Coupling of alpha(1)-Adrenoceptors to ERK1/2 in the Human Prostate

Introduction: alpha(1)-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further alpha(1)-adrenoceptor functions besides contraction. Here, we investigated whether alpha(1)-adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2). Methods: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot analysis. Expression of ERK1/2 was studied by immunohistochemistry. The effect of ERK1/2 inhibition by U0126 on phenylephrine-induced contraction was studied in organ-bath experiments. Results: Stimulation of human prostate tissue with noradrenaline (30 mu M) or phenylephrine (10 mu M) resulted in ERK activation. This was reflected by increased levels of phosphorylated ERK1/2. Expression of ERK1/2 in the prostate was observed in smooth muscle cells. Incubation of prostate tissue with U0126 (30 mu M) resulted in ERK1/2 inhibition. Dose-dependent phenylephrine-induced contraction of prostate tissue was not modulated by U0126. Conclusions: alpha(1)-Adrenoceptors in the human prostate are coupled to ERK1/2. This may partially explain previous observations suggesting a role of alpha(1)-adrenoceptors in the regulation of prostate growth. Copyright (C) 2011 S. Karger AG, Base

Activation of Nrf2/HO-1 Pathway by Nardochinoid C Inhibits Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages

The roots and rhizomes of Nardostachys chinensis have neuroprotection and cardiovascular protection effects. However, the specific mechanism of N. chinensis is not yet clear. Nardochinoid C (DC) is a new compound with new skeleton isolated from N. chinensis and this study for the first time explored the anti-inflammatory and anti-oxidant effect of DC. The results showed that DC significantly reduced the release of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated RAW264.7 cells. The expression of pro-inflammatory proteins including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were also obviously inhibited by DC in LPS-activated RAW264.7 cells. Besides, the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also remarkably inhibited by DC in LPS-activated RAW264.7 cells. DC also suppressed inflammation indicators including COX-2, PGE2, TNF-α, and IL-6 in LPS-stimulated THP-1 macrophages. Furthermore, DC inhibited the macrophage M1 phenotype and the production of reactive oxygen species (ROS) in LPS-activated RAW264.7 cells. Mechanism studies showed that DC mainly activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, increased the level of anti-oxidant protein heme oxygenase-1 (HO-1) and thus produced the anti-inflammatory and anti-oxidant effects, which were abolished by Nrf2 siRNA and HO-1 inhibitor. These findings suggested that DC could be a new Nrf2 activator for the treatment and prevention of diseases related to inflammation and oxidative stress

First simultaneous optical/near-infrared imaging of an X-ray selected, high-redshift cluster of galaxies with GROND: the galaxy population of XMMU J0338.7+0030 at z=1.1

The XMM-Newton Distant Cluster Project is a serendipitous survey for clusters of galaxies at redshifts z>=0.8 based on deep archival XMM-Newton observations. ... Low-significance candidate high-z clusters are followed up with the seven-channel imager GROND (Gamma-Ray Burst Optical and Near-Infrared Detector) that is mounted at a 2m-class telescope. ... The test case is XMMU J0338.7+0030, suggested to be at z~1.45+/-0.15 from the analysis of the z-H vs H colour-magnitude diagram obtained from the follow-up imaging. Later VLT-FORS2 spectroscopy enabled us to identify four members, which set this cluster at z=1.097+/-0.002. To reach a better knowledge of its galaxy population, we observed XMMU J0338.7+0030 with GROND for about 6 hr. The publicly available photo-z code le Phare was used. The Ks-band number counts of the non-stellar sources out of the 832 detected down to z'~26 AB-mag in the 3.9x4.3 square arcmin region of XMMU J0338.7+0030 imaged at all GROND bands clearly exceed those computed in deep fields/survey areas at ~20.5 - 22.5 AB-mag. The photo-z's of the three imaged spectroscopic members yield z=1.12+/-0.09. The spatial distribution and the properties of the GROND sources with a photo-z in the range 1.01 - 1.23 confirm the correspondence of the X-ray source with a galaxy over-density at a significance of at least 4.3 sigma. Candidate members that are spectro-photometrically classified as elliptical galaxies define a red locus in the i'-z' vs z' colour-magnitude diagram that is consistent with the red sequence of the cluster RDCS J0910+5422 at z=1.106. XMMU J0338.7+0030 hosts also a population of bluer late-type spirals and irregulars. The starbursts among the photometric members populate both loci, consistently with previous results. The analysis of the available data set indicates that XMMU J0338.7+0030 is a low-mass cluster (M_200 ~ 1E14 M_sun) at z=1.1. (Abridged)Comment: accepted for publication in Astronomy & Astrophysics Main Journal, 27 pages, 24 figures, 1 tabl

