Archivio Istituzionale della Ricerca- Università del Piemonte Orientale
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NAMPT and NNMT released via extracellular vesicles and as soluble mediators are distinguished traits of BRAF inhibitor resistance of melanoma cells impacting on the tumor microenvironment
Full text linkUnlabelled: Drugs targeting mutant BRAF and MEK oncogenes are effective in melanoma, even though resistance rapidly develops. This complex picture includes acquired intrinsic tumor and tumor microenvironmental-mediated mechanisms. Here we show that melanoma cells resistant to BRAF inhibitors (BRAFi) overexpress the rate-limiting enzymes involved in nicotinamide (NAM) metabolism nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT). Remarkably, these cells release NAMPT and NNMT both in the free-form or loaded into extracellular vesicles (EVs). NAMPT is emerging as a key mediator of resistance to BRAFi in melanoma, primarily due to its established role in NAD biosynthesis. Although previously identified as a soluble extracellular factor in this tumor, its presence within EVs released by melanoma cells has not been reported until now, highlighting a previously unrecognized mechanism through which NAMPT may influence the tumor microenvironment (TME). NNMT was revealed to increase in melanoma lesions compared to benign nevi. Here, we report for the first time its overexpression in resistant melanoma cell lines at intracellular and extracellular levels (secreted both as a soluble factor and into EVs). NNMT expression is increased in BRAF-mutated melanoma patients, suggesting a link between its upregulation and the BRAF oncogenic signaling. Moreover, NNMT levels positively correlate with gene signatures associated with pro-inflammatory signaling, immune cell migration, and chemokine-mediated pathways. NNMT pharmacological inhibition and genetic silencing significantly reduce resistant melanoma cell growth. In addition, we found that BRAFi-resistant cells are more sensitive to NNMT inhibition, highlighting a trait of vulnerability of BRAFi-resistant melanomas. Lastly, we proposed for the first time a tetrameric NNMT:TLR4 binding model offering a plausible structural and mechanistic basis for their association. Our functional results indicated that exogenous NNMT treatment is able to trigger NF-κB pathway, one of the main TLR4-dependent signaling, sharing this cytokine-like properties with NAMPT, and opening a future deeper exploration of its functional role in the extracellular space. Overall, the identification of NAMPT and, surprisingly also NNMT, included in EVs and abundantly released from resistant melanoma cells supports the impact of these moonlighting proteins involved in nicotinamide metabolism as mediators of BRAF/MEK inhibitors resistance with tumor intrinsic and potentially tumor microenvironment-mediated mechanisms. Interfering with nicotinamide metabolism could be a valid strategy to counteract drug resistance acting on the multifactorial tumor-host interactions. Supplementary information: The online version contains supplementary material available at 10.1186/s12964-025-02361-2
PROCEDIMENTALIZZAZIONE DEL CONSENSO E INFORMAZIONE NEI CONTRATTI DI CREDITO IMMOBILIARE AI CONSUMATORI
No full textLa direttiva sul credito immobiliare ai consumatori (direttiva 2014/17/UE, con l’obiettivo di tutelare il soggetto finanziato e garantir-gli una maggiore consapevolezza dell’impegno economico che andrà ad assumer, ha introdotto una disciplina che procedimentalizza il con-senso e obbliga il finanziatore a fornire una serie di informazioni al consumatore. L’articolo analizza criticamente la disciplina in questione, anche per come interpretata e applicata, evidenziando l’inidoneità della stessa a perseguire gli obiettivi che il legislatore europeo intendeva raggiungere
The effects of platinum(iv) complexes on Aβ1–42 aggregation: a synergistic inhibition upon axial coordination
No full textAmong novel metallodrugs, Pt(iv) complexes have been receiving increasing attention as alternatives to Pt(ii) analogues since they exhibit superior kinetic inertness and, hence, fewer undesirable reactions. Pt(iv) complexes have been designed as prodrugs with mechanisms of action finely tuned by properties of the axial ligands. In this context, the insertion of known bioactive molecules as axial ligands to generate multi-target drugs (MTDs) is considered a valuable drug design strategy because of the possible synergistic effects between the metal centre and the organic moiety. By employing the repurposing of drugs in different diseases, in this study, the Pt(iv) complex (OC-6-44)-acetatodiamminedichlorido(4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(iv) was investigated for its ability to modulate the self-aggregation process of the amyloid peptide Aβ1-42. Specifically, the complex features 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato (rhein) as a ligand that is a natural aromatic molecule already known as a discrete inhibitor of amyloid aggregation. Herein, several biophysical and microscopic assays, such as thioflavin T (ThT) fluorescence, dynamic light scattering (DLS) and scanning electron (SEM) and confocal microscopy, indicated that the Pt(iv) complex can inhibit and disassemble Aβ1-42 aggregation to a greater extent with respect to rhein alone. This effect is likely due to the formation of π-π interactions between the rhein moiety and the side chains of the Aβ1-42 peptide. This experimental evidence was confirmed by molecular docking studies of monomeric and tetrameric Aβ1-42. Overall, the data support the application of Pt(iv) complexes as innovative neurotherapeutics
