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Des ruptures socio-culturelles en traits ? Un réexamen de l’art azilien et épigravettien récent à la fin du Pléistocène
No full textAt the end of the Pleistocene, material culture in Western Europe underwent numerous changes, particularly in graphic expression with the development of non-figurative iconography on portable items, while realistic depictions and parietal art were getting scarce. These graphic discontinuities often interpreted as ruptures have served on the one hand as spatial cultural markers, between the Epigravettian cultures around the Mediterranean basin and the continental and Atlantic Magdalenian, and on the other hand as temporal markers between the Magdalenian and the Azilian. However, recent and ongoing studies of several assemblages of portable art from Atlantic (e.g. Rocher de l’Impératrice, Murat) and Italian (e.g. Polesini, Romanelli) contexts are offering a more nuanced picture. The graphic expressions in these two regions reveal numerous connections that challenge the perceived separation between the Epigravettian and the Magdalenian-Azilian worlds. At the same time, the apparent graphic rupture of the late Azilian increasingly appears to be a unicum, calling into question its very reality.À la fin du Pléistocène, en Europe occidentale, la culture matérielle est marquée par de nombreux changements, en particulier dans l’expression graphique avec le développement d’une iconographie non-figurative sur supports mobiliers et la raréfaction de la figuration réaliste et de l’art pariétal. Ces discontinuités graphiques – vues comme des ruptures – ont servi de marqueurs culturels spatiaux en séparant l’Épigravettien du pourtour méditerranéen du Magdalénien continental et atlantique, et temporels entre Magdalénien et Azilien. Les études récentes et en cours de plusieurs corpus d’art mobilier atlantiques (Rocher de l’Impératrice, Murat) et italiens (Polesini, Romanelli) viennent nuancer ce tableau. Les expressions graphiques des deux espaces montrent de nombreux liens interrogeant la scission des mondes épigravettien et magdalénien-azilien. Tandis que la rupture graphique de l’Azilien Récent apparaît de plus en plus comme un unicum, questionnant sa réalité
Photoevaporation can reproduce extended H2 emission from protoplanetary disks imaged by JWST/MIRI-MRS
No full textContext. Understanding the dispersal of protoplanetary disks remains a central challenge in planet formation theory. Disk winds driven by magnetohydrodynamics (MHD) and/or photoevaporation are now recognized as primary agents of dispersal. With the advent of the James Webb Space Telescope (JWST), spatially resolved imaging of these winds, particularly in H2 pure rotational lines, have become possible, revealing X-shaped morphologies and integrated fluxes of ∼10−16−10−15 erg s−1 cm−2. Aims. However, the lack of theoretical models suitable for direct comparison has limited the interpretation of these features. To address this, we present the first model of photoevaporative H2 winds tailored for direct comparison with JWST observations. Methods. Using radiation hydrodynamics simulations coupled with chemistry, we derived steady-state wind structures and postprocessed them to compute H2-level populations and line radiative transfer, including collisional excitation and spontaneous decay. Results. Our synthetic images reproduce the observed X-shaped morphology with radial extents of ≳50-300 au and semi-opening angles of ∼37°-50°, matching observations of Tau 042021 and SY Cha. While the predicted line fluxes are somewhat lower than the observed values, they remain broadly consistent for lower J transitions despite the model not being specifically tailored to these sources. Conclusions. These results suggest that photoevaporation is a viable mechanism for reproducing key features of observed H2 winds, including morphology and fluxes, though conclusive identification of the wind origin requires source-specific modeling. This conclusion challenges the reliance on geometrical structures alone to distinguish between MHD winds and photoevaporation. Based on our findings, we also discuss alternative diagnostics of photoevaporative winds. This work provides a critical first step toward interpreting spatially resolved H2 winds and motivates future modeling efforts
Optimization of Nutrition for Patients in Intensive Care Units
No full textNutrition of patients in Intensive Care Units (ICU) is a critical treatment that needs to be optimized according to the specific needs of each patient. This study concerns the problem of optimally mixing commercially available formulas for enteral nutrition to achieve any desired mix of nutrients. The mathematical model has been discussed and improved according to feedback received from physicians in ICUs; it is solved in negligible computing time by a free integer linear programming solver. A software tool has been developed with a user-friendly interface, to allow extending the testing phase to several hospitals; it allows studying the trade-off between different objective functions
Acute Kidney Injury Following Mini Percutaneous Nephrolithotomy for Renal Stones: predictors and Follow-up Evaluation in Real-life Setting
