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KRAS-SOS-1 Inhibition as New Pharmacological Target to Counteract Anaplastic Thyroid Carcinoma (ATC)
No full textAnaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer. Tumor cells have been shown to activate alternative signaling pathways, making treatments less effective. One of the major proteins involved in the progression of ATC is the proto-oncogene KRAS that belongs to a group of small guanosine triphosphate (GTP)-binding proteins. Despite its recognized importance in cancer malignancy, KRAS is considered non-druggable and has never been studied in the field of ATC. In this context, a new synthetic molecule, BAY-293, has recently been developed that selectively inhibits the KRAS–SOS-1 interaction. Based on these findings, the aim of this study was to evaluate for the first time the antitumor effect of BAY-293 using in vitro and in vivo models of ATC. The in vitro model included different thyroid cancer (TC) cell lines used to study the effect of BAY-293 on the modulation of mitogen-activated protein kinase (MAPK) pathways, apoptosis, and cell migration. To confirm the in vitro findings and better mimic the complex tumor microenvironment, an in vivo orthotopic model of ATC was used. The results of the study indicate that BAY-293, both in vitro and in vivo, effectively blocked the KRAS/MAPK/ERK pathway and β-catenin, which act as downstream effectors essential for cell migration, and increased the apoptotic process by slowing the progression of ATC. In conclusion, this study demonstrated that KRAS/SOS-1 inhibition could be a promising therapeutic target for the treatment of ATC and highlighted BAY-293 as an innovative molecule that needs further research to fully evaluate its efficacy in the field of thyroid cancer
PI3K/mTOR Signaling Pathway Dual Inhibition for the Management of Neuroinflammation: Novel Insights from In Vitro Models
No full text: Neuroinflammatory responses are central to the pathogenesis of neurodegenerative diseases, affecting cells of both neuronal and glial origin that respond to immune-driven inflammatory stimuli. The PI3K/mTOR signaling pathway is essential for the regulation of these neuroinflammatory processes and is therefore a promising target for therapeutic intervention. Here, we investigated the consequences of PI3K/mTOR pathway inhibition on neuroinflammation employing PF-04691502, an agent with combined PI3K and mTOR inhibitory activity. We treated SH-SY5Y, C6, BV-2, and Mo3.13 cell lines with PF-04691502 at concentrations of 0.1, 0.5, and 1 μM to assess the modulation of neuroinflammatory responses. To induce inflammation, cells were stimulated with lipopolysaccharide (LPS, 1 μg/mL) and interferon-gamma (IFN-γ, 100 U/mL). The results from the MTT assays demonstrated that PI3K/mTOR inhibition preserved cell viability at 0.5 and 1 μM across all of the cell lines, indicating its potential to mitigate inflammation-driven cytotoxicity. Subsequent ELISA assays revealed a marked decrease in the NF-κB and pro-inflammatory cytokine levels, confirming the effective suppression of inflammation through PI3K/mTOR inhibition. In addition, the SH-SY5Y cell line was exposed to MPP+ to simulate Parkinson's disease (PD)-like toxicity; then, cell viability, PD-associated markers, and apoptotic indicators were assessed. Our results indicate that inhibition of the PI3K/mTOR signaling axis may alleviate neurodegenerative processes by modulating both neuroinflammatory responses and apoptotic pathways. These findings highlight the therapeutic promise of targeting PI3K/mTOR in the context of neurodegenerative disorders and support the need for further validation through in vivo and clinical investigations
FINANCIAL SYSTEM AND SUSTAINABLE DEVELOPMENT: TOWARDS A NEW MODEL OF FINANCE
No full textThe digital, ecological and sustainable transition that is currently taking
place in Europe, indicates a particular process of transition from a previous
system to a new one that is able to embed different logics to pursue several
interests, both individual and of the entire community.
In this context, the financial market is called to play a central role in
supporting this transformation, creating new instruments which are set to
modify its traditional structures as well as those of the production system in
general.
The European institutions intend to carry out this transition funding
it through private resources, offering companies and investors a series of new
tools for this purpose.
In fact, in order to finance their sustainable and responsible
investments (SRI), companies in the Eurozone can take advantage of
particular instruments, regulated and offered by the new legislation adopted
in the field, such as green bonds, social bonds and green loans. These are the
main techniques related to the so called corporate sustainable finance that
can be used to achieve the objectives defined by ESG factors. However, the
effectiveness of these new tools requires the adoption of harmonised and
shared definitions and classifications regarding sustainability in the
context of financial processes, higher market transparency, higher quality,
quantity and comparability of data on environmental and social risks.
Our intention is to analize the role played by new financial instruments
with regard to new sustainable principles to assess both positive effects on
the structure of companies and the market in general and several critical
implications which, despite the original setting, are gradually arisin
Predizione del tipo di mutazione nelle malattie mitocondriali primarie tramite modelli di machine learning applicati a dati clinici non genetici né istologici.
