A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.

The Reintegration of Sex Offenders: Barriers and Opportunities for Employment

The process of reintegration of offenders after release from prison, or during a community sentence, is a key aim of criminal justice policy. This article provides details from recent research that investigated the barriers and opportunities to employment for sex offenders. The authors describe the barriers that are faced by sex offenders and the anxieties that employers experience when employing sex offenders. The authors conclude that the approach taken by the State is less than reintegrative and serves to increase the barriers and reduce the opportunities for employment for sex offenders.

Relative Biological Effectiveness Variation Along Monoenergetic and Modulated Bragg Peaks of a 62-MeV Therapeutic Proton Beam: A Preclinical Assessment

iological optimization of proton therapy critically depends on detailed evaluation of relative biological effectiveness (RBE) variations along the Bragg curve. The clinically accepted RBE value of 1.1 is an oversimplification, which disregards the steep rise of linear energy transfer (LET) at the distal end of the spread-out Bragg peak. We observed significant cell killing RBE variations dependent on beam modulation, intrinsic radiosensitivity, and LET in agreement with the LEM predicted values, indicating dose-averaged LET as a suitable parameter for biological effectiveness. Data have also been used to validate a RBE parameterized model.

Selective Targeting of Glucagon-Like Peptide-1 Signalling As a Novel Therapeutic Approach for Cardiovascular Disease in Diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the cardiovascular system where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting are limited although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1 based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting, and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.

Implications of nanotechnology for the agri-food industry: Opportunities, benefits and risks

Nanotechnology has emerged as a technological advancement that could develop and transform the entire agri-food sector, with the potential to increase agricultural productivity, food security and economic growth for industries. Though as still a relatively new concept there are concerns over its safety, regulation and acceptance by the industry and consumers. This review set out to address the implications of nanotechnology for the agri-food industry by examining the potential benefits, risks and opportunities. Existing scientific gaps in knowledge are believed to be a prohibitive factor in addition to uncertainties in the level of awareness and attitudes towards the use of nanotechnology by the industry.

Mediterranean diet interventions to prevent cognitive decline-opportunities and challenges

Cognitive decline has a profound impact on the health and quality of life of older people and their caregivers. Exploring mechanisms to delay cognitive decline has become an urgent economic priority, given the projected changes in population demographics. Systematic reviews and meta-analyses of observational studies suggest that adherence to a Mediterranean Diet (MD) is associated with reduced cognitive decline, but such an observation needs to be tested in randomised controlled trials. Intervention evidence is currently limited, and future studies need to be adequately powered, with careful attention given to choice of participants, outcomes being assessed, study duration and strategies to achieve compliance. Alongside these studies, consideration has to be given to how best promote and encourage dietary change in older people in general, and particularly in those experiencing the early stages of cognitive decline, as there may be specific factors that need to be considered when designing lifestyle behaviour change interventions in this group.

Evaluating conditions for transboundary marine spatial planning: Challenges and opportunities on the island of Ireland

Transboundary cooperation is viewed as an essential element of Marine Spatial Planning (MSP). While much of the MSP literature focuses on the need for, and benefits of, transboundary MSP, this paper explores the political and institutional factors that may facilitate the effective transition to such an approach. Drawing on transboundary planning theory and practice, key contextual factors that are likely to expedite the transition to transboundary MSP are reviewed. These include: policy convergence in neighbouring jurisdictions; prior experience of transboundary planning; and good working relations amongst key actors. Based on this review, an assessment of the conditions for transboundary MSP in the adjoining waters of Northern Ireland and the Republic of Ireland is undertaken. A number of recommendations are then advanced for transboundary MSP on the island of Ireland, including, the need to address the role of formal transboundary institutions and the lack of an agreed legal maritime boundary. The paper concludes with some commentary on the political realities of implementing transboundary MSP.

Utilising a computer game as a therapeutic intervention for youth in residential care: Some preliminary findings on use and acceptability

Mental illness is common amongst young people living in residential care, many of whom are reluctant to avail of therapeutic help. The potential value of computer games as therapeutic tools for these young people has received very little attention, despite indications of their potential for promoting engagement in therapeutic work and improving mental health outcomes. This study aimed to fill this research gap through the development, introduction, and preliminary evaluation of a therapeutic intervention in group care settings. The intervention incorporated a commercially available computer game (The SIMS Life Stories™) and emotion regulation skill coaching. Qualified residential social workers were trained to deliver it to young people in three children's homes in Northern Ireland, where therapeutic approaches to social work had been introduced. The research was framed as an exploratory case study which aimed to determine the acceptability and potential therapeutic value of this intervention. The evidence suggests that computer-game based interventions of this type may have value as therapeutic tools in group care settings and deserve further development and empirical investigation to determine their effectiveness in improving mental health outcomes.

Poverty, ethnicity and international migrants to Northern Ireland: New opportunities or new vulnerabilities?

This briefing provides a brief overview of recent patterns and processes of migration to Northern Ireland and to identify the major challenges arising for society. It is based on primary research conducted by the author during 2013 that consisted mainly of focus groups and interviews with individual migrants. This briefing paper proceeds as follows: it identifies the key features of recent migration to Northern Ireland before presenting evidence from the research to show the experiences of migrants in the labour market. The key policy questions to be considered will be the role of the state and civil society for building positive inter-group relations and the opportunities that exist for migrants to achieve economic and social mobility.

From Notation to Composition:How in my practice the exploration of notational possibilitieshas led to new compositional opportunities

This paper explores my experiments with computer animated notation. It examines how I turned to
computer animated notation to address issues with static musical notation. In particular looking at
the work of Nancarrow, Cage, Tenney, and how a number of these composers' approaches
presented difficult challenges for traditional musical notation. I then discuss how computer
animated notation can provide some interesting solutions to the notational problems provoked in
these works.
In the second part of the paper I investigate how addressing these notational challenges has led to
new prespectives on the compositional process and has introduced new considerations into my
compositional practice including time as musical material, real-time and multi-nodal interaction
with the score, networked score environments with the possibility of physically distributed
performance, performer feedback and communication, and interaction between notation and other
media including visual media and movement.