Xeroderma pigmentosum: clues to understanding cancer initiation

AbstractXeroderma pigmentosum (XP) type C is a rare autosomal recessive disorder that occurs because of inactivation of the xeroderma pigmentosum group C (XPC) protein, which is an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. As a novel photoprotective approach, lentivirus-mediated catalase overexpression in XPC human keratinocytes results in a marked decrease in sunburn cell formation, caspase-3 activation, and p53 accumulation following UVB irradiation. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be helpful in limiting photosensitivity in XP type C, as well as in other monogenic/polygenic photosensitive disorders characterized by reactive oxygen species (ROS) accumulation. Hypoxia-inducible factor-1 (HIF-1), a major transcription factor sensitive to oxygen levels, responds to various stress factors. As a common stressor of skin, UVB induces a biphasic HIF-1a variation through ROS generation in keratinocytes. HIF-1a has an important regulator effect on the expression of XPC protein and other NER genes, indicating indirect regulation of NER by ROS. The intrinsic genomic instability arising in XP type C provides a good opportunity to investigate the complex molecular mechanisms underlying the Warburg effect (the shift of mito-chondrial metabolism towards glycolysis). Overall, the monogenic disorder XP type C is a powerful tool for studying photoprotection and cancer

Sensorimotor Transformations in the Zebrafish Auditory System

Organisms use their sensory systems to acquire information from their environment and integrate this information to produce relevant behaviors. Nevertheless, how sensory information is converted into adequate motor patterns in the brain remains an open question. Here, we addressed this question using two-photon and light-sheet calcium imaging in intact, behaving zebrafish larvae. We monitored neural activity elicited by auditory stimuli while simultaneously recording tail movements. We observed a spatial organization of neural activity according to four different response profiles (frequency tuning curves), suggesting a low-dimensional representation of frequency information, maintained throughout the development of the larvae. Low frequencies (150–450 Hz) were locally processed in the hindbrain and elicited motor behaviors. In contrast, higher frequencies (900–1,000 Hz) rarely induced motor behaviors and were also represented in the midbrain. Finally, we found that the sensorimotor transformations in the zebrafish auditory system are a continuous and gradual process that involves the temporal integration of the sensory response in order to generate a motor behavior.Fil: Privat, Martin. Inserm; Francia. Centre National de la Recherche Scientifique; FranciaFil: Romano, Sebastián Alejo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Pietri, Thomas. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaFil: Jouary, Adrien. Champalimaud Centre For The Unknown; Portugal. Inserm; Francia. Centre National de la Recherche Scientifique; FranciaFil: Boulanger Weill, Jonathan. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaFil: Elbaz, Nicolas. Inserm; Francia. Centre National de la Recherche Scientifique; FranciaFil: Duchemin, Auriane. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaFil: Soares, Daphne. New Jersey Institute of Technology; Estados UnidosFil: Sumbre, Germán. Centre National de la Recherche Scientifique; Francia. Inserm; Franci

An integrated calcium imaging processing toolbox for the analysis of neuronal population dynamics

The development of new imaging and optogenetics techniques to study the dynamics of large neuronal circuits is generating datasets of unprecedented volume and complexity, demanding the development of appropriate analysis tools. We present a comprehensive computational workflow for the analysis of neuronal population calcium dynamics. The toolbox includes newly developed algorithms and interactive tools for image pre-processing and segmentation, estimation of significant single-neuron single-trial signals, mapping event-related neuronal responses, detection of activity-correlated neuronal clusters, exploration of population dynamics, and analysis of clusters' features against surrogate control datasets. The modules are integrated in a modular and versatile processing pipeline, adaptable to different needs. The clustering module is capable of detecting flexible, dynamically activated neuronal assemblies, consistent with the distributed population coding of the brain. We demonstrate the suitability of the toolbox for a variety of calcium imaging datasets. The toolbox open-source code, a step-by-step tutorial and a case study dataset are available at https://github.com/zebrain-lab/Toolbox-Romano-et-al

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo.

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05×10−23) and class II molecules (P=4.50×10−34), PTPN22 (P=1.31×10−7), LPP (P=1.01×10−11), IL2RA (P=2.78×10−9), UBASH3A (P=1.26×10−9), and C1QTNF6 (P=2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07×10−15) and GZMB (P=3.44×10−8), and in a locus containing TYR (P=1.60×10−18), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma

Common variants in FOXP1 are associated with generalized vitiligo

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10−8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10−7)

Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP

We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P3.0E-04, odds ratio (OR)1.60; meta-P for rs38069333.1E-03), XBP1 (rs6005863, P3.6E-04, OR1.17; meta-P for rs22695779.5E-09), and FOXP3 (rs11798415, P5.8E-04, OR1.19). Association of GV with CTLA4 (rs12992492, P5.9E-05, OR1.20; meta-P for rs2317751.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions

Etude de l'intérêt de la chimiothérapie néo-adjuvante pour les patients opérés de métastases pulmonaires de mélanome

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Homogénéité et conservation du statut BRAF entre mélanome primitif et métastases déterminées par immunohistochimie et biologie moléculaire

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Analyses génétiques et fonctionnelles du gène CTSC dans le syndrome de Papillon-Lefèvre et le psoriasis palmo-plantaire

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Analyse rétrospective de la série hospitalière du CHU de Bordeaux des cas de porocarcinomes eccrines de 1999 à 2009 (à propos de 24 cas)

Le porocarcinome est une tumeur cutanée annexielle maligne rare de diagnostic clinique et histologique difficile et dont la prise en charge thérapeutique n'est pas consensuelle aussi bien au stade localisé qu'à un stade avancé. Une analyse rétrospective de la série hospitalière du CHU de Bordeaux a été réalisée entre 1999 et 2009. 24 patients ont été inclus. Nous avons étudié différents paramètres (cliniques, épidémiologiques, histologiques et thérapeutiques) et avons comparé nos résultats avec ceux de la littérature. Parmi nos résultats, nous avons observé l'importance pronostique du type histologique du porocarcinome eccrine. La forme "pushing" était de très bon pronostic (aucune récidive chez les patients avec ce type histologique de porocarcinome eccrine) alors que les formes intra-épidermique pagétoïde ou infiltrante étaient plus agressives. Par ailleurs nous avons observé que les marges chirurgicales larges > 2 cm réalisées dans notre population de porocarcinomes eccrines ne semblent pas diminuer le risque de récidive. Néanmoins, une marge > 2 cm semble allonger la durée de la survie sans récidive. En conclusion, notre étude montre l'importance de bien définir le type histologique de chaque porocarcinome eccrine. Le traitement chirurgical de la lésion primitive, à un stade localisé, pourrait alors être mieux adapté. La chirurgie micrographique de Mohs devrait être proposée et mieux évaluée dans les formes infiltrantes agressives. A l'inverse il est probable qu'une chirurgie standard avec des marges limitées soit suffisante pour les formes "pushing".BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF