VDX-111, a novel small molecule, induces necroptosis to inhibit ovarian cancer progression.

Epithelial ovarian cancers that are nonhomologous recombination deficient, as well as those that are recurrent and in a platinum-resistant state, have limited therapeutic options. The objectives of this study were to characterize the mechanism of action and investigate the therapeutic potential of a small molecule, VDX-111, against ovarian cancer. We examined the ability of VDX-111 to inhibit the growth of a panel of ovarian cancer cell lines, focusing on BRCA wild-type lines. We found that VDX-111 causes a dose-dependent loss of cell viability across ovarian cancer cell lines. Reverse phase protein array (RPPA) analysis was used to identify changes in cell signaling in response to VDX-111 treatment. An RPPA analysis performed on cells treated with VDX-111 detected changes in cell signaling related to autophagy and necroptosis. Immunoblots of OVCAR3 and SNU8 cells confirmed a dose-dependent increase in LC3A/B and RIPK1. Incucyte live cell imaging was used to measure cell proliferation and death in response to VDX-111 alone and with inhibitors of apoptosis, necroptosis, and autophagy. Annexin/PI assays suggested predominantly nonapoptotic cell death, while real-time kinetic imaging of cell growth indicated the necroptosis inhibitor, necrostatin-1, attenuates VDX-111-induced loss of cell viability, suggesting a necroptosis-dependent mechanism. Furthermore, VDX-111 inhibited tumor growth in patient-derived xenograft and syngeneic murine models. In conclusion, the cytotoxic effects of VDX-111 seen in vitro and in vivo appear to occur in a necroptosis-dependent manner and may promote an antitumor immune response.

Framework for multirisk climate scenarios across system receptors with application to the Metropolitan City of Venice.

Climate change influences the frequency of extreme events that affect both human and natural systems. It requires systemic climate change adaptation to address the complexity of risks across multiple domains and tackle the uncertainties of future scenarios. This paper introduces a multirisk analysis of climate hazard, exposure, vulnerability, and risk severity, specifically designed to hotspot geographic locations and prioritize system receptors that are affected by climate-related extremes. The analysis is demonstrated for the Metropolitan City of Venice. Representative scenarios (RCP4.5 and RCP8.5) of climate threats (i.e., storm surges, pluvial flood, heat waves, and drought) are selected and represented by projections of Regional Climate Models for a 30-year period (2021-2050). A sample of results is as follows. First, an increase in the risk is largely due to drought, pluvial flood, and storm surge, depending on the areas of interest, with the overall situation worsening under the RCP8.5 scenario. Second, particular locations have colocated vulnerable receptors at higher risk, concentrated in the urban centers (e.g., housing, railways, roads) and along the coast (e.g., beaches, wetlands, primary sector). Third, risk communication of potential environmental and socio-economic losses via the multirisk maps is useful to stakeholders and public administration. Fourth, the multirisk maps recommend priorities for future investigation and risk management, such as collection of sensor data, elaboration of mitigations, and adaptation plans at hotspot locations.

Sensitivity analysis for a participatory approach to enhance the climate resilience of Venice, Italy.

Increases in the magnitudes and frequencies of climate-related extreme events are redistributing risk across coastal systems, including their environmental, economic, and social components. Consequently, stakeholders (SHs) are faced with long-term challenges and complex information when managing assets, services, and uses of the coast. In this context, SH engagement is a key step for risk management and in the preparation of resilience plans to respond and adapt to climate change. This paper develops a participatory method to identify and prioritize a set of risk measures, combining multi-criteria analysis with sensitivity analysis. The process involved local and regional authorities of the Veneto region testing the method, including national, regional, and local government, catchment officers, research organizations, natural parks managers and Non-Governmental Organizations (NGOs). SHs identified and ranked a range of adaptation measures to increase climate resilience, with a focus on coastal risk in the Venice lagoon. Results demonstrate that the sensitivity analysis provides useful information on how different sectors of expertise can influence the ranking of the identified risk management measures, highlighting the value of investigating the preferences or priorities of different SH groups within the definition of adaptation plans.

Enterprise risk management for automation in correctional facilities with pandemic and other stressors.

