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

Fuel quality/processing study. Volume 3: Fuel upgrading studies

The methods used to calculate the refinery selling prices for the turbine fuels of low quality are described. Detailed descriptions and economics of the upgrading schemes are included. These descriptions include flow diagrams showing the interconnection between processes and the stream flows involved. Each scheme is in a complete, integrated, stand alone facility. Except for the purchase of electricity and water, each scheme provides its own fuel and manufactures, when appropriate, its own hydrogen

The psychological viewpoints of William Hertzog Thompson and his contributions.

In all institutions of Metier learning there are a few personalities who are outstanding to not only the student body, but also to the community. One such personality is William Hertzog Thomson, who has been associated with the University of Omaha since 1913 when ho enrolled as a freshman. In his role of student, alumnus, Professor and Head of the Department of Psychology, Dean of Men, Director of the Child Study Service, and Dean of the College of Arts and Sciences, he has left an indelible impression on many individuals, including students in his classes and also on the citizens of this community. Since his viewpoints and appellations of psychology have influenced countless numbers of individuals, it seemed impelling that such impressions should be recorded

A Preliminary Investigation Regarding the Effect of Tennis Grunting: Does White Noise During a Tennis Shot Have a Negative Impact on Shot Perception?

Background: There is a growing chorus of critics who complain that many of the top-ranked professional tennis players who grunt when they hit the ball gain an unfair advantage because the sound of the grunt interferes with their opponent’s game. However, there is no scientific evidence to support this claim. Methodology/Principal Findings: We explored this potential detrimental effect of grunting by presenting videos of a tennis player hitting a ball to either side of a tennis court; the shot either did, or did not, contain a brief sound that occurred at the same time as contact. The participants ’ task was to respond as quickly as possible, indicating whether the ball was being hit to the left- or right-side of the court. The results were unequivocal: The presence of an extraneous sound interfered with a participants ’ performance, making their responses both slower and less accurate. Conclusions/Significance: Our data suggest that a grunting player has a competitive edge on the professional tennis tour. The mechanism that underlies this effect is a topic for future investigation. Viable alternatives are discussed. For example, the possibility that the interfering auditory stimulus masks the sound of the ball being struck by the racket or it distracts a

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/

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