans and Pyrroloindolines: Total Synthesis of (+)-Naseseazines A and B and (–)-Aspergilazine A

Tryptophan and unnatural tryptophan derivatives are important building blocks for the total synthesis of natural products, as well as the development of new drugs, biological probes, and chiral small molecule catalysts. This thesis describes various catalytic methods for the preparation of tryptophan derivatives as well as their functionalization and use in natural product total synthesis.

Herein, the tandem Friedel–Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate to provide enantioenriched trytophans is reported. This method inspired further work in the area of transition metal catalyzed arylation reactions. We report the development of the coppercatalyzed arylation of tryptamine and tryptophan derivatives. The utility of these transformations is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B. Further work on the development of a mild and general Larock indolization protocol to access unnatural tryptophans is also discussed.

Estudio de los factores de competitividad turística de las comunidades autónomas

Estudio de los factores de competitividad turística de las Comunidades Autónomas.

¿Actividad cotidiana o práctica ritual? Agrupación de 14 colgantes líticos del Magdaleniense Inferior en la cueva de Praileaitz 1 (Deba, Gipuzkoa)

Homenaje a Ignacio Barandiarán Maestu / coord. por Javier Fernández Eraso, Juan Santos Yanguas

O estado do conhecimento sobre gênero na bibliografia internacional

Esta dissertação tem como objeto os estudos sobre gênero em pesquisas internacionais. Foram explorados 50 textos selecionados a partir de uma amostra de mil documentos oriundos da biblioteca virtual da Universidade de Sydney na Austrália. O estudo de natureza bibliográfica utilizou mapas conceituais e desenvolveu análises indutivas tendo com objetivo geral estudar como gênero tem sido abordado nas pesquisas internacionais de modo a compreender o desenvolvimento do conceito de gênero, as argumentações relacionadas a este conceito nos estudos investigados. A dissertação teve como objetivos específicos: Descrever os conceitos de gênero e suas interconexões em termos teóricos-epistemológicos de modo a construir uma linha do tempo da última década; Identificar e analisar as principais questões que orientaram as pesquisas em termos das escolhas de metodologias, instrumentos de coleta, formas de análise dos dados e pertinência teórica; Estabelecer a relação entre gênero e educação; analisar e descrever os cinco principais autores recorrentes nos textos, mostrando de que modo descrevem gênero levantando as suas contribuições para os estudos de gênero investigados. Os resultados apontam para: uma super-representação de trabalhos originários dos países ocidentais e uma sub-representação nos países do sul, como assinala Connell (2007); quanto as abordagens metodológicas visualiza-se uma tendência em utilizarem pesquisas quantitativas mais que qualitativas assim como as perspectivas binárias/dualistas em detrimento às perspectivas pós-estruturalista como suporte analítico-interpretativo; dentre as 2.066 citações de teóricos, cinco autores sobressaem nos estudos, são eles: Susan Moller Okin, Raewyn Connell, Madeleine Arnot, Bronwyn Davies e Pierre Bourdieu. Finalmente, este estudo denuncia a necessidade de pesquisas mais comprometida com o enfrentamento da desigualdades de gênero, em especial as minorias silenciadas pelas pesquisas examinadas, onde o mundo foi dividido entre homens e mulheres, na perspectiva de uma ordenação única de gênero, sem levar em conta as diferentes variações, interações e opções de gênero existentes na sociedade contemporânea.

As novas faces da dualidade educacional na contemporaneidade e o ideário educacional anarquista

A presente tese nasce da hipótese da existência da dualidade educacional (DE) nas políticas contemporâneas e que se confirma nesse trabalho. Por sua vez, a DE (uma escola para elite e outra para a classe popular) existe para que a classe hegemônica possa conservar a estratificação social e a divisão do trabalho a seu favor. Tem conivência do Estado, mesmo ele se expressando enquanto uma disputa de classe em movimento. Como metodologia de trabalho, utiliza-se o materialismo histórico-dialético no intuito de abranger o conflito de interesses entre classes sociais e poder caracterizar a materialidade e a dialeticidade nas subjetivações elucidadas. O trabalho de combate à DE é feito com mediações do ideário educacional anarquista e que se aproxima do marxismo através do nascedouro iluminista, comum às duas correntes. É um trabalho de cunho humanista e vai além da lógica iluminista. Pois é possível perceber o avanço em que o anarquismo trata as categorias igualdade, liberdade e solidariedade. No intuito de abranger melhor as relações do fenômeno da DE, é considerada a conjuntura política e econômica globalizada nas novas configurações entre Estado e sociedade civil no Brasil sob a vigência do capitalismo financeiro; além de ser levado em consideração o pensamento de Florestan Fernandes no que diz respeito ao Brasil ser um país de capitalismo dependente. Em relação às parcerias público-privadas na contemporaneidade, que promovem educação financiada pelo Estado, mas controlada pela sociedade civil; na prática, esse controle é feito por grupos empresariais, tendo em vista a falta de organização da população para esse fim. Desse modo, as estratégias hegemônicas de formatação e implantação das políticas educacionais neoliberais contribuem para a identificação do próprio fenômeno da dualidade educacional, no seio de estruturas organizativas bem planejadas. As novas faces da DE nas contradições de uma educação mercantilizada e alinhada aos ditames internacionais influenciam as políticas públicas educacionais locais. Por exemplo, a Gestão Integrada da Escola (GIDE), implantada desde 2011 na rede pública fluminense, é um projeto de caráter neoliberal, mas que tem uma lógica taylorista-fordista em seu funcionalismo gerencial administrativo-pedagógico. Nesse sistema fica patente a previsibilidade do processo fabril para a construção de um conhecimento sob a chancela de uma nova versão do tecnicismo que subtrai a criatividade e autonomia profissional e escolar, elege uma grade curricular fragmentada e mínima, prioriza o caráter quantitativo dos resultados nas estatísticas que, para tal, burocratiza o trabalho do professor e da própria escola. Na contramão desse ensino instrumental e padronizado desenvolvido pela GIDE, é conveniente rever o significado do que é o ensino libertário, que é aquele que consagra a liberdade e sacrifica progressivamente a autoridade numa educação que tem como objetivo final formar homens livres e respeitadores da liberdade alheia. Essa pesquisa no campo da educação apontou como uma forte pista a federalização das unidades escolares públicas. O chão da escola precisa assumir a sua autonomia possível frente ao sistema centralizador de ensino em um processo dialético de recriação de identidade e reafirmação da escola enquanto força organizativa local junto à comunidade