No full textPurpose: To evaluate the prevalence, predictors, and progression of acute kidney injury (AKI) in patients undergoing mPCNL for nephrolithiasis. Materials and methods: We retrospectively analyzed data from 569 patients who underwent mPCNL at a single tertiary academic center (01/2016-10/2024). AKI was defined per KDIGO criteria as sCr increase >0.3 mg/dL or ≥1.5× baseline. Stone-free status was no residual stones on CT at 3-month follow-up. Complications were classified using the modified Clavien system. Kidney function was reassessed 30-90 days post-op. Descriptive statistics, logistic regression, and Cox regression were applied. Results: Median (IQR) age and stone volume were 57 (48-66) years and 2.1 (0.9-4.2) cm3. Median preoperative sCr and operative time were 0.9 (0.7-1.1) mg/dL and 90 (73-120) minutes. Post-mPCNL, 40 patients (7.0%) developed AKI. Complications occurred in 138 (24.2%) patients; 449 (78.9%) were stone-free. AKI patients had higher CCI (1.3 vs. 0.5, p=0.04), pre-op sCr (1.1 vs. 0.8 mg/dL, p<0.01), stone volume (5.7 vs. 2 cm3, p=0.02), and longer operative time (130 vs. 90 min, p=0.01). Complications were more frequent in AKI patients (42.5% vs. 22.8%, p=0.01). At multivariate analysis, operative time (OR 1.1, p=0.03), pre-op sCr (OR 3.8, p=0.001), and early complications (OR 2.5, p=0.02) were independently associated with AKI. AKI persisted in 9 (22.5%) patients, mainly those with complications (88.9% vs. 38.7%, p=0.01). On Cox analysis, lower BMI (HR 0.8, p=0.02) and absence of complications (HR 0.3, p=0.01) predicted faster AKI recovery. Conclusion: Acute kidney injury remains a clinically significant complication following mPCNL
Impact of the Area Deprivation Index on stage at diagnosis in penile squamous cell carcinoma: A statewide cohort analysis
No full textBackground: Penile cancer is a rare malignancy influenced by socioeconomic factors. The Area Deprivation Index (ADI) is a validated measure of neighborhood-level socioeconomic disadvantage, and its association with penile cancer stage at presentation has not been studied. This study aimed to assess the relationship between the ADI and advanced-stage disease at diagnosis in penile cancer. Methods: A retrospective study was conducted with the Michigan Department of Health and Human Services database of patients aged ≥18 years with penile squamous cell carcinoma from 2004 to 2019. Advanced-stage disease was defined as pathological T stage ≥2, pathological evidence of nodal metastasis, or reported presence of distal metastasis. ADI scores were compared to the national median value. Univariable and multivariable logistic regression analyses were performed to assess the association between the ADI and advanced disease after adjusting for relevant covariates. Results: Among 353 patients (median age, 72 years; 84.4% White), the median ADI score was 69. Patients were stratified into two groups on the basis of the national median; 76% were in the high-ADI group. Black patients were more prevalent in the higher ADI group (15.3% vs. 2.4%; p =.003). Advanced-stage penile cancer was more frequent in the higher ADI group (49.3% vs. 36.5%; p =.04). In multivariable analysis, each 10-point increase in the ADI was associated with 1.16-fold increased odds of advanced-stage disease (95% CI, 1.04–1.29; p =.02). Conclusions: Greater neighborhood-level socioeconomic deprivation is associated with advanced-stage disease at penile cancer diagnosis. These findings emphasize the role of social determinants in disease presentation, and may guide targeted interventions in disadvantaged populations
Towards Human-Game Interaction (HGI)
No full textAs serious games, as well as entertainment games, evolve along a continuum ranging from analog to digital, including hybrid solutions, the design and role of game interfaces have become increasingly complex and central to the player experience. This position paper proposes a conceptual shift, considering the interface not merely as a structural or aesthetic layer, but as a key mediator between game mechanics and the mental and emotional models formed by players during the game. Building on insights from previous research on interfaces and on player experience, we introduce the Human-Game Interaction (HGI) framework as a lens to systematically analyze how interfaces shape the player’s experience both in serious games and in entertainment games. By referencing design heuristics, the tripartition of the mind, and Gestalt principles, we argue for a holistic understanding of the interface and we offer new perspectives for cross-disciplinary research and practical applications, particularly in the design of serious games where usability and meaningful engagement are essential
THERANOSTIC PLATINUM-BASED COMPLEXES FOR GLIOBLASTOMA TREATMENT AND EVALUATION OF THEIR LOADING AND RELEASE FOR DRUG DELIVERY
No full textIl glioblastoma multiforme (GBM), il tumore al seno triplo negativo (TNBC) e l’adenocarcinoma duttale pancreatico (PDAC) appartengono ad una categoria di tumori conosciuta come tumori orfani. I tumori orfani sono estremamente rari, rappresentano meno dell’1% del numero totale di tumori umani, in quanto colpiscono circa una persona su 1500/2500 individui. Proprio a causa di questa rarità, le aziende farmaceutiche spesso non hanno sufficienti incentivi volti alla ricerca di nuovi farmaci perché includerebbero costi troppo elevati e un numero limitato di pazienti che ne gioverebbero. Per questo motivo, molti tumori orfani sono tutt’ora privi di trattamenti efficaci.
