Factor VIII-von Willebrand Factor Complex Inhibits Osteoclastogenesis and Controls Cell Survival

Factor VIII-von Willebrand factor (FVIII·vWF) complex, a molecule involved in coagulation, can be physically associated with osteoprotegerin (OPG). OPG is an anti-osteoclastic protein and a soluble receptor for the proapoptotic protein TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), suggesting a potential role of FVIII·vWF complex in bone and cancer biology. We, thus, assessed the effects of FVIII·vWF complex on osteoclastogenesis and cell survival. We first evidenced that FVIII·vWF complex inhibited RANKL-induced osteoclastogenesis and enhanced the inhibitory effect of OPG. Interestingly, we revealed by surface plasmon resonance that FVIII·vWF complex bound to RANKL, whereas recombinant FVIII and vWF did not. By modeling, we showed that the OPG binding domain to the A1 domain of vWF was closely located and partially overlapped to its binding site to RANKL. Then, we demonstrated that FVIII·vWF complex cancelled the inhibitory activity of OPG on TRAIL-induced apoptosis and characterized interactions between these molecules. The present work evidenced a direct activity of FVIII·vWF complex on osteoclasts and on induced cell apoptosis, pointing out its potential involvement in physiological bone remodeling or in bone damages associated with severe hemophilia and cancer development

Photoredox process induced polymerization reactions: iridium complexes for panchromatic photo-initiating systems

International audienceThe photoredox catalysis applied to the field of polymers and more particularly to the design of photoinitiating systems is briefly reviewed. Two novel phenylisoquinoline-based iridium complexes with fluorine substituents (bis[5-fluoro-2-(1-isoquinolinyl-κN)phenyl-κC](2,2,6,6-tetramethyl-3,5-heptanedionato-κO3,κO5)-iridium (III) (Ir_b) and bis[3,5-difluoro-2-(1-isoquinolinyl-κN)phenyl-κC](2,2,6,6-tetramethyl-3,5-heptanedionato-κO3,κO5)-iridium (III) (Ir_c) are proposed as photoredox catalysts (also called photoinitiator catalysts) and incorporated into suitable photoinitiating systems for cationic and radical polymerization. (3,4-Epoxycyclohexane)methyl-3,4-epoxycyclohexylcarboxylate (EPOX) and trimethylolpropane triacrylate (TMPTA) were used as benchmark monomers for cationic and radical photopolymerization. These new catalysts are compared to our very recently proposed unsubstituted catalyst compound: bis[2-(1-isoquinolinyl-κN)phenyl-κC](2,2,6,6-tetramethyl-3,5-heptanedionato-κO3,κO5)-iridium (III) (Ir_a). Remarkably, these catalysts exhibit improved light absorption properties and are characterized by a panchromatic behavior which ensures the photosensitivity of the polymerizable films to blue, green and red lights. The photochemical properties as well as the chemical mechanisms associated with these catalysts are investigated by ESR spin-trapping, laser flash photolysis, steady state photolysis, cyclic voltammetry and luminescence experiments. The structure/reactivity relationships as well as the substitution effect (by the fluorine) are discusse

Microstructural evolution and mechanical properties of SnAgCu alloys

Lead containing solder paste is now considered as an environmental threat. In order to eliminate this undesirable environmental impact associated to their production, a family of lead-free solder joint, Sn-3.8Ag-0.7Cu, is proposed. Microstructural and mechanical data of this solder joint have been acquired and compared with the most common used SnPb solder paste. The evolution of the microstructure as well as the failure mode and the mechanical properties of SnAgCu solder joint are discussed as a function of strain rate, annealing treatments, and testing temperature. Tensile tests have been performed, at temperatures ranging from –50 to +150 °C, on bulk samples. Changes of the mechanical properties of bulk tested samples are actually correlated with microstructural changes, as shown by transmission electronic microscopy investigations

Structural Effects in the Iridium Complex Series: Photoredox Catalysis and Photoinitiation of Polymerization Reactions under Visible Lights

International audienceA series of 18 iridium complexes (Ir) have been prepared and studied. Their abilities to initiate both a ring-opening cationic polymerization (CP) using an Ir/iodonium salt couple and a free radical polymerization (FRP) in the presence of an Ir/amine/alkyl halide system under very soft irradiation (i.e., halogen lamp) or upon exposure to laser diodes @457 nm and @532 nm are investigated. Interestingly, these photoinitiating systems operate through an oxidative or a reductive photoredox catalytic cycle, respectively. Excellent polymerization profiles are obtained (reactive function conversions \\textgreater70% for the CP of an epoxide and \\textgreater60% for the FRP of low viscosity triacrylate). The photochemical mechanisms are studied by fluorescence, steady state photolysis, cyclic voltammetry, and electron spin resonance spin trapping experiments

The challenge of myeloma-related thromboembolic disease: can thrombin generation assay help physicians to better predict the thromboembolic risk and personalize anti-thrombotic prophylaxis?

International audienc

Prevalence, biological phenotype and genotype in moderate/ mild hemophilia A with discrepancy between one-stage and chromogenic factor VIII activity

International audienceBackground: In most laboratories, the severity of hemophilia A is assessed by the factor VIII activity (FVIII:C) one-stage assay. However, comparisons of these results with those of two-stage assays can reveal discrepancies and suggest misdiagnosis. Patients/Methods: In this monocentric study, we measured FVIII:C with two methods (one-stage chronometric and chromogenic assays) in 307 (173 families) patients with moderate/mild hemophilia A. To compare results, we used a chronometric/chromogenic ratio. Discrepancy was defined as a ratio < 0.5 or > 1.5. We studied their putative involvement at known FVIII functional sites, their interspecies conservation status, and their spatial position within the FVIII structure. Results: Thirty-six patients from 17 families exhibited a discrepancy between the two assays: 12 (6.9%) families had a low ratio (< 0.5), and five (2.9%) families had a high ratio (> 1.5). Qualitative deficiency was diagnosed in about 16% of the families. Molecular studies were performed in 15 of these 17 families, resulting in each case in the identification of missense mutations, including three novel mutations. We were further able to propose a pathophysiologic explanation. Conclusions: In this monocentric study, we have demonstrated a discrepancy between FVIII:C assay results in 10% of families with moderate/mild hemophilia A. The prevalence of ÔinverseÕ discrepancy (i.e. low chronometric/chromogenic ratio) is high as compared with previous reports. We suggest that both FVIII:C assays are recommended in patients with moderate/mild hemophilia A for a complete biological phenotype. This could also improve our knowledge of the FVIII structure-function relationships

FVIII at the crossroad of coagulation, bone and immune biology: emerging evidence biological activities beyond hemostasis: Factor VIIIbeyond hemostasis

International audienceHemophilia A is an X-linked hereditary disorder related to the deficiency of coagulation factor VIII (FVIII) leading to spontaneous bleeding episodes particularly into joints and muscles. FVIII deficiency has been associated with altered bone remodeling, dysregulated macrophage polarization, and inflammatory processes combined with neoformation of abnormal blood vessels. Treatment based on FVIII can lead to the development of inhibitors that render FVIII concentrate infusion ineffective. In this context, hemophilia has entered a new therapeutic era with the development of new drugs (e.g. Emicizumab) to restore the hemostatic balance by bypassing pathologic acquired antibodies. The present review aims to discuss the potential extrahemostatic functions of FVIII which may be crucial information for defining the future therapies in hemophilia