University of Insubria

The mouse‐double‐minute‐2 (MDM2) protein, the main downregulator of the tumor suppressor p53 protein, represents a promising target for the development of novel anticancer therapies. However, the lack of selectivity and poor effectiveness in tumors bearing mutated‐p53 impaired the approval of several MDM2 inhibitors for the market. In this context, the possibility of generating drug‐conjugates within a MDM2 inhibitor is a growing research area aimed to overcome these drawbacks. Considering the promising MDM2 inhibition by the β‐carboline‐based 1, in this work we explored the introduction of a new functionalization on it for a future conjugation while preserving its anticancer properties. Based on preliminary docking studies, we synthesized derivatives 2 a–d having linear hydroxyalkyl chains with different lengths at the 6‐position of the β‐carboline core, which effectively preserved the submicromolar IC50 on wild‐type‐p53‐U87MG glioblastoma cell line observed with 1. Candidates 2 a, d showed the functionalization was tolerated with respect of bioactivity also on mutated‐p53‐U138MG glioblastoma cell line, and their hydroxyl groups proved to be easily accessible when coupled to 4‐pentynoic‐N,N’‐dimethylethylenediamine affording derivatives 10 a, d with high yields. In summary, our results led to generating novel 6‐hydroxyalkyl‐β‐carboline compounds displaying a suitable hydroxyl‐site useful to improve the efficacy and/or the tumor specificity of 1 through conjugation strategies.

Long interspersed nuclear elements 1 (LINE‐1) are the most abundant and the only autonomous mobile elements in the human genome. When their epigenetic repression is removed, it can lead to disease, such as autoimmune diseases and cancer. Coeliac disease (CeD) is an immune‐mediated disease triggered by an abnormal T‐cell response to dietary gluten and a predisposing condition of small bowel adenocarcinoma (SBA), frequently characterized by epigenetic alterations. The aim of this work was to assess LINE‐1 methylation by bisulphite pyrosequencing and NanoString® gene transcription analysis in 38 CeD‐SBAs compared with 25 SBAs associated with Crohn's disease (CrD‐SBAs) and 25 sporadic SBAs (S‐SBA). Both analyses were also performed in duodenal mucosae from 12 untreated CeD patients (UCD) and 19 treated CeD patients (TCD), and in 11 samples of normal intestinal mucosa to better investigate the role of LINE‐1 deregulation in CeD and in CeD‐SBA. A significant loss of LINE‐1 methylation was observed in CeD‐SBAs and in mucosae from UCD patients (with very similar methylation levels) compared with controls. By contrast, a restoration of normal LINE‐1 methylation levels was found in TCD mucosae after a strict gluten‐free diet. LINE‐1 hypomethylation does not lead to expression of ORF1 and ORF2, with the only exception being for one CeD‐SBA. The expression analysis of enzymes modulating DNA methylation and inflammatory genes confirmed that CeD‐SBA shared a very similar expression profile of UCD mucosae showing a strong upregulation of genes involved in inflammation, immune response, and T‐cell activity compared with TCD mucosae. For the first time, this work demonstrates that loss of DNA methylation is an intrinsic epigenetic feature of CeD, accompanying the immune response as a reversible mechanism in patients following a strict gluten‐free diet, and suggests the possible role of LINE‐1 hypomethylation in promoting cell adaptability during the gliadin‐related inflammatory process. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background The concept of health-related quality of life (QOL) captures the patient’s perspective on how the illness and its treatment affect their well-being. The FACE-Q Skin Cancer Module represents a validated patient-reported outcome (PRO) instrument, specifically developed for patients undergoing facial skin cancer surgery. Methods Upon authorization and licensing from the Q-Portfolio® team, the authors engaged the process of translation and cultural adaptation of this questionnaire into Italian, in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and World Health Organization (WHO) guidelines. Results In the first step, two Italian translations are produced and reconciled into one. In the second step, the reconciled Italian version is reverse-translated into English. As third step, the back-translation was reviewed and approved by the Q-Portfolio team. A representative sample of the questionnaire’s potential target was interviewed, and final refinements were made in the fourth and final step. At the end of these phases, a validated and conceptually equivalent Italian version of the FACE-Q Skin Cancer Module was achieved. Conclusions This tool is currently ready and available for clinical and research purposes. The introduction of an Italian version marks a significant step towards enhancing its accessibility and relevance, ensuring tangible benefits for both clinicians and patients. Level of Evidence Not gradable.

