FBXW7/hCDC4 controls glioma cell proliferation in vitro and is a prognostic marker for survival in glioblastoma patients

BACKGROUND: In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7 (hCDC4/hAGO/SEL10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCF(Fbxw7), a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW7 loss. RESULTS: We tested the expression of FBXW7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW7 was significantly reduced. In addition, levels of FBXW7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma. CONCLUSION: Our results show that FBXW7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW7 plays an important role in glioma malignancy by allowing the accumulation of multiple oncoproteins and that interfering with Fbxw7 or its downstream targets would constitute a new therapeutic advance

Occupational exposure to pesticides and central nervous system tumors: results from the CERENAT case-control study

BACKGROUND: The etiology of the central nervous system (CNS) tumors remains largely unknown. The role of pesticide exposure has been suggested by several epidemiological studies, but with no definitive conclusion. OBJECTIVE: To analyze associations between occupational pesticide exposure and primary CNS tumors in adults in the CERENAT study. METHODS: CERENAT is a multicenter case-control study conducted in France in 2004-2006. Data about occupational pesticide uses-in and outside agriculture-were collected during detailed face-to-face interviews and reviewed by experts for consistency and exposure assignment. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated with conditional logistic regression. RESULTS: A total of 596 cases (273 gliomas, 218 meningiomas, 105 others) and 1 192 age- and sex-matched controls selected in the general population were analyzed. Direct and indirect exposures to pesticides in agriculture were respectively assigned to 125 (7.0%) and 629 (35.2%) individuals and exposure outside agriculture to 146 (8.2%) individuals. For overall agricultural exposure, we observed no increase in risk for all brain tumors (OR 1.04, 0.69-1.57) and a slight increase for gliomas (OR 1.37, 0.79-2.39). Risks for gliomas were higher when considering agricultural exposure for more than 10 years (OR 2.22, 0.94-5.24) and significantly trebled in open field agriculture (OR 3.58, 1.20-10.70). Increases in risk were also observed in non-agricultural exposures, especially in green space workers who were directly exposed (OR 1.89, 0.82-4.39), and these were statistically significant for those exposed for over 10 years (OR 2.84, 1.15-6.99). DISCUSSION: These data support some previous findings regarding the potential role of occupational exposures to pesticides in CNS tumors, both inside and outside agriculture

Prevalence, Severity, and Clinical Management of Brain Incidental Findings in Healthy Young Adults: MRi-Share Cross-Sectional Study

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral (n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults.Programme d'investissements - Idex Bordeaux - LAPHIAStopping cognitive decline and dementia by fighting covert cerebral small vessel diseaseInvestissement d'aveni

A Whole-Genome Scan for Association With Invasion Success in the Fruit Fly Drosophila Suzukii Using Contrasts of Allele Frequencies Corrected for Population Structure

Evidence is accumulating that evolutionary changes are not only common during biological invasions but may also contribute directly to invasion success. The genomic basis of such changes is still largely unexplored. Yet, understanding the genomic response to invasion may help to predict the conditions under which invasiveness can be enhanced or suppressed. Here, we characterized the genome response of the spotted wing drosophila Drosophila suzukii during the worldwide invasion of this pest insect species, by conducting a genome-wide association study to identify genes involved in adaptive processes during invasion. Genomic data from 22 population samples were analyzed to detect genetic variants associated with the status (invasive versus native) of the sampled populations based on a newly developed statistic, we called C2, that contrasts allele frequencies corrected for population structure. We evaluated this new statistical framework using simulated data sets and implemented it in an upgraded version of the program BAYPASS. We identified a relatively small set of single-nucleotide polymorphisms that show a highly significant association with the invasive status of D. suzukii populations. In particular, two genes, RhoGEF64C and cpo, contained single-nucleotide polymorphisms significantly associated with the invasive status in the two separate main invasion routes of D. suzukii. Our methodological approaches can be applied to any other invasive species, and more generally to any evolutionary model for species characterized by nonequilibrium demographic conditions for which binary covariables of interest can be defined at the population level

The genomic basis of color pattern polymorphism in the Harlequin ladybird

© 2018 The Authors Many animal species comprise discrete phenotypic forms. A common example in natural populations of insects is the occurrence of different color patterns, which has motivated a rich body of ecological and genetic research [1–6]. The occurrence of dark, i.e., melanic, forms displaying discrete color patterns is found across multiple taxa, but the underlying genomic basis remains poorly characterized. In numerous ladybird species (Coccinellidae), the spatial arrangement of black and red patches on adult elytra varies wildly within species, forming strikingly different complex color patterns [7, 8]. In the harlequin ladybird, Harmonia axyridis, more than 200 distinct color forms have been described, which classic genetic studies suggest result from allelic variation at a single, unknown, locus [9, 10]. Here, we combined whole-genome sequencing, population-based genome-wide association studies, gene expression, and functional analyses to establish that the transcription factor Pannier controls melanic pattern polymorphism in H. axyridis. We show that pannier is necessary for the formation of melanic elements on the elytra. Allelic variation in pannier leads to protein expression in distinct domains on the elytra and thus determines the distinct color patterns in H. axyridis. Recombination between pannier alleles may be reduced by a highly divergent sequence of ∼170 kb in the cis-regulatory regions of pannier, with a 50 kb inversion between color forms. This most likely helps maintain the distinct alleles found in natural populations. Thus, we propose that highly variable discrete color forms can arise in natural populations through cis-regulatory allelic variation of a single gene. More than 200 distinct color forms have been described in natural populations of the harlequin ladybird, Harmonia axyridis. Gautier et al. show that this variation is controlled by the transcription factor Pannier. Pannier is necessary to produce black pigment, and its expression pattern prefigures the coloration pattern in each color form

