P75 neurotrophin receptor is sequestered in the Golgi apparatus of the U-87 MG human glioblastoma cell line.

International audienceThe P75 neurotrophin receptor (p75NTR) is a cell surface receptor that can induce apoptosis in many cell types. This receptor plays a major role in the development of the central nervous system and is expressed in some adult brain cells. Its implication in cell apoptosis or survival is probably of major importance in cellular homeostasis and thus p75NTR could be implicated in tumor resistance to death. In this study, we investigated the intracellular expression of p75NTR in a human glioblastoma cell line. Detection of p75NTR receptor in Golgi apparatus by immunofluorescence microscopy, or after Golgi apparatus extraction, could be correlated with a decrease of cell apoptosis leading cells to become tumorous. This hypothesis is supported by a loss of ligand-induced apoptosis in this cell line. Our observations show that p75NTR can be sequestered in the Golgi complex and could then be, in part, responsible for the cell resistance to apoptosis and for brain tumor formation

Decrease in Fas-induced apoptosis by the γ-secretase inhibitor is dependent on p75(NTR) in a glioblastoma cell line.

International audiencep75(NTR), a member of the tumor necrosis factor superfamily, plays a key role in numerous physiological processes, including cell survival or apoptosis. Yet, the associated signaling pathways remain poorly understood. Similar to Notch, γ-secretase cleavage is implicated in the p75(NTR) signaling pathway leading to nuclear translocation of the intracellular domain and cell death. Fas receptor activation was found to promote cell death apoptosis in several cell lines. The goal of this study was to determine the respective role of p75(NTR) and Notch in the resistance to Fas-induced apoptosis in the U-87 MG glioblastoma cell line. Using the γ-secretase inhibitor, we investigated the modulation of Fas-induced apoptosis dependent on p75(NTR)-Fas receptor interaction. Whereas the U-87 MG cells expressed the Fas receptor at the cell membrane, apoptosis induced by Fas activation was decreased by the γ-secretase inhibitor. These data suggest that γ-secretase is implicated in p75(NTR) and Fas interaction leading to cell death signaling

A new role under sortilin's belt in cancer.

The neurotensin receptor-3 also known as sortilin was the first member of the small family of vacuolar protein sorting 10 protein domain (Vps10p) discovered two decades ago in the human brain. The expression of sortilin is not confined to the nervous system but sortilin is ubiquitously expressed in many tissues. Sortilin has multiple roles in the cell as a receptor or a co-receptor, in protein transport of many interacting partners to the plasma membrane, to the endocytic pathway and to the lysosomes for protein degradation. Sortilin could be considered as the cells own shuttle system. In many human diseases including neurological diseases and cancer, sortilin expression has been shown to be deregulated. In addition, some studies have highlighted that the extracellular domain of sortilin is shedded into the culture media by an unknown mechanism. Sortilin can be released in exosomes and appears to control some mechanisms of exosome biogenesis. In lung cancer cells, sortilin can associate with two receptor tyrosine kinase receptors called the TES complex found in exosomes. Exosomes carrying the TES complex can convey a microenvironment control through the activation of ErbB signaling pathways and the release of angiogenic factors. Deregulation of sortilin function is now emerging to be implicated in four major human diseases- cardiovascular disease, Type 2 diabetes mellitus, Alzheimer’s disease and cancer

Targeted Sub-Attomole Cancer Biomarker Detection Based on Phase Singularity 2D Nanomaterial-Enhanced Plasmonic Biosensor

Detection of small cancer biomarkers with low molecular weight and a low concentration range has always been challenging yet urgent in many clinical applications such as diagnosing early-stage cancer, monitoring treatment and detecting relapse. Here, a highly enhanced plasmonic biosensor that can overcome this challenge is developed using atomically thin two-dimensional phase change nanomaterial. By precisely engineering the configuration with atomically thin materials, the phase singularity has been successfully achieved with a significantly enhanced lateral position shift effect. Based on our knowledge, it is the first experimental demonstration of a lateral position signal change > 340 μm at a sensing interface from all optical techniques. With this enhanced plasmonic effect, the detection limit has been experimentally demonstrated to be 10–15 mol L−1 for TNF-α cancer marker, which has been found in various human diseases including inflammatory diseases and different kinds of cancer. The as-reported novel integration of atomically thin Ge2Sb2Te5 with plasmonic substrate, which results in a phase singularity and thus a giant lateral position shift, enables the detection of cancer markers with low molecular weight at femtomolar level. These results will definitely hold promising potential in biomedical application and clinical diagnostics

The Lengthening of a Giant Protein: When, How, and Why?

Abstract Subcommissural organ (SCO)-spondin is a giant glycoprotein of more than 5000 amino acids found in Vertebrata, expressed in the central nervous system and constitutive of Reissner's fiber. For the first time, in situ hybridization performed on zebrafish (Danio rerio) embryos shows that the gene encoding this protein is expressed transitionally in the floor plate, the ventral midline of the neural tube, and later in the diencephalic third ventricle roof, the SCO. The modular organization of the protein in Echinodermata (Strongylocentrotus purpuratus), Urochordata (Ciona savignyi and C. intestinalis), and Vertebrata (Teleostei, Amphibia, Aves and Mammalia) is also described. As the thrombospondin type 1 repeat motifs represent an increasingly large part of the protein during Deuterostomia evolution, the duplication mechanisms leading to this complex organization are examined. The functional significance of the particularly well-preserved arrangement of the series of SCO-spondin repeat motifs and thombospondin type 1 repeats is discussed

Clinical management of molecular alterations identified by high throughput sequencing in patients with advanced solid tumors in treatment failure: Real-world data from a French hospital

BackgroundIn the context of personalized medicine, screening patients to identify targetable molecular alterations is essential for therapeutic decisions such as inclusion in clinical trials, early access to therapies, or compassionate treatment. The objective of this study was to determine the real-world impact of routine incorporation of FoundationOne analysis in cancers with a poor prognosis and limited treatment options, or in those progressing after at least one course of standard therapy.MethodsA FoundationOneCDx panel for solid tumor or liquid biopsy samples was offered to 204 eligible patients.ResultsSamples from 150 patients were processed for genomic testing, with a data acquisition success rate of 93%. The analysis identified 2419 gene alterations, with a median of 11 alterations per tumor (range, 0–86). The most common or likely pathogenic variants were on TP53, TERT, PI3KCA, CDKN2A/B, KRAS, CCDN1, FGF19, FGF3, and SMAD4. The median tumor mutation burden was three mutations/Mb (range, 0–117) in 143 patients with available data. Of 150 patients with known or likely pathogenic actionable alterations, 13 (8.6%) received matched targeted therapy. Sixty-nine patients underwent Molecular Tumor Board, which resulted in recommendations in 60 cases. Treatment with genotype-directed therapy had no impact on overall survival (13 months vs. 14 months; p = 0.95; hazard ratio = 1.04 (95% confidence interval, 0.48–2.26)].ConclusionsThis study highlights that an organized center with a Multidisciplinary Molecular Tumor Board and an NGS screening system can obtain satisfactory results comparable with those of large centers for including patients in clinical trials

Serum Neurotrophin Profile in Systemic Sclerosis

International audienceBACKGROUND: Neurotrophins (NTs) are able to activate lymphocytes and fibroblasts; they can modulate angiogenesis and sympathic vascular function. Thus, they can be implicated in the three pathogenic processes of systemic sclerosis (SSc). The aims of this study are to determine blood levels of Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) in SSc and to correlate them with clinical and biological data.METHODS: Serum samples were obtained from 55 SSc patients and 32 control subjects to measure NTs levels by ELISA and to determine their relationships with SSc profiles. FINDINGS: Serum NGF levels were higher in SSc patients (288.26 ± 170.34 pg/mL) than in control subjects (170.34 ± 50.8 pg/mL, p<0.001) and correlated with gammaglobulins levels and the presence of both anti-cardiolipin and anti-Scl-70 antibodies (p<0.05). In contrast, BDNF levels were lower in SSc patients than in controls (1121.9 ± 158.1 vs 1372.9 ± 190.9 pg/mL, p<0.0001), especially in pulmonary arterial hypertension and diffuse SSc as compared to limited forms (all p<0.05). NT-3 levels were similar in SSc and in the control group (2657.2 ± 2296 vs 2959.3 ± 2555 pg/mL, NS). BDNF levels correlated negatively with increased NGF levels in the SSc group (and not in controls). CONCLUSION: Low BDNF serum levels were not previously documented in SSc, particularly in the diffuse SSc subset and in patients with pulmonary hypertension or anti-Scl-70 antibodies. The negative correlation between NGF and BDNF levels observed in SSc and not in healthy controls could be implicated in sympathic vascular dysfunction in SSc

La néoneurogénèse chez l’homme

International audienceauteurs du présent article démontrent sa présence grâce à une approche combinant l'imagerie par résonance magnétique fonctionnelle (IRMf), des marquages immuno-histo-chimiques utilisant des marqueurs spécifiques et la microscopie électro-nique. Le système neurogénique ventriculo-olfactif humain (SNVO) est organisé à partir d'une zone du cerveau adjacente à une extension du ventricule latéral jusqu'au bulbe olfactif, et il contient des neuroblastes. Ces neuroblastes ont pu être identifiés par des marqueurs cellulaires spécifiques. Dans la La présence de cellules souches neuronales et leur différentiation en neurone ont été démontrées chez de nombreuses espèces de vertébrés. Leur migration reposerait principalement sur un processus appelé courant migratoire rostral (CMR) qui constituerait la principale voie utilisée par les neuroblastes nouvel-lement formés dans la zone subventriculaire (ZSV) pour migrer dans la région bulbaire. L'existence d'un tel CMR a pu être mise en évidence chez les rongeurs mais ce mécanisme n'a toujours pas été caractérisé dans le cerveau de l'homme adulte. Les La néoneurogénèse chez l'homme Human neoneurogenis Philippe THOMAS, Fabrice LALLOUE La Revue de Gériatrie, Tome 32, N°7 SEPTEMBRE 2007 549 Maître de conférences en Neurosciences (FL), EA 3842, Homéostasie cellu-laire et pathologies, Faculté de Médecine

Cyclo-oxygenase 2 tissue distribution and developmental pattern of expression in the chicken

International audience1. Cyclo-oxygenase 2 (COX-2) is implicated in multiple physiopathological processes. We have studied its physiological expression during chicken embryogenesis. 2. An original procedure was set to prepare a COX-2 probe from red blood cells. In situ hybridization, reverse transcription-polymerase chain reaction and northern blots, were performed on chick embryos from embryonic day (E) 3 to postnatal day 15. 3. In the mesonephros, the signal detected in mesonephric tubules presented a slow increase from E5 to E9, a plateau up to E12 and then a decrease, while the signal increased in the metanephros and then decreased after hatching. Transient expression of COX-2 mRNA in endothelial cells of the infundibulum of the aorta was also detected between E12 and E17. 4. This enzyme may have important roles in kidney morphogenesis during early embryonic stages and in tubular functions during development and in adult life. In the cardiovascular system, its vasodilatory effect could modulate the vasoconstrictor effect of the systolic pressure between E12 and E17 and contribute to a normal morphogenesis of the arterial tree and heart

Méthode de Bio-détection basée sur la spectroscopie diélectrique cellulaire aux fréquences radio et microondes

National audienc