Refugee Policy: A Cruel Bipartisanship

Facing the media after a reported 5.6 per cent swing against him in the Brisbane seat of Dickson, Australian Minister for Immigration and Border Protection Peter Dutton defiantly declared that the Coalition was ‘a victim of our own success’.1 ‘The fact that we stopped boats and got children out of detention’, Dutton asserted, meant the ‘issue’ of ‘border protection’ and people arriving in Australia unauthorised by boat to seek asylum ‘had gone off the radar’ (quoted in Hutchens 2016). The minister’s assertion was certainly provocative, if a little misleading. While Australia’s policies towards refugees and asylum seekers did not appear to feature prominently in the 2016 election campaign, this was largely due to a confluence of circumstances, not all of which were of the Coalition’s making. These circumstances primarily included the bipartisan support for the three key pillars of Australia’s increasingly draconian deterrence model (namely, boat turn backs, regional processing and the mandatory detention of certain asylum seekers) and the exceptional government censorship of information from inside immigration detention centres and the official secrecy surrounding the implementation of Australia’s military-led Operation Sovereign Borders (OSB). This meant that the Coalition and Labor had both orchestrated a situation where there seemed to be little political mileage to be gained from foregrounding the issue of Australia’s refugee laws and policies during the campaign. Instead, the election contest predominantly played out across more traditional issues of economic and social policy, such as job creation and the funding of healthcare. Despite being a highly volatile political issue, refugee policy could rarely be seen to determine the outcome of elections—perhaps with the exception of the Coalition’s major 2001 electoral victory in the wake of the Tampa affair. Since 2004, fewer than 10 per cent of surveyed voters have ranked the issue of ‘refugees and asylum seekers’ as the ‘most important non-economic issue’ in federal elections (McAllister and Cameron 2014: 21). Despite the lack of prominence given by the two major political parties to the issue of refugee policy relative to previous election campaigns, it nonetheless surfaced at key moments to reveal its political potency. For example, some minor political parties, certain media outlets and community activist groups were particularly vocal on the issue. This chapter argues that these moments attest to both the anxious nature of Australian nationalism and multiculturalism, and the increasingly prominent deep discursive linkages between asylum seekers, terrorism and the securitisation of migration and borders

Sensing Molecules with Metal–Organic Framework Functionalized Graphene Transistors

Graphene is inherently sensitive to vicinal dielectrics and local charge distributions, a property that can be probed by the position of the Dirac point in graphene field-effect transistors. Exploiting this as a useful sensing principle requires selectivity; however, graphene itself exhibits no molecule-specific interaction. Complementarily, metal–organic frameworks can be tailored to selective adsorption of specific molecular species. Here, a selective ethanol sensor is demonstrated by growing a surface-mounted metal–organic framework (SURMOF) directly onto graphene field-effect transistors (GFETs). Unprecedented shifts of the Dirac point, as large as 15 V, are observed when the SURMOF/GFET is exposed to ethanol, while a vanishingly small response is observed for isopropanol, methanol, and other constituents of the air, including water. The synthesis and conditioning of the hybrid materials sensor with its functional characteristics are described and a model is proposed to explain the origin, magnitude, and direction of the Dirac point voltage shift. Tailoring multiple SURMOFs to adsorb specific gases on an array of such devices thus generates a versatile, selective, and highly sensitive platform for sensing applications

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

First published online: April 23, 2015Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.Siu Chiu Chan, Luke A. Selth, Yingming Li, Michael D. Nyquist, Lu Miao, James E. Bradner, Ganesh V. Raj, Wayne D. Tilley and Scott M. Deh

The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.

The microsomal prostaglandin E2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of α-(n-hexyl)- substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino) pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC 50 = 3.4 μM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (KD = 10-14 μM). In lipopolysaccharide-stimulated human whole blood, PGE2 formation was concentration dependently inhibited (IC50 =2 μM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B2 and 6-keto PGF1α and the COX-1-derived 12(S)-hydroxy-5-cis-8,10- transheptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE2 and leukotriene B4 but also of 6-keto PGF 1α. Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo

Prostate Cancer Foundation Hormone-Sensitive Prostate Cancer Biomarker Working Group Meeting Summary.

Androgen deprivation therapy remains the backbone therapy for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). In recent years, several treatments, including docetaxel, abiraterone + prednisone, enzalutamide, and apalutamide, have each been shown to demonstrate survival benefit when used upfront along with androgen deprivation therapy. However, treatment selection for an individual patient remains a challenge. There is no high level clinical evidence for treatment selection among these choices based on biological drivers of clinical disease. In August 2020, the Prostate Cancer Foundation convened a working group to meet and discuss biomarkers for hormone-sensitive prostate cancer, the proceedings of which are summarized here. This meeting covered the state of clinical and biological evidence for systemic therapies in the mHSPC space, with emphasis on charting a course for the generation, interrogation, and clinical implementation of biomarkers for treatment selection