Biology subjects

Mattioli, M.

Publications and source records attributed to Mattioli, M..

3 recordsLinked to original sources

bioRxiv2026

Complementary cytotoxicity of GD2-targeted photoimmunotherapy and 5-aminolevulinic acid photodynamic therapy in neuroblastoma and osteosarcoma

Phototherapy, a light-activated anticancer treatment, enables localized tumor-cell killing with distinct mechanisms of action. Photoimmunotherapy (PIT) produces immunogenic tumor cell death upon near-infrared light activation of a photoabsorber through antigen-specific targeting. Photodynamic therapy (PDT) produces reactive oxygen species through red-light activation of intracellular protoporphyrin IX generated from 5-aminolevulinic acid uptake and metabolism. PIT may have limited activity in antigen-low cells, whereas PDT has less precise tumor selectivity. We combined these modalities to define their interaction, broaden cytotoxicity, and determine whether dual treatment could reduce light-dose requirements. We conjugated dinutuximab, which targets the GD2 antigen, to IRDye 700DX and characterized plasma-membrane localization by confocal and widefield microscopy. PIT and PDT monotherapies were evaluated across agent and light doses in neuroblastoma (NB) and osteosarcoma (OS) cell lines. Combination matrices were tested using interaction, highest-single-agent, and Bliss analyses. Both monotherapies demonstrated significant light-dose-dependent effects in NB and OS. PIT produced no measurable cytotoxicity in antigen-blunted control cells, whereas PDT remained effective, confirming antigen-dependence of PIT and antigen-independence of PDT. The combination interaction was significant in SK-N-BE(2) but not LM7. At selected combinations, however, dual treatment produced greater killing than the more effective matched monotherapy in both SK-N-BE(2) and LM7 (Padj<0.022). Notably, lowest combination of PIT 10 J/cm2 plus PDT 10 J/cm2 achieved 90.3% killing in SK-N-BE(2), exceeding higher light-dose PIT or PDT monotherapy, suggesting a light-dose sparing effect. These findings establish potent and complementary PIT-PDT activity, supporting dual phototherapy to broaden cytotoxicity and reduce light-dose requirements in GD2-expressing tumor phototherapy.

cancer biology↗

bioRxiv2024

CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts

Oncogene-induced replicative stress is a potent tumor-suppressive mechanism that must be kept in check for cancer cells to thrive. Thus, the identification of genes and pathways involved in replicative stress is key to understand cancer evolution and to identify prospective therapeutic targets. Here, we investigated factors that modulate replicative stress upon deregulation of the MYC oncogene. We identified the cyclin-dependent kinase CDK12 as selectively required to prevent transcription-replication conflicts and the activation of a cytotoxic DNA-damage response (DDR). At the mechanistic level, CDK12 was recruited to damaged genes by PARP-dependent DDR-signaling and elongation-competent RNAPII. Once recruited, CDK12 repressed transcription by preventing the association of CDK9 with RNAPII. Either loss or chemical inhibition of CDK12 led to DDR-resistant transcription at damaged genes. Genome-wide profiling revealed that loss of CDK12 exacerbated transcription-replication conflicts in MYC-overexpressing cells and led to the accumulation of double-strand DNA breaks (DSBs), occurring preferentially between early- replicating regions and transcribed genes, organized in a co-directional head-to-tail orientation. Overall, our data demonstrate that CDK12 protects genome integrity by repressing transcription of damaged genes, which is required for proper resolution of DSBs at oncogene-induced transcription-replication conflicts. This provides a rationale that explains both how CDK12 deficiency can promote tandem duplications of early-replicated regions during tumor evolution, and how CDK12 targeting can exacerbate replicative-stress in tumors.

cancer biology↗

bioRxiv2019

Gut microbiome structure and adrenocortical activity in dogs with aggressive and phobic behavioral disorders

Accompanying human beings since the Paleolithic period, dogs has been recently regarded as a reliable model for the study of the gut microbiome connections with health and disease. In order to provide some glimpses on the connections between the gut microbiome layout and host behavior, we profiled the phylogenetic composition and structure of the canine gut microbiome of dogs with aggressive (n = 17), phobic (n = 15) and normal behavior (n = 17). According to our findings, aggressive behavioral disorder was found to be characterized by a peculiar gut microbiome structure, with high biodiversity and enrichment in generally subdominant bacterial genera. On the other hand, phobic dogs were enriched in Lactobacillus, a bacterial genus with known probiotic and psychobiotic properties. Although further studies are needed to validate our findings, our work supports the intriguing opportunity that different behavioral phenotypes in dogs may be associated with peculiar gut microbiome layouts, suggesting possible connections between the gut microbiome and the central nervous system and indicating the possible adoption of probiotic interventions aimed at restoring a balanced host-symbiont interplay for mitigating behavioral disorders.

microbiology↗