GenIDA: an international participatory database to gain knowledge on health issues related to genetic forms of neurodevelopmental disorders.

Intellectual disability with or without manifestations of autism and/or epilepsy affects 1-2% of the population, and it is estimated that more than 30-50% of these cases have a single genetic cause. More than 1000 genes and recurrent chromosomal abnormalities are involved in these genetic forms of neurodevelopmental disorders, which often remain insufficiently described in terms of clinical spectrum, associated medical problems, etc., due to their rarity and the often-limited number of patients' phenotypes reported. GenIDA is an international online participatory database that aims to better characterise the clinical manifestations and natural histories of these rare diseases. Clinical information is reported by parents of affected individuals using a structured questionnaire exploring physical parameters, cognitive and behavioural aspects, the presence or absence of neurological disorders or problems affecting major physiological functions, as well as autonomy and quality of life. This strengthens the implication in research of the concerned families. GenIDA aims to construct international cohorts of significant size of individuals affected by a given condition. As of July 2022, GenIDA counts some 1545 documented patient records from over 60 nationalities and collaborates with clinicians and researchers around the world who have access to the anonymized data collected to generate new, medically meaningful information to improve patient care. We present the GenIDA database here, together with an overview of the possibilities it offers to affected individuals, their families, and professionals in charge of the management of genetic forms of neurodevelopmental disorders. Finally, case studies of cohorts will illustrate the usefulness of GenIDA.

The NANOTUMOR consortium - Towards the Tumor Cell Atlas.

Cancer is a multi-step disease where an initial tumour progresses through critical steps shaping, in most cases, life-threatening secondary foci called metastases. The oncogenic cascade involves genetic, epigenetic, signalling pathways, intracellular trafficking and/or metabolic alterations within cancer cells. In addition, pre-malignant and malignant cells orchestrate complex and dynamic interactions with non-malignant cells and acellular matricial components or secreted factors within the tumour microenvironment that is instrumental in the progression of the disease. As our aptitude to effectively treat cancer mostly depends on our ability to decipher, properly diagnose and impede cancer progression and metastasis formation, full characterisation of molecular complexes and cellular processes at play along the metastasis cascade is crucial. For many years, the scientific community lacked adapted imaging and molecular technologies to accurately dissect, at the highest resolution possible, tumour and stromal cells behaviour within their natural microenvironment. In that context, the NANOTUMOR consortium is a French national multi-disciplinary workforce which aims at a providing a multi-scale characterisation of the oncogenic cascade, from the atomic level to the dynamic organisation of the cell in response to genetic mutations, environmental changes or epigenetic modifications. Ultimately, this program aims at identifying new therapeutic targets using innovative drug design.

The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA.

BACKGROUND: Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. METHODS: To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients' relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. RESULTS: In total 199 participants-144 children and 45 adults-with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. CONCLUSIONS: Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.

Cerberus, an Access Control Scheme for Enforcing Least Privilege in Patient Cohort Study Platforms : A Comprehensive Access Control Scheme Applied to the GENIDA Project - Study of Genetic Forms of Intellectual Disabilities and Autism Spectrum Disorders.

Cohort Study Platforms (CSP) are emerging as a key tool for collecting patient information, providing new research data, and supporting family and patient associations. However they pose new ethics and regulatory challenges since they cross the gap between patients and medical practitioners. One of the critical issues for CSP is to enforce a strict control on access privileges whilst allowing the users to take advantage of the breadth of the available data. We propose Cerberus, a new access control scheme spanning the whole life-cycle of access right management: design, implementation, deployment and maintenance, operations. Cerberus enables switching from a dual world, where CSP data can be accessed either from the users who entered it or fully de-identified, to an access-when-required world, where patients, practitioners and researchers can access focused medical data through explicit authorisation by the data owner. Efficient access control requires application-specific access rights, as well as the ability to restrict these rights when they are not used. Cerberus is implemented and evaluated in the context of the GENIDA project, an international CSP for Genetically determined Intellectual Disabilities and Autism Spectrum Disorders. As a result of this study, the software is made available for the community, and validated specifications for CSPs are given.

Platelets favor the outgrowth of established metastases.

Despite abundant evidence demonstrating that platelets foster metastasis, anti-platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subject syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the glycoprotein VI (GPVI) platelet-specific receptor in humanized mouse models efficiently reduce the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study demonstrates therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as a molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

Mammalian frataxin controls sulfur production and iron entry during de novo Fe4S4 cluster assembly.

