Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

Objective: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting: Research laboratories of Hannover Medical School and Harvard Medical School. Patients: Septic patients/C57Bl/6 mice and human endothelial cells. Interventions: Food and Drug Administration-approved library screening. Measurements and Main Results: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

Myopia:precedents for research in the twenty-first century

The myopic eye is generally considered to be a vulnerable eye and, at levels greater than 6 D, one that is especially susceptible to a range of ocular pathologies. There is concern therefore that the prevalence of myopia in young adolescent eyes has increased substantially over recent decades and is now approaching 10-25% and 60-80%, respectively, in industrialized societies of the West and East. Whereas it is clear that the major structural correlate of myopia is longitudinal elongation of the posterior vitreous chamber, other potential correlates include profiles of lenticular and corneal power, the relationship between longitudinal and transverse vitreous chamber dimensions and ocular volume. The most potent predictors for juvenile-onset myopia continue to be a refractive error ≤+0.50 D at 5 years of age and family history. Significant and continuing progress is being made on the genetic characteristics of high myopia with at least four chromosomes currently identified. Twin studies and genetic modelling have computed a heritability index of at least 80% across the whole ametropic continuum. The high index does not, however, preclude an environmental precursor, sustained near work with high cognitive demand being the most likely. The significance of associations between accommodation, oculomotor dysfunction and human myopia is equivocal despite animal models that have demonstrated that sustained hyperopic defocus can induce vitreous chamber growth. Recent optical and pharmaceutical approaches to the reduction of myopia progression in children are likely precedents for future research, for example progressive addition spectacle lens trials and the use of the topical MI muscarinic antagonist pirenzepine.

Introduction: the media, animal conservation and environmental education

Natural History filmmaking has a long history but the generic boundaries between it and environmental and conservation filmmaking are blurred. Nature, environment and animal imagery has been a mainstay of television, campaigning organisations and conservation bodies from Greenpeace to the Sierra Club, with vibrant images being used effectively on posters, leaflets and postcards, and in coffee table books, media releases, short films and viral emails to educate and inform the general public. However, critics suggest that wildlife film and photography frequently convey a false image of the state of the world’s flora and fauna. The environmental educator David Orr once remarked that all education is environmental education, and it is possible to see all image-based communication in the same way. The Media, Animal Conservation and Environmental Education has contributions from filmmakers, photographers, researchers and academics from across the globe. It explores the various ways in which film, television and video are, and can be, used by conservationists and educators to encourage both a greater awareness of environmental and conservation issues, and practical action designed to help endangered species. This book is based on a special issue of the journal Environmental Education Research.

The media, animal conservation and environmental education

Natural History filmmaking has a long history but the generic boundaries between it and environmental and conservation filmmaking are blurred. Nature, environment and animal imagery has been a mainstay of television, campaigning organisations and conservation bodies from Greenpeace to the Sierra Club, with vibrant images being used effectively on posters, leaflets and postcards, and in coffee table books, media releases, short films and viral emails to educate and inform the general public. However, critics suggest that wildlife film and photography frequently convey a false image of the state of the world’s flora and fauna. The environmental educator David Orr once remarked that all education is environmental education, and it is possible to see all image-based communication in the same way. The Media, Animal Conservation and Environmental Education has contributions from filmmakers, photographers, researchers and academics from across the globe. It explores the various ways in which film, television and video are, and can be, used by conservationists and educators to encourage both a greater awareness of environmental and conservation issues, and practical action designed to help endangered species. This book is based on a special issue of the journal Environmental Education Research.

The media, animal conservation and environmental education

Editorial

Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and nongovernmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathway-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this.