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.

The influence of lifetime sun exposure on breast cancer stage

This thesis was a retrospective cohort study that investigated the relationship between lifetime sun exposure and breast cancer stage, as a measure of prognosis, in women newly diagnosed with breast cancer. This project was the first of its kind and aimed to enhance the understanding of the effects of sun exposure, possibly mediated by vitamin D, on breast cancer stage and provide insight into ways in which the prognosis of breast cancer can be improved. The study found no significant relationship between lifetime sun exposure and breast cancer stage.

Tumour islet Foxp3+ T-cell infiltration predicts poor outcome in nonsmall cell lung cancer

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis. Tumour- and stroma-infiltrating CD3+, CD8+ and forkhead box P3 (Foxp3)+ T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined. There was a positive association between overall survival and increased CD8+ TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3+ TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8+ islet (HR 0.48, p<0.001) and Foxp3+ stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3+ and CD8+ stromal counts and high Foxp3+ islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8+ TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3+ TI/S ratio was associated with worse survival (HR 3.91, p<0.001). Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.

Kaupunkimaineen rakentuminen. Lahden muotoilumaine epälineaarisena prosessina.

Tämän pro gradu -tutkimuksen aiheena on kaupunkimaineen tarkastelu epälineaarisena ja dynaamisena prosessina. Opinnäytteessä kaupunkimainetta tutkitaan dynaamisen onganisaatioviestinnän teorian näkökulmasta ja sen tarkoitus on hahmotella epälineaarisempaa näkemystä kaupunkimaineen rakentumisesta. Lisäksi työ siirtää kaupunkimainetutkimuksen fokusta maineen mittaamisesta sen leviämisen tutkimiseen. Tarkoituksena on siis hahmottaa sitä, miten kaupungin sisällä syntyvä maine yleisöissään leviää. Tutkimuksen tärkeimmiksi lähteiksi on valikoitu Pekka Aulan dynaamisen organisaatioviestinnän teoria sekä Aulan, Jouni Heinosen, Saku Mantereen sekä Erkki Karvosen mainenäkemykset. Lisäksi tutkimuksessa on hyödynnetty useiden kansainvälisten kaupunkitutkijoiden ajatuksia, joista tärkeimpinä lähteinä tutkimuksen kehittymisen kannalta ovat olleet Elaine Romanellin, Olga M. Khessinan sekä Patsy Healyn työt. Kaupunkia ja sen mainetta käsittelevissä osioissa tärkeään rooliin nousi myös Teppo Sintosen käsitys postmodernista organisaatiosta, jollaisena kaupunki tässä tutkimuksessa nähdään, itse tutkimuksen todellisuuskäsitys on konstruktivistinen - siinä todellisuus eli näin ollen myös kaupunki on yhteisesti rakennettua ja uusiutuu kirjoituksissa sekä puheissa. Lähteiden pohjalta on tutkimuksessa hahmoteltu ajatuksia dynaamisesta kaupunkimaineesta, joka vastaa niin maineteorioiden ajatuksiin, dynaamisen organisaatioviestinnän teorian prepositioihin kuin kriittiseen kaupunkimarkkinoinnin tutkimukseen. Työ onkin vahvasti poikkitieteellinen tutkimus, jonka takia sen teoreettinen osuus onkin erittäin laaja. Teoreettisen osuuden laajuus selittyy myös sillä, että tutkimuksessa lähestyttiin kaupunkimainetta uudesta, epälineaarisemmasta näkökulmasta. Työ on laadullinen tapaustutkimus, jossa maineen epälineaarista rakentumista on tutkittu tapauskaupunki Lahden ja tämän muotoilumaineen näkökulmasta. Tutkimus toteutettiin haastattelututkimuksena ja aineisto analysoitiin narratiiviparadigman teorian alle sijoittuvalla juonellistamisen menetelmällä. Asiantuntijahaastatteluista eritellystä aineistosta johdetut johtopäätökset osoittavat maineen rakentumiseen liittyviä epälineaarisia elementtejä sekä antavat tukea ajatukselle, jonka mukaan kaupunkimaineen tutkimuksessa saattaa olla vaatimuksia epälineaarisemmalle kaupunkimainekäsitykselle. Tutkimuksen johtopäätösten mukaan mainetta voidaan siis tarkastella epälineaarisena prosessina, joka muotoutuu vuorovaikutuksessa ympäristön ja kaupungin välillä, ja joka kehittyy ennustamattomien, luovien ja itseohjautuvien prosessien kautta.