Real-time tracking of tool and equipment inventories is a critical function of many organizations and sectors. For prisons and correctional facilities, tracking and monitoring of assets such as cookware, hardware, keys, janitorial equipment, vocational/technical specialty tools, etc., is essential for safety, security, trust, efficiency, education, etc. The performance of automated systems for this purpose can be diminished by a variety of emergent and future sociotechnical factors alone and in combination. This article introduces a methodology for contractor evaluation and selection in acquisition of innovative asset management systems, with an emphasis on evolving system requirements under uncertainty. The methodology features a scenario-based preferences analysis of emergent and future conditions that are disruptive to the performance of the asset-control system. The conditions are across technologies, operating environments, regulations, workforce behaviors, offender behaviors, prices and markets, organizations, cyber threats, etc. The methodology addresses the influence and interaction of the conditions to disrupt system priorities. Examples include: (i) infectious disease disrupting priorities among requirements and (ii)  radio-frequency identification (RFID) and wireless-technology innovations disrupting priorities among stakeholders. The combinations of conditions that most and least matter for the system acquisition are characterized. The methodology constitutes a risk register for monitoring sources of risk to project performance, schedule, and cost throughout the system lifecycle. The results will be of interest to both practitioners and scholars engaged in systems acquisition as the pandemic interacts with other factors to affect risk, uncertainty, and resilience of organizational missions and operations.

Pharmacological Approaches for the Prevention of Breast Implant Capsular Contracture.

Capsular contracture is a common complication associated with breast implants following reconstructive or aesthetic surgery in which a tight or constricting scar tissue capsule forms around the implant, often distorting the breast shape and resulting in chronic pain. Capsulectomy (involving full removal of the capsule surrounding the implant) and capsulotomy (where the capsule is released and/or partly removed to create more space for the implant) are the most common surgical procedures used to treat capsular contracture. Various structural modifications of the implant device (including use of textured implants, submuscular placement of the implant, and the use of polyurethane-coated implants) and surgical strategies (including pre-operative skin washing and irrigation of the implant pocket with antibiotics) have been and/or are currently used to help reduce the incidence of capsular contracture. In this article, we review the pharmacological approaches-both commonly practiced in the clinic and experimental-reported in the scientific and clinical literature aimed at either preventing or treating capsular contracture, including (i) pre- and post-operative intravenous administration of drug substances, (ii) systemic (usually oral) administration of drugs before and after surgery, (iii) modification of the implant surface with grafted drug substances, (iv) irrigation of the implant or peri-implant tissue with drugs prior to implantation, and (v) incorporation of drugs into the implant shell or filler prior to surgery followed by drug release in situ after implantation.

Global systemic risk and resilience for novel coronavirus in postpandemic era.

The ongoing pandemic has evolved and is posing diverse challenges for the world. Countermeasures for risks are needed to address both direct and indirect effects of disease on the healthcare system, economic and industrial sectors, governance, environment, transportation, energy, and communication systems. There are indicators of a forthcoming postpandemic era. The rethinking and reevaluation of policies adopted throughout the pandemic are ongoing to address cascading threats of emerging and reemerging infectious diseases. The first Special Issue introduced the topic. This second Special Issue describes international collaboration and innovation for pandemic risk and resilience, with a focus on future policy and operations of global systems toward a postandemic era.

Prioritization of Resilience Initiatives for Climate-Related Disasters in the Metropolitan City of Venice.

Increases in the magnitude and frequency of climate and other disruptive factors are placing environmental, economic, and social stresses on coastal systems. This is further exacerbated by land use transformations, urbanization, over-tourism, sociopolitical tensions, technological innovations, among others. A scenario-informed multicriteria decision analysis (MCDA) was applied in the Metropolitan City of Venice integrating qualitative (i.e., local stakeholder preferences) and quantitative information (i.e., climate-change projections) with the aim of enhancing system resilience to multiple climate-related threats. As part of this analysis, different groups of local stakeholders (e.g., local authorities, civil protection agencies, SMEs, NGOs) were asked to identify critical functions that needs to be sustained. Various policy initiatives were considered to support these critical functions. The MCDA was used to rank the initiatives across several scenarios describing main climate threats (e.g., storm surges, floods, heatwaves, drought). We found that many climate change scenarios were considered to be disruptive to stakeholders and influence alternative ranking. The management alternatives acting on physical domain generally enhance resilience across just a few scenarios while cognitive and informative initiatives provided resilience enhancement across most scenarios considered. With uncertainty of multiple stressors along with projected climate variability, a portfolio of cognitive and physical initiatives is recommended to enhance resilience.

