Movement disorders in oncology: From clinical features to biomarkers

Background: the study of movement disorders associated with oncological diseases and anticancer treatments highlights the wide range of differential diagnoses that need to be considered. In this context, the role of immune-mediated conditions is increasingly recognized and relevant, as they represent treatable disorders. Methods: we reappraise the phenomenology, pathophysiology, diagnostic testing, and treatment of movement disorders observed in the context of brain tumors, paraneoplastic conditions, and cancer immunotherapy, such as immune-checkpoint inhibitors (ICIs). Results: movement disorders secondary to brain tumors are rare and may manifest with both hyper-/hypokinetic conditions. Paraneoplastic movement disorders are caused by antineuronal antibodies targeting intracellular or neuronal surface antigens, with variable prognosis and response to treatment. ICIs promote antitumor response by the inhibition of the immune checkpoints. They are effective treatments for several malignancies, but they may cause movement disorders through an unchecked immune response. Conclusions: movement disorders due to focal neoplastic brain lesions are rare but should not be missed. Paraneoplastic movement disorders are even rarer, and their clinical-laboratory findings require focused expertise. In addition to their desired effects in cancer treatment, ICIs can induce specific neurological adverse events, sometimes manifesting with movement disorders, which often require a case-by-case, multidisciplinary, approach

Associations between HLA and autoimmune neurological diseases with autoantibodies

Recently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings

Synthèse et évaluation d'antalgiques originaux : les inhibiteurs de protéines à domaines PDZ

Protein-protein interactions play a central role in the regulation of biological processes and represent a promissing class of therapeutic targets. It has been recently reported that disrupting the interaction between the PDZ protein PSD-95 and the serotonin receptor 5-HT2A induced an antihyperalgesic effect in diabetic rats. In this context, the development of original ligands capable to inhibit specifically this interaction could lead to a new class of analgesic compounds.We carried out the synthesis of three generations of ligands possessing an indole moiety in order to interact with the highly conserved carboxylate-binding loop (GLGF loop) of PSD-95. Two generations of compounds were developed to find out the position and the nature of the substituents furnishing the best interactions. One generation consists of a family of 15 biligands possessing a substituted indole moiety, coupled with a linker (having from 2 to 6 carbon atoms) via an amid function, ended with various amino acids to interact with the S1 site of the protein, in order to obtain specific ligands.By various biological evaluations, NMR HSQC 1H/15N, chromatography affinity assays and in vivo experiments, we identified two promising inhibitors of the interaction PSD-95/5-HT2A with strong interactions with S0 site of PSD-95. For these compounds, we determined the structure of the complex protein/ligand by NMR NOESY experiments. The orientation of one of these molecules in the S0 site allows us to envisage a new generation of ligands capable to interact with the S1 site of the protein.Les protéines à domaine PDZ, en très grand nombre dans le génome humain, sont impliquées dans des interactions protéine-protéine. Elles participent ainsi à véhiculer des signaux à l’origine de différentes pathologies (cancer, douleur….). L’interruption de l’interaction entre la protéine à domaine PDZ, PSD-95, et le récepteur de la sérotonine, 5-HT2A, entraîne une réduction de l’hyperalgie chez le rat neuropathique. Le développement de molécules capables d’inhiber cette interaction pourrait donc conduire à une nouvelle classe d’antalgiques.Nous avons réalisé, au cours de ces travaux, la synthèse de trois générations de ligands, comportant un noyau indolique, capables d’interagir avec le site S0, site très conservé des protéines à domaines PDZ. Dans un premier temps, nous avons préparé 15 biligands possédant un noyau indolique polysubstitué lié, via un espaceur de longueur variable (2 à 6 atomes de carbone), à différents acides aminés, dans le but d’interagir avec le site S1, montrant beaucoup de diversité en fonction du domaine. Nous avons ensuite, après une étude de relation structure/activité, développé deux autres générations d’indoles polysubstitués présentant notamment des substituants hydrophobes en position 5.Nous avons montré, par RMN HSQC 1H/15N et chromatographie d’affinité, que deux de ces composés sont des inhibiteurs de l’interaction PSD-95/5-HT2A et présentent de fortes interactions avec le site S0 de PSD-95. Ces molécules présentent également des propriétés antalgiques particulièrement intéressantes in vivo. Nous avons également déterminé, par RMN NOESY, la structure du complexe protéine/ligand pour ces deux composés. L’orientation d’une de ces molécules dans le site de la protéine nous permet d’envisager le développement d’une nouvelle génération d’indoles polysubstitués, pouvant interagir avec le site S1 de la protéine et permettant ainsi d’obtenir des inhibiteurs sélectifs de l’interaction PSD-95/5-HT2A