GBM, TNBC e PDAC sono tumori molto aggressivi e, nonostante trattamenti chirurgici e farmacologici, la sopravvivenza a cinque anni è molto bassa. La procedura standard di terapia prevede la resezione chirurgica, la chemioterapia, sia utilizzata pre-intervento chirurgico che post-intervento per TNBC e PDAC, la radioterapia e infine le cure palliative, a seconda dello stadio della malattia.
Per superare la mancanza di trattamenti efficaci contro questi tumori, lo scopo della mia ricerca di dottorato è stato studiare e sintetizzare nuove serie di complessi di platino che possedessero una migliore attività farmacologica, ma anche migliori proprietà chimico-fisiche, come ad esempio una migliore solubilità del composto. Sono state inoltre introdotte delle modifiche strutturali tali da poter permettere l’utilizzo di questi nuovi complessi come agenti teranostici per una terapia più mirata e personalizzata. Tra tutte le strategie possibili, partendo dalla struttura base del complesso conosciuto come Pt-8AQ e precedentemente pubblicato, ci siamo focalizzati su tre principali approcci che hanno portato a risultati promettenti:
i) Modifiche alla struttura del complesso: abbiamo modificato il cosiddetto “carrier ligand”, l’8-amminochinolina, aggiungendo un atomo di fluoro in diverse posizioni dell’anello per migliorare la solubilità del complesso e quindi la sua biodisponibilità. I nuovi complessi così formati risultano migliori per quanto riguarda il crosslinking con il DNA e possiedono anche una promettente attività antiproliferativa, comparabile o addirittura superiore a quella del cisplatino.
ii) Modifiche alla farmacocinetica del complesso: sono state selezionate due molecole di-ossigenate, l’alizarina e la curcumina, come “leaving groups”. Entrambe queste molecole sono state scelte sia per le loro attività biologiche intrinseche, sia per la loro capacità di assorbire ed emettere la luce UV in modo da poter sintetizzare composti teranostici. L’aggiunta di queste nuove molecole ha portato ad una maggiore selettività dei complessi e una maggiore modulazione della loro attività, agendo come agenti protettori nei confronti del centro metallico e portando quindi ad avere minore reattività e minori effetti collaterali.
iii) L’utilizzo di un “ancillary ligand” a base imidazolica per ottenere dei complessi cationici che permettano una maggiore biodisponibilità e un maggiore assorbimento e un migliore uptake da parte delle cellule grazie alla possibilità di sfruttare il riconoscimento e l’internalizzazione da parte dei Trasportatori di Cationi Organici (OCTs). Inoltre, è stata adottata anche una strategia combinata in cui, a questi complessi cationici a base imidazolica è stato aggiunto un noto fluoroforo, il BODIPY, che potrebbe permettere di visualizzare e seguire il complesso all’interno del corpo e a livello cellulare. I test biologici hanno dimostrato che l’aggiunta di questo fluoroforo porta ad ottenere un complesso che può effettivamente essere utilizzato come agente teranostico e che può essere utile per studiare il vero meccanismo d’azione della molecola, senza modificare l’attività biologica del corrispondente complesso cationico di partenza.