Global Systemic Risk and Resilience for Novel Coronavirus and COVID-19.

This Special Issue is dedicated to issues and challenges related to pandemic risk and resilience, with a focus on policy and operations of global systems in the COVID-19 pandemic. The cascading effects of emerging and reemerging infectious diseases to the global economy are a critical interest. Measures to confront the ongoing pandemic are an urgent need. Data analysis at regional and global scales is helping to prioritize response and resilience across locations of high risks. The risk sciences are available for addressing human health and infection risks; the evaluation of risk management strategies and tradeoffs; risk perception as it relates to information processing and receiving risk communication; and tracking system resilience as it relates to various imposed measures.

Halogen gas exposure: toxic effects on the parturient.

The elemental halogens include chlorine, bromine, and phosgene. Halogen gas can be directly weaponized and employed in warfare or terrorism. Industrial stockpiles or halogen transport can provide targets for terrorist attack as well as an origin for accidental release creating a risk for potential mass-casualty incidents. Pregnant and post-partum women represent a substantial and vulnerable subset of the population who may be at particular risk during an attack or accidental exposure. We review the effects of halogen exposure on the parturient with a focus on bromine toxicity. Bromine is the most extensively studied agent in the context of pregnancy and to-date murine models form the basis for the majority of current knowledge. Pregnancy potentiates the acute lung injury after halogen exposure. In addition, halogen exposure precipitates a preeclamptic-like syndrome in mice. This phenotype is characterized by systemic and pulmonary hypertension, endothelial dysfunction, decreased cardiac output, placental injury and fetal growth restriction. This constellation contributes to increased maternal and fetal mortality observed after bromine exposure. Angiogenic imbalance is noted with overexpression of the soluble fms-like tyrosine kinase-1 (sFlt-1) form of the vascular endothelial growth factor receptor 1 reminiscent of human preeclampsia. Additional research is needed to further explore the effect of halogen gas exposure in pregnancy and to develop therapeutic interventions to mitigate risk to this unique population.

Integrating Stakeholder Mapping and Risk Scenarios to Improve Resilience of Cyber-Physical-Social Networks.

The future of energy mobility involves networks of users, operators, organizations, vehicles, charging stations, communications, materials, transportation corridors, points of service, and so on. The integration of smart grids with plug-in electric vehicle technologies has societal and commercial advantages that include improving grid stability, minimizing dependence on nonrenewable fuels, reducing vehicle emissions, and reducing the cost of electric vehicle ownership. However, ineffective or delayed participation of particular groups of stakeholders could disrupt industry plans and delay the desired outcomes. This article develops a framework to address enterprise resilience for two modes of disruptions-the first being the influence of scenarios on priorities and the second being the influence of multiple groups of stakeholders on priorities. The innovation of this study is to obtain the advantages of integrating two recent approaches: scenario-based preferences modeling and stakeholder mapping. Public agencies, grid operators, plug-in electric vehicle owners, and vehicle manufacturers are the four groups of stakeholders that are considered in this framework, along with the influence of four scenarios on priorities.

Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein.

α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more α-BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.

Tiered Approach to Resilience Assessment.

Regulatory agencies have long adopted a three-tier framework for risk assessment. We build on this structure to propose a tiered approach for resilience assessment that can be integrated into the existing regulatory processes. Comprehensive approaches to assessing resilience at appropriate and operational scales, reconciling analytical complexity as needed with stakeholder needs and resources available, and ultimately creating actionable recommendations to enhance resilience are still lacking. Our proposed framework consists of tiers by which analysts can select resilience assessment and decision support tools to inform associated management actions relative to the scope and urgency of the risk and the capacity of resource managers to improve system resilience. The resilience management framework proposed is not intended to supplant either risk management or the many existing efforts of resilience quantification method development, but instead provide a guide to selecting tools that are appropriate for the given analytic need. The goal of this tiered approach is to intentionally parallel the tiered approach used in regulatory contexts so that resilience assessment might be more easily and quickly integrated into existing structures and with existing policies.

Advances in Risk Analysis with Big Data.

