Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3, the active form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted “Swiss cheese-like” cribriform morphology (CM) comprising multiple abnormal “back to back” lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked 1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors.

Appropriate complexity for the prediction of coastal and estuarine geomorphic behaviour at decadal to centennial scales

Coastal and estuarine landforms provide a physical template that not only accommodates diverse ecosystem functions and human activities, but also mediates flood and erosion risks that are expected to increase with climate change. In this paper, we explore some of the issues associated with the conceptualisation and modelling of coastal morphological change at time and space scales relevant to managers and policy makers. Firstly, we revisit the question of how to define the most appropriate scales at which to seek quantitative predictions of landform change within an age defined by human interference with natural sediment systems and by the prospect of significant changes in climate and ocean forcing. Secondly, we consider the theoretical bases and conceptual frameworks for determining which processes are most important at a given scale of interest and the related problem of how to translate this understanding into models that are computationally feasible, retain a sound physical basis and demonstrate useful predictive skill. In particular, we explore the limitations of a primary scale approach and the extent to which these can be resolved with reference to the concept of the coastal tract and application of systems theory. Thirdly, we consider the importance of different styles of landform change and the need to resolve not only incremental evolution of morphology but also changes in the qualitative dynamics of a system and/or its gross morphological configuration. The extreme complexity and spatially distributed nature of landform systems means that quantitative prediction of future changes must necessarily be approached through mechanistic modelling of some form or another. Geomorphology has increasingly embraced so-called ‘reduced complexity’ models as a means of moving from an essentially reductionist focus on the mechanics of sediment transport towards a more synthesist view of landform evolution. However, there is little consensus on exactly what constitutes a reduced complexity model and the term itself is both misleading and, arguably, unhelpful. Accordingly, we synthesise a set of requirements for what might be termed ‘appropriate complexity modelling’ of quantitative coastal morphological change at scales commensurate with contemporary management and policy-making requirements: 1) The system being studied must be bounded with reference to the time and space scales at which behaviours of interest emerge and/or scientific or management problems arise; 2) model complexity and comprehensiveness must be appropriate to the problem at hand; 3) modellers should seek a priori insights into what kind of behaviours are likely to be evident at the scale of interest and the extent to which the behavioural validity of a model may be constrained by its underlying assumptions and its comprehensiveness; 4) informed by qualitative insights into likely dynamic behaviour, models should then be formulated with a view to resolving critical state changes; and 5) meso-scale modelling of coastal morphological change should reflect critically on the role of modelling and its relation to the observable world.

Evidence for the reliability and validity, but not the practical utility of the two-factor Consideration of Future Consequences Scale-14

Researchers have proposed 1-factor, 2-factor, and bifactor solutions to the 12-item Consideration of Future Consequences Scale (CFCS-12). In order to overcome some measurement problems and to create a robust and conceptually useful two-factor scale the CFCS-12 was recently modified to include two new items and to become the CFCS-14. Using a University sample, we tested four competing models for the CFCS-14: (a) a 12-item unidimensional model, (b) a model fitted for two uncorrelated factors (CFC-Immediate and CFC-Future), (c) a model fitted for two correlated factors (CFC-I and CFC-F), and (d) a bifactor model. Results suggested that the addition of the two new items has strengthened the viability of a two factor solution of the CFCS-14. Results of linear regression models suggest that the CFC-F factor is redundant. Further studies using alcohol and mental health indicators are required to test this redundancy.

The relationship between time attitudes profiles and self-efficacy, sensation seeking, and alcohol use: An exploratory study

A growing body of research has begun to report on time attitudes which specifically refers to an individual's emotional and evaluative feelings toward the past, the present, and the future. The present study used data from the first wave of a longitudinal cohort study in the United Kingdom. Sample 1 consisted of 1580 adolescents (40% female, 1.7% unreported) in Northern Ireland, while Sample 2 consisted of 813 adolescents (46.7% female, 1.4% unreported) in Scotland. Five similar time attitudes profiles emerged in both countries, with one additional "balanced" profile in Scotland. Results show that there were no substantive differences between profiles in terms of socio-demographic indicators. However, in respect of academic, social and emotional self-efficacy, best results were observed for those with Positive, Ambivalent, and Balanced profiles, with the reverse true for those with Negative, Past Negative, and Pessimistic profiles. Positives were also less likely to report using alcohol.