The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action

Mycobacterium tuberculosis is an extremely well adapted intracellular human pathogen that is exposed to multiple DNA damaging chemical assaults originating from the host defence mechanisms. As a consequence, this bacterium is thought to possess highly efficient DNA repair machineries, the nucleotide excision repair (NER) system amongst these. Although NER is of central importance to DNA repair in M. tuberculosis, our understanding of the processes in this species is limited. The conserved UvrABC endonuclease represents the multi-enzymatic core in bacterial NER, where the UvrA ATPase provides the DNA lesion-sensing function. The herein reported genetic analysis demonstrates that M. tuberculosis UvrA is important for the repair of nitrosative and oxidative DNA damage. Moreover, our biochemical and structural characterization of recombinant M. tuberculosis UvrA contributes new insights into its mechanism of action. In particular, the structural investigation reveals an unprecedented conformation of the UvrB-binding domain that we propose to be of functional relevance. Taken together, our data suggest UvrA as a potential target for the development of novel anti-tubercular agents and provide a biochemical framework for the identification of small-molecule inhibitors interfering with the NER activity in M. tuberculosis.

Correlation of Calcification on Excised Aortic Valves by Micro-Computed Tomography with Severity of Aortic Stenosis

Background and aim of the study: The quantification of incidentally found aortic valve calcification on computed tomography (CT) is not performed routinely, as data relating to the accuracy of aortic valve calcium for estimating the severity of aortic stenosis (AS) is neither consistent nor validated. As aortic valve calcium quantification by CT is confounded by wall and coronary ostial calcification, as well as motion artifact, the ex-vivo micro-computed tomography (micro-CT) of stenotic aortic valves allows a precise measurement of the amounts of calcium present. The study aim, using excised aortic valves from patients with confirmed AS, was to determine if the amount of calcium on micro-CT correlated with the severity of AS. Methods: Each of 35 aortic valves that had been excised from patients during surgical valve replacement were examined using micro-CT imaging. The amount of calcium present was determined by absolute and proportional values of calcium volume in the specimen. Subsequently, the correlation between calcium volume and preoperative mean aortic valve gradient (MAVG), peak transaortic velocity (V-max), and aortic valve area (AVA) on echocardiography, was evaluated. Results: The mean calcium volume across all valves was 603.2 +/- 398.5 mm(3), and the mean ratio of calcium volume to total valve volume was 0.36 +/- 0.16. The mean aortic valve gradient correlated positively with both calcium volume and ratio (r = 0.72, p <0.001). V-max also correlated positively with the calcium volume and ratio (r = 0.69 and 0.76 respectively; p <0.001). A logarithmic curvilinear model proved to be the best fit to the correlation. A calcium volume of 480 mm(3) showed sensitivity and specificity of 0.76 and 0.83, respectively, for a diagnosis of severe AS, while a calcium ratio of 0.37 yielded sensitivity and specificity of 0.82 and 0.94, respectively. Conclusion: A radiological estimation of calcium amount by volume, and its proportion to the total valve volume, were shown to serve as good predictive parameters for severe AS. An estimation of the calcium volume may serve as a complementary measure for determining the severity of AS when aortic valve calcification is identified on CT imaging. The Journal of Heart Valve Disease 2012;21:320-327

Maioridade penal no Brasil e na Espanha : um estudo comparativo

Traça um panorama geral da legislação referente à maioridade penal no Brasil e na Espanha. O tema é apresentado sob uma perspectiva histórica e mostra a evolução no tratamento da infância e da adolescência nos dois países. Compara a legislação de menores e as medidas socioeducativas adotadas em ambos os países com o intuito de trazer subsídios para a busca de soluções da problemática do aumento da criminalidade infanto-juvenil em nosso país.

