Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival.

Pancreatic ductal adenocarcinoma (PDAC) is generally a fatal disease with no efficacious treatment modalities. Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed. Here, we review the role of Yes-associated protein (YAP) and WW-domain-containing Transcriptional co-Activator with a PDZ-binding motif (TAZ) in the development of PDAC. These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes. We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database (www.proteinatlas.org/pathology) that allows genome-wide exploration of the impact of individual proteins on survival outcomes. Multiple YAP/TEAD-regulated genes, including AJUBA, ANLN, AREG, ARHGAP29, AURKA, BUB1, CCND1, CDK6, CXCL5, EDN2, DKK1, FOSL1,FOXM1, HBEGF, IGFBP2, JAG1, NOTCH2, RHAMM, RRM2, SERP1, and ZWILCH, are associated with unfavorable survival of PDAC patients. Similarly, components of AP-1 that synergize with YAP (FOSL1), growth factors (TGFα, EPEG, and HBEGF), a specific integrin (ITGA2), heptahelical receptors (P2Y2R, GPR87) and an inhibitor of the Hippo pathway (MUC1), all of which stimulate YAP activity, are associated with unfavorable survival of PDAC patients. By contrast, YAP inhibitory pathways (STRAD/LKB-1/AMPK, PKA/LATS, and TSC/mTORC1) indicate a favorable prognosis. These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients. We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease

Estimating the influence of different urban canopy cover types on atmospheric particulate matter (PM10) pollution abatement in London UK

In the urban environment atmospheric pollution by PM10 (particulate matter with a diameter less than 10 x 10-6 m) is a problem that can have adverse effects on human health, particularly increasing rates of respiratory disease. The main contributors to atmospheric PM10 in the urban environment are road traffic, industry and powerproduction. The urban tree canopy is a receptor for removing PM10s from the atmosphere due to the large surface areas generated by leaves and air turbulence created by the structure of the urban forest. In this context urban greening has long been known as a mechanism to contribute towards PM10 removal from the air, furthermore, tree canopy cover has a role in contributing towards a more sustainable urban environment.The work reported here has been carried out within the BRIDGE project (SustainaBle uRban plannIng Decision support accountinG for urban mEtabolism). The aim of this project is to assess the fluxes of energy, water, carbon dioxide and particulates within the urban environment and develope a DSS (Decision Support System) to aid urban planners in sustainable development. A combination of published urban canopy cover data from ground, airborne and satellite based surveys was used. For each of the 33 London boroughs the urban canopy was classified to three groups, urban woodland, street trees and garden trees and each group quantified in terms of ground cover. The total [PM10] for each borough was taken from the LAEI (London Atmospheric Emissions Inventory 2006) and the contribution to reducing [PM10] was assessed for each canopy type. Deposition to the urban canopy was assessed using the UFORE (Urban Forest Effects Model) approach. Deposition to the canopy, boundary layer height and percentage reduction of the [PM10] in the atmosphere was assessed using both hourly meterological data and [PM10] and seasonal data derived from annual models. Results from hourly and annual data were compared with measured values. The model was then applied to future predictions of annual [PM10] and future canopy cover scenarios for London. The contribution of each canopy type subjected to the different atmospheric [PM10] of the 33 London boroughs now and in the future will be discussed. Implementing these findings into a decision support system (DSS) for sustainable urban planning will also be discussed<br/

Une consommation marchandée : le cannibalisme comme dispositif d’échange et de transformationchez Baba Yaga

Cet article examine la manière dont la consommation cannibale de Baba Yaga fonctionne au sein des rapports divers établis entre la sorcière et ses victimes. Il suggère que le cannibalisme est le foyer d’un réseau d’échanges entre Baba Yaga et la victime, entre la victime et les autres membres de la société, entre les mondes différents. Ces échanges provoquent une série de transformations qui établissent les limites de ce qui peut être incorporé à la société, et de ce qui doit être exclu.This article examines the ways in which Baba Yaga’s cannibal consumption works within a context of the various relationships established between the witch and her victims. It argues that cannibalism is home to a network of exchanges between Baba Yaga and her victim, between her victim and the other members of their society, between different worlds. These exchanges provoke a series of transformations that establish the limits of what can be incorporated into society, and what must be excluded

Global green infrastructure: How is green infrastructure research translated into practice outside the UK?

