New drug therapies to kill TSC2-deficient cell lines

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder which results in the global formation of hamartomas, along with epilepsy, autism and learning difficulties. TSC is caused by mutations in TSC1 and/or TSC2 genes, which are involved in regulating the mTOR pathway, an essential pathway involved in cell cycling, proliferation, survival and growth. For non-surgically viable tumours, the use of mTOR inhibitors such as rapamycin (and rapalogs) have been shown to reduce tumour size and incidence of seizures and to improve intellectual and social development. However, these tumours will grow back rapidly when treatment ceases Research has shown that mTOR-hyperactive cells have increased basal levels of endoplasmic reticulum (ER) stress compared to wildtype cells which could be seen as a potential drug target. Several combinations containing nelfinavir, a known ER stress enhancer, have been shown to selectively target Tsc2-/- mouse embryonic fibroblasts (MEFs) and mTOR-hyperactive sporadic cancer cells while being well tolerated by wildtype cells. In this thesis, the key findings were the identification of three nelfinavir-based combinations (mefloquine, Bortezomib and cepharanthine). Results showed that optimised combinations caused selective cytotoxicity in Tsc2-/- MEFs and mTOR-hyperactive sporadic cancer cells while being tolerated by wildtype control cells (measured by DRAQ7 staining). All combinations caused cytotoxicity in a 3D environment (using tumour spheroids). The mechanism of action for each combination was investigated via several method including western blot analysis, rescue assays and RNA sequencing. Results show that mefloquine/nelfinavir and cepharanthine/nelfinavir combinations caused cell death via combined energy stress (cell death was rescued by the addition of methyl pyruvate) and potentially prolonged ER stress while the Bortezomib/nelfinavir combination caused cell death via prolonged ER stress and proteasome inhibition. This work highlights critical vulnerabilities in cancer cells with hyperactive mTORC1 activity that lack flexibility in homeostatic pathways

Energy stress-mediated cytotoxicity in tuberous sclerosis complex 2-deficient cells with nelfinavir and mefloquine treatment

To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment

International trade agreements and international migration

Despite large potential economic gains to the countries concerned, bilateral and multilateral negotiations regarding liberalization of migration have not had the high profile of trade negotiations and agreements. Migration and trade have been traditionally the prerogative of different ministries, yet there are many interdependencies between international trade, foreign investment and migration. The relevance of these interdependencies for trade negotiations has been remarkably ignored in the literature. In this paper we therefore focus on the two-way interaction between international migration and agreements designed to enhance cross-border trade or investment. Liberalization of international trade in services and the movement of people are likely to offer much more significant economic gains than liberalization of remaining barriers to goods trade. However, progress within multilateral frameworks is fraught with difficulty. Mode IV of GATS is restricted to temporary movement of service employees and has yielded little progress so far. Negotiations within more flexible unilateral and bilateral frameworks are likely to be more successful in liberalizing the movement of labour. We discuss several specific examples and conclude that trade negotiations are increasingly accommodating migration policies that favour temporary migration over permanent migration and that the migration regulatory framework is likely to be further linked to trade and investment over time

Pandemic Politics in Eurasia:Roadmap for a New Research Subfield

© 2020 Taylor & Francis Group, LLC. The sudden onset of COVID-19 has challenged many social scientists to proceed without a robust theoretical and empirical foundation upon which to build. Addressing this challenge, particularly as it pertains to Eurasia, our multinational group of scholars draws on past and ongoing research to suggest a roadmap for a new pandemic politics research subfield. Key research questions include not only how states are responding to the new coronavirus, but also reciprocal interactions between the pandemic and society, political economy, regime type, center-periphery relations, and international security. The Foucauldian concept of “biopolitics” holds out particular promise as a theoretical framework

Pandemic Politics in Eurasia:Roadmap for a New Research Subfield

The sudden onset of the coronavirus pandemic has challenged many scholars of the social sciences to proceed in the absence of a robust theoretical research foundation upon which to build. This article seeks to help scholars meet this challenge, particularly as it pertains to Eurasia, through bringing together a multinational group of scholars in order to develop the roadmap for a new pandemic politics research subfield. It begins with a discussion of how states are responding to COVID-19 before moving into an exploration of reciprocal interactions between the pandemic and society, political economy, regime type, center-periphery relations, and international security. Finally, it discusses the potential novel contributions of a theoretical foundation rooted in the Foucauldian concept of “biopolitics.” Ultimately, we hope to spark an ongoing conversation regarding how political science and the social sciences more broadly can be used to understand the impacts of the pandemic and inform policymaking amidst the current and potential future pandemics

Asthma education for school staff.

