Deliverables Documents, reports (33) in vivo animal models that induce peripheral nervous toxicities This report will describe protocols for the assessment in vivo of animal models of peripheral neuropathies using defined toxicants the document will summarize results obtained with different compounds able to induce PNSTox studies of neurotoxicity and the informative endpoints for focused noninvasive detection In particular it will summarize results obtained in terms of behavioural evaluations sensorimotor parameters painrelated measures emotion cognitionrelated parameters or electrophysiological approaches evaluation of ototoxicity Histological correlates to the neuropathic functional alterations will be also reported Pharmacokinetic data relative to the drug exposure levels in plasmasera in comparison to peripheral nervous tissue will be reported Candidate pathways and biological targets involved in P/P adverse effects This report will organize and present scientific knowledge relating to Psychological Psychiatric PP adverse effects with particular focus on immunomodulation Knowledge will be organized in two groups existing knowledge and novel hypotheses In both cases knowledge will consist of a full mechanistic description of genes targets and pathways responsible for each selected toxicity i depression and suicidal ideation and behaviour which can be assessed in animals such as anhedonia aggression and impulsivity and ii memory disorders All supporting scientific evidence from renownedwellranked journals will be listed in the bibliography section The goal of this deliverable is to provide a single comprehensive collection of existing knowledge and some novel hypotheses around Psychological Psychiatric toxicity supporting researchers wishing to assess novel compounds for their risk to develop such adverse effects In particular the nature of the relationship between immunomodulation and PP adverse effects will be investigated Candidate biomarker performance in vivo This report will summarize the responses obtained by testing the modulation in vivo of the selected biomarkers by neurotoxic drugs The effects of several neurotoxic compounds will be compared with nonneurotoxic drugs in the in vivo characterized models A panel of biomarkers sensitivity and specificity will be produced as well as an assessment of potential clinical translation Guidelines on the use of the predictive tools This report will present guidelines for the proper use of the tools developed for evaluation of Psychological Psychiatric adverse effects tools developed for WP2 The report targets scientists wishing to use the NeuroDeRisk toolbox applicable and common to all work packages and more specifically the module dedicated to this work package on PsychologicalPsychiatric changes The guidelines will aim that scientists understand the context of use input and output data target use case limitations interpretationThe report will be incorporated into the NeuroDeRisk toolbox guidelines and documentation Toolbox user manual and guidelines Manual describing the tools in the computational toolbox how to access and use the tools developed in WP4 The document will help end users understand and effectively employ the toolbox in their working environment It will include information from D43c involving performance assessments accuracy sensitivity and specificity where applicable on the predictive tools developed as part of the toolbox Communication Plan Document containing the plan for communicating the project and its results It will comprise dissemination objectives target audiences tools and activities planned "Technical and Financial Annual Reports #2" Report on technical and financial aspects of the project status after 30 months In vitro tool to characterize mechanism of effects A cell culturebased tool resulting from the refinement of potentially interesting PPTOXicity signatures selected from the omics endpoints obtained in D22 and from D24s output will be established through the mechanistic assessment of specific targets and pathways at protein andor gene levels aimed at elucidating both acute and chronic mechanisms of PP adverse effects Examples of acute effects to be monitored include the ones affecting the expression at protein and gene levels andor activity of specific receptors and neurotransmitters eg GABA glutamate NMDA receptor ligandgated ion channels or expression of cytokineschemokines eg IL1 TNFalpha IL6 Creactive protein MCP1 Chronic effects will be determined by assessing how the pharmaceuticals tested affect the transcriptome how they promote