Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Construire l'espace (étude des processus gnératifs et schématiques dans les Rougon-Macquart d'Emile Zola et leurs dossiers préparatoires)

L'oeuvre d'art est un coin de la création vu à travers un tempérament de géomètre. Ainsi pourrait se résumer cette étude, qui s'intéresse à la construction de l'espace romanesque dans les avant-textes des Rougon-Macquart d'Emile Zola, selon un point de vue qui privilégie les figures spatiales géométriques. Le point, la ligne, le carré, le cercle, la croisée et l'arbre, souvent abordés comme thèmes indépendants du roman zolien, construisent un imaginaire dense et organique, dans la genèse de l'espace. De l'ébauche aux plans, en passant par les dessins de l'écrivain, s'élabore une poïétique de la figurativité, ancrée dans l'imagerie mentale du romancier, dont cette thèse tente d'élaborer la théorie...The work of art is a part of creation seen through a geometrician's eye. That is how we could summarize this study, which concerns the construction of the novelistic space in the preliminary texts of Emile Zola's Rougon-Macquart, from a point of view which favours the geometrical space figures. The point, the line, the square, the circle, the crossing and the tree, often broached as independant themes in Zola's novel, build a compact and organic imaginative world in the space genesis. From the outline to the plans, to the writer's drawings, a poietics of figurativity, fixed in the novelist's mental imagery, is eleborated, the theory of which this thesis is trying to work out...PARIS3-BU (751052102) / SudocSudocFranceF

Revealing strategic conversations around future visions of agriculture to improve the debate

To address sustainability of agro-food systems, different innovation models are proposed, which carry underlying pathways for change. Making explicit the divergences between these visions for the future could give more visibility to alternative visions, which otherwise could be dismissed by visions of the dominant regime. The generation and discussion of future visions for agro-food systems can open up or close down options for radical change. Therefore, we aim at analysing the cross-relations between the representations of pathways for change carried by actors and their strategies for change. We follow future-oriented debates, consisting both of a corpus of future representations, and of a community of actors associated to their discussion. We focus on one case study: the future-oriented debate on agriculture and water quality, in the Seine river watershed in France (between 2000 and 2016). We organise the materials from documentary sources and interviews through a narrative of the links between the future-oriented debate and strategies. Our results highlight three types of strategies: (i) opening the map of options for change; (ii) promoting radical change for agro-food systems; (iii) using the future-oriented debate to build an intervention strategy. We identify a gap in this debate: very few explicit transition pathways exist, while it may improve their credibility. We show that some alternative visions integrate performance criteria of the dominant narrative to strengthen their credibility. We conclude by suggesting that another strategy could be to embed future visions in a consistent alternative narrative, revealing the social dimension of water management by agriculture

Juvenile amyotrophic lateral sclerosis associated with biallelic c.757delG mutation of sorbitol dehydrogenase gene

International audienceMutation in the sorbitol dehydrogenase gene (SORD) has been recently described to cause axonal Charcot-Marie-Tooth disease (CMT), intermediate CMT, and distal hereditary motor neuropathy (dHMN). We herein report the case of a 24-year-old patient diagnosed with juvenile amyotrophic lateral sclerosis (JALS) who carried the homozygous c.757delG mutation in SORD. No other pathogenic variant in frequent JALS-causative genes was found. Our findings expand the phenotype related to SORD mutation, a new and potentially treatable genetic disease

Intermediate C9orf72 repeat numbers are not ALS risk factors

International audienceIntroduction:Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. The C9orf72 repeat expansion is the most common genetic cause of the disease. Initial findings have set the pathogenic cut-off to 30 repeat. However, intermediate repeat numbers between 16 and 30 have also been proposed to be associated with ALS risk. As most studies rely on ALS patients, we performed a case-control study in a French cohort to understand the involvement of intermediate repeats on the ALS risk.Methods:In a cohort of 412 C9orf72-negative sporadic ALS patients and 327 healthy controls, the C9orf72 repeat number was assessed by Repeat-Primed PCR.Results:The most frequent alleles were two, five and eight repeats both in ALS and control groups. The highest repeat number was 22 in controls and 26 in patients. The allelic distribution was not significantly different between both groups.Conclusions:These findings show a lack of association between C9orf72 intermediate repeat numbers and the risk of developing ALS. These data suggest that repeat numbers below 30 are not an ALS risk factor in the French population and confirms the definition of theC9orf72 pathogenic cut-off

Assessing intratumor distribution and uptake with MBBG versus MIBG imaging and targeting xenografted PC12-pheochromocytoma cell line

The heterogeneity of tumor uptake is likely to substantially limit the effectiveness of metaiodobenzylguanidine (MIBG) therapy. This study was done to establish whether metabromobenzyl-guanidine (MBBG) can target neuroendocrine tumors and to provide intratumor biodistribution and uptake information in comparison to MIBG. Methods: MBBG and MIBG tumor uptake and kinetic studies were performed in experimental PC-12 pheochromocytoma grown in nude mice. Intratumor distribution studies were performed using autoradiography and secondary ion mass spectrometry (SIMS) microscopy, because the latter technique can detect and potentially quantify both drugs concomitantly within the same tumor specimen. Results: MBBG uptake in PC12 tumors was early (2 hr) and intense (80% ID/g). Retention values were similar for both drugs 24 hr postinjection. At the cellular level, MBBG mostly accumulated in the cytosol. At the multicellular level, cells exhibited staining, but in many areas, SIMS images of both drugs were not spatially correlated. Conclusion: MBBG targeted experimental pheochromocytoma efficiently with high early uptake values. Bromine-76-MBBG is a promising means of imaging and quantifying tumor uptake with PET. Both drugs were localized in the cytosol, but the correlation between the two distributions, as assessed by the values of the standardized local concentrations, was weak although significant multicellularly

Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer

International audiencePURPOSE:Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity.METHODS:Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity.RESULTS:The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed.CONCLUSIONS:Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer

Analysis of Morbidity and Clinical Implications of Laparoscopic Para-Aortic Lymphadenectomy in a Continuous Series of 98 Patients with Advanced-Stage Cervical Cancer and Negative PET–CT Imaging in the Para-Aortic Area

A series of patients with locally advanced cervical cancer, with no positive para-aortic nodes on positron emission tomography–computed tomography who had undergone a primary laparoscopic para-aortic lymphadenectomy was retrospectively reviewed. Morbidity was limited and the completion of treatment was not delayed when complications occurred

Liver X Receptor Genes Variants Modulate ALS Phenotype

International audienceAmyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics

Les répétitions intermédiaires GGGGCC du gène C9ORF72 ne sont pas un facteur de risque de SLA.

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