Chan-Vese based method to segment mouse brain MRI images: application to cerebral malformation analysis in trisomy 21

International audienceIn this paper, a semi automatic active contour method based on Chan-Vese model is proposed for the segmentation of mouse brain MR images. First, a 2 ½ D strategy is applied on the axial images to segment the 3D volume of interest. The method takes into account the special shape of the object to segment. Moreover, the user defines the limits where to search these contours and also provides an initial contour. This semi automatic method makes that human intervention is limited and the tedious manual handling is greatly reduced. Results have shown that the brain volumes estimated by the method are identical to expert manually estimated volumes. Last but not least, the new method was used in the analysis of the cerebral malformations linked to Trisomy 21: no significant difference of the brain volumes between Tri-somy 21 mice and the control ones were found

Stable tumor vessel normalization with pO_{2} increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment

Tumor hypoxia is a characteristic of cancer cell growth and invasion, promoting angiogenesis, which facilitates metastasis. Oxygen delivery remains impaired because tumor vessels are anarchic and leaky, contributing to tumor cell dissemination. Counteracting hypoxia by normalizing tumor vessels in order to improve drug and radio therapy efficacy and avoid cancer stem-like cell selection is a highly challenging issue. We show here that inositol trispyrophosphate (ITPP) treatment stably increases oxygen tension and blood flow in melanoma and breast cancer syngeneic models. It suppresses hypoxia-inducible factors (HIFs) and proangiogenic/glycolysis genes and proteins cascade. It selectively activates the tumor suppressor phosphatase and tensin homolog (PTEN) in vitro and in vivo at the endothelial cell (EC) level thus inhibiting PI3K and reducing tumor AKT phosphorylation. These mechanisms normalize tumor vessels by EC reorganization, maturation, pericytes attraction, and lowering progenitor cells recruitment in the tumor. It strongly reduces vascular leakage, tumor growth, drug resistance, and metastasis. ITPP treatment avoids cancer stem-like cell selection, multidrug resistance (MDR) activation and efficiently enhances chemotherapeutic drugs activity. These data show that counteracting tumor hypoxia by stably restoring healthy vasculature is achieved by ITPP treatment, which opens new therapeutic options overcoming hypoxia-related limitations of antiangiogenesis-restricted therapies. By achieving long-term vessels normalization, ITPP should provide the adjuvant treatment required in order to overcome the subtle definition of therapeutic windows for in vivo treatments aimed by the current strategies against angiogenesis-dependent tumors

KIT is required for hepatic function during mouse post-natal development

<p>Abstract</p> <p>Background</p> <p>The <it>Kit </it>gene encodes a receptor tyrosine kinase involved in various biological processes including melanogenesis, hematopoiesis and gametogenesis in mice and human. A large number of <it>Kit </it>mutants has been described so far showing the pleiotropic phenotypes associated with partial loss-of-function of the gene. Hypomorphic mutations can induce a light coat color phenotype while complete lack of KIT function interferes with embryogenesis. Interestingly several intermediate hypomorphic mutations induced in addition growth retardation and post-natal mortality.</p> <p>Results</p> <p>In this report we investigated the post-natal role of <it>Kit </it>by using a panel of chemically-induced hypomorphic mutations recently isolated in the mouse. We found that, in addition to the classical phenotypes, mutations of <it>Kit </it>induced juvenile steatosis, associated with the downregulation of the three genes, <it>VldlR</it>, <it>Lpin1 </it>and <it>Lpl</it>, controlling lipid metabolism in the post-natal liver. Hence, <it>Kit </it>loss-of-functions mimicked the inactivation of genes controlling the hepatic metabolism of triglycerides, the major source of energy from maternal milk, leading to growth and viability defects during neonatal development.</p> <p>Conclusion</p> <p>This is a first report involving KIT in the control of lipid metabolism in neonates and opening new perspectives for understanding juvenile steatosis. Moreover, it reinforces the role of Kit during development of the liver and underscores the caution that should be exerted in using KIT inhibitors during anti-cancer treatment.</p

Chronic exposure to glufosinate-ammonium induces spatial memory impairments, hippocampal MRI modifications and glutamine synthetase activation in mice

