Biology subjects

Ferraro, L.

Publications and source records attributed to Ferraro, L..

7 recordsLinked to original sources

bioRxiv2025

Transposable Elements and Homotypic Niches Drive Immune Dynamics and Resistance in Melanoma Epigenetic-based immunotherapy

Melanoma plasticity drives immune evasion and therapy resistance through dynamic cell-state transitions beyond genetic alterations. Epigenetic remodeling critically influences such processes, yet its role in reshaping the tumor ecosystem under therapeutic pressure remains unresolved. Here, we profiled longitudinal biopsies from melanoma patients treated in the phase Ib NIBIT-M4 epi-immunotherapy clinical trial (NCT02608437), testing the combination of a DNMT1 inhibitor with anti-CTLA4 using single-cell multiome and high-resolution spatial transcriptomics. Integrated analyses resolved seven malignant meta-programs, including a rare Wnt/{beta}-catenin-driven melanocytic state and a de-differentiated neural crest-like state enriched in non-responders. Spatial modeling revealed that homotypic clustering stabilizes resistant programs, with neural crest-like cells forming compact, centrally localized niches, whereas Wnt/{beta}-catenin subpopulations displayed a bimodal architecture, either cohesive clusters sustained by adhesion or dispersed, transcriptionally plastic cells. Responders exhibited progressive enrichment of an antigen presentation/interferon program and coordinated remodeling of the tumor microenvironment with T and B cell expansion, whereas tumors from non-responder patients maintained stable composition of neural crest-like clusters. Epigenetic therapy reactivated transposable elements, providing both regulatory signals that prime innate immunity within microenvironment and generating antigens that drive immunoediting and immunogenicity of Antigen presentation/interferon cell states in responders. Finally, NFATC2 emerged as a master regulator of neural crests-like transcriptional phenotypes and promoter of resistance to therapeutic interventions in melanoma patients. NFATC2 perturbation was able to shift tumor cells towards more differentiated and immunogenic states. These findings reveal how epigenetic-based immunotherapy reshapes melanoma ecosystems, provide mechanistic insights into how multiple transcriptional programs promote tumor plasticity and resistance to both combinatorial therapies and immune checkpoint blockade, identify spatial clustering as a principle stabilizing resistant niches, and highlight {beta}-catenin and NFATC2 as actionable vulnerabilities to overcome resistance.

genomics↗

bioRxiv2023

MOViDA: Multi-Omics Visible Drug Activity Prediction with a Biologically Informed Neural Network Model

Drug discovery is a challenging task, characterized by a protracted period of time between initial development and market release, with a high rate of attrition at each stage. Computational virtual screening, powered by machine learning algorithms, has emerged as a promising approach for predicting therapeutic efficacy. However, the complex relationships between features learned by these algorithms can be challenging to decipher. We have devised a neural network model for the prediction of drug sensitivity, which employs a biologically-informed visible neural network (VNN), enabling a greater level of interpretability. The trained model can be scrutinized to investigate the biological pathways that play a fundamental role in prediction, as well as the chemical properties of drugs that influence sensitivity. The model leverages multi-omics data obtained from diverse tumor tissue sources and molecular descriptors that encode drug properties. We have extended the model to predict drug synergy, resulting in favorable outcomes while retaining interpretability. Given the often imbalanced nature of publicly available drug screening datasets, our model demonstrates superior performance compared to state-of-the-art visible machine learning algorithms.

bioinformatics↗

bioRxiv2020

Variation in pyrethroid resistance phenotypes in Anopheles darlingi from residual malaria transmission area: warning on suspected resistance built-up in French Guiana.

Anopheles darlingi is the major vector of malaria in South America. In French Guiana, malaria transmission occurs inland and along the rivers with a particular reemergence in the lower Oyapock area. Control against malaria vector is performed using deltamethrin indoor residual spraying and long lasting impregnated bednets. For four years, the level of resistance to pyrethroids was monitored using CDC bottle tests in An. darlingi populations. Resistance built-up was suspected in a mosquito population in malaria endemic area but did not sustained, supposably due to the reintroduction of susceptible alleles. No mutation on the insecticide target genes was found, metabolic resistance is then suspected.

zoology↗

bioRxiv2020

Multi-BIRW:a network-based algorithm for drug repurposing

This paper is based on Computational Biology with an eye towards medicine. In fact our aim is to identify new indications for existing drugs with a computational approach using Systems Biology, in order to speed up the market entry, avoiding some phases of drug development (for example toxicity tests) and with a lower cost. The method that we will discuss exploits the concept of Random Walk in a heterogeneous network, formed by a drug-drug and disease-disease similarity and known drug-disease associations. This is done by combining different types of data in order to connect more effectively two drugs or two diseases with a similarity score. At the end we integrate the known associations between drugs and diseases with the purpose of finding similarity values of new couples.

bioinformatics↗

bioRxiv2019

The independent and combined influence of schizophrenia polygenic risk score and heavy cannabis use on risk for psychotic disorder: A case-control analysis from the EUGEI study.

Background: Some recent studies have challenged the direction of causality for the association between cannabis use and psychotic disorder, suggesting that cannabis use initiation is explained by common genetic variants associated with risk of schizophrenia. We used data from the European Union Gene-Environment Interaction consortium (EUGEI) case-control study to test for the independent and combined effect of heavy cannabis use, and of Schizophrenia Polygenic risk score (SZ PRS), on risk for psychotic disorder. Methods: Genome-wide data were obtained from 492 first episode psychosis patients (FEPp) and from 787 controls of European Ancestry, and used to generate SZ PRS from the summary results of an independent meta-analysis. Information on pattern of cannabis use was used to build a 7-level frequency-type composite cannabis use measure that we previously found was a strong predictor of psychotic disorder. Results: SZ PRS did not predict cannabis initiation (b=0.027; p=0.51) or how frequently controls (b=0.027; p=0.06) or FEPp (b=0.006; p=0.91) used it, or the type of cannabis they used (Controls: b = 0.032; p=0.31); FEPp: b= 0.005; p=0.89). The frequency-type composite cannabis use measure (OR=1.32; 95% CI 1.22-1.44) and SZ PRS (OR=2.29; 95%CI 1.71-3.05) showed independent effects from each other on the OR for psychotic disorder. Conclusion: SZ PRS does not predict an individual s propensity to try cannabis, frequency of use, or the potency of the cannabis used. Our findings provide the first evidence that SZ PRS and heavy cannabis use exert effects independent from each other on the risk for psychotic disorder.

genetics↗

bioRxiv2019

Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of First Episode Psychosis patients and controls

AimsFirst Episode Psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in FEP patients and controls and whether this differs between groups. MethodsWe analysed data on lifetime cannabis using patients (n=655) and controls (n=654) across 15 sites from six countries in the EU-GEI study (2010-2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use. ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences, independent of other experiences (p[≤]0.001). For psychotic-like experiences there was a significant interaction for caseness x frequency of use (p<0.001) and caseness x money spent on cannabis (p=0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no similar significant interaction for euphoric experiences (p>0.5). Conclusions and RelevanceFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher frequency and amount of cannabis use compared to controls. This suggests a specific psychotomimetic response in patients related particularly to heavy cannabis use.

neuroscience↗

bioRxiv2019

Cannabis-associated symptom profiles in patients with first episode psychosis and population controls

ObjectiveThe evidence is mixed on whether cannabis use is associated with a particular symptomatology in first episode psychosis (FEP) patients.\n\nThe authors set out to investigate a) patterns of association between cannabis use and transdiagnostic symptom dimensions; b) whether the extent of use of cannabis contributes to the variation in clinical and subclinical symptom profiles.\n\nMethodThe authors analysed data from 901 patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Item response modelling was used to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use was evaluated using linear mixed effects models analyses.\n\nResultsIn patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high potency cannabis having the highest score (B=0.35; 95%CI 0.14 to 0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B=-0.27; 95%CI -0.42 to -0.12).\n\nIn controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use.\n\nNeither patients nor controls presented differences in the depressive dimension related to cannabis use.\n\nConclusionsThe extent of use of cannabis explains part of the heterogeneous distribution of positive and negative symptoms of FEP patients.

neuroscience↗