downstream changes in electricalelectrophysiological properties or deregulate the neurogenesis process eg by measuring neurite outgrowth and by analysing the expression of specific proteins or genes involved in such process Mechanisms of toxicity will be assessed using classical molecular biology tools like Westernblot ELISAmultiplex analysis qPCR or using suitable electrophysiology methodologies such as multielectrode arrays MEAs patch clamping automatized or manual as well as imaging eg Ca2 transients Specific inhibitoractivators of molecular pathways found to be involved in PP toxicity is envisaged to clarify the critical pathways at protein and gene levels regulated by a set of validated pharmaceuticals allowing to define a small set of specific targets to design single targetcontaining hiPSC models Epigenetic modifications which comprise particularly important modulators of neuroimmune response will also be studied as RNA editing modifications long lasting changes in DNA methylation and posttranslational histone modifications have already been associated with PP disorders eg depression Novel mechanistic assessment of pathways involved in neurotoxicity modulation This report will summarize the responses obtained by testing the modulation in vivo of the selected biomarkers by neurotoxic drugs The effects of several neurotoxic compounds will be compared with nonneurotoxic drugs in the in vivo characterized models A panel of biomarkers sensitivity and specificity will be produced as well as an assessment of potential clinical translation Final Data Management Plan Update Report on the final data management plan update Ictogenic risk of compounds based on historical data Report on ictogenic risk of compounds based on historical data retrospective study This report will contain results of compound profiling and GABAA pharmacophore development In vitro tool to screen drugs Cell culturebased tools will be developed and tested towards in vitro highthroughput screening of PP safety profile of candidate pharmaceuticals at the lead optimization stage aiming to detect early signalling PP toxicity signaturesTranscriptomics analysis first tier and proteomics analysis second tier will be run on appropriate hiPSCderived neuronal and glial cell models as well as other cell lines highly responsive to immunomodulatory molecules eg neuroblastoma SHSY5Y to identify modifications occurring at gene andor protein expression levels with focus on immunomodulation Proteins andor genes that show a clear activation or suppression of their expression in these omics analysis will be selected as specific endpoints to screen PP adverse effects and to further elucidate the mechanisms of PP toxicity D25Epigenetic modifications eg RNA editing DNA methylation or histone deacetylation which have already been associated with the fine tuning of neuronal cells mechanisms at the molecular level and reported as important modulators of the neuroimmune response will also be addressed In particular distinct epigenetic alterations of the RNA editing activity on the serotonin receptor 2C 5HT2cR premRNA known to greatly impair 5HT2cR pharmacological properties will be evaluated since anomalies of serotonin biology in brain appear to be a characteristic trait underlying depression andor suicidal behaviour Sensitive biomarkers of neurotoxicity This document will describe a list of PNSTox sensitive biomarker candidates based on behavioural histological and molecular parameters as well as from in silico predictions The results of omicbased analyses microRNAs and proteins on plasmasera samples during the neuropathy induction by neurotoxic drugs will be summarized A comparison of this data with functional and histological responses will be obtained Moreover the report will indicate a selection of available useful assays to measure the expression profile of translational biomarker candidates in seraplasma from retrospective and prospective studies across species rat dogs and nonhuman primates "Technical and Financial Annual Report #1" Report on technical and financial aspects of the project status after 18 months Performance of in vitro models to screen for PNS- Tox On the base of the biomolecular and biochemical results obtained from in vivo and in vitro measurements novel mechanisms of PNSTox will be defined This report will describe novel pathways involved in the toxicity evoked by drugs in the nervous cells offering a relevant background to define predictive biomarkers use of in silico tools for PNS-Tox biomarker prediction This report M36 will summarize the results of the