Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

International audienc

Nonlinear ultrasound monitoring of fatigue microdamage accumulation in cortical bone

Accumulation of bone micro-damage is suspected to lead to severe impairment of mechanical properties with an increase in skeletal fragility and fracture risk. The objective of the study was to evaluate the potential of Nonlinear Resonant Ultrasound Spectroscopy (NRUS) for measuring micro-damage accumulation in cortical bone using four-point bending cycling fatigue. Sixteen human cortical bone specimens were machined as parallelepiped beams. Damage progression was controlled by measuring the linear elastic beam theory modulus (E LEBT ), known to reflect microdamage accumulation. Before and between each damage step, the nonlinear ultrasonic elastic coefficient was measured by NRUS. At the end of each cycling fatigue, a subset of bone samples was measured by μCT at the European Synchrotron Radiation Facility. Results showing a progressive increase of nonlinear ultrasonic elastic coefficient along fatigue cycling suggest that NRUS measurements are sensitive to micro-damage accumulation. The results mentioned above were validated using synchrotron radiation μCT. The variation of elastic nonlinearity was found to be significantly correlated to the variation of number density of small microcracks which almost doubled in damaged regionsThis research was supported by the Agence Nationale pour la Recherche (ANR), France (Grant BONUS_07BLAN0197

Etude de la réactivité vasculaire pulmonaire (approche des différents modèles physiologiques et physiopathologiques)

L hypertension artérielle pulmonaire est une pathologie rare caractérisée par l augmentation progressive des résistances artérielles pulmonaires. Dans cette thèse, nous suggérons que l acide arachidonique relaxe les artères pulmonaires humaines contractées en impliquant les canaux potassiques KATP, SKCa, BKCa, et KV. Nous montrons que la pravastatine, un inhibiteur des HMG-CoA réductase, réduit le développement de l hypertension pulmonaire induite par la monocrotaline et améliore la relaxation artérielle pulmonaire endothéliale dépendante, grâce à une diminution de l apoptose endothéliale pulmonaire et à une restauration de l expression des NO synthases endothéliales. Nous suggérons également que ces effets protecteurs pourraient ne pas être un effet de classe. Ces résultats plaident en faveur du développement d études portant sur le rôle des statines dans la prévention et le traitement de l hypertension artérielle pulmonaire chez l homme.DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Révolution à l'officine (la médication officinale bouleversée par l'arrivée du libre accès)

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Nonlinear resonant ultrasound spectroscopy is sensitive to the level of cortical bone damage

International audienceThe objective of the study was to evaluate the sensitivity of nonlinear resonant ultrasound spectroscopy (NRUS) measurements to the accumulation of damage in cortical bone by fatigue or by controlled crack propagation. Two groups of human cortical bone specimens were prepared from the femoral mid-diaphysis. The specimens from the first group were taken through a progressive fatigue protocol consisting of four steps of cyclic four-point bending. The specimens from the second group were taken through a toughness protocol consisting of initiation and controlled propagation of a stable crack induced by 4-point bending mechanical loading. Our results evidenced a progressive increase of the normalized nonlinear elastic parameter during fatigue testing or during toughness experiments. While in specimens subjected to mechanical fatigue cycling the relative variation of nonlinear elasticity was significantly related to the relative variation of the number density of small cracks assessed with micro-computed tomography, in crack propagation experiments a significant relationship was found between the level of nonlinearity and total crack length. These results strongly suggest that NRUS measurements are sensitive to damage accumulation and can be used as a marker of bone damage

Nonlinear ultrasound monitoring of single crack propagation in cortical bone

Accumulation of bone microdamage is suspected to lead to severe impairment of mechanical properties with an increase in skeletal fragility and fracture risk. The objective of the study was to evaluate the sensitivity of nonlinear resonant ultrasound spectroscopy (NRUS) measurements to the propagation in cortical bone of a single microcrack induced by 4-point bending mechanical loading. Twelve human cortical bone specimens were machined as parallelepiped beams (50*2*2mm) to unambiguously identify resonant modes for NRUS measurements. A central notch of 600{lower case mu}m was made to control crack initiation and propagation during four-point bending loading. The nonlinear hysteretic elastic coefficient ({lower case alpha} f ) was derived from NRUS measurements achieved in dry and wet conditions. Each bone specimen was probed by a swept-sine around its first compression mode, applying progressively increasing drive levels. Moreover, the buried crack length was assessed by synchrotron radiation micro-computed tomography with a spatial resolution of 1.4{lower case mu}m. Despite between-sample variability, {lower case alpha} f increased significantly in the damaged state (44.9±85.4) compared to the initial value (5.5±1.5) in the control undamaged state. Crack length was significantly correlated to the nonlinear elastic parameter {lower case alpha} f (r ² =0.78, p<0.001). These results suggest that NRUS is sensitive to damage accumulation and can be used as a marker of bone damage

Nonlinear ultrasound monitoring of single microcrack propagation in cortical bone

International audienceAccumulation of bone microdamage is suspected to lead to severe impairment of mechanical properties with an increase in skeletal fragility and fracture risk. The objective of the study was to evaluate the sensitivity of nonlinear resonant ultrasound spectroscopy (NRUS) measurements to the propagation in cortical bone of a single microcrack induced by 4-point bending mechanical loading. Twelve human cortical bone specimens were machined as parallelepiped beams (50*2*2mm) to unambiguously identify resonant modes for NRUS measurements. A central notch of 600 µm was made to control crack initiation and propagation during four-point bending loading. During stable crack propagation, load and displacement curves were recorded to extract mechanical parameters (J-integral J and stress intensity toughness K). Before and after toughness experiments, the nonlinear ultrasonic elastic coefficient (\alphaf) was monitored by NRUS for all notched samples. Despite substantial between-sample variability, \alphaf increased significantly (up to 50-fold) while no significant variation was observed for linear resonant frequency. Moreover, the crack length, assessed under epifluorescence microscope, was found to be significantly correlated to the nonlinear elastic parameter αf (r2=0.7, p=0.01). These results strongly suggest that NRUS measurements are sensitive to damage accumulation and can be used as a marker of microcrack length

In Vivo Efficacy of Ceftaroline Fosamil in a Methicillin-Resistant Panton-Valentine Leukocidin-Producing Staphylococcus aureus Rabbit Pneumonia Model.

International audienceCeftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control

Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI

International audienceMany Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xeno-grafts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-b1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer