Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed

Analysis of Friction-Induced Vibration Leading to Brake Squeal Using a Three Degree-of-Freedom Model

This is a post-peer-review, pre-copyedit version of an article published in Tribology Letters. The final authenticated version is available online at: http://dx.doi.org/10.1007/s11249-017-0887-8.Friction-induced vibration is a common phenomenon in nature and thus has attracted many researchers’ attention. Many of the mathematical models that have been proposed on the basis of mode coupling principle, however, cannot be utilized directly to analyse the generation of friction-induced vibration that occurs between two bodies because of a difficulty relating model parameters to definite physical meaning for real friction pairs. In this paper, a brake squeal experiment is firstly carried out by using a simple beam-on-disc laboratory apparatus. Experimental results show that brake squeal correlates with the bending mode of the beam and the nodal diameter out-ofplane mode of the disc as well as the cantilever length of the beam. Then, a specific three degree-of-freedom dynamic model is developed of the beam-on-disc system and the vibration behaviour is simulated by using the complex eigenvalue analysis method and a transient response analysis. Numerical simulation shows that the bending mode frequency of the beam a little greater than the frequency of the nodal diameter out-of-plane mode and a specific incline angle of the leading area to the normal line of the disc as well as a certain friction coefficient, are necessary conditions for the mode coupling of a frictional system. Results also show that when the frictional system is transited from a steady state to an unstable state for the variation of parameters, its kinetic and potential energy increase with time due to continuous feed-in energy from the friction force while the dynamic responses of the system change from the beating oscillation to the divergent, which leads to the friction-induced vibration and squeal noise

Dopamine D2/3 receptor antagonism reduces activity-based anorexia

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT(3), dopamine D(1)-like, D(2), D(3) or D(2/3) antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D(2/3) receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D(3) receptor antagonist SB277011A or D(2) receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D(2) and/or D(3) receptors robustly reduces ABA. Studies investigating the mechanisms by which D(2) and/or D(3) receptors regulate ABA, and the efficacy for D(2/3) and/or D(3) antagonists to treat AN, are warranted

N-3 fatty acids in patients with multiple cardiovascular risk factors

BACKGROUND: Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. METHODS: In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. RESULTS: Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. CONCLUSIONS: In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. Copyright © 2013 Massachusetts Medical Society