Planck Intermediate Results II: Comparison of Sunyaev-Zeldovich measurements from Planck and from the Arcminute Microkelvin Imager for 11 galaxy clusters

A comparison is presented of Sunyaev-Zeldovich measurements for 11 galaxy clusters as obtained by Planck and by the ground-based interferometer, the Arcminute Microkelvin Imager. Assuming a universal spherically-symmetric Generalised Navarro, Frenk & White (GNFW) model for the cluster gas pressure profile, we jointly constrain the integrated Compton-Y parameter (Y_500) and the scale radius (theta_500) of each cluster. Our resulting constraints in the Y_500-theta_500 2D parameter space derived from the two instruments overlap significantly for eight of the clusters, although, overall, there is a tendency for AMI to find the Sunyaev-Zeldovich signal to be smaller in angular size and fainter than Planck. Significant discrepancies exist for the three remaining clusters in the sample, namely A1413, A1914, and the newly-discovered Planck cluster PLCKESZ G139.59+24.18. The robustness of the analysis of both the Planck and AMI data is demonstrated through the use of detailed simulations, which also discount confusion from residual point (radio) sources and from diffuse astrophysical foregrounds as possible explanations for the discrepancies found. For a subset of our cluster sample, we have investigated the dependence of our results on the assumed pressure profile by repeating the analysis adopting the best-fitting GNFW profile shape which best matches X-ray observations. Adopting the best-fitting profile shape from the X-ray data does not, in general, resolve the discrepancies found in this subset of five clusters. Though based on a small sample, our results suggest that the adopted GNFW model may not be sufficiently flexible to describe clusters universally.Comment: update to metadata author list onl

Planck Intermediate Results. IV. The XMM-Newton validation programme for new Planck galaxy clusters

We present the final results from the XMM-Newton validation follow-up of new Planck galaxy cluster candidates. We observed 15 new candidates, detected with signal-to-noise ratios between 4.0 and 6.1 in the 15.5-month nominal Planck survey. The candidates were selected using ancillary data flags derived from the ROSAT All Sky Survey (RASS) and Digitized Sky Survey all-sky maps, with the aim of pushing into the low SZ flux, high-z regime and testing RASS flags as indicators of candidate reliability. 14 new clusters were detected by XMM, including 2 double systems. Redshifts lie in the range 0.2 to 0.9, with 6 clusters at z>0.5. Estimated M500 range from 2.5 10^14 to 8 10^14 Msun. We discuss our results in the context of the full XMM validation programme, in which 51 new clusters have been detected. This includes 4 double and 2 triple systems, some of which are chance projections on the sky of clusters at different z. We find that association with a RASS-BSC source is a robust indicator of the reliability of a candidate, whereas association with a FSC source does not guarantee that the SZ candidate is a bona fide cluster. Nevertheless, most Planck clusters appear in RASS maps, with a significance greater than 2 sigma being a good indication that the candidate is a real cluster. The full sample gives a Planck sensitivity threshold of Y500 ~ 4 10^-4 arcmin^2, with indication for Malmquist bias in the YX-Y500 relation below this level. The corresponding mass threshold depends on z. Systems with M500 > 5 10^14 Msun at z > 0.5 are easily detectable with Planck. The newly-detected clusters follow the YX-Y500 relation derived from X-ray selected samples. Compared to X-ray selected clusters, the new SZ clusters have a lower X-ray luminosity on average for their mass. There is no indication of departure from standard self-similar evolution in the X-ray versus SZ scaling properties. (abridged)Comment: accepted by A&

Planck intermediate results. III. The relation between galaxy cluster mass and Sunyaev-Zeldovich signal

We examine the relation between the galaxy cluster mass M and Sunyaev-Zeldovich (SZ) effect signal D_A^2 Y for a sample of 19 objects for which weak lensing (WL) mass measurements obtained from Subaru Telescope data are available in the literature. Hydrostatic X-ray masses are derived from XMM-Newton archive data and the SZ effect signal is measured from Planck all-sky survey data. We find an M_WL-D_A^2 Y relation that is consistent in slope and normalisation with previous determinations using weak lensing masses; however, there is a normalisation offset with respect to previous measures based on hydrostatic X-ray mass-proxy relations. We verify that our SZ effect measurements are in excellent agreement with previous determinations from Planck data. For the present sample, the hydrostatic X-ray masses at R_500 are on average ~ 20 per cent larger than the corresponding weak lensing masses, at odds with expectations. We show that the mass discrepancy is driven by a difference in mass concentration as measured by the two methods, and, for the present sample, the mass discrepancy and difference in mass concentration is especially large for disturbed systems. The mass discrepancy is also linked to the offset in centres used by the X-ray and weak lensing analyses, which again is most important in disturbed systems. We outline several approaches that are needed to help achieve convergence in cluster mass measurement with X-ray and weak lensing observations.Comment: 19 pages, 9 figures, matches accepted versio