work carried out in T35 with regards to the in silico prediction of PNSTox biomarkers Depending on the availability of results biomarkers interim technical documents will also be reported M24 Submission of a scientific paper on the NeuroDeRisk project Collective paper which outlines the NeuroDeRisk mission and explores the inherent challenges and our planned approaches for each of the areas the project is addressing is written and submitted It aims to publicize the consortium name and objectives Additionally it should provide a foundation article that can be cited in subsequent papers arising from consortium partners and nonconsortium papers related to druginduced neurotoxicity Lastly it should declutter subsequent consortium papers from covering the fundamental mission of NeuroDeRisk since the article could be cited Project Handbook The Project Handbook is intended to serve as quick reference manual for partners to consult management procedures It will summarise in an understandable way the key provisions of the Grant Agreement and the Consortium Agreement as well as any other operative procedures set up in relation with reporting risk management etc The deliverable will be updated as needed as new procedures in H2020 are progressively deployed by the Commission Single and combinatory safety biomarkers for detection of risk for convulsive seizures Report on single and combinatory safety biomarkers for detection of risk for convulsive seizures This report will present results from the in silicobased predictions of single and combinatory safety biomarkers for detection of risk for convulsive seizures Select In vitro models of PNS-Tox To obtain simplified highly predictive screening systems for highlighting neurotoxic compounds protocols and data obtained in vitro from rat cell cultures will be reported Neurons and glial cells cultures will allow to obtain models of neurotoxicity evoked by the selected drugs Measurements of drugs concentration in cell media and in the cytosolic fraction will be reported to individuate a parallelism with plasma and tissue toxic concentration A validation of these methods will be obtained by reproducing the same treatments in differentiated human induced pluripotent stem cells hiPSCs preparations Data about cell viability apoptotic process intracellular organelles functionality transcriptomic and proteomic analysis will be summarized New improved in vivo animal models and tools, allowing focused non- invasive detection of seizure-inducing effects during drug development Report comparing the performance of in vivo animal models for detecting seizureinducing liabiltities Sensitivity specificity and predictivity will be determined as enabled by the compound test set Particular emphasis will be placed on identifying strengths and gaps of each model system List of compounds for further testing A list of set of compounds reference andor proprietary compounds known to have ictogenic liability in animals or humans The selected compounds will cover different pharmacological mechanisms relevant for ictogenesis such as GABA receptors glutamate receptors calcium channels and sodium channels Negative controls ie compounds devoid of seizureinducing effects will also be included in the list Neuropharmacophore modeling Report on a panel of predictive quantitative next generation pharmacophore models useful for prediction of multitarget neurotoxicity outcomes defined by NeuroDeRisk and medicinal chemistry decision support as well as algorithms for using them to make predictions using AI enhanced LigandScout platform technology Contributive role of CNS barriers in achievement of extracellular and intracellular unbound compound exposure in brain regions of interest in rats in relation to seizure- inducing activity of the compounds Defining contributing role of bloodbrainbarrier in achievement of extracellular and intracellular unbound compound exposure in brain regions of interest in rats in relation to the seizurogenic activity of the compounds Key neuropharmacokinetic parameters in rats will be reported for investigated compounds Unbound free extracellular and intracellular brain exposureresponse relationship will be presented with the focus on potential contributive role of CNS barriers on modulation of brain exposure during the course of the treatment with known seizurogenic compounds Multiscale integrative modeling and novel AE biology Report on discovery analytics platform COSS to model related to Mechanism of ActionMoAtoAdverse Event AE and drugtoAE knowledge and use this information eg knowledge on biomarkers