The Centre for Sustainable Planning and Environments at the University of the West of England, Bristol have been commissioned by the Natural Environment Research Council(NERC) to conduct a review of how the evidence base for Green Infrastructure (GI) is being translated into practice across the international community. This builds on previous work that focussed on the grey literature targeted to a UK audience (Sinnett et al., 2016). This review will inform the future investment in GI from Innovation Programme and Partnershipswithin NERC.We reviewed 26 pieces of grey literature aimed at an international audience. These include those from government departments (e.g. US Department of Agriculture) and globalinstitutions (e.g. World Bank). Differences in the definition of GI internationally meant that some documents focussed almost exclusively on water management. Others included comprehensive reviews of the health and well-being outcomes associated with the use and presence of GI as well as broader evidence summaries.The review examined the extent to which academic evidence is cited in the grey literature and which ecosystem services are prioritised in these documents

Lipophilic statins inhibit YAP nuclear localization, co-activator activity and colony formation in pancreatic cancer cells and prevent the initial stages of pancreatic ductal adenocarcinoma in KrasG12D mice.

We examined the impact of statins on Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. Exposure of sparse cultures of PANC-1 and MiaPaCa-2 cells to cerivastatin or simvastatin induced a striking re-localization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEAD-regulated genes Connective Tissue Growth Factor (CTGF) and Cysteine-rich angiogenic inducer 61 (CYR61). Statins also prevented YAP nuclear import and expression of CTGF and CYR61 stimulated by the mitogenic combination of insulin and neurotensin in dense culture of these PDAC cells. Cerivastatin, simvastatin, atorvastatin and fluvastatin also inhibited colony formation by PANC-1 and MiaPaCa-2 cells in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin did not exert any inhibitory effect even at a high concentration (10 μM). Mechanistically, cerivastatin did not alter the phosphorylation of YAP at Ser127 in either PANC-1 or MiaPaCa-2 cells incubated without or with neurotensin and insulin but blunted the assembly of actin stress fiber in these cells. We extended these findings with human PDAC cells using primary KC and KPC cells, (expressing KrasG12D or both KrasG12D and mutant p53, respectively) isolated from KC or KPC mice. Using cultures of these murine cells, we show that lipophilic statins induced striking YAP translocation from the nucleus to the cytoplasm, inhibited the expression of Ctgf, Cyr61 and Birc5 and profoundly inhibited colony formation of these cells. Administration of simvastatin to KC mice subjected to diet-induced obesity prevented early pancreatic acini depletion and PanIN formation. Collectively, our results show that lipophilic statins restrain YAP activity and proliferation in pancreatic cancer cell models in vitro and attenuates early lesions leading to PDAC in vivo

