Pathogen-Mediated Proteolysis of the Cell Death Regulator RIPK1 and the Host Defense Modulator RIPK2 in Human Aortic Endothelial Cells

Porphyromonas gingivalis is the primary etiologic agent of periodontal disease that is associated with other human chronic inflammatory diseases, including atherosclerosis. The ability of P. gingivalis to invade and persist within human aortic endothelial cells (HAEC) has been postulated to contribute to a low to moderate chronic state of inflammation, although how this is specifically achieved has not been well defined. In this study, we demonstrate that P. gingivalis infection of HAEC resulted in the rapid cleavage of receptor interacting protein 1 (RIPK1), a mediator of tumor necrosis factor (TNF) receptor-1 (TNF-R1)-induced cell activation or death, and RIPK2, a key mediator of both innate immune signaling and adaptive immunity. The cleavage of RIPK1 or RIPK2 was not observed in cells treated with apoptotic stimuli, or cells stimulated with agonists to TNF-R1, nucleotide oligomerization domain receptor 1(NOD1), NOD2, Toll-like receptor 2 (TLR2) or TLR4. P. gingivalis-induced cleavage of RIPK1 and RIPK2 was inhibited in the presence of a lysine-specific gingipain (Kgp) inhibitor. RIPK1 and RIPK2 cleavage was not observed in HAEC treated with an isogenic mutant deficient in the lysine-specific gingipain, confirming a role for Kgp in the cleavage of RIPK1 and RIPK2. Similar proteolysis of poly (ADP-ribose) polymerase (PARP) was observed. We also demonstrated direct proteolysis of RIPK2 by P. gingivalis in a cell-free system which was abrogated in the presence of a Kgp-specific protease inhibitor. Our studies thus reveal an important role for pathogen-mediated modification of cellular kinases as a potential strategy for bacterial persistence within target host cells, which is associated with low-grade chronic inflammation, a hallmark of pathogen-mediated chronic inflammatory disorders

E-037 Durability of Treatment for the Penumbra SMART COIL System at One Year in Patients with Ruptured Aneurysms: Subset Analysis of the SMART Registry

IntroductionThe Penumbra SMART COIL System includes a novel generation of embolic coils comprised of complex and WAVE shape properties with varying levels of softness to promote dense packing and durable long-term occlusion. We report a subset analysis to assess the durability of treatment with SMART COIL System at one year follow-up in patients with ruptured aneurysms enrolled in the SMART registry.Materials and methodsThe SMART registry is a prospective, multi-center registry study. Procedures must employ ≥75% of the SMART, PC400, or POD coils to meet the registry criteria. SMART registry endpoints include retreatment rates through one year follow-up, procedural device-related serious adverse events (SAE), and the ability to achieve adequate occlusion at immediate post-procedure. Multivariate analysis was performed to identify predictors of outcomes at one year.ResultsOf the first 500 patients with one year follow-up, 24.2% (121/500) of patients had ruptured aneurysms (74.4% female; mean age 56.4 ± 12.7 years). Ruptured aneurysms were small ( 25 mm) in 0.8% (1/121) of patients and 30.8% (37/120) were wide-neck (dome-to-neck ratio <1.5 or neck width ≥ 4 mm). Stent-assisted coiling and balloon-assisted coiling were performed in 8.3% (10/121) and 32.2% (39/121) of patients, respectively. Median packing density for ruptured aneurysms was 29.7% (IQR 21.0–40.4).In patients with ruptured aneurysms, Raymond Class I and II was observed in 90.9% (110/121) at immediate post-procedure and 80.2% (89/111) at one year follow-up. The recanalization rate at one year was 23.4% (26/111). The retreatment rate through one year was 14.4% (17/118). Procedural device-related SAE were observed in 4.1% subjects (5/121).In multivariate models, independent predictors of Raymond Occlusion Class III at one-year follow-up included wide-neck aneurysm (odds ratio [OR]=5.69; 95% confidence intervals [CI] 1.69–19.15, p=0.0050), balloon-assisted coiling (OR=3.81; 95% CI 1.28–11.37, p=0.017), and age ≥ 65 yr (OR=0.15; 95% CI 0.027–0.78, p=0.025). Balloon-assisted coiling also predicted recanalization at one year follow-up (OR=2.54, 95% CI 1.03–6.27, p=0.043).ConclusionThis subset analysis suggests that the SMART COIL System achieves adequate embolization in ruptured aneurysms with adequate retreatment rates over one year.Disclosures D. Fiorella: 1; C; Penumbra, Inc. 3; C; Penumbra, Inc. B. Bohnstedt: None. C. Schirmer: None. R. Bellon: 3; C; Penumbra, Inc. R. DeLeacy: None. R. Starke: None. A. Spiotta: 1; C; Penumbra, Inc. 2; C; Penumbra, Inc

The Joint Programme on Nuclear Materials of the European Energy Research Alliance (EERA-JPNM) – Coordinating GenIV reactor materials research for a low-carbon Europe

SMINS 4 NEA worksho