p73α isoforms drive opposite transcriptional and post-transcriptional regulation of MYCN expression in neuroblastoma cells

MYCN activation, mainly by gene amplification, is one of the most frequent molecular events in neuroblastoma (NB) oncogenesis, and is associated with increased malignancy and decreased neuronal differentiation propensity. The frequency of concomitant loss of heterozygosity at the 1p36.3 locus, which harbours the p53 anti-oncogene homologue TP73, indicates that MYCN and p73 alterations may cooperate in the pathogenesis of NB. We have previously shown that p73 isoforms are deregulated in NB tumours and that TAp73 co-operates synergistically with p53 for apoptosis of NB cells, whereas ΔNp73 activates the expression of neuronal differentiation genes such as BTG2. Herein, using both ectopic expression and RNA interference-mediated silencing of p73 in MYCN amplified NB cells, we show that p73α isoforms inhibit MYCN expression at both transcript and protein levels, in spite of transactivator effects on MYCN promoter. To explain this paradox, we found that TAp73α exerts negative post-transcriptional effects leading to reduced MYCN mRNA stability. RNA immunoprecipitation experiments suggest that this dominant inhibitory post-transcriptional effect could be due to an interaction between the p73 protein and MYCN mRNA, a hypothesis also raised for the regulation of certain genes by the p53 protein

Professional categories in social law : a reflective contrasting between the executive and non-executive categories

Préciser la notion de catégorie professionnelle est un exercice essentiel. Les enjeux sont multiples. Ils intéressent la rémunération, le temps de travail, la protection sociale complémentaire, la représentation collective, etc. La reconnaissance des catégories professionnelles, notamment au travers de la distinction des cadres et des non-cadres, participe à l’organisation de l’entreprise et contribue au respect du principe d’égalité de traitement. Cet exercice se révèle néanmoins délicat : le législateur n’a pas précisé les contours du concept de catégorie professionnelle ; la mutation des formes de travail, se traduisant parfois par une uniformisation des fonctions dans l’entreprise, modifie le paysage. Le rôle des partenaires sociaux pour apporter quelque clarté est souvent décisif.The conceptual definition of professional classifications is an essential exercise since the stakes are high. It affects wages, working hours, complementary social security, collective representation, etc. The identification of professional categories, particularly between the executive and non-executive categories, helps in the organization of companies and contributes to the application of equal treatment principle. This exercise is nevertheless delicate because the legislator has not previously provided a precise conceptual delineation of professional categories ; the changes in the forms of work, sometimes reflected by a standardization of the roles within the company, is changing the landscape. The role of social partners is often critical in providing some clarification

Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

International audienceObjectives: To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods: Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results: The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions: Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues

L’année 2021 dans tous ses états : une synthèse digérée

International audience5548 Background: Ovarian cancer is the leading cause of death by gynecological cancer. Complete surgery remains one of the main prognostic factors. Laparoscopic exploration is mandatory to assess surgical resectability at diagnosis or after neoadjuvant chemotherapy. However, there is no clinical or biological marker that can correctly predict resectability and may be able to avoid a second laparoscopic exploration for initially unresectable diseases. Our aim was to assess circulating tumor DNA (ctDNA) value as a predictive non-invasive marker of evolution towards resectability for patients with epithelial ovarian cancer receiving first-line chemotherapy. Methods: We explored in this work one of the secondary objectives of the CIDOC study (NCT03302884). CIDOC is a multicenter prospective study aiming to explore ctDNA value as early marker of disease relapse after first-line treatment for epithelial ovarian cancer. Patients with mucinous histology or early stages not requiring chemotherapy are excluded. Plasma samples are collected at diagnosis, during neoadjuvant chemotherapy, and during follow-up. After DNA extraction, panel-based next generation sequencing is performed on both tumor samples and germline DNA, and somatic mutations of interest are selected for ctDNA monitoring. ctDNA analyses are conducted using droplet digital PCR (BioRad QX200) by measuring the variant allele fraction (VAF) of previously identified mutations. Results: This intermediary analysis has included 47 patients diagnosed between March 2017 and December 2019. Median age was 69 years old (48 – 84). Most of the patients had advanced disease (89.4% stage FIGO III or IV), serous histology (94.8%), and high grade tumor (92.3%). Most of the patients underwent complete interval cytoreductive surgery (76.3% vs 17.4% complete upfront surgery). Most of the tumors had TP53 mutations (85.1%), following by alterations involving DNA repair genes (38.3%). Median cell-free DNA concentration at baseline was 0.38 ng/µL (0 – 12.8). ctDNA was identified in 92.1% of patients at baseline with a median VAF of 1.84% (0 – 42.52%). ctDNA VAF was correlated to the peritoneal dissemination ( p= 0.039) assessed with the peritoneal cancer index. ctDNA clearance after preoperative chemotherapy tended to be correlated to achievement of complete interval surgery for patients receiving neoadjuvant chemotherapy ( p= 0.108). Conclusions: ctDNA may be a promising non-invasive marker to assess peritoneal cancer spreading and to predict surgical resectability after neoadjuvant chemotherapy. If confirmed in larger populations, this may enable to avoid additional surgical explorations for patients who remain ctDNA positive after chemotherapy. Clinical trial information: NCT03302884

Measurement of the Ωc0\Omega_c^0 lifetime at Belle II

We report on a measurement of the $\Omega_c^0$ lifetime using $\Omega_c^0 \to \Omega^-\pi^+$ decays reconstructed in $e^+e^-\to c\bar{c}$ data collected by the Belle II experiment and corresponding to $207~{\rm fb^{-1}}$ of integrated luminosity. The result, $\rm\tau(\Omega_c^0)=243\pm48( stat)\pm11(syst)~fs$, agrees with recent measurements indicating that the $\Omega_c^0$ is not the shortest-lived weakly decaying charmed baryon

Measurement of the Ωc0\Omega_c^0 lifetime at Belle II

We report on a measurement of the $\Omega_c^0$ lifetime using $\Omega_c^0 \to \Omega^-\pi^+$ decays reconstructed in $e^+e^-\to c\bar{c}$ data collected by the Belle II experiment and corresponding to $207~{\rm fb^{-1}}$ of integrated luminosity. The result, $\rm\tau(\Omega_c^0)=243\pm48( stat)\pm11(syst)~fs$, agrees with recent measurements indicating that the $\Omega_c^0$ is not the shortest-lived weakly decaying charmed baryon

Measurement of the Ωc0\Omega_c^0 lifetime at Belle II

We report on a measurement of the $\Omega_c^0$ lifetime using $\Omega_c^0 \to \Omega^-\pi^+$ decays reconstructed in $e^+e^-\to c\bar{c}$ data collected by the Belle II experiment and corresponding to $207~{\rm fb^{-1}}$ of integrated luminosity. The result, $\rm\tau(\Omega_c^0)=243\pm48( stat)\pm11(syst)~fs$, agrees with recent measurements indicating that the $\Omega_c^0$ is not the shortest-lived weakly decaying charmed baryon

Test of light-lepton universality in τ\tau decays with the Belle II experiment

International audienceWe present a measurement of the ratio $R_\mu = \mathcal{B}(\tau^-\to \mu^-\bar\nu_\mu\nu_\tau) / \mathcal{B}(\tau^-\to e^-\bar\nu_e\nu_\tau)$ of branching fractions $\mathcal{B}$ of the $\tau$ lepton decaying to muons or electrons using data collected with the Belle II detector at the SuperKEKB $e^+e^-$ collider. The sample has an integrated luminosity of 362 fb$^{-1}$ at a centre-of-mass energy of 10.58 GeV. Using an optimised event selection, a binned maximum likelihood fit is performed using the momentum spectra of the electron and muon candidates. The result, $R_\mu = 0.9675 \pm 0.0007 \pm 0.0036$, where the first uncertainty is statistical and the second is systematic, is the most precise to date. It provides a stringent test of the light-lepton universality, translating to a ratio of the couplings of the muon and electron to the $W$ boson in $\tau$ decays of $0.9974 \pm 0.0019$, in agreement with the standard model expectation of unity

Doravirine plus lamivudine two-drug regimen as maintenance antiretroviral therapy in people living with HIV: a French observational study

International audienceBackground: Two-drug regimens based on integrase strand transfer inhibitors (INSTIs) and boosted PIs have entered recommended ART. However, INSTIs and boosted PIs may not be suitable for all patients. We aimed to report our experience with doravirine/lamivudine as maintenance therapy in people living with HIV (PLWH) followed in French HIV settings.Methods: This observational study enrolled all adults who initiated doravirine/lamivudine between 1 September 2019 and 31 October 2021, in French HIV centres participating in the Dat'AIDS cohort. The primary outcome was the rate of virological success (plasma HIV-RNA < 50 copies/mL) at Week (W)48. Secondary outcomes included: rate of treatment discontinuation for non-virological reasons, evolution of CD4 count and CD4/CD8 ratio over follow-up.Results: Fifty patients were included, with 34 (68%) men; median age: 58 years (IQR 51-62), ART duration: 20 years (13-23), duration of virological suppression: 14 years (8-19), CD4 count: 784 cells/mm3 (636-889). Prior to switching, all had plasma HIV-RNA < 50 copies/mL. All but three were naive to doravirine, and 36 (72%) came from a three-drug regimen. Median follow-up was 79 weeks (IQR 60-96). Virological success rate at W48 was 98.0% (95% CI 89.4-99.9). One virological failure occurred at W18 (HIV-RNA = 101 copies/mL) in a patient who briefly discontinued doravirine/lamivudine due to intense nightmares; there was no resistance at baseline and no resistance emergence. There were three strategy discontinuations for adverse events (digestive disorders: n = 2; insomnia: n = 1). There was no significant change in CD4/CD8 ratio, while CD4 T cell count significantly increased.Conclusions: These preliminary findings suggest that doravirine/lamivudine regimens can maintain high levels of viral suppression in highly ART-experienced PLWH with long-term viral suppression, and good CD4+ T cell count