Archivio Istituzionale della Ricerca- Università del Piemonte Orientale
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Prokaryotic DNA repair systems: mechanistic characterization and valuable insights for biotechnological applications
Get PDFThis thesis aimed at characterizing DNA repair systems in bacteria. We provided new insights for the description of the Nucleotide Excision Repair (NER) system, contributing to elucidate molecular details still unclear about the pathway. On the other hand, we applied biotechnological engineering to exploit Direct Damage Reversal in order to develop useful tools that can be used to improve research outcomes. Concerning the NER project, we were able to describe additional features of the damage recognition process in Mycobacterium tuberculosis, carried out by UvrA and UvrB proteins. We conducted Cryo-EM based structural studies, obtaining four models depicting different snapshots of the dynamic damage recognition process. We were able to suggest a new mechanism of the damage recognition process, with UvrA being essential for damage identification. These results led to a publication, currently accepted in Nature Communications. Then, in collaboration with Vrije Universiteit of Amsterdam, we exploited optical tweezers and single-molecule fluorescence imaging to collect some preliminary results, indicating a different mechanism of action of UvrA towards damaged and undamaged DNA, in terms of forces applied onto the DNA molecules, movement and interaction time. Besides, we developed a new self-labeling protein tag (SLP) suitable for studies on (hyper)thermophilic organisms, by applying an integrated computational and structural approach, obtaining an engineered variant of Saccharolobus solfataricus OGT (SsOGT) able to recognize O6-benzyl-cytosine derivatives, to be used in non-permissive reaction conditions where commercial SLPs fail. The project led to a paper published in 2022 in Computational and Structural Biotechnology Journal. Starting from this technology, we employed the OGT to develop molecular rulers to measure distances between organelles in living cells. The method revealed to be specific, precise and efficient, and led to the deposition of a patent
TeenTrust-AI: A Structured Educational Framework for Empowering Teenagers to Evaluate Trustworthiness of AI
Get PDFArtificial intelligence (AI) is becoming ubiquitous, so teenagers must learn to engage with it critically, yet most school programs still ignore this need. The paper introduces the Structured Educational Framework for Trustworthy AI, called TeenTrust-AI, to fill this gap. This educational framework helps teenagers evaluate AI tools against seven ALTAI-aligned principles of trustworthiness (privacy, robustness, fairness, transparency, well-being, accountability, and human oversight) through three stages: Teaching, Learning, and Trustworthiness Verification. By using a case study with a climate-change as a reference topic and a chatbot as a AI-powered system, it provides checklist-guided activities to assess trustworthiness. Furthermore, this educational framework
is tool/topic-agnostic, and addresses practical adoption challenges to build critical, ethical AI literacy
Percorsi di sviluppo e interazione tra categorie nella pragmatica storica dell’italiano.
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Lenvatinib vs. sorafenib as second-line treatment post atezolizumab plus bevacizumab for hepatocellular carcinoma: The LEVIATHAN study
No full textBackground & Aims: Atezolizumab plus bevacizumab (A+B) is a standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, optimal sequencing strategies after A+B failure remain undefined. Methods: LEVIATHAN is a multicentre, observational study evaluating efficacy and survival outcomes in patients who progressed on A+B and subsequently received either lenvatinib or sorafenib as second-line therapy. Of 1,210 patients treated with first-line A+B between May 2018 and August 2024, 230 eligible patients were included (lenvatinib, n = 125 [54.3%]; sorafenib, n = 105 [45.7%]). Propensity score matching was applied to adjust for baseline imbalances, incorporating independent predictors of overall survival (OS) and response to prior treatment. Results: In the overall second-line cohort, lenvatinib was associated with superior median progression-free survival (5.5 vs. 2.6 months, hazard ratio [HR] 0.41, p <0.001) and median OS (11.9 vs. 7.4 months, HR 0.67, p = 0.018) compared to sorafenib. From the start of A+B, the A+B-lenvatinib sequence achieved a median OS of 22.4 months vs. 14.3 months with A+B-sorafenib (HR 0.54, p <0.001). These differences persisted in the propensity score-matched cohort (median OS: 19.6 vs. 13.9 months, HR 0.67, p = 0.024). Multivariate analysis identified treatment with lenvatinib as an independent predictor of improved OS alongside alpha-fetoprotein ≤400 ng/ml, neutrophil-to-lymphocyte ratio <3, and absence of portal vein thrombosis. Conclusions: The LEVIATHAN study supports lenvatinib as a more effective second-line option than sorafenib following A+B in unresectable HCC, including in patients with primary resistance to immunotherapy. While limited by the observational study design, these findings highlight the importance of treatment sequencing to optimise outcomes in advanced HCC. Impact and implications: Continuing active treatment after progression on frontline atezolizumab plus bevacizumab (A+B) can benefit patients with advanced hepatocellular carcinoma (HCC), but evidence to guide second-line therapy remains limited. The LEVIATHAN study addresses this gap by evaluating real-world outcomes in a large, prospective, multinational cohort treated with lenvatinib or sorafenib after A+B discontinuation. Our findings show that lenvatinib provides significantly longer progression-free and overall survival than sorafenib, even after adjusting for baseline imbalances with propensity scores. Lenvatinib also achieved higher disease control rates, including in patients with primary resistance to immunotherapy. These results challenge the assumption that all VEGFR-targeting TKIs are equivalent post-ICI and suggest lenvatinib may be superior to sorafenib following anti-VEGF–based immunotherapy. While prospective randomised trials are still needed, these real-world data offer valuable guidance for clinicians and help refine treatment sequencing in advanced HCC
Plasma pTau217/Aβ42 and pTau217 outperform pTau181/Aβ42 and pTau181 in predicting cerebrospinal fluid amyloid positivity: A real-world retrospective study
No full textBackground: Alzheimer's disease (AD) diagnosis often relies on invasive cerebrospinal fluid (CSF) sampling or expensive cerebral positron emission tomography (PET) imaging. Noninvasive tests could facilitate early detection. Plasma phosphorylated-tau (pTau) isoforms are promising AD biomarkers that correlate with brain amyloid-β (Aβ) deposition. Objective: To explore the diagnostic accuracy of pTau-based plasma biomarkers to forecast CSF amyloid-positive status in a real-world consecutive population of subjects with cognitive impairment and complete plasma and CSF biomarker profiles. Methods: We retrospectively studied 138 consecutive patients with cognitive impairment. Plasma biomarkers (pTau217, pTau181, Aβ42, Aβ40) were measured by automated immunoassay. Diagnostic accuracy for CSF amyloid status was assessed using area-under-the curve (AUC) values from receiver-operating characteristic (ROC) curve analysis. A dual-threshold strategy was used to define low- and high-risk groups and estimate how many lumbar punctures could be avoided. Results: Among 138 patients (37% CSF amyloid-positive), pTau217/Aβ42 ratio had the highest AUC (0.920) for predicting amyloid positivity, followed by pTau217 (AUC 0.904). These values exceeded the accuracy of pTau181-based markers. Using dual cut-offs, a 90% sensitivity-90% specificity strategy could avoid about 93.5% of lumbar punctures using pTau217/Aβ42 (10.9% misclassified), and 84.1% when using pTau217 (11.2% misclassified). Stricter thresholds (95%–95% and 97.5%–97.5%) further reduced misclassification rates but at the expense of fewer avoidable invasive procedures. Conclusions: Plasma pTau217 (alone or combined with Aβ42) shows high accuracy for detecting AD pathology and could serve as a scalable, noninvasive diagnostic tool. This approach may triage patients for confirmatory testing and substantially reduce the need for invasive CSF examination
From electron spin to relaxivity: a multidisciplinary perspective on first-row transition metal-based MRI probes
No full text: The electron spin is a key enabler of some of the most advanced current technologies. A prime example is the development of MRI contrast agents, where precisely engineered electron spin properties are utilized to enhance the capabilities of one of the most powerful diagnostic tools in the medical science. Clinically approved contrast agents are based on paramagnetic gadolinium(iii) complexes. However, to alleviate health and environmental concerns, as well as for specialized applications, alternatives are sought after. Due to their rich chemistry, abundance and low toxicity first-row paramagnetic transition metal ions are emerging as an appealing alternative. A large experimental effort is needed to engineer the new generation of contrast agents. The primary source of information comes from Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. While fitting these profiles can, in principle, yield all the structural and dynamic parameters that influence relaxation, the underlying theoretical models demonstrate a significant challenge. The parameters affect the NMRD profiles in highly coupled, non-separable ways, meaning that a simple, unconstrained fit often results in a non-unique solution. Consequently, the independent experimental determination of some, and preferably most, of these parameters offers a considerable advantage in obtaining reliable and physically meaningful information. This perspective outlines an integrated approach that exploits Electron Paramagnetic Resonance (EPR) spectroscopy for the accurate determination of key molecular parameters. Specifically, EPR is used to quantify the rotational correlation time, the closest proton-metal distance, and the electron spin density at the proton. This methodology is particularly relevant for contrast agents based on first-row transition metal ions. We discuss the contribution of EPR in a complementary context with well-established techniques such as NMR and DFT
On solutions to a class of degenerate equations with the Grushin operator
No full textThe Grushin Laplacian −Δ_α is a degenerate elliptic operator in R^{h+k} that degenerates on {0}×R^k. We consider weak solutions of −Δ_α u = Vu in an open bounded connected domain Ω with V ∈W^{1,σ}(Ω) and σ>Q/2, where Q=h+(1+α)k is the so-called homogeneous dimension of R^{h+k}. By means of an Almgren-type monotonicity formula we identify the exact asymptotic blow-up profile of solutions on degenerate points of Ω. As an application we derive strong unique continuation properties for solutions