No full textThis study shows that machine learning can accurately distinguish between mito-chondrial and nuclear DNA mutations in primary mitochondrial diseases using only non-ge-netic and non-histological clinical data. While language models underperform in comparison, they show potential as complementary diagnostic tools
La cappella e il culto di San Tobia nella vita di Niccolò Acciaiuoli
No full textSi analizzano i motivi per cui Niccolò Acciaiuoli ha scelto di intitolare a San Tobia la cappella della sua sepoltura nella certosa del Galluzzo da lui fondata pochi anni prima, sottolineando come tale scelta fosse legata a una dimensione di assistenza caritatevole dei poveri
Burnout Prevalence and Influencing Factors Among Italian Pediatric Surgeons and Residents: Insights From a Nationwide Survey
No full textIntroduction: Burnout (BO) is a significant issue among healthcare professionals, particularly in high-stress specialties like pediatric surgery. This study assessed BO prevalence among Italian pediatric surgeons and explored strategies to enhance workplace well-being. Methods: A 56-item electronic survey was distributed to all members via the Italian Society of Pediatric Surgery's network. BO was defined as the presence of a high score in emotional exhaustion (EE) (≥30) and depersonalization (DP) (≥12), coupled with a low score in personal accomplishment (PA) (≤33). Data were analyzed using median and interquartile range for continuous variables and absolute frequencies for categorical variables. Univariate and multivariate logistic regression analyses identified factors associated with BO. Results: Of 226 responders (88 residents), 17.3 % (39/226) met the criteria for burnout. High EE scores were observed in 50.9 % of respondents (115/226), while 64.6 % (146/226) had a low PA score, and 26.1 % (59/226) a high DP score. Univariate logistic regression identified that earning <2000€ per month, being a resident, working more than 50 h per week, having a poor relationship with chief physicians and working in understaffed departments are associated with higher risk of BO (p < 0.005). However, in the multivariate logistic regression model, only a poor relationship with chief physicians remained statistically significant (p = 0.02). Working in understaffed conditions and exceeding 50 weekly working hours approached significance (p = 0.08 and p = 0.09, respectively). Conclusions: BO significantly impacts pediatric surgeons, especially those having a poor relationship with chief physicians, residents, those working long hours or in understaffed departments. Hospitals should adopt strategies to improve pediatric surgeons' mental health like improving leadership strategies, optimizing workplace organization, fostering support networks, encouraging social interactions, and establishing coaching programs
Medium-induced modification of groomed and ungroomed jet mass and angularities in Pb–Pb collisions at √sNN = 5.02 TeV
No full textThe ALICE Collaboration presents a new suite of jet substructure measurements in Pb–Pb and pp collisions at a center-of-mass energy per nucleon pair sNN=5.02 [Figure presented]. These measurements provide access to the internal structure of jets via the momentum and angle of their constituents, probing how the quark–gluon plasma modifies jets, an effect known as jet quenching. Jet grooming additionally removes soft wide-angle radiation to enhance perturbative accuracy and reduce experimental uncertainties. We report the groomed and ungroomed jet mass mjet and jet angularities λακ using κ=1 and α>0. Charged-particle jets are reconstructed at midrapidity using the anti-kT algorithm with resolution parameter R=0.2. A narrowing of the jet mass and angularity distributions in Pb–Pb collisions with respect to pp is observed and is enhanced for groomed results, confirming modification of the jet core. By using consistent jet definitions and kinematic cuts between the mass and angularities for the first time, previous inconsistencies in the interpretation of quenching measurements are resolved, rectifying a hurdle for understanding how jet quenching arises from first principles and highlighting the importance of a well-controlled baseline. These results are compared with a variety of theoretical models of jet quenching, providing constraints on jet energy-loss mechanisms in the quark–gluon plasma
Cattafi viaggiatore tra "grandi carte azzurre" e scrittura giornalistica
No full textIl contributo studia la tematizzazione del viaggio nelle prose di Bartolo Cattafi, proponendo qualche raffronto con le prime poesie dell'autore siciliano e integrando testi editi con altri inediti reperiti presso il "Centro Apice" di Milano. Particolare rilievo è dato nello studio alla costruzione di mappe letterarie, al tema dell'insularità e all'influenza dell'attività di Cattafi come pubblicitario durante la fase milanese
Troxerutin Potentiated Temozolomide Induced Antitumor Effect in 2D and 3D Glioblastoma Models
No full textGlioblastoma (GBM) is a highly aggressive brain tumour characterised by rapid proliferation and high invasiveness. Temozolomide (TMZ) is the first-line chemotherapy, but its efficacy is often compromised by intrinsic or acquired resistance and significant side effects. Recent studies have demonstrated that combining TMZ with natural compounds can enhance therapeutic efficacy through synergistic mechanisms and reduce systemic toxicity. In this study, the adjuvant potential of troxerutin (TROX), a natural flavonoid present found in tea, coffee, cereals, fruits and vegetables, and known for its antioxidant and anti-inflammatory properties, was evaluated in an in vitro model of human U87 cells. The TROX–TMZ combination showed a significant synergistic effect, effectively reducing cell viability, clonogenic capacity, migration and epithelial-mesenchymal transition (EMT), as well as promoting apoptosis. The combined treatment also modulated oxidative stress and inflammation by activating the KEAP1/NRF2 axis, resulting in increased levels of HO-1, GSH and SOD1, and decreased ROMO1, ROS, nitrites and pro-inflammatory cytokines (IL-6, TNF-α and IL-1β). These effects were also confirmed in three-dimensional models (spheroids), suggesting that the combination exerts significant antitumor activity. These results indicate that TROX could represent an effective adjuvant in the treatment of GBM, providing a novel therapeutic strategy to potentiate the antitumor effects of TMZ
