Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1β in Cellular and Animal Infection Models

LasB elastase is a broad-spectrum exoprotease and a key virulence factor of Pseudomonas aeruginosa, a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1 beta. Furthermore, inhibition of LasBmediated IL-1 beta activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in P. aeruginosa infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen

SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Robots, automates et robomates en officine : état du marché français à fin 2008

Depuis qu'il est arrivé sur Terre, l'homme a toujours cherché à rendre son travail moins pénible. Au cours des siècles, il a utilisé tous les moyens à sa disposition pour imaginer des outils toujours plus performants. Grâce à l'électricité et à l'informatique, les machines sont omniprésentes dans notre vie quotidienne. L'apparition des automates et robots est récente dans la pharmacie d'officine. Aujourd'hui cinq fabricants se partagent un marché en phase de stabilisation. Les systèmes combinés ou robomates constituent les machines les plus polyvalentes. De plus, l'intervention humaine est de plus en plus restreinte depuis l'apparition des chargeurs automatiques. Une enquête réalisée auprès des pharmaciens montre que, malgré un investissement lourd, l'automatisation permet de gagner de la place, d'optimiser le backoffice et d'améliorer la qualité de dispensation en étant plus présent au comptoir. Soulagé de ses tâches matérielles, le pharmacien peut alors pleinement jouer son rôle de professionnel de santé.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Contribution à la modélisation de la décontamination par mousse liquide (étude expérimentale et théorique de l'écoulement de la mousse et du film liquide formé en paroi)

Parmi les techniques chimiques de décontamination, l'utilisation de mousses humides est particulièrement intéressante car elle permet de réduire la quantité de réactifs et le volume d'effluents. L'amélioration de ce procédé passe par une meilleure connaissance du comportement de la mousse au contact de la paroi à nettoyer. Notre travail s'est orienté vers la caractérisation de la mousse et du film liquide formé sur la paroi d'une part, et vers le développement d'un modèle de drainage permettant de guider le dimensionnement du procédé d'autre part. Des sondes à conductance affleurantes à la paroi ont été développées afin de déterminer l'épaisseur du film liquide pariétal et la fraction liquide de la mousse. L'influence de la présence de la mousse sur la structure du film et sur l'interprétation de la mesure d'épaisseur a été discutée. Le procédé étudié consiste à remplir progressivement l'enceinte de mousse, puis à la laisser reposer. Dans cette configuration, l'épaisseur du film est comprise entre quelques microns et 50 [mu]m et dépend de la position et du temps. De plus, cette épaisseur est fortement corrélée à la fraction liquide de la mousse. Par ailleurs, un modèle de dérive a été développé afin de décrire le drainage de la mousse en écoulement ascendant ou au repos. La résolution par la méthode des caractéristiques conduit à des solutions analytiques et permet de visualiser sur un simple graphique l'évolution de la fraction liquide. Les paramètres de la relation de fermeture ont été déterminés expérimentalement. La confrontation avec les expériences a montré que le modèle est bien adapté. Le laboratoire dispose désormais d'un outil expérimental et théorique lui permettant d'étudier tout type de mousse. Enfin, le modèle a été appliqué à quelques exemples de dimensionnement afin d'expliciter la démarche à adopter.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Structure, Formation, and Dynamics of Mo12 and Mo16 Oxothiomolybdenum Rings Containing Terephtalate Derivatives

