Identification of molecular signatures specific for distinct cranial sensory ganglia in the developing chick

Background The cranial sensory ganglia represent populations of neurons with distinct functions, or sensory modalities. The production of individual ganglia from distinct neurogenic placodes with different developmental pathways provides a powerful model to investigate the acquisition of specific sensory modalities. To date there is a limited range of gene markers available to examine the molecular pathways underlying this process. Results Transcriptional profiles were generated for populations of differentiated neurons purified from distinct cranial sensory ganglia using microdissection in embryonic chicken followed by FAC-sorting and RNAseq. Whole transcriptome analysis confirmed the division into somato- versus viscerosensory neurons, with additional evidence for subdivision of the somatic class into general and special somatosensory neurons. Cross-comparison of distinct ganglia transcriptomes identified a total of 134 markers, 113 of which are novel, which can be used to distinguish trigeminal, vestibulo-acoustic and epibranchial neuronal populations. In situ hybridisation analysis provided validation for 20/26 tested markers, and showed related expression in the target region of the hindbrain in many cases. Results One hundred thirty-four high-confidence markers have been identified for placode-derived cranial sensory ganglia which can now be used to address the acquisition of specific cranial sensory modalities.</p

J. Biol. Chem.

Rap1 is a small GTPase that is involved in signal transduction cascades. It is highly homologous to Ras but it is down- regulated by its own set of GTPase activating proteins (GAPs). To investigate the mechanism of the GTP-hydrolysis reaction catalyzed by Rap1GAP, a catalytically active fragment was expressed in Escherichia coli and characterized by kinetic and mutagenesis studies. The GTPase reaction of Rap1 is stimulated 10(5)-fold by Rap1GAP and has a k(cat) of 6 s(-1) at 25 degreesC. The catalytic effect of GAPs from Ras, Rho, and Rabs depends on a crucial arginine which is inserted into the active site. However, all seven highly conserved arginines of Rap1GAP can be mutated without dramatically reducing V-max of the GTP- hydrolysis reaction. We found instead two lysines whose mutations reduce catalysis 25- and 100-fold, most likely by an affinity effect. Rap1GAP does also not supply the crucial glutamine that is missing in Rap proteins at position 61. The Rap1(G12V) mutant which in Ras reduces catalysis 10(6)-fold is shown to be efficiently down-regulated by Rap1GAP. As an alternative, Rap1(F64A) is shown by kinetic and cell biological studies to be a Rap1GAP-resistant mutant. This study supports the notion of a completely different mechanism of the Rap1GAP- catalyzed GTP-hydrolysis reaction on Rap1

Adénopathies cervicales métastasiques d'un carcinome épidermoïde sans primitif retrouvé (étude rétrospective de 30 cas)

La prise en charge des adénopathies cervicales métastatiques d'un carcinome épidermoïde occulte, qui représentent seulement 3% de la carcinologie cervico faciale, ne fait actuellement pas l'objet d'un consensus malgré de nombreuses publications. A partir d'une étude rétrospective de 30 cas pris en charge entre 1995 et 2006, nous avons voulu préciser la démarche diagnostique, les facteurs pronostiques et la stratégie thérapeutique, en confrontant nos résultats avec ceux de la littérature. L'étude histologique des pièces d'amygdalectomie est plus fiable que de simples biopsies. Elle montre une prévalence accrue, de l'ordre de 30%, des tumeurs amygdaliennes occultes par rapport aux données antérieures. Le retentissement thérapeutique de l'identification d'une tumeur primitive justifie la réalisation systématique de ce geste dans le bilan initial, de façon au moins ipsilatérale à l'adénopathie cervicale et idéalement bilatérale. L'imagerie par TEP-TDM doit compléter le bilan initial, avant l'endoscopie, tant pour la mise en évidence d'une tumeur primitive que pour le bilan d'extension. Sa valeur pronostique et son apport dans l'évaluation d'une poursuite évolutive ganglionnaire ne sont pas encore clairement définis. La stratégie thérapeutique comporte une chirurgie première, complétée d'une irradiation cervicale en cas de facteurs pronostiques péjoratifs : un stade ganglionnaire avancé, la fixité de l'adénopathie et classiquement une rupture capsulaire. Pour les stades précoces (N1 et N2a), un traitement unique (curage cervical ou radiothérapie) est proposé par certains. La place de la chimiothérapie n'est à ce jour pas définie, nous la réalisons en présence de facteurs pronostiques péjoratifs. Aucun traitement n'a fait la preuve de son efficacité sur l'apparition de métastases viscérales à distance, qui conditionne, avec la récidive locorégionale, le pronostic de ces patients et justifie leur surveillance prolongée.ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Cancer Res.

The nonsteroidal anti-inflammatory drug Sulindac has chemopreventive and antitumorigenic properties. Its metabolites induce apoptosis and inhibit signaling pathways critical for malignant transformation, including the Ras pathway. Here we show that the new Sulindac derivative IND 12 reverses the phenotype of Ras-transformed MDCK-f3 cells and restores an untransformed epithelioid morphology characterized by growth in monolayers with regular cell-cell adhesions. Moreover, IND 12 treatment induces the expression at membranes of the cell adhesion protein E-cadherin and increases the level of the E- cadherin-bound beta-catenin. As a consequence, IND 12-treated MDCK-f3 cells lose their invasion capacity and regain the ability to aggregate. In the presence of IND 12, MDCK-f3 cells show regenerated expression and activity ratios of the small GTPases Rac and Rho normally found in untransformed MDCK cells. Strikingly, IND 12 treatment decreases the levels of phosphorylated mitogen-activated protein kinases, which are downstream substrates of the Ras-regulated Raf/mitogen- activated protein kinase pathway, and the level of Ras-induced activation of gene expression. Our findings identify a novel drug with high potential in cancer therapy by targeting Ras- induced cell transformation