We present a detailed study of an asymmetrically driven quantum Otto engine with a time-dependent harmonic oscillator as its working medium. We obtain analytic expressions for the upper bounds on the efficiency of the engine for two different driving schemes having asymmetry in the expansion and compression work strokes. We show that the Otto cycle under consideration cannot operate as a heat engine in the low-temperature regime. Then, we show that the friction in the expansion stroke is significantly more detrimental to the performance of the engine as compared to the friction in the compression stroke. Further, by comparing the performance of the engine with sudden expansion, sudden compression, and both sudden strokes, we uncover a pattern of connections between different operational points. Finally, we analytically characterize the complete phase diagram of the Otto cycle for both driving schemes and highlight the different operational modes of the cycle as a heat engine, refrigerator, accelerator, and heater.

In this explanatory study, we aim to determine the predictors of repetition avoidance or reproduction in the translation of reporting verbs from English into Italian and Polish, using a sample of 11 novels. We fit multiple negative binomial regression models with fixed effects to assess the impact of five predictor variables (i.e. frequency of a source-text verb, number of its translation equivalents in lexical databases, its number of senses, semantic-pragmatic category of verb, and length in characters) on the response variable, i.e., the number of different target language verb types into which a source text reporting verb is translated. The overall model fit per the lowest Akaike Information Criterion (AIC) value obtained through backward elimination reveals that verb category, frequency of a source-text reporting verb, and number of translation equivalents make the largest individual contributions to explaining the proportion of variation in the response variable in the Italian data; for the Polish translations the corresponding variables are verb category, frequency, the number of senses, and the interaction between the number of translation equivalents and the number of senses. The summaries of the final models provide a detailed multifactorial picture of when repetition of reporting verbs is maintained or avoided in literary translation. (OPEN ACCESS AT: https://doi.org/10.1556/084.2024.00911)

Objective To investigate the potential role of dual-energy spectral computer tomography (CT) quantitative parameters in the definition of bladder cancer (BCa) pathological grading. Methods This retrospective study evaluated the use of spectral CT imaging features for BCa. From 2021 to 2023, 63 patients with histologically-confirmed BCa diagnosis were examined at our Institution. The patients were pathologically divided, following international guidelines, into two groups: low-grade (n = 24) and high-grade urothelial carcinoma group (n = 39). The iodine concentrations (IC), the normalized iodine concentrations (NIC), and the slope of the spectrum curve (SLOPE) were calculated along with the measure of each lesion CT value on the monochromatic image from 40 to 120 keV. The diagnostic performance was assessed by Receiver operator characteristic curve (ROC) analysis. Results The high-grade group showed significantly higher mean values of IC, SLOPE, and HU in 40 KeV monoenergetic images (VMI40 HU). AUC values for NIC, SLOPE, IC, and VMI40 HU were 0,677, 0,745, 0,745, and 0,755 respectively. In multivariate logistic regression models with backward stepwise, including all quantitative parameters, only VMI40 HU remained statistically significant to correlate with high-grade tumors. Conclusion Preliminary data shows that quantitative parameters of dual-energy spectral CT can be helpful to characterize low-grade and high-grade urothelial bladder tumors. The prediction of high-grade BCa with non-invasive methods (e.g. dlCT) can aid in early detection of muscle-invasive and worse prognostic tumors that need more aggressive and timely treatments, personalizing the management on the risk of recurrence.

Objectives Major studies have defined clinical rules to regulate the use of computed tomography in children after head trauma. Infants younger than 3 months are considered at higher risk of brain injuries than older children and at the same time at higher risk of radiation-induced damage. Hence, it would be desirable to have clinical decision rules more adapted to this subset of patients. The objectives of this study are to compare the rate of brain injuries in children younger than 3 months or 3 to 24 months and to assess predictors of clinically important traumatic brain injuries (ciTBIs) (the ones causing death, neurosurgical intervention, long intubation, or hospitalization for 2 days or more) in the former group. Methods Records of children younger than 24 months evaluated in a single emergency department for minor head trauma during a 3 years period were retrospectively reviewed. The rates of brain injuries were compared in children younger or older than 3 months. Variables associated with severe lesions were assessed in younger children. Results The study included 744 patients, 86 (11.6%) aged 0 to 90 days and 658 (88.4%) aged 91 to 730 days. Within the young group, we found higher rates of traumatic brain injuries (14.0% vs 4.1%, P = 0.0008) and ciTBI (8.1% vs 1.5%, P = 0.002) compared with the old group. A significant correlation with ciTBI in the young group was observed for heart rate (odds ratio [OR], 12.3; 95% confidence interval [CI], 2.4–62.4), nonfrontal scalp hematoma (OR, 9.2; 95% CI, 1.8–46.1), severe mechanism (OR, 5.6; 95% CI, 1.1–27.6), presence of hematoma (OR, 6.1; 95% CI, 1.2–30.0), hematoma size >3 cm (OR, 23.8; 95% CI, 4.2–135.6), and hematoma location (OR, 9.2; 95% CI, 1.8–46.1). Conclusions Children younger than 3 months presenting after minor head trauma constitute a relevant population. Available clinical predictors well correlate with ciTBIs in this age group.