With cloud computing, Internet-of-things, wireless sensors, social media, fast storage and retrieval, etc., organizations and enterprises have access to unprecedented amounts and varieties of data. Current risk analysis methodology and applications are experiencing related advances and breakthroughs. For example, highway operations data are readily available, and making use of them reduces risks of traffic crashes and travel delays. Massive data of financial and enterprise systems support decision making under risk by individuals, industries, regulators, etc. In this introductory article, we first discuss the meaning of big data for risk analysis. We then examine recent advances in risk analysis with big data in several topic areas. For each area, we identify and introduce the relevant articles that are featured in the special issue. We conclude with a discussion on future research opportunities.

Resilience Analytics with Application to Power Grid of a Developing Region.

Infrastructure development of volatile regions is a significant investment by international government and nongovernment organizations, with attendant requirements for risk management. Global development banks may be tasked to manage these investments and provide a channel between donors and borrowers. Moreover, various stakeholders from the private sector, local and international agencies, and the military can be engaged in conception, planning, and implementation of constituent projects. Emergent and future conditions of military conflict, politics, economics, technology, environment, behaviors, institutions, and society that stress infrastructure development are prevalent, and funding mechanisms are vulnerable to fraud, waste, and abuse. This article will apply resilience analytics with scenario-based preferences to identify the stressors that most influence a prioritization of initiatives in the electric power sector of Afghanistan. The resilience in this article is conceived in terms of the degree of disruption of priorities when stressors influence the preferences of stakeholders, and ultimately a prioritization of initiatives. The ancillary results include an understanding of which initiatives contribute most and least across strategic criteria and which criteria have the most impact for the analysis. The article concludes with recommendations for risk monitoring and risk management of the portfolio of stressors through the life cycle and horizon of grid capacity expansion.

Steroid receptor-DNA interactions: toward a quantitative connection between energetics and transcriptional regulation.

Steroid receptors comprise an evolutionarily conserved family of transcription factors. Although the qualitative aspects by which individual receptors regulate transcription are well understood, a quantitative perspective is less clear. This is primarily because receptor function is considerably more complex than that of classical regulatory factors such as phage or bacterial repressors. Here we discuss recent advances in placing receptor-specific transcriptional regulation on a more quantitative footing, specifically focusing on the role of macromolecular interaction energetics. We first highlight limitations and challenges associated with traditional approaches for assessing the role of energetics (more specifically, binding affinity) with functional outcomes such as transcriptional activation. We next demonstrate how rigorous in vitro measurements and straightforward interaction models quantitatively relate energetics to transcriptional activity within the cell, and follow by discussing why such an approach is unexpectedly effective in explaining complex functional behavior. Finally, we examine the implications of these findings for considering the unique gene regulatory properties of the individual receptors.

Glucocorticoid Receptor-DNA Dissociation Kinetics Measured in Vitro Reveal Exchange on the Second Time Scale.

The glucocorticoid receptor (GR) is a member of the steroid receptor family of ligand-activated transcription factors. Recent live cell imaging studies have revealed that interactions of GR with chromatin are highly dynamic, with average receptor residence times of only seconds. These findings were surprising because early kinetic studies found that GR-DNA interactions in vitro were much slower, having calculated residence times of minutes to hours. However, these latter analyses were conducted at a time when it was possible to work with only either partially purified holoreceptor or its purified but isolated DNA binding domain. Noting these limitations, we reexamined GR-DNA dissociation kinetics using a highly purified holoreceptor shown to be amenable to rigorous study. We first observe that GR-DNA interactions in vitro are not slow as previously thought but converge with in vivo behavior, having residence times of only seconds to tens of seconds. This rapid exchange is seen at six individual response elements and the multisite MMTV promoter used in live cell imaging. Second, GR dissociation rates are identical for all response elements. Thus, previously observed differences in receptor affinity toward these sequences are not due to differences in off rate but in on rate. Finally, dissociation kinetics are biphasic in character. A minimal kinetic model consistent with the data is that in which DNA-bound GR interconverts between states on a second time scale, with dissociation occurring via a multistep process. We speculate that receptor interconversion in this time frame can be recognized by the coregulatory proteins that interact with GR, leading to unique transcriptional responses.

Ozone-induced airway hyperresponsiveness: roles of ROCK isoforms.

Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736-L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1(+/-) and ROCK2(+/-) mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR.