Troubles post-traumatiques chez des sujets ayant été victimes de violences sexuelles avant l'âge de 15 ans : aspects cliniques, thérapeutiques et médico-économiques

Post-traumatic disorders in patients who have experienced sexual violence before the age of 15: clinical, therapeutic and medico-economic aspects.Before their majority, up to 10% of women and 5% of men are victims of sexual violence. The legal framework provided consensual definition of this acts. Epidemiological data and publications help us characterize risk factors, the psychopathology and comorbidities observed in victims. Like so, most are women, know their assaulter in three quarter of cases; them, mainly men, have for half, less than 20 years. Disorders reported, including post-traumatic stress disorder, depression, personality disorder and somatic troubles, must have taken specific care, following several axes: psychotherapy (in first line cognitive-behavioral therapy), medication, but also social and juridical. International studies have examined the broad cost of these assaults. At our level, we seek to assess the direct cost for health, in people who have suffered sexual violences before 15 years old. With 15 subjects followed in 2012 at Tenon Hospital in Paris, despite our small sample, the calculated annual total medical consumption is significantly ten times higher then the french national average. By their societal, financial, moral and mental cost, sexual abuse of minors, should be a public health concern. In these times of financial reflexion, funds could be deployed to medical, legal and social training, in order to improve the prevention, screening and care of victims but also their kinfolk.Avant leur majorité, jusqu’à 10% des femmes et 5% des hommes sont victimes de violences sexuelles. Le cadre juridique fournit les définitions consensuelles de ces actes. Les données épidémiologiques et de la littérature aident à caractériser les facteurs de risques, la psychopathologie et les comorbidités observés chez les victimes. Ainsi, majoritairement féminines, elles connaissent leur agresseur dans trois quart des cas ; eux, surtout masculins, ont pour la moitié moins de 20 ans. Les troubles rapportés, dont l’état de stress post traumatique, la dépression, les troubles de personnalité et les manifestations somatiques, doivent bénéficier de prises en charge spécifiques suivant plusieurs axes : psychothérapeutique (en première ligne les thérapies cognitivo-comportementales), médicamenteux, mais aussi social et juridique. Des études internationales se sont penchées sur les coûts au sens large de ces agressions. À notre échelle, nous cherchons à évaluer les dépenses directes de santé, chez des sujets ayant été victimes de violences sexuelles avant l’âge de 15 ans. Chez 15 sujets suivis en 2012 à l’hôpital Tenon de Paris, la consommation médicale totale annuelle calculée est dix fois supérieure à la moyenne nationale française, de manière significative et ce malgré notre petit échantillon. Les violences sexuelles sur mineurs, de par leur coût sociétal, financier, moral et psychique, devraient être une préoccupation de santé publique. En ces temps de réflexion budgétaire, des moyens pourraient être donnés aux formations médicales, juridiques et sociales, améliorant le travail de prévention, de repérage et de prise en charge des victimes mais aussi de leur entourage

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

International audienceTubulin is subject to a wide variety of posttranslational modifications, which, as part of the tubulin code, are involved in the regulation of microtubule functions. Glycylation has so far predominantly been found in motile cilia and flagella, and absence of this modification leads to ciliary disassembly. Here, we demonstrate that the correct functioning of connecting cilia of photoreceptors, which are non-motile sensory cilia, is also dependent on glycylation. In contrast to many other tissues, only one glycylase, TTLL3, is expressed in retina. Ttll3 −/− mice lack glycylation in photoreceptors, which results in shortening of connecting cilia and slow retinal degeneration. Moreover, absence of glycylation results in increased levels of tubulin glutamylation in photoreceptors, and inversely, the hyperglutamylation observed in the Purkinje cell degeneration (pcd) mouse abolishes glycylation. This suggests that both posttranslational modifications compete for modification sites, and that unbalancing the glutamylation-glycylation equilibrium on axonemes of connecting cilia, regardless of the enzymatic mechanism, invariably leads to retinal degeneration

Cortical branched actin determines cell cycle progression

International audienc

Expression analysis of mitotic spindle checkpoint genes in breast carcinoma: role of NDC80/HEC1 in early breast tumorigenicity, and a two-gene signature for aneuploidy

