Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study.

INTRODUCTION: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS. METHODS: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion. RESULTS: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9). CONCLUSIONS: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis.

CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors.

BACKGROUND: Tumor initiating cells (TICs) provide a new paradigm for developing original therapeutic strategies. METHODS: We screened for TICs in 47 human adult brain malignant tumors. Cells forming floating spheres in culture, and endowed with all of the features expected from tumor cells with stem-like properties were obtained from glioblastomas, medulloblastoma but not oligodendrogliomas. RESULTS: A long-term self-renewal capacity was particularly observed for cells of malignant glio-neuronal tumors (MGNTs). Cell sorting, karyotyping and proteomic analysis demonstrated cell stability throughout prolonged passages. Xenografts of fewer than 500 cells in Nude mouse brains induced a progressively growing tumor. CD133, CD15/LeX/Ssea-1, CD34 expressions, or exclusion of Hoechst dye occurred in subsets of cells forming spheres, but was not predictive of their capacity to form secondary spheres or tumors, or to resist high doses of temozolomide. CONCLUSIONS: Our results further highlight the specificity of a subset of high-grade gliomas, MGNT. TICs derived from these tumors represent a new tool to screen for innovative therapies.

S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage.

During the postnatal development, astrocytic cells in the neocortex progressively lose their neural stem cell (NSC) potential, whereas this peculiar attribute is preserved in the adult subventricular zone (SVZ). To understand this fundamental difference, many reports suggest that adult subventricular GFAP-expressing cells might be maintained in immature developmental stage. Here, we show that S100B, a marker of glial cells, is absent from GFAP-expressing cells of the SVZ and that its onset of expression characterizes a terminal maturation stage of cortical astrocytic cells. Nevertheless, when cultured in vitro, SVZ astrocytic cells developed as S100B expressing cells, as do cortical astrocytic cells, suggesting that SVZ microenvironment represses S100B expression. Using transgenic s100b-EGFP cells, we then demonstrated that S100B expression coincides with the loss of neurosphere forming abilities of GFAP expressing cells. By doing grafting experiments with cells derived from beta-actin-GFP mice, we next found that S100B expression in astrocytic cells is repressed in the SVZ, but not in the striatal parenchyma. Furthermore, we showed that treatment with epidermal growth factor represses S100B expression in GFAP-expressing cells in vitro as well as in vivo. Altogether, our results indicate that the S100B expression defines a late developmental stage after which GFAP-expressing cells lose their NSC potential and suggest that S100B expression is repressed by adult SVZ microenvironment.

Zfp423 controls proliferation and differentiation of neural precursors in cerebellar vermis formation.

Neural stem cells and progenitors in the developing brain must choose between proliferation with renewal and differentiation. Defects in navigating this choice can result in malformations or cancers, but the genetic mechanisms that shape this choice are not fully understood. We show by positional cloning that the 30-zinc finger transcription factor Zfp423 (OAZ) is required for patterning the development of neuronal and glial precursors in the developing brain, particularly in midline structures. Mutation of Zfp423 results in loss of the corpus callosum, reduction of hippocampus, and a malformation of the cerebellum reminiscent of human Dandy-Walker patients. Within the cerebellum, Zfp423 is expressed in both ventricular and external germinal zones. Loss of Zfp423 results in diminished proliferation by granule cell precursors in the external germinal layer, especially near the midline, and abnormal differentiation and migration of ventricular zone-derived neurons and Bergmann glia.

Nuclear expression of S100B in oligodendrocyte progenitor cells correlates with differentiation toward the oligodendroglial lineage and modulates oligodendrocytes maturation.

The S100B protein belongs to the S100 family of EF-hand calcium binding proteins implicated in cell growth and differentiation. Here, we show that in the developing and the adult mouse brain, S100B is expressed in oligodendroglial progenitor cells (OPC) committed to differentiate into the oligodendrocyte (OL) lineage. Nuclear S100B accumulation in OPC correlates with the transition from the fast dividing multipotent stage to the morphological differentiated, slow proliferating, pro-OL differentiation stage. In the adult, S100B expression is down-regulated in mature OLs that have established contacts with their axonal targets, suggesting a nuclear S100B function during oligodendroglial cells maturation. In vitro, the morphological transformation and maturation of pro-OL cells are delayed in the absence of S100B. Moreover, mice lacking S100B show an apparent delay in OPC maturation in response to demyelinating insult. We propose that nuclear S100B participates in the regulation of oligodendroglial cell maturation.