Enhancing Skin Cancer Prevention and Awareness in the Italian Population: Insights from the “Save Your Skin” Screening Campaign
Full text linkIntroduction: Skin cancer prevention campaigns aim to reduce modifiable risk factors, yet high-risk groups often maintain inadequate protection practices. Objectives: This study analyzed data from Italy's 2023 "Save Your Skin" campaign, which provided free skin checks nationwide. Methods: Data from 1,773 participants across 29 centers in 13 regions were collected to assess sun exposure, photoprotection habits, and skin cancer awareness, identifying gaps in prevention efforts. Results: Most participants were female (70.16%), with a median age of 36, and 96.61% were born in Italy. While 71.24% joined for prevention reasons, others participated due to changes in a nevus (12.35%) or personal (2.31%) or family (7.33%) history of skin cancer. Self-assessments of nevi often did not align with dermatologists' evaluations, but family and personal history reporting was more accurate. Participants showed confusion about nevi and melanoma: only 52.7% correctly identified nevi as benign, while 67.2% recognized melanoma as malignant. On average, participants answered 1.57 out of three knowledge questions correctly, with those having a family or personal history of skin cancer performing better. High-risk sun exposure behaviors were identified in 37.78% of participants. Older adults used sunscreen less frequently but relied more on hats and shade, while younger individuals reported less sun exposure at work. Notably, participants with actinic damage demonstrated lower awareness and provided fewer correct answers on photoprotection. Conclusions: These findings underscore the need for targeted public health strategies to improve education on skin cancer prevention, particularly among high-risk and older populations
Esperienze di pazienti e operatori coinvolti nel processo di transizione dai servizi pediatrici ai centri dell’adulto per giovani con diabete di tipo 1 in Italia: lo studio TransiDEA (II fase)
No full textIntroduction. Type 1 diabetes mellitus (T1D) is a common chronic condition in children and adolescents, with increasing incidence. Adequate management is crucial for glycemic control and the prevention of complications. The transition from pediatric care centers to adult care centers is a critical phase, and its effectiveness varies among different countries and even within different areas of the same country. Materials and methods. In this qualitative study conducted in 2023, at least 30 patients with T1D who had undergone the transition between 2017 and 2022 were invited to participate by completing an online semi-structured questionnaire regarding their transition experiences. Additional questionnaires were administered to healthcare professionals to gather information on organizational barriers and patient expectations. Results. The survey conducted on 52 young adults with T1D from 5 Italian diabetes centers revealed that the transition to adult care typically occurs at an average age of 19.6 years. At the time of the survey, 73% of participants had not experienced acute complications, and 55.7% had optimal metabolic control prior to the transition. However, many patients encountered issues in the operational management of the transition, with about 40% describing the process as difficult, highlighting in some cases a feeling of “abandonment” and a desire for greater support and communication between pediatric and adult services. The majority of respondents reported an increase in autonomy in managing their diabetes. Discussion and conclusions. Although the transition process for patients with T1D is structured, the study reveals some gaps in communication and support between pediatric and adult care centers. A well-coordinated pathway is essential, considering the individual needs of patients and strengthening collaboration between care teams
Obesity in Italy: An Empirical Analysis of Healthcare Consumption, Quality of Life and Comorbidities
No full textBackground and Objectives: Obesity is a health condition that significantly augments
the risk of several chronic diseases and is a major public health concern. In Italy, this
phenomenon has highly increased in the last few decades, raising alarm about both NHS sustainability and population health. We investigate whether and to what extent obesity impacts three different categories of outcomes, namely healthcare consumption, quality of life and the presence of relevant comorbidities. Materials and Methods: We use data from the European Health Interview Survey, 2019, a micro dataset that displays more than 45,000 observations, providing detailed information on the health status and healthcare access, demographics and socioeconomic characteristics among Italian individuals aged 15 and over. We first provide a descriptive analysis of the socioeconomic gradient of obesity, and then we implement propensity score matching to detect the effects of this condition on healthcare use, quality of life and comorbidities. To the best of our knowledge, this is the first empirical paper to jointly consider the healthcare consumption, declared comorbidities and quality of life of Italian obese individuals. Results: The findings show that obese individuals consume more health services, have a lower quality of life and present a higher rate of comorbidities compared to non-obese individuals with the same observable characteristics.