Planejamento estratégico do Detaq : um histórico e seus primeiros resultados

Aborda o processo de planejamento estratégico do Departamento de Taquigrafia (Detaq), destacando as iniciativas e os eventos relacionados à renovação de práticas administrativas.

Os efeitos da Emenda Constitucional nº 45, de 2004, nos tratados e convenções internacionais sobre direitos humanos

Discute e reflete sobre os Tratados Internacionais de Direitos Humanos, sua história, a incorporação deles ao sistema jurídico e as consequências da Emenda Constitucional nº 45, de 2004, no processo de constitucionalização. Analisa, por outro lado, como as Constituições da Argentina, Peru e do Brasil foram alteradas procurando ou não trazer para os textos constitucionais, documentos internacionais ratificados pelos Estados Nacionais. Entre os objetivos propostos, o estudo buscou desenvolver a evolução histórica dos direitos humanos, dos tratados que versam sobre o mesmo tema, bem como nos mecanismos de proteção dos direitos humanos no âmbito internacional. Relata as nuances - a construção, os avanços e limites - dos tratados sobre direitos humanos nos processos constitucionais, especialmente no "Caso Brasileiro".

Direito humano à alimentação adequada e o parlamento brasileiro

Discute e faz reflexões sobre o tratamento e a tramitação de propostas sobre a segurança alimentar e nutricional, tanto pelo parlamento como por parte da mídia, em especial a Proposta de Emenda à Constituição (PEC nº 47 de 2003), que inclui no rol dos Direitos Sociais a alimentação. Entre os objetivos propostos, o estudo buscou também aprofundar a reflexão sobre a evolução histórica dos direitos humanos à alimentação no mundo e, especificamente, no âmbito brasileiro.

Juventude em revolta : o Pró-Sinase e a realidade do Distrito Federal

Trata do Programa de Implementação do Sistema Nacional de Atendimento Socioeducativo (Pró-Sinase) e a realidade no Distrito Federal, assunto relevante para o contexto atual, objetivando analisar a realidade das Unidades Executoras das medidas socioeducativas de internação, internação provisória, e semiliberdade. Pretende verificar, à luz do Estatuto da Criança e do Adolescente, da Resolução nº 46 do Conselho Nacional dos Direitos da Criança e do Adolescente (Conanda) e das diretrizes do Pró-Sinase, qual o provável distanciamento das condições das Unidades de Atendimento Socioeducativo em relação ao que determinam os instrumentos legais, nos seguintes aspectos: gestão dos programas, parâmetros de gestão pedagógica no atendimento socioeducativo e os parâmetros arquitetônicos para Unidades de Atendimento Socioeducativo.

A identificação de metadados de assunto para a legislação federal brasileira : o caso do Sistema Legin Web da Câmara dos Deputados

Aponta aspectos que devem ser considerados na identificação de metadados de assunto granulares para a legislação federal brasileira. O objeto de estudo foi o Sistema de Legislação Informatizada (Legin Web) disponível no Portal da Câmara dos Deputados. Os objetivos específicos foram: identificar tipos de assuntos amplamente utilizados na indexação da legislação federal brasileira e aspectos do contexto de busca de informação que interferissem na identificação dos metadados de assunto; analisar possibilidades de metadados de assunto para a legislação federal com base em padrões de metadados e modelos de organização da informação abordados na literatura; e, com isso, propor metadados de assunto para a legislação federal brasileira. A ideia é usar esses metadados para diminuir a imprecisão dos resultados das pesquisas na legislação federal, tornando o processo mais rápido e eficiente.

Avaliação dos discursos parlamentares na Legislatura de 1999 a 2003 sobre o terceiro setor

Análise dos discursos parlamentares proferidos no Plenário da Câmara dos Deputados na 51ª Legislatura, anos de 1999 a 2003, sobre o tema terceiro setor. Na metodologia utilizada foi criada uma base de dados específica da massa documental dos discursos e utilizadas atribuições de positividade e negatividade. Observou-se a necessidade de mais entrosamento entre as Ongs e o Congresso Nacional para o desenvolvimento de ações que propiciem melhores condições de vida para a população brasileira.