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

Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung cancer, LKB1 is somatically inactivated in 25-30% of cases, often concurrently with activating KRAS mutation. Here, we employed an integrative approach to define novel therapeutic targets in KRAS-driven LKB1 mutant lung cancers. High-throughput RNAi screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling demonstrated that Lkb1-null cells had striking decreases in multiple nucleotide metabolites as compared to the Lkb1-wt cells. Thus, LKB1 mutant lung cancers have deficits in nucleotide metabolism conferring hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors

Fraction of Clumpy Star-forming Galaxies at 0.5 ≤ z ≤ 3 in UVCANDELS: Dependence on Stellar Mass and Environment

High-resolution imaging of galaxies in rest-frame UV has revealed the existence of giant star-forming clumps prevalent in high-redshift galaxies. Studying these substructures provides important information about their formation and evolution and informs theoretical galaxy evolution models. We present a new method to identify clumps in galaxies’ high-resolution rest-frame UV images. Using imaging data from CANDELS and UVCANDELS, we identify star-forming clumps in an HST/F160W ≤ 25 AB mag sample of 6767 galaxies at 0.5 ≤ z ≤ 3 in four fields, GOODS-N, GOODS-S, EGS, and COSMOS. We use a low-passband filter in Fourier space to reconstruct the background image of a galaxy and detect small-scale features (clumps) on the background-subtracted image. Clumpy galaxies are defined as those having at least one off-center clump that contributes a minimum of 10% of the galaxy’s total rest-frame UV flux. We measure the fraction of clumpy galaxies ( f _clumpy ) as a function of stellar mass, redshift, and galaxy environment. Our results indicate that f _clumpy increases with redshift, reaching ∼65% at z ∼ 1.5. We also find that f _clumpy in low-mass galaxies ( $9.5\leqslant \mathrm{log}({M}_{* }/{M}_{\odot })\leqslant 10$ ) is 10% higher compared to that of their high-mass counterparts ( $\mathrm{log}({M}_{* }/{M}_{\odot })\gt 10.5$ ). Moreover, we find no evidence of significant environmental dependence of f _clumpy for galaxies at the redshift range of this study. Our results suggest that the fragmentation of gas clouds under violent disk instability remains the primary driving mechanism for clump formation, and incidents common in dense environments, such as mergers, are not the dominant processes