Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Circulating IgM Requires Plasma Membrane Disruption to Bind Apoptotic and Non-Apoptotic Nucleated Cells and Erythrocytes

<div><p>Autoimmunity is associated with defective phagocytic clearance of apoptotic cells. IgM deficient mice exhibit an autoimmune phenotype consistent with a role for circulating IgM antibodies in apoptotic cell clearance. We have extensively characterised IgM binding to non-apoptotic and apoptotic mouse thymocytes and human Jurkat cells using flow cytometry, confocal imaging and electron microscopy. We demonstrate strong specific IgM binding to a subset of Annexin-V (AnnV)⁺PI (Propidium Iodide)⁺ apoptotic cells with disrupted cell membranes. Electron microscopy studies indicated that IgM⁺AnnV⁺PI⁺ apoptotic cells exhibited morphologically advanced apoptosis with marked plasma membrane disruption compared to IgM^-AnnV⁺PI⁺ apoptotic cells, suggesting that access to intracellular epitopes is required for IgM to bind. Strong and comparable binding of IgM to permeabilised non-apoptotic and apoptotic cells suggests that IgM bound epitopes are 'apoptosis independent' such that IgM may bind any cell with profound disruption of cell plasma membrane integrity. In addition, permeabilised erythrocytes exhibited significant IgM binding thus supporting the importance of cell membrane epitopes. These data suggest that IgM may recognize and tag damaged nucleated cells or erythrocytes that exhibit significant cell membrane disruption. The role of IgM <i>in vivo</i> in conditions characterized by severe cell damage such as ischemic injury, sepsis and thrombotic microangiopathies merits further exploration.</p></div

Abstract P3-14-02: Incidence of venous thromboembolism in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta- analysis of randomized controlled trials

Abstract Background: The cyclin dependent kinases (CDK) along with their partners, the cyclins, have a crucial role in regulation of the cell cycle. Several CDK-targeted agents have been employed in hormone receptor positive metastatic breast cancer (MBC) with noteworthy safety concerns. Nevertheless, the impact of this agent on risk of venous thromboembolism (VTE) remains uncertain. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of VTE among patients with hormone receptor-positive HER2-negative MBC treated with CDK 4/6 inhibitors. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through June 2017. Trials that mention deep vein thrombosis and pulmonary embolism as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Pooled VTE rates were estimated as follows: we multiplied the median follow-up duration by the sample size. Crude study-specific VTE rates were then calculated by dividing the number of incident VTE cases by the total number of person-months follow-up. Results: A total of 2671 patients with hormone receptor-positive HER2-negative MBC from four phase 3 studies and one phase 2 study were eligible for analysis. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole and abemaciclib-fulvestrant while the control arm utilized placebo in combination with letrozole or fulvestrant. The I2 statistic for heterogeneity was 13.6, and the heterogeneity X2 (Cochran's Q) was 4.6 (P= 0.3), suggesting homogeneity of results among the randomized trials. The VTE incidence was 24 (1.46%) in CDK 4/6 group vs 4 (0.39%) in control group. The pooled RR for VTE was 2.736 (95% CI: 1.115 – 6.714, P = 0.028) and the absolute RD was 0.010 (95% CI: 0.002 – 0.018, P = 0.010) according to the fixed effects model. By the random effects model, the pooled RR was 2.411 (95% CI: 0.809 – 7.181, P = 0.114) and RD was 0.009 (95% CI: 0.0 – 0.019, P = 0.048). Over median follow up of 36 months, the RR for VTE was 3.792 (95% CI: 1.838 – 7.822, P &amp;lt; 0.0001) and RD was 0.024 (95% CI: 0.014 – 0.034, P &amp;lt; 0.0001) with the fixed effects model. By the random effects model, the pooled RR for VTE was 4.248 (95% CI: 0.952- 18.959, P = 0.058) and RD was 0.026 (95% CI: 0.004 – 0.021, P &amp;lt; 0.0001). The pooled rate of VTE among CDK 4/6 group was 2.99 per person years compared to 0.50 per person years among control arm. Conclusion: Approximately 1% of patients on letrozole or fulvestrant alone developed VTE in previous studies. Our meta-analysis demonstrated that the addition of CDK 4/6 inhibitors to letrozole or fulvestrant, contribute to higher incidence of VTE. More randomized trials are required to determine the actual relation and definitive incidence of VTE, a major cause of morbidity and mortality among these patients. Citation Format: Thein KZ, Zaw MH, Tun AM, Jones C, Radhi S, Hardwicke F, Oo TH. Incidence of venous thromboembolism in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta- analysis of randomized controlled trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-02.</jats:p

Influence of renewable fuels and nanoparticles additives on engine performance and soot nanoparticles characteristics

The fuel combustion in diesel engines can be improved by adding nanomaterials to the fuel which result in an reduction in pollutant emissions and enhance the quality of fuel combustion. The engine performance and soot nanoparticles characteristics were evaluated in this study with adding nanoparticles of copper oxide (CuO2) to the rapeseed methyl ester (RME) and diesel under variable engine speeds. The addition of CuO2 to the RME significantly improve brake thermal efficiency (BTE) and decline the brake specific fuel consumption (BSFC) by 23.6% and 7.6%, respectively, compared to the neat RME and diesel fuel. The inclusion CuO2 nanoparticles into the RME and diesel led to decrease the concentration and number of particulate matter (PM) by 33% and 17% in comparison with neat RME and diesel without nano additives, respectively. Moreover, PM is significantly decreased by 31.5% during the RME combustion in comparison with neat RME and diesel under various engine speeds. It was also obtained that the number of emitted particles (npo) reduced by 23.5% with adding nanoparticles to the RME in comparison with diesel, while the diameter of soot nanoparticles (dpo) increased by 8.6% in comparison with diesel. Furthermore, the addition CuO2 to the RME decreased the size and number of particles more than to the diesel fuel

Influence of renewable fuels and nanoparticles additives on engine performance and soot nanoparticles characteristics

The fuel combustion in diesel engines can be improved by adding nanomaterials to the fuel which result in an reduction in pollutant emissions and enhance the quality of fuel combustion. The engine performance and soot nanoparticles characteristics were evaluated in this study with adding nanoparticles of copper oxide (CuO2) to the rapeseed methyl ester (RME) and diesel under variable engine speeds. The addition of CuO2 to the RME significantly improve brake thermal efficiency (BTE) and decline the brake specific fuel consumption (BSFC) by 23.6% and 7.6%, respectively, compared to the neat RME and diesel fuel. The inclusion CuO2 nanoparticles into the RME and diesel led to decrease the concentration and number of particulate matter (PM) by 33% and 17% in comparison with neat RME and diesel without nano additives, respectively. Moreover, PM is significantly decreased by 31.5% during the RME combustion in comparison with neat RME and diesel under various engine speeds. It was also obtained that the number of emitted particles (npo) reduced by 23.5% with adding nanoparticles to the RME in comparison with diesel, while the diameter of soot nanoparticles (dpo) increased by 8.6% in comparison with diesel. Furthermore, the addition CuO2 to the RME decreased the size and number of particles more than to the diesel fuel