Human PODXL blocking peptide

Background: Urothelial bladder cancer (UBC) is a disease that often is discovered when the tumour is non-muscle invasive, i.e. in Ta or T1 stage. Some patients will progress into muscle-invasive disease, a potentially deadly condition. Although there are some prognostic models, the need for prognostic and predictive biomarkers is considerate and urgent. Membranous expression of podocalyxin-like protein 1 (PODXL) and low expression of the RNA-binding motif 3 (RBM3) has previously been shown to be associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer, including UBC. In this study, we sought to validate the prognostic impact of PODXL and RBM3 in an independent cohort of UBC. Methods: Using tissue microarrays and immunohistochemistry, PODXL and RBM3 expression was evaluated in 272 incident UBC cases from the prospective, population-based cohort study Malmo Diet and Cancer. Kaplan-Meier analysis and Cox proportional hazards modelling were used to evaluate the prognostic impact of these markers on 5-year overall survival (OS). Results: In line with previous studies, both membranous PODXL expression and low RBM3 expression was significantly associated with disadvantageous clinicopathological features. Membranous PODXL expression was significantly associated with a reduced 5-year overall survival in the entire cohort (univariable HR 3.28; 95% CI 1.89-5.69), but this association did not remain significant in multivariable analysis. In T1 tumours, PODXL was significantly associated with reduced survival in univariable analysis (HR = 2.83; 95% CI 1.04-7.72) and borderline significant in multivariable analysis (HR = 2.60; 95% CI 0.91-7.39). Low RBM3 expression was an independent predictor of a reduced survival in the entire cohort (univariable HR 3.19; 95% CI 2.02-5.04, and multivariable HR 1.85; 95% CI 1.11-3.09), and in T1 tumours (univariable HR 2.64; 95% CI 1.11-6.27, and multivariable HR 2.63; 95% CI 1.01-6.84). Conclusions: A link between membranous PODXL expression and clinically more aggressive tumours was further confirmed, but PODXL expression was not an independent prognostic biomarker in this study. Low RBM3 expression was validated as an independent factor of poor prognosis in UBC, including T1 disease. These findings suggest that these biomarkers could be useful in stratifying patients with non-muscle invasive disease for more aggressive first line treatment.

Background: Increased neutrophil infiltration and the ensuing inflammatory response represent a hallmark event in cardiac ischemia-reperfusion injury (IRI). It remains poorly defined how the epigenetic machinery contributes to this process. Methods and results: Here we report that mice with endothelial specific deletion of brahma related gene 1 (BRG1), a chromatin remodeling protein, exhibited amelioration when subjected to cardiac ischemia-reperfusion as evidenced by a reduction in infarct size as well as better recovery of heart function. Endothelial BRG1 deficiency also attenuated cardiac fibrosis following IRI when compared to wild type littermates. Interestingly, ablation of BRG1 in the endothelium suppressed neutrophil infiltration and down-regulated the levels of proinflammatory mediators in the heart following IRI. Further studies revealed that BRG1 activated the transcription of PODOCALYXIN (PODXL), an L-SELECTIN ligand crucial for neutrophil adhesion, in vascular endothelial cells in response to hypoxia-reoxygenation (HR). BRG1 knockdown by small interfering RNA abrogated HR-induced PODXL expression and blocked the adhesion of neutrophils to endothelial cells. Mechanistically, BRG1 alters the chromatin structure surrounding the PODXL promoter by interacting with JMJD2B, a histone H3K9 demethylase. Depletion of JMJD2B abrogated PODXL induction by HR and inhibited the adhesion of neutrophils to endothelial cells. Conclusion: Our data suggest that trans-activation of PODXL by the BRG1-JMJD2B complex in endothelial cells may promote neutrophil infiltration and consequently the pathogenesis of cardiac ischemia-reperfusion injury. (c) 2018 Published by Elsevier B.V.