pathways targets in order to feed and improve in vivo in vitro toxicity assessment tools and machine learning models and tools for using them for predictions The report will include all supporting evidence relevant literature data etc in a fitforpurpose format suitable for implementation as an algorithm SOP or invitrovivo assay characteristic Interim technical reports will present and structure all knowledge existing and novel gained from the in silico in vitro an in vivo tools in an attempt to construct elements of an AOP eg mechanistic interpretation of drug characteristics key initiating events molecular cellular and physiological etc and adverse outcomes pertinent to each of the three categories PNS CNS PP of interest to the project Final Report on Dissemination Activities and Use of Results Report on all dissemination activities undertaken through the project and tools produced to support these activities Preliminary assessment on use of project results with reference to IPR issues as needed Pharmaceuticals reported to induce P/P adverse events This report will summarize scientific knowledge underlying the selection of a set of about 20 pharmaceuticals known for their ability to cause PP adverse effects in clinical use In order to have a diverse set of compounds they will be selected from different pharmacological classes 1 or 2 representative of each and therapeutic areas with either low molecular weight or biological structures Adverse events will be limited to behavioural domains associated with depression and suicidal ideation and behaviour which can be assessed in animals such as anhedonia aggression and impulsivity in addition to possible cognitive impairment Two additional pharmaceuticals devoid of the above adverse events serving as negative controls will also be selected The report will present the pharmacological profile of each compound primary and secondary targets the chemicalbiological structure the description of the adverse events nature incidence severity population in relation to PK in clinical setting and the preclinical findings in vitro in vivo wherever available This panel of compounds will be used to select the most appropriate ones for testing in the frame of Objective 22 Data exchange SOPs, QA guidelines, and Data Management Plan Report on established SOPs and QA guidelines as well as on the NeuroDeRisk Data Management Plan NDMP The report will cover recommendations and outline the established operating procedures for uploading and downloading data from the project database including formats and quality assurance measures that will be measured and governed throughout the project The report will be included in the training material for consortium members involved in preparing data and uploading it from the respective WPs to project database The report will also contain the first version of the Data Management Plan of the NeuroDeRisk project Evaluation report of the toolbox performance This report will present the results of the performance testing of all WP2 in vitro in vivo tools using a retrospective assessment approach For each tool the document will present a full description of the experimental method used ROC analysis test results and implications for the use of the tools The report will be included in the NeuroDeRisk database and in the NeuroDeRisk toolbox documentationPerformance criteria will includeSensitivitySpecificityPositivenegative predictive valueAccuracy or concordancePrevalence observed vs actualLikelihood ratiosValue added positivenegative predictive value95 confidence intervals generated from all of that data NeuroDeRisk Toolbox Report on the NeuroDeRisk Toolbox integrated with a searchable project database predictive 3Dneurotoxicophores and machine learning models COSS derived models related to mechanism of actionMoAtoadverse event AE and drugtoAE knowledge and adverse outcome pathways information algorithms for data mining making predictions and established APIs for communication with EFPIA partner IT platforms Data Mining Software Report on data mining software developed in task 42c to be used for mining public and private EFPIA data sources Data will be mined in the context of the different WPs in order to find novel correlations between compound characteristics and the adverse events of interest New improved in vitro tool for screening seizure-inducing liabilities, especially using stem cell systems Report comparing the performance of human iPSCbased and rodent primary neuronal models for detecting seizureinducing liabiltities Sensitivity specificity and predictivity