We also find that obesity is rooted in socioeconomic drivers, with richer and more educated individuals being less likely to present with this condition. Conclusions: The findings call for policy measures aimed at monitoring and contrasting the rising phenomenon of obesity in Italy, with a tailored approach across socioeconomic groups
Thermodynamic vs Kinetic Control of Brush Composition in Grafting to Reactions of Disperse Polymer Systems in Melt
No full textGrafting to reactions are one of the most investigated approaches to producing polymer brushes due to their unique capability to control both the brush thickness and grafting density. Despite their widespread use, some aspects of the grafting to reactions remain not fully understood. Among these, particularly relevant is the preferential grafting of the shortest chains in dispersed polymer systems. This phenomenon is investigated in the present paper by grafting on silicon oxide substrates polystyrene blends containing equimolar amounts of two telechelic polystyrenes with different molecular weights to model disperse polymer systems. Furthermore, for each blend, different end groups, namely, hydroxy or phosphate end groups, are considered. For hydroxy-terminated polystyrene blends, a preferential grafting of the shortest component is observed and derives from the lower entropy loss for short chains when the reactive end group approaches the surface, but the brush composition, in terms of the ratio between short and long chains, is independent of grafting time and temperature. In contrast, at a short time, the grafting of phosphate-terminated polystyrene blends takes place with an increase of short chains definitely higher than the one observed for the hydroxy-terminated blends. In turn, after a sufficiently long time, the brush composition converges to the same final composition of the hydroxy-terminated polystyrenes. This result indicates that at short times the control of the brush composition is dictated by a fast absorption of the short chains on the surface substrate due to the strong polarity of the phosphate group. This adsorption takes place before the grafting to process and results in an observed excess of grafted short chains. In turn, as grafting proceeds, the brush composition evolves toward the thermodynamic composition, which is therefore equal to the one of the hydroxy-terminated polymer blends
Un enigma rinascimentale: le armi e i libri di Pietro del Monte (1457-1509)
Full text linkLa mia ricerca esplora alcune opere di Pietro Monte, pubblicate a Milano fra il 1492 e il 1509, dedicate a vari argomenti quali scherma, duelli, lotta, fisiognomia, filosofia, teologia, scienze naturali e via dicendo; l'identità dell'autore è tutt'ora incerta, anche se doveva trattarsi di un personaggio piuttosto noto viste le sue frequentazioni con Leonardo da Vinci e Baldassarre Castiglione, che lo elogia ripetutamente nel Libro del Cortegiano. Data la notevole conoscenza della lingua spagnola e degli usi militari iberici si è ipotizzato che fosse un maestro d'armi spagnolo emigrato in Italia (Anglo 1989, 2000; Forgeng 2014, 2018) tuttavia propendo per una teoria alternativa che lo identifica in Pietro del Monte Santa Maria (Fontaine 1991, 1992; van Houdt e Sperber, 2014; Brioist 2014, 2016, 2019; attualmente la famiglia si chiama Bourbon del Monte). Costui era un condottiero inizialmente al servizio di Firenze dove conosce Machiavelli, per poi passare a Venezia nel 1507; morto nella battaglia di Agnadello del 1509, la sua fine viene ricordata con toni eroici da numerosi autori coevi, fra cui Marin Sanuto, Luigi Guicciardini e Pietro Bembo. Dopo aver ricostruito la biografia di quest'ultimo e discusso delle problematiche relative alla sua identità, la mia ricerca presenta un'ampia esposizione della letteratura schermistica italiana ed europea fino al tardo XVI secolo, per poi analizzare gli Exercitiorum atque Artis militaris Collectanea (1509), la pubblicazione più nota del Monte, e studiarne gli insegnamenti bellici inserendoli nel più ampio contesto della scherma europea del periodo
Influenza Vaccination of Nurses and Other Health Care Workers in Different Occupational Settings: A Classic and AI Mixed Approach for Time-to-Event Data
