Biology subjects

Severgnini, M.

Publications and source records attributed to Severgnini, M..

4 recordsLinked to original sources

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

A comparison between Greengenes, SILVA, RDP, and NCBI reference databases in four published microbiota datasets

Inaccurate bacterial taxonomic assignment in 16S-based microbiota experiments could have deleterious effects on research results, as all downstream analyses heavily rely on the accurate assessment of microbial taxonomy: a bias in the choice of the reference database can deeply alter microbiota biodiversity (alpha-diversity), composition (beta-diversity), and taxa profile (bacterial relative abundances). In this paper, we explored the influence of the reference 16S rRNA collection by performing a classification against four of the main databases used by the scientific community (i.e. Greengenes, SILVA, RDP, NCBI); the consequences of database clustering at 97% were also explored. To investigate the effects of the database choice on real and representative microbiome samples from different ecosystems, we performed a comparative analysis on four already published datasets from various sources: stools from a mouse model experiment, bovine milk, human gut microbiota stool samples, and swabs from the human vaginal environment. We took into consideration the computational time needed to perform the taxonomic classification as well. Although values in both alpha- and beta-diversity varied a lot, sometimes even statistically, according to the dataset chosen and the eventual clustering, the final outcome of the analysis was a concordance in the capability to retrieve the original experimental group differences over the various datasets. However, in the taxonomy classification, we found several inconsistencies with taxonomies correctly assigned in only some of the four databases. The degree of concordance among the databases was related to both the complexity of the environment and its degree of completeness in the reference databases. IMPORTANCE16S rRNA sequencing is, nowadays, the most commonly used strategy for microbiota profiling in many different ecosystems, ranging from human-associated to animal models, food matrices, and environmental samples. The ability of this kind of analysis to correctly capture differences in the microbiota composition is related to the taxonomic classification of the fragments obtained from sequencing and, thus, to the choice of the best reference database. This paper deals with four of the most popular microbial databases, which were evaluated in their ability to reproduce the experimental evidence from four already published datasets. The knowledge of the advantages and drawbacks of the database choice can be pivotal for planning future experiments in the field, making researchers aware of the repercussions of such a choice according to the different environments under scrutiny. Moreover, this work can also shed new light upon past results, partially explaining discordant evidence.

bioinformatics↗

bioRxiv2020

Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder with specific clinical signs and neurodevelopmental impairment. The two known proteins altered in the majority of RSTS patients are the histone acetylation regulators CBP and p300. For assessing possible ameliorative effects of exogenous and endogenous HDAC inhibitors (HDACi), we exploited in vivo and in vitro RSTS models. First, HDACi effects were tested on Drosophila melanogaster, showing molecular rescue. In the same model, we observed a shift in gut microbiota composition. We then studied HDACi effects in RSTS cell lines compared to healthy donor cells. We observed patients-specific molecular rescue of acetylation defects at subtoxic concentrations. Finally, we assessed commensal gut microbiota composition in a cohort of RSTS patients compared to healthy siblings. Intriguingly, we observed a significant depletion in butyrate-producing bacteria in RSTS patients. In conclusion, this study reports the possibility of modulating acetylation equilibrium by HDACi treatments and the importance of microbiota composition in a chromatinopathy.

genetics↗

bioRxiv2017

Antenatal microbial colonisation of mammalian gut

The widely accepted dogma of intrauterine sterility and initial colonisation of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations, and to assess foetal colonisation before parturition. To ascertain antenatal microbial colonisation in mammals, we analysed sterilely collected intestinal tissues from rodent foetuses in parallel with experimental controls, and tissues from autoptic human foetuses. Next generation sequencing (NGS) showed the presence of pioneer microbes in both rat and human intestines, as well as in rodent placentas and amniotic fluids. Live microbes were isolated from culture-dependent analyses from homogenized rat foetal intestines.\n\nMicrobial communities showed foetus- and dam-dependent clustering, confirming the high interindividual variability of microbiota even in the antenatal period. Fluorescent in situ hybridisation analysis confirmed the microbes existence in the lumen of the developing gut.\n\nThese findings have vast implications for an emerging field of enhancing the management of healthy pregnancies, and for understanding how the infant microbiome starts and it is thus shaped.

microbiology↗