Bindarit inhibits human coronary artery smooth muscle cell proliferation, migration and phenotypic switching

Bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs) synthesis, reduces neointimal formation in animal models of vascular injury and recently has been shown to inhibit in-stent late loss in a placebo-controlled phase II clinical trial. However, the mechanisms underlying the efficacy of bindarit in controlling neointimal formation/restenosis have not been fully elucidated. Therefore, we investigated the effect of bindarit on human coronary smooth muscle cells activation, drawing attention to the phenotypic modulation process, focusing on contractile proteins expression as well as proliferation and migration. The expression of contractile proteins was evaluated by western blot analysis on cultured human coronary smooth muscle cells stimulated with TNF-α (30 ng/mL) or fetal bovine serum (5%). Bindarit (100-300 µM) reduced the embryonic form of smooth muscle myosin heavy chain while increased smooth muscle α-actin and calponin in both TNF-α- and fetal bovine serum-stimulated cells. These effects were associated with the inhibition of human coronary smooth muscle cell proliferation/migration and both MCP-1 and MCP-3 production. The effect of bindarit on smooth muscle cells phenotypic switching was confirmed in vivo in the rat balloon angioplasty model. Bindarit (200 mg/Kg/day) significantly reduced the expression of the embryonic form of smooth muscle myosin heavy chain, and increased smooth muscle α-actin and calponin in the rat carodid arteries subjected to endothelial denudation. Our results demonstrate that bindarit induces the differentiated state of human coronary smooth muscle cells, suggesting a novel underlying mechanisms by which this drug inhibits neointimal formation

Mean field and corrections for the Euclidean Minimum Matching problem

Consider the length $L_{MM}^E$ of the minimum matching of N points in d-dimensional Euclidean space. Using numerical simulations and the finite size scaling law $= \beta_{MM}^E(d) N^{1-1/d}(1+A/N+... )$, we obtain precise estimates of $\beta_{MM}^E(d)$ for $2 \le d \le 10$. We then consider the approximation where distance correlations are neglected. This model is solvable and gives at $d \ge 2$ an excellent ``random link'' approximation to $\beta_{MM}^E(d)$. Incorporation of three-link correlations further improves the accuracy, leading to a relative error of 0.4% at d=2 and 3. Finally, the large d behavior of this expansion in link correlations is discussed.Comment: source and one figure. Submitted to PR

Devenir, former, recruter un géomaticien : Petit guide pratique de la géomatique à destination des employeurs, des candidats et des formateurs

Document pdf disponible sur le site de l'AFIGEOPublié à l'occasion du Colloque national " Métiers et compétences en géomatique : des formations aux emplois " le 14 novembre 2013 au CNAM, ce guide est le fruit d'une réflexion collective menée au sein du Pôle Formation-Recherche de l'AFIGEO. S'appuyant sur de nombreuses ressources (issues des résultats d'une enquête métier réalisée en 2013 avec GeoRezo et le GDR Magis, d'analyse de fiches de poste, de l'observatoire des GeoFormations, de la démarche de reconnaissance des métiers), il s'organise autour de 4 chapitres : - QU'EST-CE QUE LA GEOMATIQUE ? - A QUOI SERT UN GEOMATICIEN ? - SE FORMER A LA GEOMATIQUE ? - RECRUTER UN GEOMATICIEN ? En s'adressant aux étudiants, formateurs, recruteurs, géomaticiens débutants ou plus expérimentés, ce guide vise à apporter un éclairage pédagogique, concret sur le vaste monde de la géomatique, sur les spécificités des compétences, des métiers et des formations associés. Pour recevoir la version numérique du Guide, nous vous remercions de compléter le formulaire de demande suivant : https://docs.google.com/forms/d/1MYxjzslEeLd4VwsdOKwtxJyZwVLaLNv7d_lBj_mPGlM/viewfor

The cavity method for large deviations

A method is introduced for studying large deviations in the context of statistical physics of disordered systems. The approach, based on an extension of the cavity method to atypical realizations of the quenched disorder, allows us to compute exponentially small probabilities (rate functions) over different classes of random graphs. It is illustrated with two combinatorial optimization problems, the vertex-cover and coloring problems, for which the presence of replica symmetry breaking phases is taken into account. Applications include the analysis of models on adaptive graph structures.Comment: 18 pages, 7 figure

Prospective, observational, multicenter study on minimally invasive gastrectomy for gastric cancer: robotic, laparoscopic and open surgery compared on operative and follow-up outcomes - IMIGASTRIC II study protocol: IMIGASTRIC II

Background:Several meta-analyses have tried to defi ne the role of minimally invasive approaches. However, further evidence to get a wider spread of these methods is necessary. Current studies describe minimally invasive surgery as a possible alternative to open surgery but deserving further clarifi cation. However, despite the increasing interest, the difficulty of planning prospective studies of adequate size accounts for the low level of evidence, which is mostly based on retrospective experiences.A multi-institutional prospective study allows the collection of an impressive amount of data to investigate various aspects of minimally invasive procedures with the opportunity of developing several subgroup analyses.A prospective data collection with high methodological quality on minimally invasive and open gastrectomies can clarify the role of diff erent procedures with the aim to develop specifi c guidelines.Methods and analysis:a multi-institutional prospective database will be established including information on surgical, clinical and oncological features of patients treated for gastric cancer with robotic, laparoscopic or open approaches and subsequent follow-up.The study has been shared by the members of the International study group on Minimally Invasive surgery for GASTRIc Cancer (IMIGASTRIC)The database is designed to be an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centers.Ethics:This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevantlaws/regulations.Trial registration number:NCT0275108

Coxiella burnetii, the Agent of Q Fever, Replicates within Trophoblasts and Induces a Unique Transcriptional Response

Q fever is a zoonosis caused by Coxiella burnetii, an obligate intracellular bacterium typically found in myeloid cells. The infection is a source of severe obstetrical complications in humans and cattle and can undergo chronic evolution in a minority of pregnant women. Because C. burnetii is found in the placentas of aborted fetuses, we investigated the possibility that it could infect trophoblasts. Here, we show that C. burnetii infected and replicated in BeWo trophoblasts within phagolysosomes. Using pangenomic microarrays, we found that C. burnetii induced a specific transcriptomic program. This program was associated with the modulation of inflammatory responses that were shared with inflammatory agonists, such as TNF, and more specific responses involving genes related to pregnancy development, including EGR-1 and NDGR1. In addition, C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways, which both modulate STAT3. Taken together, these results revealed that trophoblasts represent a protective niche for C. burnetii. The activation program induced by C. burnetii in trophoblasts may allow bacterial replication but seems unable to interfere with the development of normal pregnancy. Such pathophysiologocal processes should require the activation of immune placental cells associated with trophoblasts

Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force

BackgroundNeuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma.MethodsThe International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force.ResultsGuidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation.ConclusionsMetaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy

New Frontiers-class Uranus Orbiter: Exploring the feasibility of achieving multidisciplinary science with a mid-scale mission

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Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis