Biology subjects

Cifola, I.

Publications and source records attributed to Cifola, I..

4 recordsLinked to original sources

bioRxiv2026

Early AMPA receptor potentiation modifies synaptic maturation and disease progression in Rett models

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in MECP2 and characterized by impaired neuronal maturation and synaptic dysfunction. Positive allosteric modulators of AMPA receptors (AMPAR-PAMs) have shown therapeutic promise in RTT models, but the determinants of treatment responsiveness remain unclear. Here, we evaluated the clinically advanced AMPAR-PAM CX1632 in Mecp2-null male and Mecp2-heterozygous female mice across developmental stages and treatment regimens. Therapeutic efficacy was strongly influenced by developmental stage, disease severity, and treatment schedule. Brief neonatal treatment produced long-lasting improvements in survival, disease progression, motor function, and cognition, whereas later intervention was markedly less effective in symptomatic null mice but remained beneficial in less severely affected heterozygous females. Repeated intermittent administration further enhanced selected benefits. Mechanistically, early CX1632 treatment induced sustained activation of neuronal and synaptic gene programs, restored synaptic organization and neuronal activity, and rescued AMPA receptor-mediated transmission weeks after drug withdrawal. These findings identify disease stage as a key determinant of responsiveness to AMPA receptor potentiation and support developmentally informed therapeutic strategies for MECP2-related disorders.

neuroscience↗

bioRxiv2025

Red Blood Cell-derived Extracellular Vesicles enable Cisplatin and Cetuximab Synergistic Therapy against Triple-Negative Breast Cancer

BackgroundTriple-negative breast cancer is an aggressive breast cancer subtype characterized by the absence of human epidermal growth factor receptor 2, estrogen and progesterone receptors, limiting targeted therapy options. Cisplatin, a chemotherapeutic agent, induces DNA damage and exhibits some efficacy against triple-negative breast cancer, but its effectiveness is often reduced by chemoresistance and systemic toxicity. A very promising strategy to augment cisplatin treatment can be based on combining it with the biologic Cetuximab, an epidermal growth factor receptor inhibitor, which boosts cisplatin efficacy by inducing ferroptosis. ResultsTo optimize this strategy in a biocompatible and precise manner, we developed a nanoplatform based on red blood cell-derived extracellular vesicles for the combined delivery of Cetuximab and cisplatin, enabling immune evasion, and the possibility of autologous personalization and GMP-compliant production. Owing to their DNA-free lumen and lack of EGFR, RBC-EVs preserve cisplatin activity and prevent interference with cetuximab. This formulation enhances cisplatins cytotoxicity by up to 50%, as shown in vitro and in patient-derived organoids. It effectively reduces chemoresistance by downregulating hypoxia-related genes and promoting ferroptosis, additionally, it improves cisplatins cytotoxic effects while reducing hemotoxicity compared to the administration of free cisplatin. ConclusionsThese findings highlight the potential of red blood cell-derived extracellular vesicles as a biocompatible delivery system enabling combined therapy and offering a promising strategy to overcome current limitations in TNBC treatment.

cell biology↗

bioRxiv2023

Human iPSC-derived neural stem cells display a radial glia-like signature in vitro and favorable long-term safety in transplanted mice

Human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NSCs) are a promising source for cell therapy approaches to treat neurodegenerative and demyelinating disorders. Despite ongoing efforts to characterize hiPSC-derived cells in vitro and in vivo, we lack comprehensive genome- and transcriptome-wide studies addressing hiPSC-NSC identity and safety, which are critical for establishing accepted criteria for prospective clinical applications. Here, we evaluated the transcriptional and epigenetic signatures of hiPSCs and differentiated hiPSC-NSC progeny, finding that the hiPSC-to-NSC transition results in a complete loss of pluripotency and the acquisition of a radial glia-associated transcriptional signature. Importantly, hiPSC-NSCs share with somatic human fetal NSCs (hfNSCs) the main transcriptional and epigenetic patterns associated with NSC-specific biology. In vivo, long-term observation (up to 10 months) of mice intracerebrally transplanted as neonates with hiPSC-NSCs showed robust engraftment and widespread distribution of human cells in the host brain parenchyma. Engrafted hiPSC-NSCs displayed multilineage potential and preferentially generated glial cells. No hyperproliferation, tumor formation, or expression of pluripotency markers was observed. Finally, we identified a novel role of the Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) in the regulation of astroglial commitment of hiPSC-NSCs. Overall, these comprehensive in vitro and in vivo analyses provide transcriptional and epigenetic reference datasets to define the maturation stage of NSCs derived from different hiPSC sources, and to clarify the safety profile of hiPSC-NSCs, supporting their continuing development as an alternative to somatic hfNSCs in treating neurodegenerative and demyelinating disorders.

neuroscience↗

bioRxiv2022

scMuffin: an R package for resolving solid tumor heterogeneity from single-cell expression data

INTRODUCTIONSingle-cell (SC) gene expression analysis is crucial to dissect the complex cellular heterogeneity of solid tumors, which is one of the main obstacles for the development of effective cancer treatments. Such tumors typically contain a mixture of cells with aberrant genomic and transcriptomic profiles affecting specific sub-populations that might have a pivotal role in cancer progression, whose identification eludes bulk RNA-sequencing approaches. We presentscMuffin, an R package that enables the characterization of cell identity in solid tumors on the basis of a various and complementary analyses on SC gene expression data. RESULTSscMuffin provides a series of functions to calculate qualitative and quantitative scores, such as: expression of marker sets for normal and tumor conditions, pathway activity, cell state trajectories, CNVs, transcriptional complexity and proliferation state. Thus, scMuffin facilitates the combination of various evidences that can be used to distinguish normal and tumoral cells, define cell identities, cluster cells in different ways, link genomic aberrations to phenotypes and identify subtle differences between cell subtypes or cell states. We analysed public SC expression datasets of human high-grade gliomas as a proof-of-concept to show the value of scMuffin and illustrate its user interface. Nevertheless, these analyses lead to interesting findings, which suggest that some chromosomal amplifications might underlie the invasive tumor phenotype and the presence of cells that possess tumor initiating cells characteristics. CONCLUSIONSThe analyses offered by scMuffin and the results achieved in the case study show that our tool helps addressing the main challenges in the bioinformatics analysis of SC expression data from solid tumors.

bioinformatics↗