From revelation to revolution:apocalypticism in green politics

Apocalyptic narratives in green politics have provoked much controversy about questions of rhetoric and framing. Critics argue that constant warnings about impending environmental collapse demoralise and demobilise the public, while advocates argue that dire predictions embody a realism necessary if the radical collective action required for a green transition is to be taken. This is not just a debate about the tactics of presentation; at a substantive ideological level, the multilayered questions raised by apocalypticism cut to the heart of significant divisions in the green movement between radical and mainstream currents concerning their orientation to structures of political and economic power. Comparisons with the contested historical tradition of apocalyptics in Christian theology shed light upon the dynamic tensions between movement insurgency and institutionalisation. Apocalypticism has played a key role in framing the green critique of capitalist modernity and is intrinsically connected to the formulation of utopic alternatives. In both theory and practice, it remains the animating spirit of radical environmentalism

Contracting the right to roam

In recent decades, the emergence of environmental ethics has added extra dimensions of complexity to the leisure political terrain upon which the right to roam is contested. In this chapter, two very different but influential versions of the social contract will be juxtaposed to bring the key arguments into high relief. On the one hand, Hardin’s eco-Hobbesian Tragedy of the Commons (1968/2000) thesis, and on the other, Rawls’ Kant-inspired A Theory of Justice (1971). It will be argued that Hardin’s pessimistic, exclusionary and potentially authoritarian conclusions are incompatible with the allocation of rights and duties in liberal democratic societies. Hardin should therefore be rejected in favour of an interpretative development of Rawls which designates the right to roam as a primary social good that is compatible with a conception of justice as sustainable fairness—an ideal which can be used to inform an inclusive environmentally sensitive leisure citizenship

Neoantigens in ovarian cancer: embarrassment of riches or needles in a haystack?

Comprehensive genomic and transcriptomic analysis demonstrates that tumor-infiltrating T lymphocytes that react to mutated neo-epitopes could be identified in recurrent ovarian cancer. Two of these T cell populations reacted against TP53 hotspot missense mutations that are present in a wide variety of malignancies

Safety and efficacy of the tumour-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial

Background Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. Methods We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. Results Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies. Conclusions Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer. Trial registration number NCT02028117

Tumors defective in homologous recombination rely on oxidative metabolism: Relevance to treatments with PARP inhibitors

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination‐defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP‐ribose) polymerase (PARP)‐dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient‐derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors

Modulation of endothelial cell KCa3.1 Channels during endothelium-derived hyperpolarizing factor signaling in mesenteric resistance arteries

Arterial hyperpolarization to acetylcholine (ACh) reflects coactivation of KCa3.1 (IKCa) channels and KCa2.3 (SKCa) channels in the endothelium that transfers through myoendothelial gap junctions and diffusible factor(s) to affect smooth muscle relaxation (endothelium-derived hyperpolarizing factor [EDHF] response). However, ACh can differentially activate KCa3.1 and KCa2.3 channels, and we investigated the mechanisms responsible in rat mesenteric arteries. KCa3.1 channel input to EDHF hyperpolarization was enhanced by reducing external [Ca2+]o but blocked either with forskolin to activate protein kinase A or by limiting smooth muscle [Ca2+]i increases stimulated by phenylephrine depolarization. Imaging [Ca2+]i within the endothelial cell projections forming myoendothelial gap junctions revealed increases in cytoplasmic [Ca2+]i during endothelial stimulation with ACh that were unaffected by simultaneous increases in muscle [Ca2+]i evoked by phenylephrine. If gap junctions were uncoupled, KCa3.1 channels became the predominant input to EDHF hyperpolarization, and relaxation was inhibited with ouabain, implicating a crucial link through Na+/K+-ATPase. There was no evidence for an equivalent link through KCa2.3 channels nor between these channels and the putative EDHF pathway involving natriuretic peptide receptor-C. Reconstruction of confocal z-stack images from pressurized arteries revealed KCa2.3 immunostain at endothelial cell borders, including endothelial cell projections, whereas KCa3.1 channels and Na+/K+-ATPase {alpha}2/{alpha}3 subunits were highly concentrated in endothelial cell projections and adjacent to myoendothelial gap junctions. Thus, extracellular [Ca2+]o appears to modify KCa3.1 channel activity through a protein kinase A-dependent mechanism independent of changes in endothelial [Ca2+]i. The resulting hyperpolarization links to arterial relaxation largely through Na+/K+-ATPase, possibly reflecting K+ acting as an EDHF. In contrast, KCa2.3 hyperpolarization appears mainly to affect relaxation through myoendothelial gap junctions. Overall, these data suggest that K+ and myoendothelial coupling evoke EDHF-mediated relaxation through distinct, definable pathways