The relationship between river hydrology and microplastic (MP) pollution is complex: increased discharge does not always mobilize more MPs, but floods can effectively flush out MPs from river catchments. Climate change and water resource management further influence MP pollution and its fate by altering river hydro-sedimentary regimes. This review investigates the interconnected impacts of these factors from a comprehensive perspective, focusing on how they affect MP concentration in freshwater ecosystems, particularly in regulated rivers and associated reservoirs. Our review reveals a scarcity of studies that jointly analyze the interrelated issues of MP pollution, water resource management, and climate change. Key findings indicate that variations in river discharge significantly influence MP mobilization, mainly depending on catchment land use, channel morphology, position within the catchment, and MP characteristics. Reservoirs function as both sinks and sources of MPs, underscoring their complex role in MP dynamics and the need for sustainable sediment management strategies. The increasing frequency of extreme weather events, driven by climate change, along with prolonged droughts intensified by water management practices, exacerbates MP pollution. These changes contribute to the local concentration of MPs, posing direct physical threats to aquatic organisms, particularly benthic species, through pollution and habitat alterations. Current policies on plastic pollution, water resources and climate change are underdeveloped, as these topics have been treated separately so far. In conclusion, this review provides perspectives on future research and policy directions to address challenges posed by MPs and to preserve rivers against multiple stressors.

This study examines the contingency effect of infrastructure (disaggregated into physical and digital) in the relationship between foreign aid and inclusive growth in Sub‐Saharan Africa (SSA). We employ macro data for 41 SSA countries and the dynamic system GMM estimator for the empirical analysis. We find that (i) foreign aid promotes inclusive growth in SSA, (ii) whereas transport infrastructure enhances inclusive growth, energy infrastructure, sanitation infrastructure, and digital infrastructure are statistically insignificant, and (iii) only transport infrastructure amplifies the inclusive growth‐enhancing effect of foreign aid. Across the digital and physical infrastructure domains, we find that the contingency effect of the latter is rather remarkable. Our threshold analysis also indicates that for digital infrastructure and transport infrastructure to condition complementary policies to foster inclusive growth in SSA, minimum thresholds of 22% and 57.8% are required. We conclude that comprehensive transport infrastructural development is key if foreign aid is to enhance inclusive growth in SSA.

This study aims to identify toxic potential and environmental hazardousness of antimicrobials. In this regard, the available experimental toxicity data with rat and mouse acute oral toxicity have been gathered from ChemID Plus database (n = 202) and subjected to data curation. Upon the data curation 51 and 68 compounds were left for the rat and mouse respectively for the modeling. The quantitative structure toxicity relationship (QSTR) and interspecies correlation analysis by quantitative toxicity-toxicity relationship (QTTR) modeling was approached in this study. The models were developed from 2D descriptors under OECD guidelines by using multiple linear regressions (MLR) with genetic algorithm (GA) for feature selection as a chemometric tool. The developed models were robust (Q2LOO = 0.600–0.679) and predictive enough (Q2Fn = 0.626–0.958, CCCExt = 0.840–0.893). The leverage approach of applicability domain (ad) analysis assures the model’s reliability. The antimicrobials without experimental toxicity values were classified as high, moderate and low toxic based on prediction and ad. The occurrence of the same classification from QSTR and QTTR models revealed the reliability of QTTR models.Finally, the applied “sensitivity factor analysis” typifies the sensitivity of chemicals toward each species. Overall, the first report will be helpful in the toxicity assessment of upcoming antimicrobials in rodents.