will be determined as enabled by the compound test set Particular emphasis will be placed on identifying strengths and gaps of each model system In vivo models and endpoints To develop and evaluate preclinical models that detect pharmaceuticalinduced changes associated with i depression and ii suicidal ideation and behaviour especially in those behavioural domains which can be more readily assessed in animals such as anhedonia aggression and impulsivity iii in addition to possible cognitive impairment Perform proofofconcept in nonclinical models with pharmaceuticals known to induce such adverse effects in humans Evaluate the ability of nonclinical models across species to accurately predict pharmaceuticalinduced psychologicalpsychiatric changes in humans The following animal species will be considered Zebrafish rat and nonrodents Decision about the selection of the nonrodent species dog andor nonhuman primate will be influenced by the results obtained in rats Novel modelstests or sets of endpoints will need to be established with certain level of fitforpurpose validation conducted Special focus on specific brain areas will be considered as necessary Open Research Data Pilot (1) Protocols for Toolbox Verification Report on developed protocols for verifying predictivity of models and algorithms developed for the NeuroDeRisk computational toolbox The report will include findings related to the predictive accuracy sensitivity and specificity of the predictive tools developed in WP4 based on testing by EFPIA and academicSME partners There will be a report section dedicated to each tool assessed as well as a full description of the assessment methodology and data used per tool We envisage two versions of this deliverable A full version available as a downloadable document and a collection of short texts suitable for onlineelectronic delivery or as part of the HELPFAQ parts of the tools themselves The assessment of the performance accuracy sensitivity specificity of the predictive tools will be developed within WP4 Based on this performance usage guidelines will be developed for use by EFPIA member researchers endusers Publications Peer reviewed articles (17) GABAA receptor-mediated seizure liabilities: a mixed-methods screening approach Author(s): Konstantina Bampali, Filip Koniuszewski, Florian D. Vogel, Jure Fabjan, Christos Andronis, Eftychia Lekka, Vassilis Virvillis, Thomas Seidel, Annie Delaunois, Leandro Royer, Michael G. Rolf, Chiara Giuliano, Martin Traebert, Gautier Roussignol, Magali Fric-Bordat, Ludmilla Mazelin-Winum, Sharon D. Bryant, Thierry Langer, Margot Ernst Published in: Cell Biology and Toxicology, 2023, ISSN 0742-2091 Publisher: Kluwer Academic Publishers DOI: 10.1007/s10565-023-09803-y Apo2ph4: A Versatile Workflow for the Generation of Receptor-based Pharmacophore Models for Virtual Screening Author(s): Jörg Heider, Jonas Kilian, Aleksandra Garifulina, Steffen Hering, Thierry Langer, and Thomas Seidel Published in: J. Chem. Inf. Model., Issue monthly, 2023, Page(s) 101-110, ISSN 1549-9596 Publisher: American Chemical Society DOI: 10.1021/acs.jcim.2c00814 QPHAR: quantitative pharmacophore activity relationship: method and validation Author(s): Stefan M. Kohlbacher, Thierry Langer, Thomas Seidel Published in: Journal of Cheminformatics, Issue 13/1, 2021, ISSN 1758-2946 Publisher: Chemistry Central DOI: 10.1186/s13321-021-00537-9 Gene Expression Profile as a Predictor of Seizure Liability Author(s): Anssi Lipponen, Natallie Kajevu, Teemu Natunen, Robert Ciszek, Noora Puhakka, Mikko Hiltunen, Asla Pitkänen Published in: International Journal of Molecular Sciences, Issue 24(4), 2022, ISSN 1422-0067 Publisher: Multidisciplinary Digital Publishing Institute (MDPI) DOI: 10.3390/ijms24044116 Neuronal alarmin IL-1α evokes astrocyte-mediated protective signals: Effectiveness in chemotherapy-induced neuropathic pain Author(s): Lorenzo Di Cesare Mannelli, Laura Micheli, Chiara Cervetto, Alessandra Toti, Elena Lucarini, Carmen Parisio, Manuela Marcoli, Carla Ghelardini Published in: Neurobiology of Disease, Issue 168, 2022, Page(s) 105716, ISSN 0969-9961 Publisher: Academic Press DOI: 10.1016/j.nbd.2022.105716 Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms Author(s): Konstantina Bampali, Filip Koniuszewski, Luca L. Silva, Sabah Rehman, Florian D. Vogel, Thomas Seidel, Petra Scholze, Florian Zirpel, Arthur Garon, Thierry Langer, Matthäus Willeit, Margot Ernst Published in: Britisch Journal of Pharmacology, 2022, ISSN 0007-1188 Publisher: Wiley-Blackwell DOI: 10.1111/bph.15807 Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood–brain