Human tissue legislation in the United Kingdom 1952- 2006: a history and comparative analysis of policy development

PhDThis is a study of the genesis of the Corneal (Grafting) Act 1952, the Human Tissue Act 1961, the Human Tissue Act 2004, and the Human Tissue (Scotland) Act 2006. The aim has been to understand why so much had apparently changed between 1952-61 and 2004-06, both in society and in medical practice, as an explanation of why the earlier Acts were essentially ‘enabling/permissive’, whereas the later Acts were ‘regulatory/restraining’. A comparison between the Human Tissue Act 2004 and the separate Human Tissue (Scotland) Act 2006 (both Acts concerned with ‘human tissue’ and with origins in ‘retention of organs without consent’, but with significant differences in their respective provisions), has allowed a finer dissection and comparative analysis of the possible factors involved. The Thesis focuses on the ‘inspiration’, ‘deliberation/ formulation’ and ‘legitimation’ phases of the legislative process (using the terminology of Drewry)-that is, the genesis of the various Acts- and has not sought to study the later (Drewry) phases of ‘implementation’ of the law nor subsequent ‘feedback’. The methodology has been to ‘interrogate the sources’ through in depth study of archived records, using publicly available documents, certain confidential papers made available by the Royal College of Pathologists and the Royal College of Physicians (London), papers released under Freedom of Information Acts, and analysis of the scholarly literature. The findings suggest that a complexity of factors contributed to shaping the 2004 and 2006 legislation, in addition to the proximate ‘organ scandals’. The study may contribute specifically to any wish of Government and the medical/scientific professions to review their processes of consultation and negotiation prior to developing new legislation with an impact on research; and more generally to the case for more regular use of pre-legislative scrutiny of Bills

Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery

Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IKCa channels alone, contrasting with peripheral vessels where block of both IKCa and SKCa is required. As the contribution of IKCa and SKCa to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SKCa might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions. METHODS: Rat middle cerebral arteries (approximately 175 microm) were mounted in a wire myograph. The effect of KCa channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 micromol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial KCa channels revealed with immunohistochemistry. RESULTS: SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IKCa (TRAM-34, 1 micromol/L) or SKCa (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SKCa and IKCa within the endothelium. CONCLUSIONS: In the absence of NO, IKCa underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SKCa contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SKCa expression may be altered

Confronting the Illusion of Technological Expertise Among College and University Students

Over the past 20 years, the faculty and administration of colleges and universities have been debating how technology will change the face of higher education in delivering content to students. Associated with the discussion is research on the acceptability of various devices (e.g. desk-top computers, laptop computers, e-readers, tablets) as replacements for paper textbooks. In most studies, students report their preference for paper textbooks over digital materials for studying and learning. A recent Canadian study examined the preference for paper textbooks. In this study, we repeat key areas of that study with Israeli students and collect comparison data using an online survey. Students in both countries believe that paper textbooks better support their learning and studying processes and are more likely to lead to academic success. However, we note some differences in terms of the Israeli students being less distracted when online, and reporting greater comfort using digital content when searching for information. What has been overlooked in the change from paper to digital delivery of information is how students will make the transition from learning and studying on paper to digital only or simultaneous use of both paper and digital. This study provides ideas as to how educators can better support students and areas where additional research is needed