References of "Wéra, Odile"
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See detailPlatelets contribute to the initiation of colitis-associated cancer by promoting immunosuppression
Servais, Laurence ULiege; Wéra, Odile ULiege; Dibato Epoh, John et al

in Journal of Thrombosis and Haemostasis (in press)

Background: Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, though the mechanisms are not fully understood. Beyond thrombosis and hemostasis ... [more ▼]

Background: Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, though the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors of inflammation; they also have been involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective: To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods: We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and their reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at pre-tumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results: At pre-tumoral stage, hyperactive platelets were a major source of circulating pro-tumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of plasma SAA, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells as well as their infiltration in tumors, while tissue CD8 T cells were augmented. Platelets or releasates of platelets from cancer mice both were able to polarize myeloid cells toward an immunosuppressive phenotype. Conclusions: Thus, platelets promote initiation of colitis-associated cancer by enhancing myeloid cell dependent immunosuppression. Antiplatelet agents may help prevent inflammation-elicited carcinogenesis by restoring antitumor immunity. [less ▲]

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See detailComparison of nanofluidic and ultra-high performance liquid chromatography-tandem mass spectrometry for high sensitive pharmacokinetic studies of estrogens starting from whole blood microsampling
Nys, Gwenaël ULiege; COBRAIVILLE, Gaël ULiege; Kok, Miranda ULiege et al

in Journal of Chromatography. A (2017), 1524

Pharmacokinetic (PK) studies on small animals are challenging as only small volumes of samples are available, in which the analyte is present at low concentration in a complex matrix. In this context, the ... [more ▼]

Pharmacokinetic (PK) studies on small animals are challenging as only small volumes of samples are available, in which the analyte is present at low concentration in a complex matrix. In this context, the use of miniaturized analytical techniques may provide undeniable advantages in terms of sensitivity, sample and solvent consumption compared to the reference UHPLC-MS/MS methods In this study, we present the development of a nanofluidic-LC-MS/MS method to analyze two model analytes of therapeutic interest, namely estradiol (E2) and estetrol (E4) after microsampling with volumetric absorptive microsampling (VAMS) devices, an innovative sampling technique to collect small volumes of whole blood. The nanofluidic LC-MS/MS method was developed using an experimental design to find the optimal conditions to analyze both E2 and E4 with the highest sensitivity. Subsequently, the optimized method was validated according to ICH guidelines and compared to a previously developed UHPLC-MS/MS method. A limit of quantitation of 50. pg/ml was reached with the LC-chip method, which is 50 times better than UHPLC-MS/MS. Both methods were then critically evaluated from the analytical and operational points of view. Finally, the quantitation of estrogens after whole blood microsampling was compared with the results obtained with the corresponding plasma samples. © 2017 Elsevier B.V. [less ▲]

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See detailPlatelets promote immunosuppression and colorectal tumor formation: inhibition by clopidogrel
Servais, Laurence ULiege; Delierneux, Céline; Wéra, Odile ULiege et al

Poster (2017, July)

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See detailTargeting of C-type lectin-like receptor 2 or P2Y12 for the prevention of platelet activation by immunotherapeutic CpG oligodeoxynucleotides
Delierneux, Céline ULiege; Donis, Nathalie ULiege; servais, laurence et al

in Journal of Thrombosis and Haemostasis (2017), 15(5), 983-997

Background: Synthetic phosphorothioate-modified CpG oligodeoxynucleotides (CpG ODNs) display potent immunostimulatory properties that are widely exploited in clinical trials of anticancer treatment ... [more ▼]

Background: Synthetic phosphorothioate-modified CpG oligodeoxynucleotides (CpG ODNs) display potent immunostimulatory properties that are widely exploited in clinical trials of anticancer treatment. Unexpectedly, a recent study indicates that CpG ODNs activate human platelets via the immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor glycoprotein VI. Objective: To further analyze the mechanisms of CpG ODN-induced platelet activation and identify potential inhibitory strategies. Methods: In vitro analyses were performed on human and mouse platelets, and on cell lines expressing platelet ITAM receptors. CpG ODN platelet activating effects were evaluated in a mouse model of thrombosis. Results: We demonstrated platelet uptake of CpG ODNs, resulting in platelet activation and aggregation. The C-type lectin-like receptor 2 (CLEC-2) expressed in DT40 cells bound CpG ODNs. CpG ODN uptake did not occur in CLEC-2-deficient mouse platelets. Inhibition of human CLEC-2 with a blocking antibody inhibited CpG ODN-induced platelet aggregation. CpG ODNs caused CLEC-2 dimerization, and provoked its internalization. They induced dense granule release before the onset of aggregation. Accordingly, pretreating platelets with apyrase, or inhibiting P2Y12 with cangrelor or clopidogrel prevented CpG ODN platelet activating effect. In vivo, intravenously injected CpG ODN interacted with platelets adhered to mouse injured endothelium, and promoted thrombus growth, which was inhibited by CLEC-2 deficiency or by clopidogrel. Conclusions: CLEC-2 and P2Y12 are required for CpG ODN-induced platelet activation and thrombosis and might be targeted to prevent adverse events in patients at risk. [less ▲]

