STAT5-and hypoxia-dependent upregulation of AXL

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones

Antimicrobial activity of zinc oxide particles on five micro-organisms of the Challenge Tests related to their physicochemical properties

International audienc

Démarche de prévention dans le secteur médico-social : MESOCAP

International audienc

Coronary artery stenosis: direct comparison of four-section multi-detector row CT and 3D navigator MR imaging for detection--initial results.

PURPOSE: To prospectively compare the diagnostic accuracy of multi-detector row computed tomography (CT) and of three-dimensional (3D) navigator magnetic resonance (MR) imaging in patients referred for conventional coronary angiography for detection of coronary artery stenosis. MATERIALS AND METHODS: All patients gave written informed consent for the study, which was approved by the local ethics committee. Twenty-seven patients underwent multi-detector row CT and 3D navigator free-breathing MR imaging a mean of 5 days before undergoing invasive coronary angiography. The acquired multi-detector row CT and MR images were graded for the presence of greater than 50% stenosis in vessels larger than 1.5 mm in diameter. The diagnostic accuracies of the two examinations were compared with that of quantitative coronary angiography (QCA) by using the McNemar test. RESULTS: Owing to claustrophobia, MR images were not acquired in one patient; thus, 26 patients were included for analysis. According to QCA findings, 21 of the 26 patients had significant coronary artery disease and 58 (20%) of a total of 294 coronary artery segments larger than 1.5 mm in diameter had significant (>50%) stenosis. Multi-detector row CT had significantly higher sensitivity (46 [79%] of 58 segments) than MR imaging (36 [62%] segments, P < .05) for detection of segments with significant stenosis. Conversely, MR imaging had significantly higher specificity (198 [84%] of 236 segments) than did CT (168 [71%] segments, P < .001) for exclusion of segmental coronary artery stenosis. Both examinations had high negative predictive value for exclusion of segmental stenosis: 93% (168 of 180 segments) for CT and 90% (198 of 220 segments) for MR imaging. The overall diagnostic accuracy of MR imaging (80% [234 of 294 segments]) was significantly higher than that of CT (73% [214 segments], P < .05). CONCLUSION: MR imaging had significantly higher diagnostic accuracy than multi-detector row CT in the evaluation of coronary artery stenosis. Both techniques have high negative predictive value, making them particularly useful for ruling out coronary artery disease in symptomatic patients

Head-to-head comparison of 3-D navigator gated magnetic resonance imaging and 16-slice computed tomography to detect coronary artery stenosis in patients

Recent advancements in imaging technology enable the noninvasive assessment of atherosclerotic plaques in arteries throughout the body. High-resolution multisclice computed tomography (MSCT) - sometimes referred to as multidetector spriral or just MDCT - and cardiac magnetic resonance (MR) provide information about the arterial wall that is unavailable with the most other methods, including angiography. Moreover, MSCT and MR are making great strides in the characterizatuion of plaque composition and microanatomy, thus leading to the identification of lesions that are vulnerable to rupture or erosion. This information may aid in the selection of patients most likely to benefit from early intervention, including lipid-lowering drug regimens. There would be considerable advantage, too, in developing a noninvasive means of detecting coronary artery stenosis. Until now, QCA has been invaluable for detecting stenosis while ultrafast computed tomography (CT) and cardiac MR have shown promise for showing details of the plaques that are detected. However, 16-slice CT and three-dimensionalm, navigator-directed MR have been proposed for the noninvasive detection of coronary artery stenosis

Head-to-head comparison of three-dimensional navigator-gated magnetic resonance imaging and 16-slice computed tomography to detect coronary artery stenosis in patients.

OBJECTIVES: The purpose of this research was to compare the diagnostic accuracy of three-dimensional navigator-gated magnetic resonance (MR) imaging and 16-slice multidetector row computed tomography (MDCT) versus quantitative coronary angiography (QCA) for the detection of coronary artery stenosis in patients. BACKGROUND: Both MR and MDCT are novel non-invasive tests, which have been proposed for noninvasive detection of coronary artery disease. Yet their diagnostic accuracy has not been directly compared in the same population. METHODS: Fifty-two patients underwent coronary MR and 16-slice MDCT before invasive coronary angiography. Diameter stenosis (DS) severity in vessels >1.5-mm reference diameter were graded visually and measured quantitatively on both MR and MDCT images. Diagnostic accuracy of both methods was compared using QCA as the reference test. RESULTS: According to QCA, 81 of 452 (18%) coronary segments with >1.5 mm diameter had >50% DS. By visual analysis, MR and MDCT had similar sensitivity (75% vs. 82%, p = NS), specificity (77% vs. 79%, p = NS), and diagnostic accuracy (77%, vs. 80%, p = NS) for detection of >50 % DS. Quantitative measures of DS by MR (r = 0.60, p < 0.001) and MDCT (r = 0.75, both p < 0.001) correlated well with QCA. Receiver-operating characteristic analysis demonstrated that quantification of DS severity improved the diagnostic accuracy of MDCT (area under curve [AUC] 0.81 vs. 0.92, p < 0.001) but not that of MR (AUC 0.78 vs. 0.83, p = NS). CONCLUSIONS: Visual assessment of coronary diameter stenosis severity by MR or MDCT allows identification of significant coronary artery disease with a similar high diagnostic accuracy. Quantitative analysis significantly further improves the diagnostic accuracy of MDCT but not that of MR

Détermination de la surface équivalente radar d'une cible à partir d'un modèle de mesures multistatiques en champ proche exploitant les matrices de répartition du système de mesure

CERGY PONTOISE-BU Neuville (951272102) / SudocSudocFranceF