Performing the image: improvisational and collaborative practices in non-scripted film making. Film as a catalyst for encounters.

This thesis inquires into the performative qualities of audiovisual productions developed through improvisational and collaborative techniques. It focuses on processes in which the act of filming becomes the catalyst for the emergence of encounters. This approach to audiovisual production lies at the crossing of performative gestures and filmmaking, in order to think about what kind of situations and relations a film is putting forward during its making and in the way it circulates. The thesis includes the making of three short films, made in collaboration with children in Mexico and the Dominican Republic

GALD: new diagnostic tip for early diagnosis - a case report and literature review

Objective: Gestational alloimmune liver disease is a rare and serious condition caused by a maternal-fetal alloimmune disorder. There are not many studies about the antenatal treatment (IVIG infusion) of affected fetuses as the diagnosis is generally made postnatally. The possibility of an early diagnosis by means of ultrasonography and a gynecologist's assesment can provide prompt treatment of this disease. Case report: We report the case of 38-year-old pregnant woman referred to our centre in view of severe fetal hydrops seen by ultrasound at 31 weeks + 1 day gestation. A male infant was born and subsequently died after developing liver failure. Postmortem examination revealed the presence of diffuse hepatic fibrosis in the absence of hemosiderin deposits and no extrahepatic siderosis. Immunohistochemical analysis was also performed which showed diffuse hepatocyte positivity for the terminal complement complex (C5b-C9) confirming the suspicion of GALD. Methods: A comprehensive literature search published from 2000 to 2022 was conducted on PubMed and Scopus. Paper selection was performed following the PRISMA guidelines. Fifteen retrospective studies were identified and selected. Results: A total of 15 manuscripts describing 26 cases were finally included in our research. Twenty-two fetuses/newborns with suspected GALD were studied, of which 11 had a confirmed histopathological diagnosis of GALD. Prenatal diagnosis of gestational alloimmune liver disease is difficult because ultrasound findings may be absent or nonspecific. Only one case report described fetal hydrops similar to our clinical case. As highlighted by the current case, in fetuses presenting with hydrops, once the most common etiologies have been excluded, hepatobiliary complications and liver failure caused by GALD should be considered Conclusions: Global knowledge of this disorder and its wide spectrum of presentations may help to increase the number of cases that are diagnosed early and accurately. The recurrence rate of an infant being affected with GALD in another pregnancy is more that 90%. Recurrence however can be prevented by treatment with IVIG during pregnancy. This highlights the importance of having obstetricians and pediatricians familiar with gestational alloimmune liver disease

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors

Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors [e.g., human leukocyte antigen (HLA)] was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis

Perampanel as add-on therapy in epilepsies with known etiology: A single center experience with long-term follow-up

We report a retrospective monocentric study performed on 63 patients affected by epilepsy with known etiology, receiving perampanel as add-on therapy with at least 12-month follow-up. The purpose of our study was to evaluate efficacy and tolerability of perampanel in this group of epilepsies. Patients were classified into 2 groups based on the presence/absence of a single focal brain lesion on MRI, as epilepsy etiology: 48 subjects were affected by focal lesional epilepsy and 15 by non-focal lesional epilepsy. The retention rate was 76.2% and 53.9% at 12 and 24 months respectively. At 12 months, at least 40% of patients resulted responders, with a significant reduction in seizure frequency (p = 0.01), confirmed at 24 months. Considering epilepsy etiology, we found a better PER response in patients with focal lesional epilepsy. A significant correlation was observed between responder rates and EEG pattern. Only 30% of patients reported mild-moderate adverse events. Efficacy and tolerability of PER, in our study, are in line with the results reported in other real-world studies. Our data suggest the possibility of better PER response in patients with focal brain lesions, which indicates that this drug could be a therapeutic option in this population

Efficacy of Perampanel in Refractory and Super-Refractory Status Epilepticus with Suspected Inflammatory Etiology: A Case Series

(1) Background: Increasing evidence supports the anti-inflammatory and neuroprotective role of perampanel (PER), mediated by decreased expression of pro-inflammatory cytokines and by interference with apoptosis processes. Therefore, the use of PER to treat status epilepticus (SE) with suspected inflammatory etiology is appealing and deserves further investigation. (2) Methods: We retrospectively analyzed seven patients (five F, two M; median age: 62 years) with refractory and super-refractory SE due to a probable or defined inflammatory etiology and treated with PER. (3) Results: PER was administered as the third (4/7) or fourth drug (3/7), with a median loading dose of 32 mg/day (range: 16–36 mg/day) and a median maintenance dose of 10 mg/day (range: 4–12 mg/day). In five cases, SE was focal, while in two patients, it was generalized. SE was caused by systemic inflammation in three patients, while in the other four subjects, it was recognized to have an autoimmune etiology. SE resolution was observed after PER administration in all cases, particularly within 24 h in the majority of patients (4/7, 57.1%). (4) Conclusions: Our data support the efficacy of PER in treating SE when first- and second-line ASMs have failed and suggest a possible earlier use in SE cases that are due to inflammatory/autoimmune etiology

Long-term legacy of land-use change in soils from a subtropical rainforest: Relating microbiological and physicochemical parameters

Tropical and subtropical ecosystems are widely affected by the expansion of agriculture over pristine lands. Despite research efforts, knowledge of the impact of land-use change on soil is still limited by intrinsic variability, inconsistent results and inadequate replication. This study aimed to better understand the consequences of land-use change by focusing on long-term effects on both soil biotic and abiotic parameters. For this purpose, we selected three productive farms under similar management, each of them with pristine forest sites and agricultural sites that had been deforested for ~15 and ~30 years. In each site, we analysed soil microbiological (phospholipid fatty acids [PLFAs], biomass and activity) and physicochemical parameters. Long-term land-use change caused a detriment in soil microbial biomass, activity and fungal abundance, but only small changes in PLFA composition. In fact, PLFA composition was more affected by soil physicochemical properties such as carbon-to-nutrient ratios and labile carbon than by land use. Some physicochemical parameters (e.g., organic carbon and nutrients) were also negatively affected by land-use change and were more sensitive to time under agricultural use than microbiological parameters. The lower sensitivity of microbiological parameters could be the result of severe drought conditions at sampling, which may have affected soil microbial communities in both land uses. We were also able to detect associations between specific microbiological and physicochemical parameters. Among these, we identified some that seemed to result from their co-variation in response to land-use change and others that seemed to be independent of land use. Overall, our results show that soils can suffer further deterioration several years after deforestation. In order to restore soil health in these degraded lands, we need to keep on investigating the physical, chemical and biological mechanisms responsible for this deterioration. Highlights: Land-use change affected soil microbiological and physicochemical parameters. Microbiological parameters seemed to stabilize after continuous agriculture. Soil organic C, total N and fine particles were still reduced after long-term cultivation. Microbiological parameters were mostly associated with C-to-nutrient ratios and labile C. Drought conditions may have affected microbial response to land-use change.Fil: Tosi, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; ArgentinaFil: Chludil, Hugo Daniel. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Biología Aplicada y Alimentos; ArgentinaFil: Correa, Olga Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; ArgentinaFil: Vogrig, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; ArgentinaFil: Montecchia, Marcela Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; Argentin