<p>Abstract</p> <p>Background</p> <p>Aneuploidy and chromosomal instability (CIN) are common abnormalities in human cancer. Alterations of the mitotic spindle checkpoint are likely to contribute to these phenotypes, but little is known about somatic alterations of mitotic spindle checkpoint genes in breast cancer.</p> <p>Methods</p> <p>To obtain further insight into the molecular mechanisms underlying aneuploidy in breast cancer, we used real-time quantitative RT-PCR to quantify the mRNA expression of 76 selected mitotic spindle checkpoint genes in a large panel of breast tumor samples.</p> <p>Results</p> <p>The expression of 49 (64.5%) of the 76 genes was significantly dysregulated in breast tumors compared to normal breast tissues: 40 genes were upregulated and 9 were downregulated. Most of these changes in gene expression during malignant transformation were observed in epithelial cells.</p> <p>Alterations of nine of these genes, and particularly <it>NDC80</it>, were also detected in benign breast tumors, indicating that they may be involved in pre-neoplastic processes.</p> <p>We also identified a two-gene expression signature (<it>PLK1 </it>+ <it>AURKA</it>) which discriminated between DNA aneuploid and DNA diploid breast tumor samples. Interestingly, some DNA tetraploid tumor samples failed to cluster with DNA aneuploid breast tumors.</p> <p>Conclusion</p> <p>This study confirms the importance of previously characterized genes and identifies novel candidate genes that could be activated for aneuploidy to occur. Further functional analyses are required to clearly confirm the role of these new identified genes in the molecular mechanisms involved in breast cancer aneuploidy. The novel genes identified here, and/or the two-gene expression signature, might serve as diagnostic or prognostic markers and form the basis for novel therapeutic strategies.</p

Up-regulation of flotillins, new marker of metastatic development, induces cell invasion and metastatic development

Flotillin 1 and 2 are two ubiquitous, highly conserved and related proteins present in man

Fractalkine Expression Induces Endothelial Progenitor Cell Lysis by Natural Killer Cells

BACKGROUND: Circulating CD34(+) cells, a population that includes endothelial progenitors, participate in the maintenance of endothelial integrity. Better understanding of the mechanisms that regulate their survival is crucial to improve their regenerative activity in cardiovascular and renal diseases. Chemokine-receptor cross talk is critical in regulating cell homeostasis. We hypothesized that cell surface expression of the chemokine fractalkine (FKN) could target progenitor cell injury by Natural Killer (NK) cells, thereby limiting their availability for vascular repair. METHODOLOGY/PRINCIPAL FINDINGS: We show that CD34(+)-derived Endothelial Colony Forming Cells (ECFC) can express FKN in response to TNF-α and IFN-γ inflammatory cytokines and that FKN expression by ECFC stimulates NK cell adhesion, NK cell-mediated ECFC lysis and microparticles release in vitro. The specific involvement of membrane FKN in these processes was demonstrated using FKN-transfected ECFC and anti-FKN blocking antibody. FKN expression was also evidenced on circulating CD34(+) progenitor cells and was detected at higher frequency in kidney transplant recipients, when compared to healthy controls. The proportion of CD34(+) cells expressing FKN was identified as an independent variable inversely correlated to CD34(+) progenitor cell count. We further showed that treatment of CD34(+) circulating cells isolated from adult blood donors with transplant serum or TNF-α/IFN-γ can induce FKN expression. CONCLUSIONS: Our data highlights a novel mechanism by which FKN expression on CD34(+) progenitor cells may target their NK cell mediated killing and participate to their immune depletion in transplant recipients. Considering the numerous diseased contexts shown to promote FKN expression, our data identify FKN as a hallmark of altered progenitor cell homeostasis with potential implications in better evaluation of vascular repair in patients

Identification of 5 novel genes methylated in breast and other epithelial cancers

<p>Abstract</p> <p>Background</p> <p>There are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer.</p> <p>Results</p> <p>Using this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; <it>EMILIN2, SALL1</it>, <it>DBC1</it>, <it>FBLN2 </it>and <it>CIDE-A</it>. Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of <it>EMILIN2 </it>was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers.</p> <p>Conclusion</p> <p>The combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy.</p

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7–3.4 mM–1·s–1, at 1.41 T and 37 °C)

Upregulated flotillins and sphingosine kinase 2 derail AXL vesicular traffic to promote epithelial-mesenchymal transition

Altered endocytosis and vesicular trafficking are major players during tumorigenesis. Flotillin overexpression, a feature observed in many invasive tumors and identified as a marker of poor prognosis, induces a deregulated endocytic and trafficking pathway called upregulated flotillin-induced trafficking (UFIT). Here, we found that in non-tumoral mammary epithelial cells, induction of the UFIT pathway promotes epithelial-to-mesenchymal transition (EMT) and accelerates the endocytosis of several transmembrane receptors, including AXL, in flotillin-positive late endosomes. AXL overexpression, frequently observed in cancer cells, is linked to EMT and metastasis formation. In flotillin-overexpressing non-tumoral mammary epithelial cells and in invasive breast carcinoma cells, we found that the UFIT pathway-mediated AXL endocytosis allows its stabilization and depends on sphingosine kinase 2, a lipid kinase recruited in flotillin-rich plasma membrane domains and endosomes. Thus, the deregulation of vesicular trafficking following flotillin upregulation, and through sphingosine kinase 2, emerges as a new mechanism of AXL overexpression and EMT-inducing signaling pathway activation.This work was supported by the Fondation pour la Recherche Médicale (DEQ20161136700) and the Fondation ARC pour la recherche sur le cancer (ARCPJA32020060002078). Collection of breast tumor samples was supported by the Russian Science Foundation (19-75-30016). C.G.-R. was supported by the Institut National de la Santé et de la Recherche Médicale.Peer reviewe