Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families

The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on similar to 4000 additional individuals by comparing the affected to healthy family members, as well as in a case-control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26-1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case-control dataset (1.49 [1.38-1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment.Peer reviewe

Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients.

INTRODUCTION: Somatic inactivation of the TP53 gene in breast tumors is a marker for poor outcome, and breast cancer outcome might also be affected by germ-line variation in the TP53 gene or its regulators. We investigated the effects of the germ-line single nucleotide polymorphisms TP53 R72P (215G>C) and MDM2 SNP309 (-410T>G), and p53 protein expression in breast tumors on survival. METHODS: We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both TP53 R72P and MDM2 SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models. RESULTS: Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1), P = 0.001. Within the patient group with p53-negative tumors, TP53 rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%, P = 0.07; HR 1.8 (1.1 to 3.1), P = 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53 C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%, P = 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0), P = 0.01. We found no evidence for a differential effect of MDM2 SNP309 by p53 protein expression on survival. CONCLUSIONS: The TP53 R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of TP53 R72P and MDM2 SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the TP53 Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Mapping Meaning : Critical Cartographies for Participatory Water Management in Taita Hills, Kenya

Participation of local people is often neglected in natural resource management, which leads to failure to understand the social aspects and historical construction of environmental problems. Participatory mapping can enhance the communication of local spatial knowledge for management processes and challenge the official maps and other spatial representations produced by state authorities and scientists. In this study, we analyze what kind of social meanings can be revealed through a multimethod participatory mapping process focusing on water resources in Taita Hills, Kenya. The participatory mapping clearly complicates the simplified image of the physical science mappings, typically depicting natural water supply, by addressing the impacts of contamination, inadequate infrastructure, poverty, distance to the sources, and restrictions in their uses on people's access to water. Moreover, this shared exercise is able to trigger discussion on issues that cannot always be localized but still contribute to place making. Local historical accounts reveal the social and political drivers of the current water-related problems, making explicit the political ecology dynamics in the area.Peer reviewe

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D-2 receptor occupancy of olanzapine in rats

A mechanism-based PK-PD model was developed to predict the time course of dopamine D-2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug. A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D2RO profile obtained experimentally at various doses (0.01-40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D-2 receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling . Plasma, brain concentration profiles and time course of D2RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and in vitro values from literature. This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D2RO in rats. Moreover, this modeling framework can be applied to scale the in vitro and preclinical information to clinical receptor occupancy

Online peer assessment in higher education: a systematic review of literature in educational practices

Neste artigo procedemos a uma revisão sistemática da literatura sobre Online Peer Assessment (OPA) no Ensino Superior, mediadas por Tecnologias Digitais de Informação e Comunicação (TIC). Identificamos suas características, centrais e opcionais e mapeamos exemplos práticos (procedimentos e TIC) de OPA que poderão ser transversais, adaptáveis e aplicáveis em diversas unidades curriculares e regimes educacionais. Os resultados apontam para a utilização da OPA como uma estratégia que potencia a “avaliação para a aprendizagem”. Os referenciais teóricos subjacentes, os métodos de avaliação e os tipos de TIC utilizadas indicam seu direcionamento para um maior envolvimento e responsabilidade do aluno na sua aprendizagem. Evidenciamos na literatura que se busca desenvolver essas competências, dando ao aluno oportunidades com alguma regularidade para autoavaliar-se e avaliar seus pares por meio de feedback construtivo. Há também evidências de que dar ou produzir feedback é mais benéfico para a aprendizagem do que apenas recebê-lo, como também é cognitivamente mais exigente e envolve os alunos de forma mais ativa e os direciona ao pensamento crítico e a processos metacognitivos. A partir dos resultados alcançados, consideramos que a OPA, enquanto ferramenta cognitiva, contribui para a construção do conhecimento e para a reflexão sobre a aprendizagem. Um desafio que se coloca diz respeito ao desenvolvimento criativo com foco na diversificação e na inovação das práticas de avaliação no sentido de potenciar aprendizagens e resultados acadêmicos, em atenção às necessidades de aprendizagem que se manifestam frente às expectativas da educação atual e futura e às exigências da sociedade.In this research a systematic review of literature about Online Peer Assessment (OPA) in higher education, mediated by Information and Communication Technology (ICT), was carried out. Optional and central characteristics and its practices (procedures and ICT) were identified and mapping. These procedures and practices may be transversal, adaptable and applied in several curriculum units and educational regimes. The results point to the use of OPA as a strategy that enhances “assessment for learning”. The theoretical framework, the methods of assessment and the kinds of ICT used indicate directions for greater involvement and responsibility from the part of the student in his/her learning. Theoretical framework identifies the need to develop students’ skills, providing them with opportunities for self-assessment and peer assessment on a regular basis through constructive feedback. There is also evidence that to give or receive feedback is more beneficial for learning than just receiving it. It is also cognitively more demanding and directs the students to critical thinking and metacognitive processes. From the results obtained, OPA is seen as a cognitive tool, contributing to the building of knowledge and to reflection about learning. Issues for further reflection are also identified such as the creative development of assessment methods with a focus on diversity and innovation in order to enhance students’ learning and academic results, taking into account their learning needs in face of the expectations of current and future education and the demands of society.CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT), PortugalFundos Nacionais através da FCT (Fundação para a Ciência e a Tecnologia) e cofinanciado pelo Fundo Europeu de Desenvolvimento Regional (FEDER) através do COMPETE 2020 – Programa Operacional Competitividade e Internacionalização (POCI) com a referência POCI-01-0145-FEDER-007562info:eu-repo/semantics/publishedVersio

Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications

Introduction: Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. Methods: In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. Results: We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels. Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions: We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation