Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements

This work aimed to evaluate whether ETS transcription factors frequently involved in rearrangements in prostate carcinomas (PCa), namely ERG and ETV1, regulate specific or shared target genes. We performed differential expression analysis on nine normal prostate tissues and 50 PCa enriched for different ETS rearrangements using exon-level expression microarrays, followed by in vitro validation using cell line models. We found specific deregulation of 57 genes in ERG-positive PCa and 15 genes in ETV1-positive PCa, whereas deregulation of 27 genes was shared in both tumor subtypes. We further showed that the expression of seven tumor-associated ERG target genes (PLA1A, CACNA1D, ATP8A2, HLA-DMB, PDE3B, TDRD1, and TMBIM1) and two tumor-associated ETV1 target genes (FKBP10 and GLYATL2) was significantly affected by specific ETS silencing in VCaP and LNCaP cell line models, respectively, whereas the expression of three candidate ERG and ETV1 shared targets (GRPR, KCNH8, and TMEM45B) was significantly affected by silencing of either ETS. Interestingly, we demonstrate that the expression of TDRD1, the topmost overexpressed gene of our list of ERG-specific candidate targets, is inversely correlated with the methylation levels of a CpG island found at -66 bp of the transcription start site in PCa and that TDRD1 expression is regulated by direct binding of ERG to the CpG island in VCaP cells. We conclude that ETS transcription factors regulate specific and shared target genes and that TDRD1, FKBP10, and GRPR are promising therapeutic targets and can serve as diagnostic markers for molecular subtypes of PCa harboring specific fusion gene rearrangements.

Nuclear cataract shows significant familial aggregation in an older population after adjustment for possible shared environmental factors.

PURPOSE: To quantify the association between siblings in age-related nuclear cataract, after adjusting for known environmental and personal risk factors. METHODS: All participants (probands) in the Salisbury Eye Evaluation (SEE) project and their locally resident siblings underwent digital slit lamp photography and were administered a questionnaire to assess risk factors for cataract including: age, gender, lifetime sun exposure, smoking and diabetes history, and use of alcohol and medications such as estrogens and steroids. In addition, blood pressure, body mass index, and serum antioxidants were measured in all participants. Lens photographs were graded by trained observers masked to the subjects' identity, using the Wilmer Cataract Grading System. The odds ratio for siblings for affectedness with nuclear cataract and the sibling correlation of nuclear cataract grade, after adjusting for covariates, were estimated with generalized estimating equations. RESULTS: Among 307 probands (mean age, 77.6 +/- 4.5 years) and 434 full siblings (mean age, 72.4 +/- 7.4 years), the average sibship size was 2.7 per family. After adjustment for covariates, the probability of development of nuclear cataract was significantly increased (odds ratio [OR] = 2.07, 95% confidence interval [CI], 1.30-3.30) among individuals with a sibling with nuclear cataract (nuclear grade > or = 3.0). The final fitted model indicated a magnitude of heritability for nuclear cataract of 35.6% (95% CI: 21.0%-50.3%) after adjustment for the covariates. CONCLUSIONS: Findings in this study are consistent with a genetic effect for age-related nuclear cataract, a common and clinically significant form of lens opacity.

Cortical, but not posterior subcapsular, cataract shows significant familial aggregation in an older population after adjustment for possible shared environmental factors.

PURPOSE:

To quantify the risk for age-related cortical cataract and posterior subcapsular cataract (PSC) associated with having an affected sibling after adjusting for known environmental and personal risk factors.

DESIGN:

Sibling cohort study.

PARTICIPANTS:

Participants in the ongoing Salisbury Eye Evaluation (SEE) study (n = 321; mean age, 78.1+/-4.2 years) and their locally resident siblings (n = 453; mean age, 72.6+/-7.4 years) were recruited at the time of Rounds 3 and 4 of the SEE study. INTERVENTION/TESTING METHODS: Retroillumination photographs of the lens were graded for the presence of cortical cataract and PSC with the Wilmer grading system. The residual correlation between siblings' cataract grades was estimated after adjustment for a number of factors (age; gender; race; lifetime exposure to ultraviolet-B light; cigarette, alcohol, estrogen, and steroid use; serum antioxidants; history of diabetes; blood pressure; and body mass index) suspected to be associated with the presence of cataract.

RESULTS:

The average sibship size was 2.7 per family. Multivariate analysis revealed the magnitude of heritability (h(2)) for cortical cataract to be 24% (95% CI, 6%-42%), whereas that for PSC was not statistically significant (h(2) 4%; 95% CI, 0%-11%) after adjustment for the covariates. The model revealed that increasing age, female gender, a history of diabetes, and black race increased the odds of cortical cataract, whereas higher levels of provitamin A were protective. A history of diabetes and steroid use increased the odds for PSC.

CONCLUSIONS:

This study is consistent with a significant genetic effect for age-related cortical cataract but not PSC.

Bringing down the walls: Is the notion of ‘promoting shared space’ commensurate with effective transformation of contested places in Belfast?

This article is a reflexive and critical examination of recent empirical research on effective practice in the management and ‘transformation’ of contested urban space at sectarian interfaces in Belfast. By considering the development of interfaces, the areas around them and policy responses to their persistence, the reality of contested space in the context of ‘peace building’ is apparent; with implications for local government as central to the statutory response. Belfast has developed an inbuilt absence of connectivity; where freedom of movement is particularly restricted and separation of contested space is the policy default position. Empirical research findings focus attention on the significance of social and economic regeneration and fall into three specific areas that reflect both long-term concerns within neighbourhoods and the need for adequate policy responses and action ‘on the ground’. Drawing on Elden and Sassen we reconfigure the analytical framework by which interfaces are defined, with implications for policy and practice in post-conflict Belfast. Past and current policy for peace-building in Northern Ireland, and transforming the most contested space, at interfaces in Belfast, is deliberately ambiguous and offers little substance having failed to advance from funding-led linguistic compliance to a sustainable peace-building methodology.

The Evolution of Extreme Cooperation via Shared Dysphoric Experiences

Willingness to lay down one’s life for a group of non-kin, well documented in the
historical and ethnographic records, represents an evolutionary puzzle. Here we
present a novel explanation for the willingness to fight and die for a group, combining evolutionary theorizing with empirical evidence from real-world human groups. Building on research in social psychology, we develop a mathematical model showing how conditioning cooperation on previous shared experience can allow extreme (i.e., life-threatening) pro-social behavior to evolve. The model generates a series of predictions that we then test empirically in a range of special sample populations (including military veterans, college fraternity/sorority members, football fans, martial arts practitioners, and twins). Our results show that sharing painful experiences produces “identity fusion” – a visceral sense of oneness – more so even than bonds of kinship, in turn motivating extreme pro-group behavior, including willingness to fight and die for the group. These findings have theoretical and practical relevance. Theoretically, our results speak to the origins of human cooperation, as we offer an explanation of extremely costly actions left unexplained by existing models.
Practically, our account of how shared dysphoric experiences produce identity fusion, which produces a willingness to fight and die for a non-kin group, helps us better understand such pressing social issues as suicide terrorism, holy wars, sectarian violence, gang-related violence, and other forms of intergroup conflict.

A critical narrative analysis of shared decision-making in acute, inpatient mental health care

Shared decision-making (SDM) is a high priority in healthcare policy and is complementary to the recovery philosophy in mental health care. This agenda has been operationalised within the Values-Based Practice (VBP) framework, which offers a theoretical and practical model to promote democratic interprofessional approaches to decision-making. However, these are limited by a lack of recognition of the implications of power implicit within the mental health system. This study considers issues of power within the context of decision-making and examines to what extent decisions about patients? care on acute in-patient wards are perceived to be shared. Focus groups were conducted with 46 mental health professionals, service users, and carers. The data were analysed using the framework of critical narrative analysis (CNA). The findings of the study suggested each group constructed different identity positions, which placed them as inside or outside of the decision-making process. This reflected their view of themselves as best placed to influence a decision on behalf of the service user. In conclusion, the discourse of VBP and SDM needs to take account of how differentials of power and the positioning of speakers affect the context in which decisions take place.

Trophic Level Asynchrony in Rates of Phenological Change For Marine, Freshwater and Terrestrial Environments

Recent changes in the seasonal timing (phenology) of familiar biological events have been one of the most conspicuous signs of climate change. However, the lack of a standardised approach to analysing change has hampered assessment of consistency in such changes among different taxa and trophic levels and across freshwater, terrestrial and marine environments. We present a standardised assessment of 25 532 rates of phenological change for 726 UK terrestrial, freshwater and marine taxa. The majority of spring and summer events have advanced, and more rapidly than previously documented. Such consistency is indicative of shared large-scale drivers. Furthermore, average rates of change have accelerated in a way that is consistent with observed warming trends. Less coherent patterns in some groups of organisms point to the agency of more local scale processes and multiple drivers. For the first time we show a broad scale signal of differential phenological change among trophic levels; across environments advances in timing were slowest for secondary consumers, thus heightening the potential risk of temporal mismatch in key trophic interactions. If current patterns and rates of phenological change are indicative of future trends, future climate warming may exacerbate trophic mismatching, further disrupting the functioning, persistence and resilience of many ecosystems and having a major impact on ecosystem services

Rhetoric and Realities of London 2012 Olympic Education and Participation ‘Legacies’: Voices from the Core and Periphery

A legacy emphasis was one of the fundamental pillars of the London 2012 Olympic Games. The notion of an Olympic legacy was predicated on assumptions that the event’s value would not purely derive from the sporting spectacle, but rather, from the ‘success’ of enduring effects met out in London and across the country. For physical education students and practitioners, Olympic legacy agendas translated into persistent pressure to increase inspiration, engagement, participation and performance in the subject, sport and physical activity. Responding to this context, and cogniscent of significant disciplinary scholarship, this paper reports initial data from the first phase of a longitudinal study involving Key Stage Three (students aged 11-13) cohorts in two comparable United Kingdom schools: the first an inner-city (core) London school adjacent to the Olympic Park in Stratford, East London (n=150); the second, a (peripheral) school in the Midlands (n=198). The research involved the use of themed questionnaires focusing on self-reported attitudes toward the Olympic Games, and, experiences of physical education, sport and physical activity. Students from both schools demonstrated a wide variety of attitudes toward physical education and sport; yet, minor variances emerged regarding extreme enthusiasm levels. Both cohorts also expressed considerably mixed feelings toward the impending Olympic Games. Strong and variable responses were also reported regarding inspiration levels, ticketing acquisition and engagement levels. Consequently, this investigation can be read within the broader context of legacy debates, and, aligns well with physical educationalists’ on-going discomfort regarding legacy imperatives being enforced upon the discipline and its practitioners. Our work reiterates a shared disciplinary scepticism that while an Olympic Games may temporarily affect young peoples’ affectations for sport (and maybe physical education and physical activity), it may not provide the best, or most appropriate, mechanism for sustained attitudinal and/or social changes en masse.

Creating shared value – a nova abordagem estratégica de Responsabilidade social empresarial

Dissertação de Mestrado apresentada ao Instituto Supeior de Contabilidade e Administração do Porto para a obtenção do grau de Mestre em Marketing Digital, sob a orientação da Doutora Sandrina Francisca Teixeira