Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Transnational Threat Indications and Warning: The Utility of Network Analysis

This paper uses the case of the Japanese cult Aum Shinrikyo to illustrate how network constructions can aid in the development of indications and warning for transnational threats. Following a brief primer on Aum, the paper describes Aum's organizational and transactional networks, and examines how analysts could have used these representations to generate indications and warnings. The main conclusions are that link analysis can create organizational and transactional network representations that are well suited to develop indications and warning for transnational threats, and that the Aum Shinrikyo case can suggest useful points of departure for link analysis. Introduction On [20 March 1995], at the height of the morning rush hour, several members of a religious cult which preached Armageddon between the United States and Japan unleashed a sarin gas attack on the innocent civilian riders of the Tokyo subway system... Twelve persons were killed and over 5,000 were inj..

Multigroup, Spatially Dependent Studies of Mild Excursions in Large Fast Reactors

163 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1971.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Turkish foreign terrorist fighters and the emergence of a new kind of radicalization

This article is an attempt to answer a number of questions asked in the literature on radicalization and extremism: What motivates foreign terrorist fighters (FTFs) from Turkey to join the Islamic State of Iraq and Syria (ISIS)? In what kind of environment does violent extremism become the choice for Turkish nationals to join ISIS in Syria and Iraq? How can Turkish nationals who join ISIS be profiled in terms of their socio-economic and cultural traits and how do these traits compare people from other nations who join and fight in terrorist organizations? Though their numbers remained minimal compared to the overall population, how can we explain the case of Turkish FTFs, when a peaceful and tolerant Anatolian/Sufi Islam' has reigned in the country and Muslims are well integrated in the social, economic, and political life of the country under the 13-year long rule of Islamic-oriented Justice and Development Party (AK Party)? What do these answers to these questions mean for Turkish Islam and possible de-radicalization programs? These questions will be addressed by semi-structured interviews conducted both with Turkish FTFs who have joined ISIS and with family members of some of those who have returned from fighting with ISIS