304Nuclear targeting apelin induces phenotypic transition of vascular smooth muscle cells

Background: Apelin, and its receptor APJ, are a peptidic system playing a crucial role in vascular diseases. However, the role of apelin in atherogenesis and smooth muscle cell (SMC) proliferation remains unclear. We isolated 2 distinct SMC phenotypes from porcine coronary artery: spindle-shaped (S) and rhomboid (R). Biological features of R-SMCs (i.e. enhanced proliferative and migratory activities as well as poor level of differentiation) explain their capacity to accumulate into the intima. S100A4 is a marker of R-SMCs in vitro and of intimal SMCs, both in pig and human. S100A4 is a Ca2+-binding protein that can also be secreted; it has extracellular functions probably via the receptor for advanced glycation end products (RAGE). Purpose: Investigate the effects of apelin on SMC phenotypic transition and S100A4 expression and release. Methods and Results: We observed that apelin was highly expressed in R-SMCs particularly in their nucleus. P-SORT software analysis of preproapelin sequence suggested that N-terminal truncated apelin may target the nucleus, and we confirmed this in SMCs by overexpression of mutated preproapelin-His-tag. Transfection of mutated preproapelin-His-tag encoding plasmid in differentiated S-SMCs induced a transition towards a R-phenotype associated with increased proliferative activity, downregulation of SMC differentiation markers (i.e. alpha-smooth muscle actin), and increased nuclear expression and release of S100A4. In contrast, transfection of S-SMCs with wild type preproapelin-His-tag encoding plasmid did not induce nuclear targeting of Apelin or S100A4, and did not change the S-phenotype. Stimulation of S-SMCs with PDGF-BB, known to induce a transition to the R-phenotype, yielded nuclear targeting of both apelin and S100A4. In vivo, Apelin was expressed in SMC nuclei of stent-induced intimal thickening while its expression in the media was mainly cytoplasmic. Conclusions: Our results suggest that nuclear targeting of apelin in SMCs acts on S100A4 expression and release, cell proliferation and differentiation. The pathophysiological consequences of this retargeting could be instrumental in the understanding of artherosclerosi

Processing of functional fine scale ceramic structures by ink-jet printing

International audienceThis review illustrates the potentiality of ink-jet printing for the fabrication of functional fine scale ceramic structures corresponding to two different kinds of micro-pillar arrays i.e. (i) PZT skeletons, etc..

An adult cystic fibrosis patient presenting with persistent dyspnea: case report

BACKGROUND: Persistent dyspnea is a common finding in the cystic fibrosis patient that typically leads to further work up of an alternative pulmonary etiology. Adult cystic fibrosis patients; however, are growing in numbers and they are living into the ages in which coronary artery disease becomes prevalent. Coronary disease should be included in the consideration of diagnostic possibilities. CASE PRESENTATION: A 52-year-old white male with cystic fibrosis was evaluated for exertional dyspnea associated with vague chest discomfort. Diagnostic testing revealed normal white blood cell, hemoglobin and platelet count, basic metabolic panel, fasting lipid profile, HbA1c, with chest radiograph confirming chronic cystic findings unchanged from prior radiographs and an electrocardiogram that revealed sinus rhythm with left anterior fascicular block. Stress thallium testing demonstrated a reversible anteroseptal perfusion defect with a 55% left ventricular ejection fraction. Heart catheterization found a 99% occlusion of the left anterior descending artery extending into the two diagonal branches, with 100% obstruction of the left anterior descending artery at the trifurcation and 70% lesion affecting the first posterior lateral branch of the circumflex artery. CONCLUSION: This case report represents the first description in the medical literature of a cystic fibrosis patient diagnosed with symptomatic coronary artery disease. Applying a standard clinical practice guide proved useful toward evaluating a differential diagnosis for a cystic fibrosis patient presenting with dyspnea and chest discomfort

Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors

Introduction: Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs).Methods: A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated.Results: Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively).Conclusion: Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival. (C) 2019 Elsevier Ltd. All rights reserved.</p

derived neutrophil to lymphocyte ratio dnlr change between baseline and cycle 2 is correlated with benefit during immune checkpoint inhibitors ici in advanced non small cell lung cancer nsclc patients

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Parameter Estimation for Personalization of Liver Tumor Radiofrequency Ablation

International audienceMathematical modeling has the potential to assist radiofrequency ablation (RFA) of tumors as it enables prediction of the extent of ablation. However, the accuracy of the simulation is challenged by the material properties since they are patient-specific, temperature and space dependent. In this paper, we present a framework for patient specific radiofrequency ablation modeling of multiple lesions in the case of metastatic diseases. The proposed forward model is based upon a computational model of heat diffusion, cellular necrosis and blood flow through vessels and liver which relies on patient images. We estimate the most sensitive material parameters, those need to be personalized from the available clinical imaging and data. The selected parameters are then estimated using inverse modeling such that the point to-mesh distance between the computed necrotic area and observed lesions is minimized. Based on the personalized parameters, the ablation of the remaining lesions are predicted. The framework is applied to a dataset of seven lesions from three patients including pre- and post-operative CT images. In each case, the parameters were estimated on one tumor and RFA is simulated on the other tumor(s) using these personalized parameters, assuming the parameters to be spatially invariant within the same patient. Results showed significantly good correlation between predicted and actual ablation extent (average point-to-mesh errors of 4.03 mm)

Protamine is an antagonist of Apelin receptor, and its activity is reversed by heparin

In the accompanying Comment, Suzuki et al. confirmed our previous findings that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) does not functionally inhibit the NMDAR at concentrations relevant to its antidepressant actions recently reported in mice (that is, approximately 10 μM)