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See detailTargeting of C-type lectin-like receptor 2 or P2Y12 for the prevention of platelet activation by immunotherapeutic CpG oligodeoxynucleotides: reply.
Delierneux, Céline; Donis, Nathalie ULiege; Servais, Laurence ULiege et al

in Journal of Thrombosis and Haemostasis (2017)

We provide here a new set of data supporting the involvement of multiple platelet receptors in CpG ODN platelet activating effects. We observed some sequence-specific features of platelet responses to ... [more ▼]

We provide here a new set of data supporting the involvement of multiple platelet receptors in CpG ODN platelet activating effects. We observed some sequence-specific features of platelet responses to phosphorothioate-modified CpG ODNs types A, B, and C that could be useful for future development of safe therapeutic CpG ODNs. Additional investigations are needed in order to further delineate these sequence specificities, and to address the importance of higher-order structures, as well as of possible interactions with cofactors for the effects of CpG ODN on platelets. [less ▲]

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See detailThe Dual Role of Neutrophils in Inflammatory Bowel Diseases
Wéra, Odile ULiege; Lancellotti, Patrizio ULiege; Oury, Cécile ULiege

in Journal of clinical medicine (2016), 5(12),

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration ... [more ▼]

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn's disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD. [less ▲]

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See detailP2X1 ion channel is critical for vascular integrity in inflammation
Wéra, Odile ULiege; Delierneux, Céline; Servais, Laurence ULiege et al

Poster (2016, November)

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See detailP2X1 ion channel is critical for vascular integrity in inflammation
Wéra, Odile ULiege; Delierneux, Céline; Hego, Alexandre ULiege et al

Conference (2016, September)

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See detailFunctional analysis of protein tyrosine phosphatases in thrombosis and haemostasis
Rahmouni, Souad ULiege; Hego, Alexandre ULiege; Delierneux, Céline ULiege et al

in Protein Tyrosine Phosphatases: Methods and Protocols (2016)

Platelets are small blood cells derived from cytoplasmic fragments of megakaryocytes and play an essential role in thrombosis and haemostasis. Platelet activation depends on the rapid phosphorylation and ... [more ▼]

Platelets are small blood cells derived from cytoplasmic fragments of megakaryocytes and play an essential role in thrombosis and haemostasis. Platelet activation depends on the rapid phosphorylation and dephosphorylation of key signaling molecules, and a number of kinases and phosphatases have been identified as major regulators of platelet function. However, the investigation of novel signaling proteins has suffered from technical limitations due to the anucleate nature of platelets and their very limited levels of mRNA and de novo protein synthesis. In the past, experimental methods were restricted to the generation of genetically modified mice and the development of specific antibodies. More recently, novel (phospho)proteomic technologies and pharmacological approaches using specific small-molecule inhibitors have added additional capabilities to investigate specific platelet proteins. In this chapter, we report methods for using genetic and pharmacological approaches to investigate the function of platelet signaling proteins. While the described experiments focus on the role of the dual-specificity phosphatase 3 (DUSP3) in platelet signaling, the presented methods are applicable to any signaling enzyme. Specifically, we describe a testing strategy that includes 1) aggregation and secretion experiments with mouse and human platelets, 2) immunoprecipitation and immunoblot assays to study platelet signaling events, 3) detailed protocols to use selected animal models in order to investigate thrombosis and haemostasis in vivo, and 4) strategies for utilizing pharmacological inhibitors on human platelets. [less ▲]

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See detailPurinergic control of inflammation and thrombosis: Role of P2X1 receptors
Oury, Cécile ULiege; LECUT, Christelle ULiege; Hego, Alexandre ULiege et al

in Computational and Structural Biotechnology Journal (2015), 13

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between ... [more ▼]

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In thismodel, by using P2X1−/−mice,we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Intriguingly, in a model of endotoxemia, P2X1−/−mice exhibited aggravated oxidative tissue damage, along with exacerbated thrombocytopenia and increased activation of coagulation, which translated into higher susceptibility to septic shock. Thus, besides its ability to recruit neutrophils and platelets on inflamed endothelia, the P2X1 receptor also contributes to limit the activation of circulating neutrophils under systemic inflammatory conditions. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets, neutrophils and thrombosis. We propose that activation of these receptors by ATP on neutrophils and platelets represents a new mechanism that regulates thrombo-inflammation. [less ▲]

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