An Antimicrobial Peptide Regulates Tumor-Associated Macrophage Trafficking via the Chemokine Receptor CCR2, a Model for Tumorigenesis

Tumor-associated macrophages (TAMs) constitute a significant part of infiltrating inflammatory cells that are frequently correlated with progression and poor prognosis of a variety of cancers. Tumor cell-produced human β-defensin-3 (hBD-3) has been associated with TAM trafficking in oral cancer; however, its involvement in tumor-related inflammatory processes remains largely unknown., applying a cross-desensitization strategy of CCR2 and its pharmacological inhibitor (RS102895), respectively, was also carried out. outcome and demonstrates the importance of the innate immune system in the development of tumors

The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells. © 2013 Haas et al

Scale-adaptive simulation (SAS) of dynamic stall on a wind turbine

Scale-adaptive simulation (SAS) approach is employed to investigate the complex dynamic stall phenomena occurring on a wind turbine blade. The results are com-pared with the more popular less computationally-expensive unsteady Reynolds-averaged Navier-Stokes (URANS) approach where the latter is validated using three sets of experimental data. The comparison reveals that the two approaches have similar predictions of the instant of the formation/bursting/shedding of the laminar separation bubble (LSB) and dynamic stall vortex (DSV), the size of the LSB and aerodynamic loads during the upstroke. This is while the two approach-es exhibit dissimilar predictions of the trailing-edge vortex characteristics, its in-teraction with the DSV, number of secondary vortices and aerodynamic loads during the downstroke

Modulation by simvastatin of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine coronary artery smooth muscle cells

Background and Purpose: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca 2+- activated K + (BK Ca) channels. Experimental Approaches: Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BK Ca channel gatings of porcine coronary artery smooth muscle cells were evaluated. Key Results: Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 μM) (hydrophobic), but not simvastatin Na + (hydrophilic), inhibited the BK Ca channels with a minimal recovery upon washout. Isopimaric acid (10 μM)-mediated enhancement of the BK Ca amplitude was reversed by external simvastatin. Simvastatin Na + (10 μM, applied internally), markedly attenuated isopimaric acid (10 μM)-induced enhancement of the BK Ca amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 μM) and geranylgeranyl pyrophosphate (20 μM) only prevented simvastatin (1 and 3 μM)-induced responses. simvastatin (10 μM) caused a rottlerin (1 μM)-sensitive (cycloheximide (10 μM)-insensitive) increase of PKC-δ protein expression. Conclusions and Implications: Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BK Ca channels of the arterial smooth muscle cells through multiple intracellular pathways. © 2007 Nature Publishing Group All rights reserved.link_to_subscribed_fulltex

Novel nonsense variants in SLURP1 and DSG1 cause palmoplantar keratoderma in Pakistani families

Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene.This article is freely available online via Open Access. Click on the Publisher URL to access the full-text via the publisher's site