Coalition governance and foreign policy decision making

This article explores processes of coalition governance in foreign policy. Specifically, it argues that such processes are shaped by two interrelated dimensions of coalition set-up: first, the allocation of the foreign ministry to the senior or a junior coalition partner and, second, the degree of policy discretion which is delegated to that ministry. Bringing these two dimensions together, the article distinguishes four types of coalition arrangement for the making of foreign policy, which are expected to have predictable implications for the process of foreign policy-making and, ultimately, for the foreign policy outputs of multi-party coalitions and their quality

LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models

Background: Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7. Methods: We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7. Results: Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments. Conclusion: LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted

Androgens modulate autophagy and cell death via regulation of the endoplasmic reticulum chaperone glucose-regulated protein 78/BiP in prostate cancer cells

Pro-survival signalling mediated by the androgen receptor (AR) is implicated as a key contributor to prostate carcinogenesis. As prostate tumours are characterized by nutrient-poor, hypoxic and acidified microenvironments, one mechanism whereby AR signalling may contribute to survival is by promoting adaptation to cellular stress. Here we have identified a novel role for AR in the inhibition of autophagy induced by serum withdrawal. This blockade is attributed to AR-mediated upregulation of the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78/BiP (Grp78/BiP), and occurs independently of ER stress response pathway activation. Interestingly, AR activation did not affect serum starvation-induced mammalian target of rapamycin inhibition, illustrating that the adaptive role for androgens lies not in the ability to modulate nutrient sensing, but in the promotion of ER stability. Finally, we show that the adaptive advantage conferred by AR-mediated Grp78/BiP upregulation is temporary, as upon chronic serum starvation, AR activation delayed but did not suppress the onset of autophagy and cell death. This study reveals a novel mechanism whereby maintained AR signalling promotes temporary adaptation to cellular stress and in turn may contribute to the evasion of prostate tumour cell death

Casting for a sovereign role:Socialising an aspirant state in the Scottish independence referendum

This article examines international reactions to Scotland’s 2014 bid for independence as an instance of socialisation of an aspirant state, what we term ‘pre-socialisation’. Building on and contributing to research on state socialisation and role theory, this study proposes a nexus between roles and sovereignty. This nexus has three components: sovereignty itself is a role casted for by an actor; the sovereign role is entangled with the substantive foreign policy roles the actor might play; and the sovereign role implicates the substantive foreign policy roles of other actors. The Scottish debate on independence provides an effective laboratory to develop and explore these theoretical dimensions of pre-socialisation, revealing the contested value and meaning of sovereignty, the possible roles that an independent Scotland could play, and the projected implications for the role of the UK and other international actors. Our analysis of the Scottish case can provide insights for other cases of pre-socialisation and is more empirically significant following the UK’s 2016 referendum to leave the European Union.PostprintPeer reviewe

Taking It to the Extreme:The Effect of Coalition Cabinets on Foreign Policy

Institutional constraints have been offered by some scholars as an explanation for why multiparty coalitions should be more peaceful than single-party cabinets. Yet others see the same institutional setting as a prescription for more aggressive behavior. Recent research has investigated these conflicting expectations, but with mixed results. We examine the theoretical bases for these alternative expectations about the effects of coalition politics on foreign policy. We find that previous research is limited theoretically by confounding institutional effects with policy positions, and empirically by analyzing only international conflict data. We address these limitations by examining cases of foreign policy behavior using the World Event/Interaction Survey (WEIS) dataset. Consistent with our observation that institutional constraints have been confounded with policy positions, we find that coalitions are neither more aggressive nor more peaceful, but do engage in more extreme foreign policy behaviors. These findings are discussed with regard to various perspectives on the role of institutions in shaping foreign policy behavior.</p

Metabolomic Profiling Reveals a Role for Androgen in Activating Amino Acid Metabolism and Methylation in Prostate Cancer Cells

Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression. Genomic and proteomic studies have implicated a role for androgen in regulating metabolic processes in prostate cancer. However, there have been no metabolomic profiling studies conducted thus far that have examined androgen-regulated biochemical processes in prostate cancer. Here, we have used unbiased metabolomic profiling coupled with enrichment-based bioprocess mapping to obtain insights into the biochemical alterations mediated by androgen in prostate cancer cell lines. Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells. Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen. These findings provide insight into the potential biochemical processes regulated by androgen signaling in prostate cancer. Clinically, if validated, these pathways could be exploited to develop therapeutic strategies that supplement current androgen ablative treatments while the observed androgen-regulated metabolic signatures could be employed as biomarkers that presage the development of castrate-resistant prostate cancer