BACKGROUND: Teachers and school staff should be competent in managing asthma in schools. Demonstrated low levels of asthma knowledge mean that staff may not know how best to protect a child with asthma in their care, or may fail to take appropriate action in the event of a serious attack. Education about asthma could help to improve this knowledge and lead to better asthma outcomes for children. OBJECTIVES: To assess the effectiveness and safety of asthma education programmes for school staff, and to identify content and attributes underpinning them. SEARCH METHODS: We conducted the most recent searches on 29 November 2016. SELECTION CRITERIA: We included randomised controlled trials comparing an intervention to educate school staff about asthma versus a control group. We included studies reported as full text, those published as abstract only and unpublished data. DATA COLLECTION AND ANALYSIS: At least two review authors screened the searches, extracted outcome data and intervention characteristics from included studies and assessed risk of bias. Primary outcomes for the quantitative synthesis were emergency department (ED) or hospital visits, mortality and asthma control; we graded the main results and presented evidence in a 'Summary of findings' table. We planned a qualitative synthesis of intervention characteristics, but study authors were unable to provide the necessary information.We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all with a random-effects model. We assessed clinical, methodological and statistical heterogeneity when performing meta-analyses, and we narratively described skewed data. MAIN RESULTS: Five cluster-RCTs of 111 schools met the review eligibility criteria. Investigators measured outcomes in participating staff and often in children or parents, most often at between 1 and 12 months.All interventions were educational programmes but duration, content and delivery varied; some involved elements of training for pupils or primary care providers. We noted risk of selection, performance, detection and attrition biases, although to a differing extent across studies and outcomes.Quanitative and qualitative analyses were limited. Only one study reported visits to the ED or hospital and provided data that were too skewed for analysis. No studies reported any deaths or adverse events. Studies did not report asthma control consistently, but results showed no difference between groups on the paediatric asthma quality of life questionnaire (mean difference (MD) 0.14, 95% confidence interval (CI) -0.03 to 0.31; 1005 participants; we downgraded the quality of evidence to low for risk of bias and indirectness). Data for symptom days, night-time awakenings, restricted activities of daily living and school absences were skewed or could not be analysed; some mean scores were better in the trained group, but most differences between groups were small and did not persist to 24 months.Schools that received asthma education were more adherent to asthma policies, and staff were better prepared; more schools that had received staff asthma training had written asthma policies compared with control schools, more intervention schools showed improvement in measures taken to prevent or manage exercise-induced asthma attacks and more staff at intervention schools reported that they felt able to administer salbutamol via a spacer. However, the quality of the evidence was low; results show imbalances at baseline, and confidence in the evidence was limited by risk of bias and imprecision. Staff knowledge was higher in groups that had received asthma education, although results were inconsistent and difficult to interpret owing to differences between scales (low quality).Available information about the interventions was insufficient for review authors to conduct a meaningful qualitative synthesis of the content that led to a successful intervention, or of the resources required to replicate results accurately. AUTHORS' CONCLUSIONS: Asthma education for school staff increases asthma knowledge and preparedness, but studies vary and all available evidence is of low quality. Studies have not yet captured whether this improvement in knowledge has led to appreciable benefits over the short term or the longer term for the safety and health of children with asthma in school. Randomised evidence does not contribute to our knowledge of content or attributes of interventions that lead to the best outcomes, or of resources required for successful implementation.Complete reporting of the content and resources of educational interventions is essential for assessment of their effectiveness and feasibility for implementation. This applies to both randomised and non-randomised studies, although the latter may be better placed to observe important clinical outcomes such as exacerbations and mortality in the longer term

Economic evaluation of complete revascularization for patients with multivessel disease undergoing primary percutaneous coronary intervention

Objective: To determine the cost-effectiveness of complete revascularisation at index admission compared to infarct-related artery (IRA) treatment only, in patients with multi-vessel disease undergoing Primary percutaneous coronary intervention (P-PCI) for ST-segment elevation Myocardial Infarction (STEMI). Methods: Economic evaluation of a multi-centre randomised trial comparing complete revascularisation at index admission to IRA-only P-PCI in patients with multi-vessel disease (12 month follow-up). Overall hospital costs (costs for P-PCI procedure(s), hospital stay and any subsequent readmissions) were estimated. Outcomes were major adverse cardiac events (MACE, a composite of all-cause death, recurrent myocardial infarction, heart failure, and ischemia-driven revascularisation) and quality-adjusted life years (QALYs) derived from the EQ-5D-3L. Multiple imputation was undertaken. The mean incremental cost and effects, with associated 95% confidence intervals (95%CI), the incremental cost-effectiveness ratio (ICER) and the cost-effectiveness acceptability curve (CEAC) were estimated. Results: Based on 296 patients, the mean incremental overall hospital cost for complete revascularisation was estimated to be –£215.96 (–£1,390.20 to £958.29), compared to IRA-only, with a per-patient mean reduction in MACE events of 0.170 (0.044 to 0.296) and a QALY gain of 0.011 (-0.019 to 0.041). According to the CEAC, the probability of complete revascularisation being cost-effective was estimated to be 72.0% at willingness to pay of £20,000 per QALY. Conclusions: Complete revascularisation at index admission was estimated to be more effective (in terms of MACE and QALYs) and cost-effective (overall costs were estimated to be lower and complete revascularisation thereby dominated IRA-only). There was, however, some uncertainty associated with this decision