Citations

Background— Afterload reduction is a cornerstone in the management of patients with heart failure (HF) and reduced ejection fraction. However, arterial load and the effect of HF therapies on afterload might vary between individuals. Tailoring vasoactive medicines to patients with HF based upon better understanding of arterial afterload may enable better individualization of therapy. Methods and Results— Subjects with HF and reduced ejection fraction underwent aggressive titration of vasoactive HF therapies with assessment of central aortic waveforms analyzed using pulse wave, wave separation, and arterial reservoir models. Clinical response to treatment was assessed using the 6-minute walk test distance, which increased in 25 subjects and decreased or remained unchanged in 13. Subjects with improvement on therapy displayed higher aortic pressure wave pulsatility (central pulse pressure [PP], reflected pressure wave, and reservoir pressure) at study entry compared with subjects without improvement (all P <0.05). Parameters derived by the arterial analysis methods were strongly correlated with one another and displayed similar ability to predict improvement. Aortic pressure pulsatility significantly decreased in subjects with functional improvement, whereas no change was observed in patients without functional improvement ( P for interaction <0.05). These differences in arterial load at baseline and on therapy were not apparent from conventional brachial artery cuff pressure assessments. Conclusions— Increased aortic pressure wave pulsatility and greater decrease in pulsatility on treatment are associated with functional improvement in patients with HF and reduced ejection fraction receiving aggressive vasodilator titration. These differences are not identifiable using brachial cuff pressures. Central aortic waveform analysis may enable better individualization of vasoactive therapies in chronic HF and reduced ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00588692.

Background Healthcare resources vary geographically, but associations between hospital‐based resources and acute stroke quality and outcomes remain unclear. Methods and Results Using Get With The Guidelines‐Stroke and Dartmouth Atlas of Health Care data, we examined associations between healthcare resource availability, stroke care, and outcomes. We categorized hospital referral regions with high‐, medium‐, or low‐resource levels based on the 2006 national per‐capita availability median of 6 relevant acute stroke care resources. Using multivariable logistic regression, we examined healthcare resource level and in‐hospital quality and outcomes. Of 1 480 308 admitted ischemic stroke patients (2006–2013), 28.8% were hospitalized in low‐, 44.4% in medium‐, and 26.9% in high‐resource hospital referral regions. Quality‐of‐care/timeliness metrics, adjusted length of stay, and in‐hospital mortality were similar across all resource levels. Conclusions Significant variation exists in regional availability of healthcare resources for acute ischemic stroke treatment, yet among Get With the Guidelines‐Stroke hospitals, quality of care and in‐hospital outcomes did not differ by regional resource availability.

ABSTRACT Angiogenesis and inflammation are regarded as important factors in the pathogenesis of chronic inflammation, cancer, and wound healing. Recent studies have supported prior evidence that common signaling pathways are involved in angiogenesis and inflammatory responses; however, key factors controlling both processes remain unclear. Although tripartite motif‐containing (TRIM)‐28 is known to have an immunosuppressive role in immune cells, its expression level and role in endothelial cells (ECs) are still unclear. In this study, we investigated the role of TRIM28 in inflammatory responses and angiogenic activity of ECs for the first time. We showed that TRIM28 is the most abundant TRIM family member and is localized in nuclei of ECs. Small interfering RNA‐mediated knockdown of TRIM28 strikingly suppressed expression of TNF receptor (TNFR)‐1 and −2, decreased TNFα‐induced phosphorylation of IKKα/β and IκBα and degradation of IκBα and nuclear translocation of p65, and suppressed basal level and TNF‐α‐induced expression of chemokines and adhesion molecules, including VCAM‐1, IL‐6, ICAM‐1, E‐selectin, and monocyte chemoattractant protein (MCP)‐1. Unexpectedly, IL‐8 was potentiated by TRIM28 knockdown in ECs in an NF‐κB‐inducing kinase–dependent manner. Meanwhile, knockdown of TRIM28 inhibited expression of VEGF receptor 2 and suppressed VEGF‐induced proliferation and tube formation by ECs. Finally, knockdown of TRIM28 suppressed recruitment of ECs in vivo in a murine synthetic basement membrane model. In summary, we found that TRIM28 acts as a central factor in controlling endothelial inflammatory responses and angiogenic activities by retaining expression of TNFR‐1 and −2 and VEGF receptor 2 in ECs.—Wang, Y., Li, J., Huang Y., Dai, X., Liu, Y., Liu, Z., Wang, Y., Wang, N., Zhang, P. Tripartite motif–containing 28 bridges endothelial inflammation and angiogenic activity by retaining expression of TNFR1 and −2 and VEGFR2 in endothelial cells. FASEB J. 31, 2026–2036 (2017). www.fasebj.org

Abstract Purpose: Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer. Experimental Design: DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed. Results: Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34–0.90), P = 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44–1.40), P = 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months; P = 0.08) or differentiated subtype (3.7 months; P = 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27–0.74), P = 0.0015]. Conclusions: Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost. Clin Cancer Res; 23(14); 3794–801. ©2017 AACR.