Raising the standard: Developing a benchmark for green infrastructure

© 2018 WIT Press Green infrastructure (GI) is globally recognised as an essential component of liveable and sustainable places. It is valued for its multifunctionality and the connectedness of the individual features to each other, the surrounding countryside and urban populations. It brings together many land uses (e.g. parks, gardens, cemeteries, allotments, nature reserves, surface water), urban design (e.g. street trees, landscaping) and functional features (e.g. sustainable urban drainage systems, green roofs) operating at differing spatial scales. It is widely acknowledged that GI is the primary mechanism for delivering ecosystem services in towns and cities, and there is a substantial body of research demonstrating the multiple benefits of GI to urban populations. Despite this evidence base, there is still considerable uncertainty about the best way to design, deliver and maintain GI. This paper presents an emerging benchmark that has been developed through a combination of literature review and engagement with key stakeholders. It provides a suite of standards that are flexible enough to be used across different spatial scales depending on the specific needs of the location, covering the form and function of GI including nature conservation, water management, health and well-being, environmental and design quality. It allows an assessment of GI policy, and the planning, design, delivery and long-term management of GI in new and existing places, ensuring that current good practice is adopted at all stages. The development of the benchmark to date is summarised along with the outcome of preliminary testing using the outline planning applications for two contrasting mixed-use developments. This found that the benchmark performed well, with standards set at a level to ensure that high-quality GI is rewarded but without requiring a level of GI provision and quality that would only be expected on truly exemplary developments. Plans for the future development and testing of the benchmark are provided

National benchmark for green infrastructure: A feasibility study

This research examines whether a market exists for a national benchmark for green infrastructure (GI) in England. It is funded through a Natural Environment Research Council Innovation Fund (Grant Reference: NE/N016971/1). This builds on a Knowledge Transfer Partnership between the University of the West of England (UWE) and Gloucestershire Wildlife Trust, a project which includes the development of a local benchmark for Gloucestershire and the West of England and which focusses, naturally, on local priorities.This project sought to answer three main questions:•What is the demand for a GI benchmark in the built environment sector?•What types of GI and corresponding ecosystem services should the benchmark include?•What is the most appropriate model to ensure the long-term success of the benchmark?First, a desktop review of relevant assessment systems was conducted to examine a) if, and how, GI is incorporated into such systems and b) their overall operation to understand current practice within the built environment sector. The desktop review included 22 assessment systems, including benchmarks for green developments (building and community-scale) and other infrastructure, and audits, awards, guidance and tool kits that related more specifically to GI, green space or biodiversity.Second, five Expert Symposia were held to test the findings of the review as well as the initial work completed in the KTP on experts from the built environment and GI professions. Thus, the five symposia were co-hosted by the Royal Institution of Chartered Surveyors (RICS), Landscape Institute, Royal Town Planning Institute (RTPI), The Royal Society of Wildlife Trusts (RSWT), and Town and Country Planning Association (TCPA). Whilst the first three of these were quite profession specific, the latter two included participants from a broader range of backgrounds. A total of 55 experts participated in the symposia

The translation and use of green infrastructure evidence

The success of green infrastructure (GI) depends on the sharing of good practice and research between disciplines and sectors. This paper presents findings from a study to examine how GI research is shared with non-academic audiences. GI has been an active research area in recent years, with a wealth of evidence coming from the academic community. This has been mirrored by a body of grey literature aimed at different disciplines and sectors. But it is important to understand which evidence is being used in this grey literature and what the gaps are either in research or in its translation. In this study, 25 pieces of grey literature were reviewed to identify what research is represented; presented as the benefits or ecosystem services provided by different types of GI. This review was presented to around 70 academics, policy makers and practitioners working in GI through two workshops. Attendees were asked questions in order to further understanding of how research is translated and used, and the mechanisms by which it can be more effectively shared. The paper provides insights into how those working in GI can work collaboratively to ensure research findings are relevant and usable

Building with nature - a new benchmark for green infrastructure

This paper outlines the aims, development and proposed operation of Building with Nature, a new benchmark for appraising the quality of green infrastructur

Setting the Standard for Green Infrastructure: The Need for, and Features of, a Benchmark in England

© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Green infrastructure is an essential component of health and sustainable places. The quality of green infrastructure often represents a missed opportunity to achieve this. This paper presents a review examining how built environment assessment systems evaluate the quality of green infrastructure. This was used to develop proposals for a new benchmark, which were examined by experts in terms of the demand, scope and operation. The findings suggest that current systems are not providing a robust assessment of green infrastructure and that a benchmark for green infrastructure would overcome some of the challenges associated with its planning, design and delivery