barrier Author(s): Dominika Luptáková, Theodosia Vallianatou, Anna Nilsson, Reza Shariatgorji, Margareta Hammarlund-Udenaes, Irena Loryan, Per E. Andrén Published in: Molecular Psychiatry, 2021, ISSN 1359-4184 Publisher: Nature Publishing Group DOI: 10.1038/s41380-021-01267-y Applications of the Novel Quantitative Pharmacophore Activity Relationship Method QPhAR in Virtual Screening and Lead-Optimisation Author(s): Kohlbacher, S.M.; Schmid, M.; Seidel, T.; Langer Published in: Pharmaceuticals, Issue 15, 2022, Page(s) 1122, ISSN 1424-8247 Publisher: Multidisciplinary Digital Publishing Institute (MDPI) DOI: 10.3390/ph15091122 Novel alpha6 preferring GABA-A receptor ligands based on loreclezole Author(s): Xenia Simeone, Margot Ernst, Thomas Seidel, Joerg Heider, Doris Enz, Serena Monticelli, Florian Daniel Vogel, Filip Koniuszewski, Thierry Langer, Petra Scholze, Vittorio Pace, Margherita Miele Published in: European Journal of Medicinal Chemistry, Issue monthly, 2022, Page(s) 114780, ISSN 0223-5234 Publisher: Elsevier BV DOI: 10.1016/j.ejmech.2022.114780 Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice Author(s): Micheli, L.; Testai, L.; Angeli, A.; Carrino, D.; Pacini, A.; Margiotta, F.; Flori, L.; Supuran, C.T.; Calderone, V.; Ghelardini, C.; Di Cesare Mannelli, L Published in: Int. J. Mol. Sci., Issue 23, 2022, Page(s) 6229, ISSN 1422-0067 Publisher: Multidisciplinary Digital Publishing Institute (MDPI) DOI: 10.3390/ijms23116229 VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody Author(s): Laura Micheli, Carmen Parisio, Elena Lucarini, Alessia Vona, Alessandra Toti, Alessandra Pacini, Tommaso Mello, Serena Boccella, Flavia Ricciardi, Sabatino Maione, Grazia Graziani, Pedro Miguel Lacal, Paola Failli, Carla Ghelardini, Lorenzo Di Cesare Mannelli Published in: Journal of Experimental & Clinical Cancer Research, Issue 40/1, 2021, ISSN 1756-9966 Publisher: Springer Nature DOI: 10.1186/s13046-021-02127-x A Semi-Automatic Method for the Quantification of Astrocyte Number and Branching in Bulk Immunohistochemistry Images Author(s): Sandra I. Marques, Helena Carmo, Félix Carvalho, Susana I. Sá, João Pedro Silva Published in: International Journal of Molecular Sciences, 2023, ISSN 1422-0067 Publisher: Multidisciplinary Digital Publishing Institute (MDPI) DOI: 10.3390/ijms24054508 Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis Author(s): Christos Andronis, João Pedro Silva, Eftychia Lekka, Vassilis Virvilis, Helena Carmo, Konstantina Bampali, Margot Ernst, Yang Hu, Irena Loryan, Jacques Richard, Félix Carvalho, Miroslav M. Savić Published in: Archives of Toxicology, Issue 94/8, 2020, Page(s) 2829-2845, ISSN 0340-5761 Publisher: Springer Verlag DOI: 10.1007/s00204-020-02788-1 Neurofilament light chain in plasma as a sensitive diagnostic biomarker of peripheral neurotoxicity: In Vivo mouse studies with oxaliplatin and paclitaxel - NeuroDeRisk project Author(s): David Balayssac, Jérôme Busserolles, Catherine Broto, Cristelle Dalbos, Laetitia Prival, Sylvain Lamoine, Damien Richard, Mercedes Quintana, Aurélia Herbet, Sandrine Hilairet, Yang Hu, Irena Loryan, Warren E. Glaab, Laura Micheli, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Olivier Perrault, Mohamed Slaoui Published in: Biomedicine & Pharmacotherapy, Issue 167, 2023, Page(s) 115535, ISSN 0753-3322 Publisher: Elsevier Masson DOI: 10.1016/j.biopha.2023.115535 Oxaliplatin-Induced Neuropathy: Genetic and Epigenetic Profile to Better Understand How to Ameliorate This Side Effect Author(s): Jacopo Junio Valerio Branca, Donatello Carrino, Massimo Gulisano, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Alessandra Pacini Published in: Frontiers in Molecular Biosciences, Issue 8, 2021, ISSN 2296-889X Publisher: Frontiers Media S.A. DOI: 10.3389/fmolb.2021.643824 A new set of KNIME nodes implementing the QPhAR algorithm Author(s): Stefan Kohlbacher, Gökhan Ibis, Christian Permann, Sharon Bryant, Thierry Langer, Thomas Seidel Published in: Molecular Informatics, 2023, ISSN 1868-1743 Publisher: Wiley - VCH Verlag GmbH & CO. KGaA DOI: 10.1002/minf.202200245 Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels Author(s): Filip Koniuszewski, Florian D. Vogel, Konstantina Bampali, Jure Fabjan, Thomas Seidel, Petra Scholze, Philip B. Schmiedhofer, Thierry Langer and Margot Ernst Published in: Frontiers in Molecular Biosciences, Issue 9, 2022, Page(s) 860246, ISSN 2296-889X Publisher: Frontiers DOI: 10.3389/fmolb.2022.860246 Searching for OpenAIRE data... There was an error trying to search data from OpenAIRE No results available