Evaluation of absorbent materials for use as ad hoc dry decontaminants during mass casualty incidents as part of the UK’s Initial Operational Response (IOR)

Copyright: © 2017 Kassouf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The UK's Initial Operational Response (IOR) is a revised process for the medical management of mass casualties potentially contaminated with hazardous materials. A critical element of the IOR is the introduction of immediate, on-scene disrobing and decontamination of casualties to limit the adverse health effects of exposure. Ad hoc cleansing of the skin with dry absorbent materials has previously been identified as a potential means of facilitating emergency decontamination. The purpose of this study was to evaluate the in vitro oil and water absorbency of a range of materials commonly found in the domestic and clinical environments and to determine the effectiveness of a small, but representative selection of such materials in skin decontamination, using an established ex vivo model. Five contaminants were used in the study: methyl salicylate, parathion, diethyl malonate, phorate and potassium cyanide. In vitro measurements of water and oil absorbency did not correlate with ex vivo measurements of skin decontamination. When measured ex vivo, dry decontamination was consistently more effective than a standard wet decontamination method ("rinse-wipe-rinse") for removing liquid contaminants. However, dry decontamination was ineffective against particulate contamination. Collectively, these data confirm that absorbent materials such as wound dressings and tissue paper provide an effective, generic capability for emergency removal of liquid contaminants from the skin surface, but that wet decontamination should be used for non-liquid contaminants.Peer reviewedFinal Published versio

Planck intermediate results. VIII. Filaments between interacting clusters

About half of the baryons of the Universe are expected to be in the form of filaments of hot and low density intergalactic medium. Most of these baryons remain undetected even by the most advanced X-ray observatories which are limited in sensitivity to the diffuse low density medium. The Planck satellite has provided hundreds of detections of the hot gas in clusters of galaxies via the thermal Sunyaev-Zel'dovich (tSZ) effect and is an ideal instrument for studying extended low density media through the tSZ effect. In this paper we use the Planck data to search for signatures of a fraction of these missing baryons between pairs of galaxy clusters. Cluster pairs are good candidates for searching for the hotter and denser phase of the intergalactic medium (which is more easily observed through the SZ effect). Using an X-ray catalogue of clusters and the Planck data, we select physical pairs of clusters as candidates. Using the Planck data we construct a local map of the tSZ effect centered on each pair of galaxy clusters. ROSAT data is used to construct X-ray maps of these pairs. After having modelled and subtracted the tSZ effect and X-ray emission for each cluster in the pair we study the residuals on both the SZ and X-ray maps. For the merging cluster pair A399-A401 we observe a significant tSZ effect signal in the intercluster region beyond the virial radii of the clusters. A joint X-ray SZ analysis allows us to constrain the temperature and density of this intercluster medium. We obtain a temperature of kT = 7.1 +- 0.9, keV (consistent with previous estimates) and a baryon density of (3.7 +- 0.2)x10^-4, cm^-3. The Planck satellite mission has provided the first SZ detection of the hot and diffuse intercluster gas.Comment: Accepted by A&

Quantitative-spatial assessment of soil contamination in S. Francisco de Assis due to mining activity of the Panasqueira mine (Portugal)

Through the years, mining and beneficiation processes produces large amounts of As-rich mine wastes laid up in huge tailings and open-air impoundments (Barroca Grande and Rio tailings) that are the main source of pollution in the surrounding area once they are exposed to the weathering conditions leading to the formation of AMD and consequently to the contamination of the surrounding environments, in particularly soils. In order to investigate the environmental contamination impact on S. Francisco de Assis (village located between the two major impoundments and tailings) agricultural soils, a geochemical survey was undertaken to assess toxic metals associations, related levels and their spatial distribution, and to identify the possible contamination sources. According to the calculated contamination factor, As and Zn have a very high contamination factor giving rise to 65.4 % of samples with a moderate to high pollution degree; 34.6 % have been classified as nil to very low pollution degree. The contamination factor spatial distribution put in evidence the fact that As, Cd, Cu, Pb, and Zn soils contents, downstream Barroca Grande tailing, are increased when compared with the local Bk soils. The mechanical dispersion, due to erosion, is the main contamination source. The chemical extraction demonstrates that the trace metals distribution and accumulation in S. Francisco de Assis soils is related to sulfides, but also to amorphous or poorly crystalline iron oxide phases. The partitioning study allowed understanding the local chemical elements mobility and precipitation processes, giving rise to the contamination dispersion model of the study area. The wind and hydrological factors are responsible for the chemical elements transport mechanisms, the water being the main transporter medium and soils as one of the possible retention media

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients.This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy.Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease