A new potential anti-cancer beta-carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation

Gliomas remain highly fatal due to their high resistance to current therapies. Deregulation of protein synthesis contributes to cancer onset and progression and is a source of rising interest for new drugs. CM16, a harmine derivative with predicted high blood–brain barrier penetration, exerts antiproliferative effects partly through translation inhibition. We evaluated herein how CM16 alters the proteome of glioma cells. The analysis of the gel-free LC/MS and auto-MS/MS data showed that CM16 induces time- and concentration-dependent significant changes in the total ion current chromatograms. In addition, we observed spontaneous clustering of the samples according to their treatment condition and their proper classification by unsupervised and supervised analyses, respectively. A two-dimensional gel-based approach analysis allowed us to identify that treatment with CM16 may downregulate four key proteins involved in glioma aggressiveness and associated with poor patient survival (HspB1, BTF3, PGAM1, and cofilin), while it may upregulate galectin-1 and Ebp1. Consistently with the protein synthesis inhibition properties of CM16, HspB1, Ebp1, and BTF3 exert known roles in protein synthesis. In conclusion, the downregulation of HspB1, BTF3, PGAM1 and cofilin bring new insights in CM16 antiproliferative effects, further supporting CM16 as an interesting protein synthesis inhibitor to combat glioma.     

Three-dimensional visual guidance improves the accuracy of calculating right ventricular volume with two-dimensional echocardiography.

Three-dimensional guidance programs have been shown to increase the reproducibility of 2-dimensional (2D) left ventricular volume calculations, but these systems have not been tested in 2D measurements of the right ventricle. Using magnetic fields to identify the probe location, we developed a new 3-dimensional guidance system that displays the line of intersection, the plane of intersection, and the numeric angle of intersection between the current image plane and previously saved scout views. When used by both an experienced and an inexperienced sonographer, this guidance system increases the accuracy of the 2D right ventricular volume measurements using a monoplane pyramidal model. Furthermore, a reconstruction of the right ventricle, with a computed volume similar to the calculated 2D volume, can be displayed quickly by tracing a few anatomic structures on 2D scans.     

Local delivery of mutant CCL2 protein‐reduced orthopaedic implant wear particle‐induced osteolysis and inflammation in vivo

Total joint replacement (TJR) has been widely used as a standard treatment for late‐stage arthritis. One challenge for long‐term efficacy of TJR is the generation of ultra‐high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle‐induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle‐induced osteolysis and the effects of 7ND treatment were evaluated using micro‐CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle‐induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle‐induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:58–64, 2016.     

Acute systemic inflammation induces central mitochondrial damage and mnesic deficit in adult Swiss mice

The aim of this study was to investigate how the brain is affected during systemic inflammation. For this purpose, Swiss mice were challenged with a single intraperitoneal dose of lipopolysaccharide (LPS; 250microg/mouse) to mimic aspects of systemic infection. Spatial learning in Y-maze test demonstrated a differential learning profile during the training test between control and LPS-treated mice, with an alteration in the latter group. We show that systemic LPS-induced inflammation and oxidative injury as assessed by reactive oxygen species (ROS) and nitrites/nitrates (NOx) production associated with reduced glutathione (GSH) depletion, cyclooxygenase-2 (COX-2) expression, and lipid peroxidation. LPS also induced a loss in mitochondrial integrity as shown by a significant decrease in membrane potential and impairment in mitochondrial redox activity. Thus, peripheral inflammation by producing brain inflammation and oxidative injury causes mnesic deficits. It remains to determine whether such events can induce neuronal dysfunction/degeneration and, with time, lead to cholinergic deficiency, amyloid deposits and cognitive impairments as they occur in Alzheimer's disease.     

Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice

Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-beta (A beta) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyperphosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged A beta-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged tau-depositing B6/P301L transgenic mice were infused. To further study A beta-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although A beta deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high A beta plaque load. The present results suggest that both extract-derived A beta species and deposited fibrillary A beta can induce the formation of tau neurofibrillary pathology. The observation that infused A beta can trigger the tau pathology in the absence of A beta deposits provides an explanation for the discrepancy between the neuroanatomical location of A beta deposits and the development and spreading of tau lesions in Alzheimer's disease brain.     

Prise en charge d’un patient adulte atteint de mucoviscidose

The authors describe the case report of a patient with cystic fibrosis. The nutritional management is discussed during the different stages of disease treatment and progression.     

Use of a case-mix approach to study the trends in the incidence of second primary cancers

Purpose

To analyze trends in second primary cancer (SPC) incidence by using a case-mix approach to standardize on first cancer site distribution.

Cost of rheumatoid arthritis in france: comparison leflunomide/etanercept

Treatment of rheumatoid arthritis was deeply modified with the availability since 1999 of anti-TNFalpha. The clinical superiority of these drugs compared to traditional treatments is proven, but can one make the assumption that the cost of these innovative treatments is partially compensated by a reduction of consumption of other health resources? A retrospective observational study was carried out in the Midi-Pyrenees area, from the point of view of health insurance, to compare the consumed health resources between two cohorts of patients, one treated by etanercept (Enbrel) and the other by leflunomide (Arava). Two hundred and fifty three patients were included in the etanercept cohort and 539 in the leflunomide cohort. The average annual PR cost for a patient treated with etanercept is 13 936 euro and 5 764 euro for a patient treated with leflunomide. The health costs avoided by recourse to etanercept do not compensate the high cost of this drug.