Full text linkBackground: Seasonal influenza currently remains a major public health concern for the community and, in particular, the health care worker (HCW). According to the World Health Organization, HCWs are among the high-risk categories for which vaccination is recommended, due to the derived absenteeism, productivity loss, and high probability of transmitting the disease to vulnerable individuals or patients. Therefore, an HCW vaccination policy should be adopted by every health care provider. There is growing evidence that a time effect of the vaccination event is probable, which may influence vaccine effectiveness. We designed and conducted an observational study to investigate the time to anti-influenza vaccination event of different categories of HCWs belonging to different occupational settings in a tertiary hospital during three seasons in order to retrieve some insight about HCW prioritization when designing vaccination campaigns. Materials and Methods: We retrospectively analyzed the results of two HCW anti-influenza vaccination campaigns (2022 and 2023) to assess any difference regarding job typology and unit typology (critical care, surgical, medical, service). We first fitted a classic Cox proportional hazard model and then an AI random forest model to assess variable importance. We used R, RStudio, and the survex package. Results: Overall, other HCWs reported a lower vaccination rate compared to nurses (HR 0.77; 95%CI 0.62–0.97), and service unit personnel appeared to more likely be vaccinated (HR 1.42; 95%CI 1.01–1.99) compared to those belonging to the critical care units. As expected, older workers tended to be vaccinated more frequently (HR 1.70 for the (46, 65] category compared to the younger one; 95%CI 1.39–2.09). The variable importance analysis showed consistent superiority of the ward typology and age category variables with respect to time. During the entire timeline, the ward typology appeared to be more important than the HCW typology. Conclusions: Our results suggest a prioritization policy based firstly on the unit typology followed by the job typology for HCW anti-influenza campaigns
Identifying key competencies for supporting second victims in different contexts: a scoping review
Full text linkBackground: Providing support to second victims in workplaces is crucial for maintaining high-quality performance. Peer support approach has proven to be one of the most effective and well-accepted approaches. However, the specific competencies required for peer supporters remain unclear. This review aims to address this gap by identifying and categorising these competencies. Objective: This scoping review examines the competencies (skills, attitudes and knowledge) needed to support workers where the pressure of their roles may lead to errors that could cause harm to others. In such situations, these individuals may experience intense feelings of responsibility, potentially impacting their ability to perform their duties. In the healthcare sector, these workers are commonly referred to as 'second victims'. Eligibility criteria: This review includes studies that define the competencies necessary for peer supporters assisting second victims in any industry. It covers all professional roles susceptible to human errors affecting people's well-being. The focus is on peer support and psychological first aid, encompassing relevant competencies, attitudes and knowledge for addressing safety-related incidents and workplace errors. Sources of evidence: The scoping review was conducted following Arksey and O'Malley's framework and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Studies were identified through a comprehensive search of databases, including Embase, ProQuest, PsycINFO, PubMed, Scopus and Web of Science. References from eligible studies were also considered. Charting methods: Data were extracted and categorised into competency domains through a standardised process. Two reviewers independently performed data extraction, with discrepancies resolved by consensus. Results: A total of 34 studies were included in the review. Across five identified domains, 91 specific and 30 general competencies were categorised. Additionally, the review identified 29 types of peer-based interventions designed to support professionals following incidents or stressful situations. Conclusions: The findings underscore the need for well-defined competencies for peer supporters of second victims, emphasising training in communication, emotional support and role-specific knowledge. Tailoring peer support programmes to the professional context and industry-specific characteristics is essential for providing effective assistance