Citations

Background —Risks of coronary artery bypass graft surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA) may be different in the presence of peripheral vascular disease (PVD). Methods and Results —We analyzed outcomes of 550 patients with PVD enrolled in the Bypass Angioplasty Revascularization Investigation randomized trial and registry. Compared with 1770 patients without PVD, those with PVD were older and had a greater prevalence of medical comorbid conditions. No significant differences in coronary anatomy or PTCA success rates were found. The risk of any major complication (death, myocardial infarction, stroke, coma, or emergency revascularization) after PTCA was significantly higher among patients with PVD (11.7% versus 7.8%, P =0.027). In multivariate analysis, this represented a 50% increase in the odds of having any major complication (multivariate odds ratio, 1.5; P =0.032). Among patients undergoing CABG, the risk of major complications was found to be markedly higher for patients with PVD (12%) than those without (6.1%, P =0.003) even after controlling for baseline differences (multivariate odds ratio, 1.8; P =0.018). Major differences between the PTCA and CABG groups were related primarily to a higher risk of neurological complications in PVD patients who had CABG (multivariate odds ratio, 2.8; P <0.001). Conclusions —We conclude that patients with PVD are at high risk for periprocedural complications after myocardial revascularization, in particular neurological events.

AbstractVEGF induces vascular permeability (VP) in ischemic diseases and cancer, leading to many pathophysiological consequences. The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood and in vivo models that easily facilitate real-time, genetic studies of VP do not exist. In the present study, we report a heat-inducible VEGF transgenic zebrafish (Danio rerio) model through which VP can be monitored in real time. Using this approach with morpholino-mediated gene knock-down and knockout mice, we describe a novel role of phospholipase Cβ3 as a negative regulator of VEGF-mediated VP by regulating intracellular Ca2+ release. Our results suggest an important effect of PLCβ3 on VP and provide a new model with which to identify genetic regulators of VP crucial to several disease processes.

Abstract Purpose: The therapeutic benefit of temozolomide in glioblastoma multiforme (GBM) is limited by resistance. The goal of this study was to elucidate mechanisms of temozolomide resistance in GBM. Experimental Design: We developed an in vivo GBM model of temozolomide resistance and used paired parental and temozolomide-resistant tumors to define the mechanisms underlying the development of resistance and the influence of histone deacetylation (HDAC) inhibition. Results: Analysis of paired parental and resistant lines showed upregulation of O6-methylguanine-DNA methyltransferase (MGMT) expression in 3 of the 5 resistant xenografts. While no significant change was detected in MGMT promoter methylation between parental and derivative-resistant samples, chromatin immunoprecipitation showed an association between MGMT upregulation and elevated acetylation of lysine 9 of histone H3 (H3K9-ac) and decreased dimethylation (H3K9-me2) in GBM12 and GBM14. In contrast, temozolomide resistance development in GBM22 was not linked to MGMT expression, and both parental and resistant lines had low H3K9-ac and high H3K9-me2 within the MGMT promoter. In the GBM12TMZ-resistant line, MGMT reexpression was accompanied by increased recruitment of SP1, C-JUN, NF-κB, and p300 within the MGMT promoter. Interestingly, combined treatment of GBM12 flank xenografts with temozolomide and the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) favored the evolution of temozolomide resistance by MGMT overexpression as compared with treatment with temozolomide alone. Conclusion: This study shows, for the first time, a unique mechanism of temozolomide resistance development driven by chromatin-mediated MGMT upregulation and highlights the potential for epigenetically directed therapies to influence the mechanisms of resistance development in GBM. Clin Cancer Res; 18(15); 4070–9. ©2012 AACR.

Abstract Rationale The immune response in sepsis is characterized by overt immune dysfunction. Studies indicate immunostimulation represents a viable therapy for patients. One study suggests a potentially protective role for interleukin 5 (IL-5) in sepsis; however, the loss of eosinophils in this disease presents a paradox. Objectives To assess the protective and eosinophil-independent effects of IL-5 in sepsis. Methods We assessed the effects of IL-5 administration on survival, bacterial burden, and cytokine production after polymicrobial sepsis. In addition, we examined the effects on macrophage phagocytosis and survival using fluorescence microscopy and flow cytometry. Measurements and Main Results Loss of IL-5 increased mortality and tissue damage in the lung, IL-6 and IL-10 production, and bacterial burden during sepsis. Therapeutic administration of IL-5 improved mortality in sepsis. Interestingly, IL-5 administration resulted in neutrophil recruitment in vivo. IL-5 overexpression in the absence of eosinophils resulted in decreased mortality from sepsis and increased circulating neutrophils and monocytes, suggesting their importance in the protective effects of IL-5. Furthermore, novel data demonstrate IL-5 receptor expression on neutrophils and monocytes in sepsis. IL-5 augmented cytokine secretion, activation, phagocytosis, and survival of macrophages. Importantly, macrophage depletion before the onset of sepsis eliminated IL-5–mediated protection. The protective effects of IL-5 were confirmed in humans, where IL-5 levels were elevated in patients with sepsis. Moreover, neutrophils and monocytes from patients expressed the IL-5 receptor. Conclusions Taken together, these data support a novel role for IL-5 on noneosinophilic myeloid populations, and suggest treatment with IL-5 may be a viable therapy for sepsis.