Somatic PDGFRB activating variants in fusiform cerebral aneurysms

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors

Challenges in assessing and managing multi-hazard risks: a European stakeholders perspective

The latest evidence suggests that multi-hazards and their interrelationships (e.g., triggering, compound, and consecutive hazards) are becoming more frequent across Europe, underlying a need for resilience building by moving from single-hazard-focused to multi-hazard risk assessment and management. Although significant advancements were made in our understanding of these events, mainstream practice is still focused on risks due to single hazards (e.g., flooding, earthquakes, droughts), with a limited understanding of the stakeholder needs on the ground. To overcome this limitation, this paper sets out to understand the challenges for moving towards multi-hazard risk management through the perspective of European stakeholders. Based on five workshops across different European pilots (Danube Region, Veneto Region, Scandinavia, North Sea, and Canary Islands) and an expert workshop, we identify five prime challenges: i) governance, ii) knowledge of multi-hazards and multi-risks, iii) existing approaches to disaster risk management, iv) translation of science to policy and practice, and v) lack of data. These challenges are inherently linked and cannot be tackled in isolation with path dependency posing a significant hurdle in transitioning from single- to multi-hazard risk management. Going forward, we identify promising approaches for overcoming some of the challenges, including emerging approaches for multi-hazard characterisation, a common understanding of terminology, and a comprehensive framework for guiding multi-hazard risk assessment and management. We argue for a need to think beyond natural hazards and include other threats in creating a comprehensive overview of multi-hazard risks, as well as promoting thinking of multi-hazard risk reduction in the context of larger development goals

Invited perspectives: A research agenda towards disaster risk management pathways in multi-(hazard-)risk assessment

Whilst the last decades have seen a clear shift in emphasis from managing natural hazards to managing risk, the majority of natural-hazard risk research still focuses on single hazards. Internationally, there are calls for more attention for multi-hazards and multi-risks. Within the European Union (EU), the concepts of multi-hazard and multi-risk assessment and management have taken centre stage in recent years. In this perspective paper, we outline several key developments in multi-(hazard-)risk research in the last decade, with a particular focus on the EU. We present challenges for multi-(hazard-)risk management as outlined in several research projects and papers. We then present a research agenda for addressing these challenges. We argue for an approach that addresses multi-(hazard-)risk management through the lens of sustainability challenges that cut across sectors, regions, and hazards. In this approach, the starting point is a specific sustainability challenge, rather than an individual hazard or sector, and trade-offs and synergies are examined across sectors, regions, and hazards. We argue for in-depth case studies in which various approaches for multi-(hazard-)risk management are co-developed and tested in practice. Finally, we present a new pan-European research project in which our proposed research agenda will be implemented, with the goal of enabling stakeholders to develop forward-looking disaster risk management pathways that assess trade-offs and synergies of various strategies across sectors, hazards, and spatial scales

D1.2 Handbook of multi-hazard, multi-risk definitions and concepts

This report is the first output of Work Package 1: Diagnosis of the MYRIAD-EU project: Handbook of Multi-hazard, Multi-Risk Definitions and Concepts. The aim of the task was to (i) acknowledge the differences and promote consistency in understanding across subsequent work packages in the MYRIAD-EU project, (ii) improve the accessibility of our work to a broad array of stakeholders and (iii) strengthen consensus across the hazard and risk community through a common understanding of multi-hazard, multi-risk terminology and concepts. The work encompassed a mixed-methods approach, including internal consultations and data-generating exercises; literature reviews; external stakeholder engagement; adopting and building on a rich existing body of established glossaries. 140 terms are included in the glossary, 102 related to multi-hazard, multi-risk, disaster risk management and an additional 38 due to their relevance to the project, acknowledging the need for a common understanding amongst an interdisciplinary project consortium. We also include extended definitions related to concepts particularly of relevance to this project deliverable, including ‘multi-hazard’, ‘hazard interrelationships’, ‘multi-risk’ and ‘direct and indirect loss and risk’. Underpinned by a literature review and internal consultation, we include a specific section on indicators, how these might be applied within a multi-hazard and multi-risk context, and how existing indicators could be adapted to consider multi-risk management. We emphasise that there are a number of established glossaries that the project (and risk community) should make use of to strengthen the impact of the work we do, noting in our literature review a tendency in papers and reports to define words afresh. We conclude the report with a selection of key observations, including terminology matters – for all aspects of disaster risk management, for example communication, data collection, measuring progress and reporting against Sendai Framework targets. At the same time, we discuss when is it helpful to include ‘multi-‘ as a prefix, questioning whether part of the paradigm shift needed to successfully address complex challenges facing an interconnected world is through inherently seeing vulnerability, exposure and disaster risk through the lens of multiple, interrelated hazards. We emphasise that there is likely to be an evolution of the terminology throughout the project lifetime as terms are emerge or shift as the project evolves. Finally, we propose a roadmap for developing and testing draft multi-risk indicators in MYRIAD-EU. The WP1 team would like to acknowledge all the contributions of the consortium on this task and the feedback from the External Advisory Board, in particular the chair of the board Virginia Murray, Head of Global Disaster Risk Reduction at the UK Health Security Agency, and the contribution of Jenty Kirsch-Wood, Head of Global Risk Management and Reporting at UNDRR, for her reflections on the findings of this work

Extrachromosomal Circular DNA from TCGA Tumors Is Generated from Common Genomic Loci, Is Characterized by Self-Homology and DNA Motifs near Circle Breakpoints

Extrachromosomal circular DNA has emerged as a frequent genomic alteration in tumors. High numbers of circular DNAs correspond to poor prognosis suggesting an important function in tumor biology. However, despite mounting evidence supporting the importance of circular DNA, little is known about their production, maintenance, or selection. To provide insight into these processes, we analyzed circular DNA elements computationally identified in 355 TCGA tumors spanning 22 tumor types. Circular DNAs originated from common genomic loci irrespective of cancer type. Genes found in circularized genomic regions were more likely to be expressed and were enriched in cancer-related pathways. Finally, in support of a model for circle generation through either a homology or microhomology-mediated process, circles exhibit homology near their breakpoint. These breakpoints are also enriched in specific DNA motifs. Our analysis supports a model where gene-containing circles emerge from common, highly transcribed regions through a homology-mediated process

The right ventricular fibroblast secretome drives cardiomyocyte dedifferentiation.

RationaleIn virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We've previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells.ObjectiveTo determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture.Methods and resultsBrief exposure (ConclusionsThese data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction

Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery

High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas

Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. Methods: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Results: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. Conclusions: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use