BMC Cancer

BACKGROUND: Although some countries have observed a stabilization in the incidence of CNS, an increasing incidence has been reported from multiple studies. Recent observations point out to the heterogeneity of incidence trends according to histological subtypes, gender and age-groups. Using a high-quality regional CNS tumor registry, this article describes the trends of CNS tumor incidence for main histological subtypes, including benign and malignant tumors, in the French department of Gironde from 2000 to 2012. METHODS: Crude and age-standardized incidence rates were calculated globally, by histological subtypes, malignant status, gender and age groups. For trends, annual percent changes (APC) were obtained from a piecewise log-linear model. RESULTS: A total of 3515 CNS tumors was registered during the period. The incidence of overall CNS tumors was 19/100000 person-years (8.3/100000 for neuroepithelial tumors and 7.3/100000 for meningeal tumors). An increased incidence of overall CNS tumors was observed from 2000 to 2012 (APC = + 2.7%; 95%-confidence interval (CI): 1.8-3.7). This trend was mainly explained by an increase in the incidence of meningiomas over the period (APC = + 5.4%, 95%-CI: 3.8-7.0). The increased incidence rate of CNS tumors was more pronounced in female and in older patients even though the incidence rate increased in all age groups. CONCLUSIONS: Part of the temporal variation may be attributed to improvement in registration, diagnosis and clinical practices but also to changes in potential risk factors. Thus, etiological studies on CNS tumors are needed to clarify this rising trend

Topographie de la récidive des glioblastomes traités par chirurgie et radio-chimiothérapie

OBJECTIFS : Description de la topographie de la récidive des glioblastomes en fonction de la réponse au traitement par chirurgie et radio-chimiothérapie concomitante. MATERIELS ET METHODES : Cinquante-trois patients ayant bénéficié d'une exérèse chirurgicale entre avril 2007 et décembre 2009 pour un glioblastome cérébral suivie d'une radio chimiothérapie ont été inclus. La qualité de la réponse au traitement a été évaluée un mois après la fin de la radiochimiothérapie. La topographie des sites de récidives a été évaluée rétrospectivement après fusion de l'imagerie de récidive avec les imageries de référence pour décrire leur rapport avec le site opératoire et le volume effectif traité 95 % de la dose d'irradiation prescrite. RESULTATS : Les patients en poursuite évolutive (41,5 % ; 22/53) avaient tendance à former des foyers de récidive multiples disséminés (p < 0,2), situés au contact et à distance de la cavité opératoire (p < 0,2), préférentiellement sur le résidu tumoral post opératoire (p = 0,016). Bien que les patients en réponse optimale ou rémission (32,1 % ; 17/53) aient récidivé surtout localement, ils avaient tendance à développer plus de lésions soit au contact du cortex (p < 0,09) soit au contact des ventricules cérébraux, plus souvent à plus de 1 cm du site opératoire (p = 0,037) mais souvent dans le volume irradié par au moins 97 % de la dose. Les patients en réponse suboptimale (26,4 %, 14/53) avaient un profil de récidive intermédiaire. La médiane de survie globale était respectivement de 25,1 mois en cas de réponse optimale, de 19,2 mois en cas de réponse suboptimale et de 11,1 mois en cas de poursuite évolutive (p < 0,0001). CONCLUSION : La mise en rémission des patients constatée un mois après la fin du traitement multimodal n'a pas modifié de manière évidente la topographie de la récidive. Néanmoins, la qualité de la réponse initiale semblerait être liée à des profils de récidive différents.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Expression des métalloprotéases dans les médulloblastomes

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

Stabilisation de l'équation de la chaleur commandée en flux

On considère une barre finie, chauffée à une extrêmité, la température de l'autre extrêmité étant mesurée. Des méthodes sont proposées pour stabiliser le système, autrement dit déterminer le flux de chaleur en fonction de la température de façon à ce que la température atteigne asymptotiquement une valeur prescrite. Une approche symbolique est utilisée. Il est bien connu que l'équation de la chaleur à une dimension d'espace conduit à un transfert qui est rationnel en la racine carrée de la variable de Laplace et en son exponentielle. Cela permet d'adapter des méthodes connues de stabilisation des systèmes à retards. Les lois de commande obtenues sont convolutives: le flux de chaleur est déterminé par une convolution de la température et, éventuellement, de sa dérivée