MicroRNA-21 is immunosuppressive and pro-metastatic via separate mechanisms

MiR-21 was identified as a gene whose expression correlated with the extent of metastasis of murine mammary tumours. Since miR-21 is recognised as being associated with poor prognosis in cancer, we investigated its contribution to mammary tumour growth and metastasis in tumours with capacity for spontaneous metastasis. Unexpectedly, we found that suppression of miR21 activity in highly metastatic tumours resulted in regression of primary tumour growth in immunocompetent mice but did not impede growth in immunocompromised mice. Analysis of the immune infiltrate of the primary tumours at the time when the tumours started to regress revealed an influx of both CD4+ and CD8+ activated T cells and a reduction in PD-L1+ infiltrating monocytes, providing an explanation for the observed tumour regression. Loss of anti-tumour immune suppression caused by decreased miR-21 activity was confirmed by transcriptomic analysis of primary tumours. This analysis also revealed reduced expression of genes associated with cell cycle progression upon loss of miR-21 activity. A second activity of miR-21 was the promotion of metastasis as shown by the loss of metastatic capacity of miR-21 knockdown tumours established in immunocompromised mice, despite no impact on primary tumour growth. A proteomic analysis of tumour cells with altered miR-21 activity revealed deregulation of proteins known to be associated with tumour progression. The development of therapies targeting miR-21, possibly via targeted delivery to tumour cells, could be an effective therapy to combat primary tumour growth and suppress the development of metastatic disease.Lap Hing Chi, Ryan S. N. Cross, Richard P. Redvers, Melissa Davis, Soroor Hediyeh-zadeh, Suresh Mathivanan, Monisha Samuel, Erin C. Lucas, Kellie Mouchemore, Philip A. Gregory, Cameron N. Johnstone, and Robin L. Anderso

Decision making in regeneration practice

Cities are faced with complex challenges in urban governance, integrating the many and varied voices of the city into decision-making frameworks. This is particularly the case in the arena of urban regeneration, where (at times) opposing interests are involved in governance processes at the level of neighbourhood regeneration. The aim of this chapter is to explore the key players that are involved in the process of regeneration, from national governments through to local public sector bodies, private sector involvement, and the engagement of community groups and civil society, and to analyse how the balance of interests between these players has changed over time with the evolution of policy towards urban regeneration since the 1980s. Urban regeneration is an umbrella term that refers to ‘those policies and strategies that have been designed to deal with urban decline, decay and social and economic transformation’ (Imrie et al. 2009: 4). Given its broad remit, the term ‘urban regeneration’ implies an integrated perspective on the problems and potentials of cities, and the areas peripheral to them. However, this integrated perspective also necessarily brings many voices to the table, which can itself present challenges in finding a consensus for a way forward. It is also worth noting that the roles of the different stakeholders in urban regeneration (public, private and civil society) vary markedly in different contexts. Each socio-political and institutional system at the national level is embedded with different cultural and ideological norms that influence the role of actors in the regeneration process, and thus the dynamics of decision-making processes can vary considerably between different national contexts. This chapter is based on the experience of urban regeneration in the UK, which it could be argued, has led the way internationally in relation to public-private partnerships and decision-making in a regeneration context. Other national contexts will differ depending on the particular circumstances, but most follow the pattern followed by the UK in relation to the shifts in stakeholder involvement that have taken place since the 1980s. The chapter is divided into three main parts. First, the key theoretical debates related to urban governance more generally, and more specifically regeneration governance are outlined. Second, the history of urban regeneration in the post-war period is examined to illustrate how the evolution of approaches to regeneration has impacted on the composition of actors involved in decision-making, from public, to private, to greater community involvement. Third, the post-2008 context and the implications for regeneration decisionmaking and potential outcomes are explored. The chapter concludes with an overview of the implications of decision-making structures for the future of urban regeneration

The causation of disease - the practical and ethical consequences of competing explanations.

The prevention, treatment and management of disease are closely linked to how the causes of a particular disease are explained. For multi-factorial conditions, the causal explanations are inevitably complex and competing models may exist to explain the same condition. Selecting one particular causal explanation over another will carry practical and ethical consequences that are acutely relevant for health policy. In this paper our focus is two-fold; (i) the different models of causal explanation that are put forward within current scientific literature for the high and rising prevalence of the common complex conditions of coronary artery disease (CAD) and type 2 diabetes mellitus (T2D); and (ii) how these explanations are taken up (or not) within national health policy guidelines. We examine the causal explanations for these two conditions through a systematic database search of current scientific literature. By identifying different causal explanations we propose a three-tier taxonomy of the most prominent models of explanations: (i) evolutionary, (ii) lifecourse, and (iii) lifestyle and environment. We elaborate this taxonomy with a micro-level thematic analysis to illustrate how some explanations are semantically and rhetorically foregrounded over others. We then investigate the uptake of the scientific causal explanations in health policy documents with regard to the prevention and management recommendations of current National Service Frameworks for CAD and T2D. Our findings indicate a lack of congruence between the complexity and frequent overlap of causal explanations evident in the scientific literature and the predominant focus on lifestyle recommendations found in the mainstream health policy documents