Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis

Autoimmune encephalitides constitute a diverse group of immune-mediated central nervous system disorders mainly characterized by the presence of antibodies targeting neuronal or glial antigens. Despite the notable contribution of antibody discovery to the understanding of their physiopathology, the specific immune cells and inflammatory mediators involved in autoimmune encephalitis are still poorly defined. However, cytokines have recently emerged as crucial signalling molecules in the pathogenesis of autoimmune encephalitis. Cytokines are biologically active, soluble, low-molecular-weight proteins or glycoproteins involved in a wide variety of physiological functions, including central nervous system development and homeostasis, immune surveillance, as well as proliferation and maturation of immune cells. Since unbalanced cytokine expression is considered a hallmark of many autoimmune central nervous system disorders, their identification and quantification has become an essential element in personalized medicine applied to the field of neuroimmunology. Several studies have explored the cytokine profile of autoimmune encephalitis, but their interpretation and comparison is challenging due to their small sample sizes and extremely high heterogeneity, especially regarding the cytokines analysed, type of sample used, and associated neural antibody. Only the cytokine profile of anti-N-methyl-D-aspartate receptor encephalitis has extensively been investigated, with findings suggesting that, although humoral immunity is the main effector, T cells may also be relevant for the development of this disorder. A better understanding of cytokine dynamics governing neuroinflammation might offer the opportunity of developing new therapeutic strategies against specific immune cells, cytokines, antibodies, or intracellular signalling cascades, therefore leading to better outcomes and preventing undesired side effects of the presently used strategies. In this review, we first summarize the current knowledge about the role of cytokines in the pathogenesis of autoimmune encephalitis, combining theoretical analysis with experimental validations, to assess their suitability as clinical biomarkers. Second, we discuss the potential applicability of the novel targeted immunotherapies in autoimmune encephalitis depending on the immunobiology of the associated antibody, their limitations, as well as the main limitations that should be addressed in future studies

Kinetic and Product Study of the S-oxidation vs HAT Chemoselectivity in Reactions Promoted by Nonheme Iron(IV)-oxo Complex/NHPI Mediator System

The chemoselectivity between S-oxidation and hydrogen atom transfer (HAT) from C−H bonds has been investigated in the oxidations of a series of aryl sulfides, alkyl aromatic compounds and benzylic alcohols promoted by the iron(IV)-oxo complex [(N4Py)FeIV(O)]2+ (N4Py: N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)-methylamine) either alone or in the presence of the N-hydroxyphthalimide (NHPI) mediator via kinetic and product studies. Kinetic analyses indicate a generally higher reactivity of [(N4Py)FeIV(O)]2+ for S-oxidation process while HAT is favored in the reactions promoted by phthalimide-N-oxyl radical (PINO) deriving from NHPI oxidation. Product analysis in intermolecular competitive oxidations confirms the kinetic results with sulfoxides obtained as major products in the oxidation promoted by [(N4Py)FeIV(O)]2+. Conversely, when NHPI is employed as a mediator, significant differences in terms of chemoselectivity are observed, and HAT-derived products are obtained in higher yields which translate into an inversion of selectivity in the case of the substrates containing activated C−H bonds like diphenylmethane, triphenylmethane and benzylic alcohols. A similar change of chemoselectivity is also observed in the oxidation of aromatic substrates containing both a sulfur atom and α to OH benzylic C−H bonds, with the sulfoxide product more abundant in the absence of NHPI and carbonyl products prevailing with the [(N4Py)FeIV(O)]2+/NHPI system

Recurrent glioblastoma: From molecular landscape to new treatment perspectives

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients

Etude expérimentale de l'écoulement autour d'un cylindre en rotation perpendiculairement à l'écoulement moyen

Dans un écoulement, l étude des zones décollées revêt un intérêt certain de part les phénomènes nuisibles qu elles engendrent. Il est donc important de contrôler ce décollement, voire même le supprimer. Le moyen de contrôle utilisé ici repose sur la rotation d un cylindre perpendiculairement à un écoulement. Deux techniques de mesures ont été utilisées : la Vélocimétrie par Images de Particules (PIV) et la Vélocimétrie Laser par effet Doppler (LDV). Les mesures ont été réalisées pour trois nombres de Reynolds et pour différentes valeurs de (rapport entre la vitesse périphérique du cylindre et celle de l écoulement). Cette étude a permis de montrer que le nombre de Strouhal augmente avec et de vérifier le critère de décollement suggéré par Moore, Rott et Sears. Nous avons montré que le maximum du taux de fluctuation de vitesse tangentielle constitue un excellent critère pour localiser le décollement autour du cylindre en rotation. Le critère basé sur le maximum de la composante radiale permet de déterminer qualitativement la position du point de décollement. Le champ de vitesse fourni par la PIV a permis de localiser la position du point d arrêt qui se déplace dans le sens opposé à la rotation du cylindre. L analyse du champ de vorticité montre que c est dans la région où le cylindre se déplace dans le sens opposé de l écoulement que l iso-vorticité est la plus intense. On montre que la vorticité disparaît, quand la vitesse périphérique du cylindre est quatre fois supérieure à celle de l écoulement. Les résultats obtenus à l aide de simulations numériques de type (k- ) ont montré leur limite quant à leur prédiction de l écoulement en dehors de la zone de sillage.In a flow, the study of separated zones presents a major interest because of the perturbation that it generates. It is thus significant to control this separation, and even to remove it. The control used here is based on a rotating cylinder in cross flow. Two measurement techniques were used: Particle Image Velocimetry (PIV) and Laser-Doppler Velocimetry (LDV). Measurements were carried out for three Reynolds numbers and for various values of (ratio between the peripheral speed of the cylinder and the free stream velocity). This study shows that the Strouhal number increases with and to verify the criterion of separation suggested by Moore, Rott and Sears. We showed that the maximum of the tangential velocity fluctuation rate is an excellent criterion to localize separation around the rotating cylinder. The criterion based on the maximum of the radial velocity component permits to determine qualitatively the position of the separation point. It is noted that the vorticity disappears, when the speed of the cylinder is four times higher than the free stream velocity. The velocity field provided by the PIV permits to locate the stagnation point which moves with an opposing motion to that of the cylinder. The analysis of the vorticity field shows that it is in the region where the cylinder moves in the opposite direction of the flow that the iso-vorticity is much more strong. The results obtained by the (k- ) numerical simulations fail to predict the flow field around the rotating cylinder except in the wake of the cylinder.VALENCIENNES-BU Sciences Lettres (596062101) / SudocSudocFranceF

Immune checkpoint inhibitors-induced neuromuscular toxicity: from pathogenesis to treatment

Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumour types. Despite the favourable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti-PD-1, anti-PDL-1 and anti-CTLA-4 treatment, and include myositis, myasthenia gravis and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment. Despite initial severity, neurological irAEs often respond to immune-modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multidisciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange and other immune-modulating treatments should be considered in more severe cases. Consideration of rechallenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs. This article is protected by copyright. All rights reserved

Advances in treatments of patients with classical and emergent neurological toxicities of anticancer agents

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