International audienceThe influence of rigid orsemirigid dicarboxylate anions,terephtalate (TerP2),isophtalate (IsoP2),and phenylenediacetate (PDA2) on the self-condensation process of the {Mo2O2S2]2+ dioxothio cation has been investigated. Three new molybdenum rings,[Mo 12O12S12(OH)) have been isolated and unambiguously characterized in the solid state by single-crystal X-ray studies and in solution by various NMR methods and especially by diffusion- correlated NMR (1H DOSY) spectroscopy,which was shown to be a powerful tool for the characterization and speciation of templated molybdenum ring systems in solution. Characterization by FT-IR and elemental analysis are also reported. The dynamicand thermodynamic properties of both the sixteen-membered rings were studied in aqueous medium. Specific anddistinct behaviors were revealed for each system. The IsoP2/ACHTUNGTRENUNG[Mo2O2S2]2+ system gave rise to equilibrium,involving mono-templated [Mo12IsoP]2 and bis-templated [Mo(IsoP)2]4 ions.Thermodynamic parameters have been determined and showed that the driving- force for the formation of the[Mo16(IsoP)2]4 is entropically governed. However,whatever the conditions (temperature,proportio n of reactants),the PDA2/[Mo2O2S2]2+ system led only to a single compound,the [Mo16ACHTUNGTRENUNG(PDA)2]4 ion. The latter exhibits dynamic behavior,consisten t with the gliding of both the stacked aromatic groups. Stability and dynamics of both Mo16 rings was related to weak hydrophobic or pi–pi stacking inter-template interactions and inner hydrogen-bondnetwork occurring within the [Mo16(IsoP)2]4 and [Mo16ACHTUNGTRENUNG(PDA)2]4 ions

Early metabolic response of breast cancer to neoadjuvant endocrine therapy: Comparison to morphological and pathological response

International audienceBackground: Neoadjuvant endocrine therapy (NET) has shown efficacy in terms of clinical response and surgical outcome in postmenopausal patients with estrogen receptor-positive / HER2-negative breast cancer (ER+/HER2- BC) but monitoring of tumor response is challenging. The aim of the present study was to investigate the value of an early metabolic response compared to morphological and pathological responses in this population. Methods: This was an ancillary study of CARMINA 02, a phase II clinical trial evaluating side-by-side the efficacy of 4 to 6 months of anastrozole or fulvestrant. Positron Emission Tomography/Computed Tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) scans were performed at baseline (M0), early after 1 month of treatment (M1) and pre-operatively in 11 patients (74.2 yo ± 3.6). Patients were classified as early "metabolic responders" (mR) when the decrease of SUVmax was higher than 40%, and "metabolic non-responders" (mNR) otherwise. Early metabolic response was compared to morphological response (palpation, US and MRI), variation of Ki-67 index, pathological response according to the Sataloff classification and also to Preoperative Endocrine Prognostic Index (PEPI) score. It was also correlated with overall survival (OS) and recurrence-free survival (RFS). Results: Tumor size measured on US and on MRI was smaller in mR than mNR, with the highest statistically significant difference at M1 (p = 0.01 and 7.1 × 10- 5, respectively). No statistically significant difference in the variation of tumor size between M0 and M1 assessed on US or MRI was observed between mR and mNR. mR had a better clinical response: no progressive disease in mR vs 2 in mNR and 2 partial response in mR vs 1 partial response in mNR. One patient with a pre-operative complete metabolic response had the best pathological response. Pathological response did not show any statistically significant difference between mR and mNR. mR had better OS and RFS (Kaplan-Meier p = 0.08 and 0.06, respectively). All cancer-related events occurred in mNR: 3 patients died, 2 of them from progressive disease. Conclusions: FDG-PET/CT imaging could become a "surrogate marker" to monitor tumor response, especially as NET is a valuable treatment option in postmenopausal women with ER+/HER2- BC

Heparan sulphate saccharides modify focal adhesions: Implication in mucopolysaccharidosis neuropathophysiology.

International audienceMucopolysaccharidoses type III (MPSIII, Sanfilippo syndrome) are genetic diseases due to deficient heparan sulphate saccharide digestion by lysosomal exoglycanases. Progressive accumulation of undigested saccharides causes early onset behavioural and cognitive symptoms. The precise role of these saccharides in the pathophysiological cascade is still unclear. We showed that exposure of wild type neural cells to exogenous soluble heparan sulphate fragments of at least eight saccharides activated integrin-based focal adhesions, which attach cells to the extracellular matrix. Focal adhesions were constitutively activated in MPSIII type B astrocytes or neural stem cells unless undigested saccharides were cleared by exogenous supply of the missing exoglycanase. Defective cell polarisation and oriented migration in response to focal extracellular stimuli in affected cells suggest improper sensing of the environment. We consistently observed abnormal organisation of the rostral migratory stream in the brain of adult mice with MPSIII type B. These results suggest that cell polarisation and oriented migration defects participate to the neurological disorders associated with Sanfilippo syndrome