Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Simultaneous subarachnoid hemorrhage and cerebellar infarct revealing vertebral artery aneurysm : acute MRI assessment

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Mycophenolate mofetil may be effective in CNS sarcoidosis but not in sarcoid myopathy.

International audienceOBJECTIVE: To describe effectiveness, steroid-sparing effect, and tolerance of the antiproliferative immunosuppressant mycophenolate mofetil (MMF) in neurosarcoidosis. METHODS: We describe a retrospective case series of 10 consecutive patients with a diagnosis of neurosarcoidosis who were treated with MMF, alone or in association with corticosteroids, in our teaching hospital. RESULTS: At the time of our study, the mean duration of MMF treatment was 21 months. All but one patient with CNS involvement (n = 8) were in remission (except for hormonal dysfunction) which was complete in 6 patients. MMF was efficient as single-agent induction therapy in one patient. The 3 patients who received MMF as a maintenance therapy after initial response to corticosteroids did not relapse even though steroids were stopped. Out of 4 subjects who demonstrated insufficient response to prior therapy including corticosteroids and immunosuppressive agents, 3 demonstrated significant clinical and radiologic improvement. However, the 2 patients who presented muscular sarcoidosis did not respond to MMF. Among patients treated with steroids at MMF introduction and after excluding those with sarcoid myopathy, the mean dose of corticosteroids was 6 mg/day at the end of the follow-up while it was 59 mg/day at the initiation of MMF. No significant side effects were observed. CONCLUSIONS: These data suggest that MMF is effective in CNS sarcoidosis but not in sarcoid myopathy, with a corticosteroid sparing effect and a better tolerance profile than other immunosuppressive agents

Metabotropic Glutamate Receptor Type 1 Autoantibody-Associated Cerebellitis A Primary Autoimmune Disease?

Objectives: To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. Design: Case report. Setting: University hospital. Patient: A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. Results: Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and wholebody fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. Conclusions: Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible

Le cynips du châtaignier : mise en œuvre et développement de la maitrise de ce ravageur par des moyens de contrôle biologique

Pour répondre aux dégâts causés par l’arrivée du cynips (Dryocosmus kuriphilus) dans la châtaigneraie française, un programme de travail financé par le ministère de l’Agriculture dans le cadre du CASDAR a été initié avec l’ensemble des partenaires de la recherche et de l’expérimentation. Le travail de formation à la reconnaissance du parasite et à la mise en œuvre de la lutte biologique avec le parasitoïde Torymus sinensis a permis de suivre la progression du ravageur et de déployer la lutte biologique sur le territoire au fur et à mesure de l’extension du cynips. Six laboratoires régionaux ou nationaux sont aujourd’hui en capacité de faire émerger et d’élever le parasitoïde. Son installation dans les châtaigneraies est un succès et son développement laisse augurer d’un futur rétablissement de la situation technico-économique de la châtaigneraie dans les prochaines années. L’identification de cultivars peu sensibles ou résistants parmi des sélections récentes issues du programme de création national est une avancée complémentaire pour la filière castanéicole, avec la perspective de disposer pour ses replantations futures d’une gamme de cultivars adaptée à la présence du ravageur.In order to address the damage caused since the arrival of the gall wasp (Dryocosmus kuriphilus) in French chestnut groves, a work program financed by the Ministry of Agriculture was initiated with research and experimentation partners. The work on training people to recognize the parasite and to implement biological control with the parasitoid Torymus sinensis has led to the parasite being monitored and biological control methods being introduced as gall wasp populations built up. Six regional or national laboratories are currently able to rear the parasitoid. Population build-up of the parasitoid has been successful in chestnut groves and its progression promises a recovery of the technical and economic situation over the next few years. The identification of less susceptible or resistant cultivars among recent cultivars from the national breeding program is a complementary step for castaniculture sector, with the prospect of having a range of cultivars adapted to the presence of the gall wasp for future replanting

History of multiple sclerosis in 2 successive pregnancies: A French and Italian cohort

Objective: To evaluate the risk of relapses during pregnancy and in the first 3 months after delivery in 2 successive pregnancies in a cohort of French and Italian women with multiple sclerosis (MS). Methods: A total of 93 women were included if they had had 2 pregnancies followed prospectively after MS onset between January 1993 and 2013. The association of a relapse during pregnancy or the first postpartum trimester in pregnancy 1 and pregnancy 2 was evaluated by univariate logistic regression. Results: A majority of women did not experience any exacerbation in the 3 months after delivery (31.2% and 23.7%, respectively, relapsed after pregnancy 1 and 2; p 0.32). A total of 7.6% had a relapse after both pregnancies. The risk of relapse after pregnancy 2 was not associated with the number of relapses in the prepregnancy year (odds ratio [OR] 1.52 [0.57-4.05]) or during pregnancy (OR 1.57 [0.52-4.79]) or with the occurrence of a relapse after pregnancy 1 (OR 0.86 [0.29-2.50]). Conclusions: Our work provides original data on the evolution of successive pregnancies in MS, showing a similar (and even lower) disease activity in the second pregnancy. There was no correlation of activity in successive pregnancies. Therefore, counseling of women with MS who consider having a second baby should be the same as for the first one