Tutti i complessi sintetizzati sono e saranno inoltre valutati per la loro capacità di essere caricati su cellule stromali mesenchimali (MSCs), le quali tendono a localizzarsi selettivamente nel microambiente tumorale, rilasciando in situ il farmaco veicolato. In tal modo, l’agente antitumorale può esercitare la propria attività direttamente sulla massa neoplastica, riducendo al minimo gli effetti collaterali sistemici.
In conclusione, i risultati ottenuti supportano l’ipotesi che una progettazione razionale dei leganti e l’impiego di funzionalizzazioni mirate possano condurre allo sviluppo di una nuova generazione di complessi di platino(II) caratterizzati da una maggiore efficacia, selettività e da un maggiore potenziale diagnostico.Glioblastoma multiforme (GBM), triple negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) belong to a class of tumor known as orphan tumors. Orphan tumors are extremely rare, representing less than 1% of all human oncological pathologies. They affect one in every 1,500 to 2,500 individuals, with fewer than 200,000 cases reported in the United States. Due to their rarity, pharmaceutical companies often lack incentives to invest in developing new drugs for their therapy, given the high costs involved and the relatively small patient population. As a result, many rare tumors still lack effective treatments.
GBM, TNBC and PDAC are extremely aggressive and associated with a very low 5-year survival rate, despite the surgical and pharmacological treatments. The standard treatment involves the surgical resection, the chemotherapy, as adjuvant or neoadjuvant treatment for both TNBC and PDAC, the radiotherapy and the palliative care, depending on the stage of the neoplasm.
In order to overcome the lack of treatment for these types of tumors, the aim of this PhD research was to prepare a new series of platinum complexes endowed with higher pharmacological activity and better physicochemical properties. Some structural modifications were also introduced to allow their use as theranostic probes for a more targeted and personalized therapy. Starting from the already published Pt-8AQ, the lead compound of the synthesized series during this PhD work, three approaches have been applied to the lead compound structure with promising outcomes:
i) The modifications to the carrier ligand of the lead compound Pt-8AQ.: 8-aminoquinoline ligand was modified by introducing a fluorine atom in different positions of both rings of the quinoline core to enhance the solubility of the complex and consequently its bioavailability. The new synthesized complexes demonstrated enhanced DNA crosslinking properties and promising antiproliferative activity, comparable or superior to cisplatin (complexes 5 and 7 IC50 = Glioblastoma U87-MG cell line: 10.44 ± 0.92 mM and 10.61 ± 1.05 mM respectively; Pancreatic Ductal Adenocarcinoma CFPAC-1 cell line: 13.53 ± 0.25 mM and 12.91 ± 0.36 mM respectively).
ii) The modifications to the pharmacokinetics of the lead compound Pt-8AQ: two di-oxygenated molecules, alizarin and curcumin, were selected and introduced as leaving groups. Both these molecules have some biological activities by themselves, but they are also able to absorb and emit light in the UV-Vis range thus introducing the possibility to develop new theranostic compounds once inserted in the platinum complexes’ structure, for in-real-time imaging. We found out that these new leaving groups could modulate the selectivity and the reactivity of the complex, acting like protector groups for the platinum center and leading the formation of less active complexes with lower side effects but endowed with interesting antioxidant and antibacterial properties.
iii) The introduction of a further ancillary ligand with an alkyl-imidazole moiety in the lead compound structure to afford the corresponding cationic platinum complexes: this approach aimed to increase the cellular uptake and the bioavailability by enabling recognition and internalization via Organic Cation Transporters (OCTs). In addition, a combined strategy involved the synthesis of a cationic theranostic platinum complex by introducing the well-known BODIPY moiety at the distal position of the alkyl chain on the imidazole function to track the complex within the body and at cellular levels. Both biological and spectroscopic assays revealed that the addition of this fluorophore did not affect the biological activity of the lead compound Pt-8AQ, opening the possibility to use it for real-time imaging and to study the exact mechanism of action.
Furthermore, all these new complexes will be studied for their ability to be loaded within Mesenchymal Stromal Cells (MSCs) exploiting their intrinsic ability to reach the stroma of cancer cells, and to release the loaded drug directly inside the tumoral microenvironment. In this way, the drug could exert its anticancer activity directly in situ, thus reducing systemic side effects.