International audienceGlufosinate-ammonium (GLA), the active compound of a worldwide-used herbicide, acts by inhibiting the plant glutamine synthetase (GS) leading to a lethal accumulation of ammonia. GS plays a pivotal role in the mammalian brain where it allows neurotransmitter glutamate recycling within astroglia. Clinical studies report that an acute GLA ingestion induces convulsions and memory impairment in humans. Toxicological studies performed at doses used for herbicidal activity showed that GLA is probably harmless at short or medium range periods. However, effects of low doses of GLA on chronically exposed subjects are not known. In our study, C57BL/6J mice were treated during 10 weeks three times a week with 2.5, 5 and 10 mg/kg of GLA. Effects of this chronic treatment were assessed at behavioral, structural and metabolic levels by using tests of spatial memory, locomotor activity and anxiety, hippocampal magnetic resonance imaging (MRI) texture analysis, and hippocampal GS activity assay, respectively. Chronic GLA treatments have effects neither on anxiety nor on locomotor activity of mice but at 5 and 10 mg/kg induce (1) mild memory impairments, (2) a modification of hippocampal texture and (3) a significant increase in hippocampal GS activity. It is suggested that these modifications may be causally linked one to another. Since glutamate is the main neurotransmitter in hippocampus where it plays a crucial role in spatial memory, hippocampal MRI texture and spatial memory alterations might be the consequences of hippocampal glutamate homeostasis modification revealed by increased GS activity in hippocampus. The present study provides the first data that show cerebral alterations after chronic exposure to GLA

Développement de méthodes d'imagerie par résonance magnétique pour l'étude de l'articulation (application au suivi de rats arthritiques)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Etude in vivo de la dégénérescence discale par IRM à 9,4 T (application à la validation de méthodes de réparation discale chez le lapin)

Dans notre société, la lombalgie est une pathologie fréquente représentant un vrai problème de santé publique au coût important et en constante augmentation. Il est maintenant largement admis que la dégénérescence du disque intervertébral (DIV) est la principale cause de lombalgie. Cette dégénérescence est un processus complexe caractérisé par des changements biochimiques et structuraux intervenant dans les différents tissus du DIV. Aujourd hui, seuls des traitements médicaux symptomatiques de la lombalgie sont disponibles et il n existe pas de traitement spécifique de la dégénérescence discale. L imagerie par résonance magnétique (IRM) est une technique reconnue comme un outil non invasif et totalement atraumatique de diagnostic chez l homme. L IRM permet de caractériser la morphologie et la physiologie d un être vivant à partir des modifications de l état de l eau dans ses tissus. De part la composition du DIV (principalement de l eau) l IRM s avère être particulièrement adaptée à l étude du DIV sain ou dégénératif, ainsi qu à sa régénération dans le cadre de l évaluation de l efficacité d un traitement. Les objectifs de ce projet ont d abord été de développer un protocole d IRM in vivo du DIV chez le lapin, capable de différencier des DIV sains et pathologiques et de mettre en évidence différents stades de dégénérescence discale. Ce protocole a ensuite permis d évaluer l efficacité de nouvelles techniques de réparation discale développées par la société Abbott Spine SA. En parallèle de ce travail chez le lapin, l IRM in vivo du DIV de souris a été développée, dans le but d utiliser des modèles transgéniques de pathologies articulaires et d étudier leur impact sur le DIV.ORLEANS-BU Sciences (452342104) / SudocSudocFranceF

Développement de méthodes de spectroscopie RMN localisée 1D filtrée (exposant 1) H (-exposant 13) C double voxel (Application à l exploration d une pathologie cérébrale focale chez le petit animal)

Nous avons développé une méthode de Spectroscopie de Résonance Magnétique pour l exploration dynamique du métabolisme cérébral chez le rat lors de lésions focales, basée sur le suivi de métabolites marqués carbone 13. Dans ce but, nous avons développé et mis au point des séquences de SRM à une dimension (1D) localisée filtrées 1H(-13C) combinées au codage d Hadamard. Ces séquences ont été testées avec les différents systèmes de bobines 1H/13C que nous avons construits. L exploration des atteintes cérébrales focales résultant, chez le rat, de l administration intracérébrale d un agent excitotoxique, l acide quinolinique, a été utilisée pour tester l'efficacité du couple optimal de séquence système de bobines. Cette étude spectroscopique a été associée à une étude par Imagerie de Résonance Magnétique pondérée en diffusion et pondérée en T2 afin de suivre l évolution du volume de la zone lésée dans le même modèle expérimental.We developed a Magnetic Resonance Spectroscopy method for local dynamic investigations of the rat brain metabolism, based on the monitoring of carbon 13 labelled metabolites. For such investigations, we developed and optimized one dimension (1D) localized MRS 1H(-13C) filtered sequences combined with Hadamard encoding. The efficiency of the sequences was tested with the different system of 1H/13C coils we built. The best association of coil device and sequence was applied to the investigation of a focal cerebral injury resulting of the intracerebral administration of an excitotoxic compound, the quinolinic acid. This spectroscopic study was associated to diffusion and T2 weighted imaging studying in order to monitor the evolution of the volume of the injured area in the sameEVRY-BU (912282101) / SudocSudocFranceF