Iron-sulfur (Fe-S) cluster-containing proteins are essential components of cells. In eukaryotes, Fe-S clusters are synthesized by the mitochondrial iron-sulfur cluster (ISC) machinery and the cytosolic iron-sulfur assembly (CIA) system. In the mammalian ISC machinery, preassembly of the Fe-S cluster on the scaffold protein (ISCU) involves a cysteine desulfurase complex (NFS1/ISD11) and frataxin (FXN), the protein deficient in Friedreich's ataxia. Here, by comparing the biochemical and spectroscopic properties of quaternary (ISCU/NFS1/ISD11/FXN) and ternary (ISCU/NFS1/ISD11) complexes, we show that FXN stabilizes the quaternary complex and controls iron entry to the complex through activation of cysteine desulfurization. Furthermore, we show for the first time that in the presence of iron and L-cysteine, an [Fe(4)S(4)] cluster is formed within the quaternary complex that can be transferred to mammalian aconitase (mACO2) to generate an active enzyme. In the absence of FXN, although the ternary complex can assemble an Fe-S cluster, the cluster is inefficiently transferred to ACO2. Taken together, these data help to unravel further the Fe-S cluster assembly process and the molecular basis of Friedreich's ataxia.

Biomechanics: a driving force behind metastatic progression.

Metastatic progression, which begins with the invasion and migration of tumor cells from a primary tumor, marks a major turning point in the evolution of cancer. Indeed, it eventually leads to the formation of secondary tumors, the metastases, which are very often responsible for the patient's death. Understanding the mechanisms controlling the different steps of this process, as well as those explaining the fundamental phenomenon of organotropism (i.e. the distribution of metastases in distant organs by a non-random and tumor-specific process), is essential to define new innovative therapeutic solutions. In this review paper, we will present how biomechanics is an essential element to this understanding, and will emphasize the importance of this orthogonal and promising angle of study as well as our laboratory's focus on the late stages of dissemination, arrest and extravasation of circulating cancer cells and factors secreted by the primary tumor such as extracellular vesicles.

La progression métastatique, qui débute par l'invasion et la migration de cellules tumorales depuis une tumeur primaire, marque un tournant majeur dans l'évolution du cancer. En effet, elle conduit à terme à la formation des tumeurs secondaires, les métastases, responsables très souvent de la mort du patient. Comprendre les mécanismes contrôlant les différentes étapes de ce processus, ainsi que ceux expliquant le phénomène fondamental d'organotropisme (c'est-à-dire la distribution des métastases dans les organes distants par un processus non aléatoire et tumeur-spécifique), est essentiel pour définir de nouvelles solutions thérapeutiques innovantes. Dans ce document de synthèse, nous présenterons comment la biomécanique est un élément essentiel à cette compréhension, et insisterons sur l'importance de cet angle d'étude orthogonal et prometteur ainsi que la focalisation de notre laboratoire sur les étapes tardives de dissémination, d'arrêt et d'extravasation des cellules cancéreuses circulantes et des facteurs sécrétés par la tumeur primaire comme les vésicules extracellulaires.

Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex.

BACKGROUND: Frataxin, the mitochondrial protein deficient in Friedreich ataxia, a rare autosomal recessive neurodegenerative disorder, is thought to be involved in multiple iron-dependent mitochondrial pathways. In particular, frataxin plays an important role in the formation of iron-sulfur (Fe-S) clusters biogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We present data providing new insights into the interactions of mammalian frataxin with the Fe-S assembly complex by combining in vitro and in vivo approaches. Through immunoprecipitation experiments, we show that the main endogenous interactors of a recombinant mature human frataxin are ISCU, NFS1 and ISD11, the components of the core Fe-S assembly complex. Furthermore, using a heterologous expression system, we demonstrate that mammalian frataxin interacts with the preformed core complex, rather than with the individual components. The quaternary complex can be isolated in a stable form and has a molecular mass of ≈190 kDa. Finally, we demonstrate that the mature human FXN(81-210) form of frataxin is the essential functional form in vivo. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the interaction of frataxin with the core ISCU/NFS1/ISD11 complex most likely defines the essential function of frataxin. Our results provide new elements important for further understanding the early steps of de novo Fe-S cluster biosynthesis.