Increased platelet expression of FcGammaRIIa and its potential impact on platelet reactivity in patients with end stage renal disease

<p>Abstract</p> <p>Background</p> <p>Increased platelet reactivity has been implicated in cardiovascular disease – the major cause of death in patients with end stage renal disease (ESRD). FcGammaRIIA is a component of glycoprotein VI and Ib-IX-V that mediate activation of platelets by collagen and von Willebrand factor. To determine whether expression of FcGammaRIIA impacts platelet reactivity we quantified its expression and platelet reactivity in 33 patients with ESRD who were undergoing hemodialysis.</p> <p>Methods</p> <p>Blood samples were obtained from patients immediately before hemodialysis and before administration of heparin. Platelet expression of FcGammaRIIA and the activation of platelets in response to low concentrations of convulxin (1 ng/ml, selected to mimic effects of collagen), thrombin (1 nM), adenosine diphosphate (ADP, 0.2 uM), or platelet activating factor (PAF, 1 nM) were determined with the use of flow cytometry in samples of whole blood anticoagulated with corn trypsin inhibitor (a specific inhibitor of Factor XIIa).</p> <p>Results</p> <p>Patients were stratified with respect to the median expression of FcGammaRIIA. Patients with high platelet expression of FcGammaRIIA exhibited 3-fold greater platelet reactivity compared with that in those with low expression in response to convulxin (p < 0.01) and 2-fold greater activation in response to thrombin, ADP, and PAF (p < 0.05 for each). For each agonist, expression of FcGammaRIIA correlated modestly but positively with platelet reactivity. The strongest correlation was with thrombin-induced activation (r = 0.6, p < 0.001).</p> <p>Conclusion</p> <p>Increased platelet reactivity in response to low concentrations of diverse agonists is associated with high expression of FcGammaRIIA and may contribute to an increased risk of thrombosis in patients with ESRD.</p

Antioxidants in Diets and Food

none3noNowadays, the society looks with increasing interest in the diet, which is no longer simply a means by which to take the necessary nutrients but has become a means by which it is possible to preserve the health state. German philosopher Ludwig Feuerbach once said: “We are what we eat.” This statement is even truer today because of the hectic life, people often tend to eat frugal, fast, and often very fat and unhealthy meals. Today, there is a very high attention both from the social point of view and by the scientific community to the so-called functional foods. These foods, which contain several bioactive compounds, exert innumerable biological properties and therefore can help to preserve the health state. In addition, the use of nutraceuticals has taken the upper hand, unfortunately, often also to the detriment of functional foods, which unlike the former still remain foods and, as such, with a certainly better efficacy-safety profile. The term nutraceutical, indeed, does not refer to a food but rather to a formulation containing one or more compounds isolated from plant extracts or one or more titrated plant extracts. Moreover, some formulations (capsules, tablets, powders, etc.) are rarely studied before being commercialized, and their effectiveness remains rather doubtful in light of a very lax regulation in many countries worldwide.mixedAntonella Smeriglio, Laura Cornara, Domenico TrombettaSmeriglio, Antonella; Cornara, Laura; Trombetta, Domenic

Cellular senescence: from growth arrest to immunogenic conversion

Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a pro-inflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, well-established triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established “atypical” senescent states that may occur independent of DNA damage

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial

Background Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies.Methods This phase 3, two-ann, randomised, double-blind, placebo-controlled, inulticentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by v irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89).Findings Between June 27, 2011, and April 11,2017,5286 patients were randomly assigned to receive VZV vaccine inactivated by gamma irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6.7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18.5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63.6% (97.5% CI 36.4 to 79.1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22.5%) of 1322 patients who received the vaccine and in 283 (21.0%) of 1346 patients who received placebo (risk difference 1.5%, 95% CI -1.7 to 4.6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16.8% (95% CI -17.8 to 41.3).Interpretation The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. Copyright (C) 2019 Elsevier Ltd. All rights reserved