CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo.

Novel combinations targeting new molecular vulnerabilities are needed to improve the outcome of patients with acute myeloid leukemia. We recently identified WEE1 kinase as a novel target in leukemias. To identify genes that are synthetically lethal with WEE1 inhibition, we performed a short interfering RNA screen directed against cell cycle and DNA repair genes during concurrent treatment with the WEE1 inhibitor MK1775. CHK1 and ATR, genes encoding two replication checkpoint kinases, were among the genes whose silencing enhanced the effects of WEE1 inhibition most, whereas CDK2 short interfering RNA antagonized MK1775 effects. Building on this observation, we examined the impact of combining MK1775 with selective small molecule inhibitors of CHK1, ATR and cyclin-dependent kinases. The CHK1 inhibitor MK8776 sensitized acute myeloid leukemia cell lines and primary leukemia specimens to MK1775 ex vivo, whereas smaller effects were observed with the MK1775/MK8776 combination in normal myeloid progenitors. The ATR inhibitor VE-821 likewise enhanced the antiproliferative effects of MK1775, whereas the cyclin-dependent kinase inhibitor roscovitine antagonized MK1775. Further studies showed that MK8776 enhanced MK1775-mediated activation of the ATR/CHK1 pathway in acute leukemia cell lines and ex vivo. These results indicate that combined cell cycle checkpoint interference with MK1775/MK8776 warrants further investigation as a potential treatment for acute myeloid leukemia.

The Right to Mental Health in Yemen: A Distressed and Ignored Foundation for Peace.

Mental health issues are all too common consequences of conflict and atrocity crimes, often causing upwards of one-quarter of the postconflict, post-atrocity population to suffer from physical and mental sequelae that linger long after weapons have been silenced. After more than six years of ongoing conflict, Yemen's already weak health care system is on the brink of collapse, and population resilience has been severely stressed by indiscriminate attacks, airstrikes, torture, food insecurity, unemployment, cholera, and now the COVID-19 pandemic. This paper examines Yemen's responsibilities regarding the right to mental health and details the few actions the government has taken to date toward fulfilling this right. It also presents the current status of mental health care in Yemen, discussing some of the barriers to accessing the available care, as well as alternative models of mental health support being used by the population. In light of the pandemic presently facing the world, the paper also discusses COVID-19's impact on Yemen, detailing its further degrading effects on the country's health care system and people's mental health. Finally, the paper highlights the importance of addressing mental health in furtherance of the peace process.

CERCLA-linked environmental impact and benefit analysis: Evaluating remedial alternatives for the Portland Harbor Superfund Site, Portland, Oregon, USA.

This analysis focused on evaluating the environmental consequences of remediation, providing indicators for the environmental quality pillar of 3 "pillars" of the Portland Harbor Sustainability Project (PHSP) framework (the other 2 pillars are economic viability and social equity). The project an environmental impact and benefit analysis (EIBA) and an EIBA-based cost-benefit analysis. Metrics developed in the EIBA were used to quantify and compare remedial alternatives' environmental benefits and impacts in the human and ecological domains, as a result of remedial actions (relative to no action). The cost-benefit results were used to evaluate whether remediation costs were proportionate or disproportionate to the environmental benefits. Alternatives B and D had the highest overall benefit scores, and Alternative F was disproportionately costly relative to its achieved benefits when compared to the other remedial alternatives. Indeed, the costlier alternatives with larger remedial footprints had lower overall EIBA benefit scores-because of substantially more air emissions, noise, and light impacts, and more disturbance to business, recreational access, and habitat during construction-compared to the less costly and smaller alternatives. Put another way, the adverse effects during construction tended to outweigh the long-term benefits, and the net environmental impacts of the larger remedial alternatives far outweighed their small incremental improvements in risk reduction. Results of this Comprehensive Environmental Response Compensation and Liability Act (CERCLA)-linked environmental analysis were integrated with indicators of economic and social impacts of remediation in a stakeholder values-based sustainability framework. These tools (EIBA, EIBA-based cost-benefit analysis, economic impact assessment, and the stakeholder values-based integration) provide transparent and quantitative evaluations of the benefits and impacts associated with remedial alternatives, and should be applied to complex remediation projects to aid environmental decision making. Integr Environ Assess Manag 2018;14:22-31. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Stakeholder value-linked sustainability assessment: Evaluating remedial alternatives for the Portland Harbor Superfund Site, Portland, Oregon, USA.

Regulatory decisions on remediation should consider affected communities' needs and values, and how these might be impacted by remedial options; this process requires that diverse stakeholders are able to engage in a transparent consideration of value trade-offs and of the distribution of risks and benefits associated with remedial actions and outcomes. The Stakeholder Values Assessment (SVA) tool was developed to evaluate remedial impacts on environmental quality, economic viability, and social equity in the context of stakeholder values and priorities. Stakeholder values were linked to the pillars of sustainability and also to a range of metrics to evaluate how sediment remediation affects these values. Sediment remedial alternatives proposed by the US Environmental Protection Agency (USEPA) for the Portland Harbor Superfund Site were scored for each metric, based upon data provided in published feasibility study (FS) documents. Metric scores were aggregated to generate scores for each value; these were then aggregated to generate scores for each pillar of sustainability. In parallel, the inferred priorities (in terms of regional remediation, restoration, planning, and development) of diverse stakeholder groups (SGs) were used to evaluate the sensitivity and robustness of the values-based sustainability assessment to diverse SG priorities. This approach, which addresses social indicators of impact and then integrates them with indicators of environmental and economic impacts, goes well beyond the Comprehensive Environmental Response, Compensation and Liability Act's (CERCLA) 9 criteria for evaluating remedial alternatives because it evaluates how remedial alternatives might be ranked in terms of the diverse values and priorities of stakeholders. This approach identified trade-offs and points of potential contention, providing a systematic, semiquantitative, transparent valuation tool that can be used in community engagement. Integr Environ Assess Manag 2018;14:43-62. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).