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Plan-les-Ouates, Switzerland

Odolczyk N.,Polish Academy of Sciences | Fritsch J.,French Institute of Health and Medical Research | Fritsch J.,University of Paris Descartes | Norez C.,University of Poitiers | And 28 more authors.
EMBO Molecular Medicine | Year: 2013

The deletion of Phe508 (ΔF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The ΔF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between ΔF508-NBD1 and housekeeping proteins prevents ΔF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to ΔF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of ΔF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous ΔF508-CFTR mice. The proposed compounds disrupt keratin8-ΔF508-CFTR interaction in ΔF508-CFTR HeLa cells. Structural analysis of ΔF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of ΔF508-CFTR trafficking defect known to date. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. Source


Lupo J.,University Hospital of Grenoble | Lupo J.,French National Center for Scientific Research | Schuffenecker I.,French National Enterovirus Parechovirus Reference Center | Morel-Baccard C.,University Hospital of Grenoble | And 10 more authors.
Journal of Clinical Microbiology | Year: 2015

We report a fatal case of acute lower respiratory tract disease with human rhinovirus C (HRV-C) as the unique cause in a 19- month-old girl with a history of repeated episodes of bronchiolitis. HRV-C type 8 nucleic acids were observed in respiratory, stool, and cerebrospinal fluid samples, and infectious virions were isolated from patient serum after inoculation onto reconstituted airway epithelia. Copyright © 2015, American Society for Microbiology. All Rights Reserved. Source


Behrsing H.,Institute for in Vitro science Inc. | Raabe H.,Institute for in Vitro science Inc. | Manuppello J.,PETA International Science Consortium Ltd. | Bombick B.,R.J. Reynolds Tobacco Company | And 17 more authors.
ATLA Alternatives to Laboratory Animals | Year: 2016

The Family Smoking Prevention and Tobacco Control Act of 2009 established the Food and Drug Administration Center for Tobacco Products (FDA-CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 8-10 December 2014, IIVS organised a workshop conference, entitled Assessment of In Vitro COPD Models for Tobacco Regulatory Science, to bring together stakeholders representing regulatory agencies, academia, industry and animal protection, to address the research priorities articulated by the FDA-CTP. Specific topics were covered to assess the status of current in vitro technologies as they are applied to understanding the adverse pulmonary events resulting from tobacco product exposure, and in particular, the progression of chronic obstructive pulmonary disease (COPD). The four topics covered were: a) Inflammation and Oxidative Stress; b) Ciliary Dysfunction and Ion Transport; c) Goblet Cell Hyperplasia and Mucus Production; and d) Parenchymal/Bronchial Tissue Destruction and Remodelling. The 2.5 day workshop included 18 expert speakers, plus poster sessions, networking and breakout sessions, which identified key findings and provided recommendations to advance the in vitro technologies and assays used to evaluate tobaccoinduced disease etiologies. The workshop summary was reported at the 2015 Society of Toxicology Annual Meeting, and the recommendations led to an IIVS-organised technical workshop in June 2015, entitled Goblet Cell Hyperplasia, Mucus Production, and Ciliary Beating Assays, to assess these assays and to conduct a proof-of-principle multi-laboratory exercise to determine their suitability for standardisation. Here, we report on the proceedings, recommendations and outcomes of the December 2014 workshop, including paths forward to continue the development of non-animal methods to evaluate tissue responses that model the disease processes that may lead to COPD, a major cause of mortality worldwide. Source


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: NMP.2011.2.2-2 | Award Amount: 4.09M | Year: 2012

Lung cancer is the most common cancer in terms of both incidence and mortality, worldwide. With a median age at diagnosis of 71, lung cancer is mainly affecting the aging population. Airway stenosis is a key problem with significant morbidity and premature death. Endobronchial stenting is a proven therapy to keep the airways open. Nevertheless the currently used clinical stents have major disadvantages either by rapid re-occlusion due to tumour ingrowths (metal stents) or massive mucus retention due to the interrupted mucociliary function (coated stents). The aim of the project is to develop a viable endobronchial stent (syn. PulmoStent) for the treatment of broncho-tracheal cancer diseases. The concept is based on the combination of stent technologies with the principles of tissue engineering. The PulmoStent is a multi-layered structure providing (1) a functional respiratory epithelium on the luminal side, which allows the maintenance of the mucociliary function in the stented area, (2) an embedded micro- or nanosphere formulations, enabling the sustained, local release of tumour-specific therapeutics in combination with (3) a mechanical separating layer on the external side, enabling a local tumour suppression to avoid stent displacement and restenosis by a growing tumour. The PulmoStent is a step change beyond the state-of-the-art from a passive to a viable and functional active implant tailored to the patient. It focuses on a clearly identified clinical need for the treatment of lung cancer. The combination of different kinds of biomaterials to a co-scaffold system for the bio-functionalization of the stent will lead to an improved performance of endobronchial stents and thereby to longer durability. The novel PulmoStent will improve the quality of life and increase the life expectancy of lung cancer patients, because of the reduced mucus retention in the stented area, and herewith the reduced risk of life-threatening pneumonia and the local tumour suppression.


Dechecchi M.C.,University of Verona | Nicolis E.,University of Verona | Mazzi P.,University of Verona | Cioffi F.,University of Verona | And 8 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2011

The investigation of novel targets for the treatment of cystic fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistent with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in mice and patients with CF, SLs were identified as targets for treating pulmonary disorders, including CF. Because miglustat, an inhibitor of the synthesis of glycosphingolipids, reduces the Pseudomonas aeruginosa-dependent transcription of the IL-8 gene in bronchial cells, we examined the effects of miglustat and amitriptyline, another drug affecting ceramide metabolism, on the expression of 92 genes implicated in host immune defense. Infection with the P. aeruginosa strain PAO1 up-modulated the expression of 14 (27%) genes in IB3-1 cells and 15 (29%) genes in CF primary respiratory epithelia grown at an air-liquid interface, including chemokines (IL-8, growth-regulated Gro-α/β/ γ proteins, and granulocyte chemotactic peptide-2 [GCP-2]), proinflammatory cytokines (IL-1α/β, IL-6, and TNF-α), and the intercellular adhesion molecule-1, nuclear factor kB1, toll like receptor 2, and human defensin B4 genes, confirming that bronchial epithelium is an important source of inflammatory mediators. Both miglustat and amitriptyline reduced the immune response, an effect that paralleled a decrease in the P. aeruginosa-induced accumulation of ceramide. Miglustat (100mg/kg), given to C57BL/6 mice once daily for a period of 3 consecutive days before lipopolysaccharide (LPS) challenge, strongly reduced the number of neutrophils recruited in the airways and the expression of the keratinocyte-derived chemokine in lung extracts. Collectively, these results indicate that targeting the metabolism of SLs can down-modulate the recruitment of neutrophils into the lung. Source

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