Mario Negri Institute for Pharmacological Research

The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC) yet benefits only about half of patients. Using patient-derived xenografts, we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, whereas HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, nongenetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients. SIGNIFICANCE:FOLFIRI response biomarkers in mCRC are lacking. Evidence in patient-derived xenografts, tumoroids, and patients shows that chemosensitivity arises from functional relaxation, rather than (epi)genetic inactivation, of the HR DNA repair pathway. Integrative analyses yield a chemopredictive algorithm centered on the expression of the RAD51 recombinase, with potential to refine patient stratification.

The integration of artificial intelligence (AI) into chemical risk assessment (CRA) is emerging as a powerful approach to enhance the interpretation of complex toxicological data and accelerate safety evaluations. However, the regulatory uptake of AI remains limited due to concerns about transparency, explainability, and trustworthiness. The European Partnership for the Assessment of Risks from Chemicals (PARC) project ReadyAI was established to address these challenges by developing a readiness scoring system to evaluate the maturity and regulatory applicability of AI-based models in CRA. The project unites a multidisciplinary consortium of academic, regulatory, and legal experts to define transparent and reproducible criteria encompassing data curation, model development, validation, explainability, and uncertainty quantification. Current efforts focus on identifying key priorities, including harmonized terminology, rigorous data quality standards, case studies, and targeted training of regulatory scientists. ReadyAI aims to deliver a practical, evidence-based scoring system that enables regulators to assess whether AI tools are sufficiently reliable for decision-making and guides developers toward compliance with regulatory expectations. By bridging the gap between AI innovation and regulatory applicability, ReadyAI contributes to the responsible integration of AI into chemical safety assessment frameworks, ultimately supporting human and environmental health protection.

Obesity and metabolic syndrome (MS) represent two of the most pressing global public health challenges, often coexisting and synergistically increasing the risk of cardiovascular and renal complications. Over the past decade, advances in our understanding of the pathophysiological mechanisms underlying chronic kidney disease (CKD) have reshaped our approach to patients with coexisting obesity and CKD. The identification of distinct phenotypes associated with an elevated risk of CKD progression and cardiovascular events, along with the development of novel therapeutic strategies, has contributed to a paradigm shift in clinical management. Currently, therapeutic options such as sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and their combination with the non-steroidal mineralocorticoid receptor antagonist finerenone-when added to standard renin-angiotensin-aldosterone system blockade-are available and have shown potential for cardiorenal protection in patients with obesity and/or MS and CKD. In this review, we highlight the complex interplay between obesity and CKD, emphasizing the need for an integrated, multidisciplinary approach. The use of multitargeted therapeutic strategies holds promise in substantially altering the natural course of disease progression, ultimately improving patient outcomes.

This multicenter study focuses on the latest (2020-2024) trends in candidemia in 155 Italian ICUs, stressing its frequency and lethality, with a shift toward non-albicans, fluconazole-resistant species, namely C. parapsilosis. In this study, resistance to fluconazole prolonged ICU stays without increasing mortality, while non-catheter-related episodes had a more severe prognosis. Candidemia is the leading fungal bloodstream infection (BSI) in the ICU and carries high mortality. After the COVID-19 pandemic, non-albicans, fluconazole-resistant species increased in Europe, yet contemporary ICU-acquired data are scarce. The primary outcome of this study was to evaluate the incidence of ICU-acquired candidemia per 1,000 “at risk” ICU admissions (ICU length of stay [LOS] ≥ 48 h). Secondary analyses compared ICU-acquired candidemia with ICU-acquired bacterial BSI and assessed species distribution, fluconazole susceptibility, and outcomes by fluconazole resistance and by source of infection. Data were drawn from the PROSAFE network, a prospective multicentric observational project conducted across 192 Italian ICUs (2014–2023). Among 179,590 ICU admissions, 95,662 were at risk. ICU-acquired candidemia occurred in 373 patients (3.9‰ of at-risk admissions). Compared with ICU-acquired bacterial BSI, candidemia patients had longer intra-ICU and hospital LOS (32 vs 24 days and 44 vs 36 days, respectively; p < 0.001) and higher mortality (intra-ICU 41.3

AIM:To compare the pattern of psychotropic drug prescriptions in adolescents who started a drug therapy after the COVD-19 pandemic and in adolescents who began before the pandemic. METHODS:A healthcare database from Italy's Lombardy region was analysed to compare the prescription profiles of psychotropic drugs (N05 and N06 groups of the Anatomical Therapeutic Chemical classification system) and access to healthcare services among two cohorts of adolescents aged 12-17 years. One cohort received their first psychotropic drug prescription in 2018 (pre-pandemic), and the other received theirs in 2021 (post-pandemic). The incidence, number of prescriptions and persistence of therapy within 12 months of the first prescription date and prevalence of polytherapy (prescription of more than one psychotropic class) were evaluated. Additionally, access to healthcare services was monitored before and after the index prescription. RESULTS:The incident users were 1734 in 2018 and 2943 in 2021; the incidence increased from 3.01 per 1000 to 4.97 per 1000 (incidence rate ratio [IRR] 1.64; 95% CI 1.55-1.74), with the largest rise in girls aged 12-14 (IRR 2.35; 95% CI 2.01-2.77). Among girls, the median number of prescriptions (+50%), prevalence of polytherapy (+57%) and persistence at 12 months (+31%) all increased post-pandemic, while no significant changes were observed among boys. Healthcare service use was higher prior to initiation in 2021 (65.7%) than in 2018 (58.4%). CONCLUSIONS:The increase in incidence and intensity of psychotropic drug prescriptions in adolescent girls confirms the existence of sex-related differences in mental health during the pandemic.