Biology subjects

Italia, M.

Publications and source records attributed to Italia, M..

4 recordsLinked to original sources

bioRxiv2026

Hippocampal Ring Finger Protein 10-dependent signaling supports cognitive flexibility

The ability to flexibly adapt behavior to changing environmental contingencies is a core component of brain function and relies on experience-dependent remodeling of neural circuits. While cognitive flexibility has been primarily attributed to prefrontal-striatal networks, the contribution of hippocampus and their underlying molecular substrates remains less understood. Here, we show that the dorsal hippocampus has a key role in cognitive flexibility. In particular, Ring Finger Protein 10 (RNF10)-mediated signaling, linking activation of synaptic NMDARs to specific transcriptional programs in the dorsal CA1, is necessary for cognitive flexibility. In fact, in vivo downregulation, through gene deletion and silencing of RNF10, resulting in impaired long-term synaptic plasticity, suppressed cognitive flexibility. This was reflected in the impaired ability to disengage from previously acquired contextual, visual, and spatial information and to adapt behavior to changed context. Overall, our results identified RNF10 as a key in vivo player necessary for the balance between cognitive stability and flexibility.

animal behavior and cognition↗

bioRxiv2025

Radiopharmaceutical therapy for metastatic prostate cancer: Insights from mechanistic modeling and in silico trials

Radiopharmaceutical therapy (RPT) has rapidly evolved into a key precision-oncology modality, with radioligands now approved or in late-stage development for multiple solid tumors, including neuroendocrine and prostate cancers. RPT with [177Lu]Lu-PSMA (Prostate-Specific Membrane Antigen) has recently been approved as a life-prolonging treatment for metastatic castration-resistant prostate cancer (mCRPC), but its clinical use still relies on non-personalized, empirically chosen fixed schedules. Here, we develop a mechanistic, patient-personalizable mathematical model simulating mCRPC response and organ-at-risk toxicity during [177Lu]Lu-PSMA RPT. The model integrates tumor growth dynamics, radiobiological response, and organ-resolved pharmacokinetics inferred from mass data and standardized uptake values obtained from positron emission tomography studies. Parameters were derived from the literature, although the framework allows personalization by fitting to patient-specific data such as imaging and prostate-specific antigen levels. Using virtual patient (VP) cohorts generated via stochastic parameter sampling, we conducted in silico trials and validated the model by comparing simulated outcomes with published dosimetry and survival data for [177Lu]Lu-PSMA trials. We then explored dosing and scheduling strategies to optimize efficacy-toxicity trade-offs. Consolidated regimens with fewer, higher-activity injections improved overall survival (OS) in silico but increased toxicity, especially in kidneys. Cycle length had a weaker influence on OS within a 2-9 week window, while it clearly affected toxicity, whereas excessive delays (> 12 weeks) markedly reduced efficacy. Global sensitivity analysis identified tumor growth, uptake, and radiosensitivity parameters as key drivers of interpatient variability, and convergence testing confirmed robustness with respect to VP cohort size. These methodological findings illustrate how mechanistic modeling and in silico trials can inform the design and personalization of RPT regimens. Author summaryStandard radiopharmaceutical therapy regimens for metastatic castration-resistant prostate cancer deliver the same doses at fixed intervals, without accounting for interpatient variability in tumor growth, drug uptake, or organ tolerance. Here, we focus on [177Lu]Lu-PSMA radiopharmaceutical therapy, which is now approved for these patients but still administered using one-size-fits-all protocols. We present a mechanistic mathematical model that simulates tumor and radiopharmaceutical dynamics in individual patients using a virtual patient framework. With appropriate patient-specific data, such as quantitative imaging and prostate-specific antigen levels, this model can be used to generate digital twins and evaluate personalized treatment strategies. By adjusting injection schedules and cycle timing in silico, we explored how standard treatment protocols could be optimized to improve survival while maintaining acceptable toxicity. We found that a 9 week treatment cycle achieved survival outcomes comparable to the standard 6 week protocol, with a significant reduction in toxicity, whereas longer cycle extensions led to loss of therapeutic efficacy. These results provide a quantitative basis for optimizing radiopharmaceutical therapy and highlight the potential of virtual patients and in silico trials to support patient-adapted treatments in modern oncology.

cancer biology↗

bioRxiv2025

EGFR-Driven Phenotypes Dictate Differential Therapeutic Response to Radiotherapy and Temozolomide in Glioblastoma.

Despite the established Stupp regimen, glioblastoma (GBM) remains a highly lethal cancer with a 5-year survival rate below 10%. The epidermal growth factor receptor (EGFR) is frequently amplified or mutated in GBM, and we have previously shown that different EGFR statuses correlate with distinct tumor phenotypes and responses to temozolomide (TMZ). In this study, we investigated the differential response of two mouse GBM models, one overexpressing EGFRwt (EGFRwt/amp) and the other with overexpressing the EGFRvIII variant, to radiotherapy (RT) alone and in combination with TMZ. While both tumor models were sensitive to RT in vitro, in vivo experiments showed no significant survival benefit from RT for mice carrying EGFRwt/amp GBM, regardless of the RT schedule. Moreover, for these tumors, different combinations of RT with TMZ were not significantly better than spaced TMZ treatment alone. In contrast, EGFRvIII tumors responded well to RT alone, and spacing out the RT doses offered no additional benefit. Although a Stupp-like protocol provided a small benefit compared to RT alone in this model, the combinatorial treatment also induced the expression of several resistance markers, such as MGMT or NF-{kappa}b phosphorylation. Our retrospective analysis of patient data supports these findings, suggesting that RT alone may not improve survival for patients with EGFRwt/amp GBM, whereas for GBM with EGFRvIII mutations, adding RT or TMZ and RT, does provide a clear survival benefit to surgery or to surgery and RT, respectively. These results suggest that EGFR status could serve as a crucial biomarker to predict tumor response and guide personalized treatment decisions, particularly in cases where minimizing toxicity is a priority.

cancer biology↗

bioRxiv2025

A Novel Prognostic Metric Resolves the MYCN enigma in Silico and Points to a Biosynthetic Regulatory Shift Driven by MYCN Amplification in Neuroblastoma

Neuroblastoma (NB) is the most common extra-cranial solid tumour in children. Although MYCN amplification is typically indicative of a poor prognosis, the expression level of MYCN has a non-monotonic relationship with the clinical outcome. This paper proposes an explanation for this phenomenon, which is called the MYCN enigma in the literature. The p53/MYCN metric, which is a measure of the p53 protein level relative to the MYCN protein level in a NB tumour, is the key concept. Our hypothesis is that the metric has a positive relationship with the outcome of a patient. It is presented as a binary classification system, where the prognosis is favourable when p53/MYCN>3.5. The mathematical model presented in this paper describes the dynamics between MYCN, p53, ARF, and MDM2; their genes; and their mRNA transcripts. Simulations were carried out by solving the model numerically in a series of initial value problems. The results are aligned with a list of clinical and experimental observations. We extracted association rules with the Apriori algorithm and explored the parametric space stochastically. Assuming that MYCN enables biogenesis in NB tumours, our results support the prediction that MYCN amplification shifts the balance towards producing MYCN. When a wild-type tumour is deficient in MYCN, stress responses may restore biogenesis in general and preferentially produce MYCN in a negative feedback loop. Another prediction is that MYCN - amplified tumours, without treatment, require hard-to-attain biosynthetic rates and stress responses to achieve good outcomes.

systems biology↗