To conclude, all these findings support the idea that a rational design of the ligands and a strategic functionalization enable the development of next-generation platinum-based metallodrugs with improved efficacy, selectivity and imaging capabilities
PRINTING MUCOADHESIVE AND ORODISPERSIBLE FILMS FOR THE PERSONALIZATION OF THERAPY
No full textCustomizable oromucosal dosage forms such as orodispersible films (ODF) and mucoadhesive films (MAF) are increasingly recognized as valuable tools for addressing unmet therapeutic needs in populations requiring flexible, easy-to-administer medicines, such as paediatric and dysphagic patients. Among the proposed manufacturing techniques, extrusion-based 3D printing technologies, specifically direct powder extrusion (DPE) and semisolid extrusion (SSE) 3D printing, appear to be the most promising for the on-demand point-of-care preparation of personalized dosage forms, since they are simple processes that only require a desktop 3D printer and can potentially be carried out in a pharmacy setting. The aim of this PhD project is therefore to demonstrate the suitability of such techniques for the extemporaneous compounding of MAF (via DPE 3D printing) and ODF (via SSE 3D printing). Using DPE, MAF containing clobetasol propionate and lidocaine were obtained, achieving uniform drug loading, suitable mucoadhesive properties, controlled drug release, and favourable mucosa penetration of the loaded drug, supporting their suitability for oral inflammation and local analgesia. Then, since DPE entails exposure of the formulation components to high temperatures, hot-melt ram-extrusion (HMRE) 3D printing was tested as a milder alternative in the preparation of ODF containing the enzyme β-galactosidase, and compared with solvent casting. While HMRE resulted in the thermal degradation of the protein, enzymatic activity was completely preserved in the ODF obtained by solvent casting, which were able to digest lactose contained in milk in simulated gastric media. The attention was therefore directed toward prototyping a 3D printer that could print slurries similar to those used for solvent casting operating at room temperature, making it compatible with heat-sensitive molecules. The versatility of the resulting SSE printer was tested by preparing ODF loaded with β-galactosidase, CBD oil, and diclofenac-loaded lipid microparticles. In all cases, ODF with satisfactory properties were obtained and the payload was not negatively impacted by the process. Finally, to test the feasibility of obtaining sustained-release ODF by SSE 3D printing, a trihexyphenidyl/clay hybrid was prepared and successfully loaded into ODF, resulting in a controlled release of the drug over a 6-hour period. In conclusion, this work demonstrates the versatility of extrusion-based 3D printing technologies and their potential for the extemporaneous preparation of personalized dosage forms
Cistus x incanus L. extract as a complex polyphenolic blend with retained anti-adhesive and anti-inflammatory properties in a model of E. coli-induced UTI following simulated digestion
No full textEthnopharmacological relevance: Cistus x incanus L. is a Mediterranean plant traditionally used to treat infective conditions, including urinary tract infections (UTI). However, experimental validation against uropathogenic Escherichia coli (UPEC) is limited. Aim of the study: To investigate the antibacterial and anti-inflammatory effects of a hydroalcoholic extract of aerial parts (CE) in an E. coli-induced UTI model, evaluating stability and efficacy after intestinal digestion.
Materials and methods: T24 bladder epithelial cells were infected with UPEC CFT073 and treated with CE before and after simulated intestinal digestion (CEd). IL-6 release, bacterial growth, and adhesion were evaluated.
Polyphenol content and stability were analyzed using colorimetric assays and LC-MS/MS. A methanol-insoluble fraction (IF) of CE was also tested.
Results: CE inhibited IL-6 release with an IC50 of 16.05 μg/mL during infection and 0.43 μg/mL upon TNF-α stimulation; IL-8 was also reduced. CE markedly decreased UPEC adhesion to T24 cells (-79 % at 200 μg/mL).
After digestion, CEd retained anti-inflammatory activity (IC50 for IL-6: 19.05 μg/mL during infection; 1.69 μg/mL with TNF-α). Flavonols remained relatively stable post-digestion, while catechins and procyanidins decreased. IF, rich in glycosidic flavonols and tannins, preserved its anti-inflammatory and antibacterial activity before and after digestion. Conclusions: These findings support, for the first time, the traditional use of Cistus x incanus in UTI, highlighting its ethnopharmacological relevance in the treatment of urinary infections. The mechanism of action, which includes anti-inflammatory and anti-adhesive activities of the extracts, has been investigated. The efficacy was observed at micromolar concentrations, which are supposed to be reached in vivo consuming Cistus x incanus food supplements. These findings lay groundwork for preclinical UTI models. Moreover, the outcomes in the present study warrant clinical investigations to consolidate our findings