Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli"
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Deep Anterior Lamellar Keratoplasty Using Dehydrated Versus Standard Organ Culture Stored Donor Corneas: Prospective Randomized Trial
No full textAbstract
Purpose: To compare the outcomes of deep anterior lamellar keratoplasty (DALK) using dehydrated versus standard organ culture-stored donor corneas for eyes with keratoconus.
Methods: In prospective, randomized, single-center, institutionally funded, 2-arm, parallel-group noninferiority clinical trial, adult patients (age ≥18 years) with keratoconus scheduled for elective DALK with successful type 1 bubble pneumatic dissection were randomized during surgery to receive either dehydrated or standard organ culture-stored donor corneas. The primary study outcome was best spectacle-corrected visual acuity (BSCVA) 12 and 24 months after surgery. Secondary outcomes were refractive astigmatism (RA), endothelial cell density (ECD), and complication rates.
Results: Postoperative BSCVA did not significantly differ between groups at both time points (p>0.05). No significant differences between groups were observed in terms of postoperative RA and ECD at all time points (p>0.05). In the first 3 days after DALK, an epithelial defect was present in 10 patients in the organ culture cornea group and in 29 patients in the dehydrated cornea group. Complete re-epithelialization was achieved by day 7 in all patients in both groups. No patient developed immune rejection or graft failure within the 24-month follow-up period.
Conclusions: The study provides evidence that the use of dehydrated corneas is noninferior to the use of standard organ culture donor corneas for DALK. Corneal tissue dehydration represents a viable solution that can allow long-term cornea preservation and avoid wastage of unused corneas
Prevalence and management of lower limb segmental overgrowth in patients with NF1: an observational study
No full textBackground
Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder characterized by a potential multisystemic involvement. The musculoskeletal system is frequently affected (i.e.: scoliosis, thorax anomalies, tibial dysplasia). The segmental overgrowth of lower limb (SOLL) is rarely reported, albeit it severely affects patients’ wellbeing. The resulting leg length discrepancy (LLD) negatively impacts the development of the musculoskeletal system and may require appropriate correction, which could include surgery. Our objective was to evaluate the prevalence, the management, and the outcomes in patients with SOLL and NF1. We retrospectively evaluated 553 pediatric patients seen between 1992 and 2024 with a diagnosis of NF1. All patients presenting with SOLL were included in the study. For each patient, we assessed the degree of LLD at the initial evaluation, at the time of surgery (if any), at the point of maximum discrepancy, and at last visit. Demographic data, associated deformities, presence and location of plexiform neurofibroma (PN) were registered. Each patient and/or their parents were also evaluated using the Gait Outcome Assessment List for lower-limb differences (GOAL-LD) questionnaire to assess the health-related quality of life of pediatric patients with LLD.
Results
7 patients (4 males) with a mean age at diagnosis of SOLL of 4.67 years met our inclusion criteria. The detected discrepancies ranged from 0.5 cm to 6 cm (mean 4.30). Five children underwent surgery for the discrepancy (3 with epiphysiodesis and 2 with external fixation limb lengthening). All patients but one presented a plexiform neurofibroma in the district of SOLL that has been treated by selumetinib in 3 cases. Two patients were treated conservatively using lifted insoles. The GOAL-LD questionnaire revealed low scores in all the domains evaluated (function and mobility, pain and fatigue, physical and recreational activity, gait appearance, use of braces and walking aids, body image, and self-esteem).
Conclusions
SOLL-related LLD in patients with NF1 is a complex condition with significant impact on quality of life. Outcomes are often suboptimal, underlying the need for individualized, multidisciplinary management and structured follow-up. Early detection of progression is crucial to guide timely therapeutic decisions. Further prospective, multicenter studies are needed to better clarify pathogenic mechanisms and to develop standardized treatment protocols
Per una nuova edizione del papiro Sulla Gratitudine di Filodemo di Gadara
No full textThis dissertation presents a new critical edition of Philodemus’ On Gratitude (PHerc. 1414), combining papyrological, bibliological, and palaeographical analysis with digital reconstruction. It reassesses the text, its structure, and its philosophical significance within Epicurean ethics, highlighting gratitude as a key relational and ethical principle
Glycolytic heterogeneity drives metabolic-targeted therapy in pancreatic ductal adenocarcinoma
No full textPancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach—including metabolomics, proteomics, and lipidomics—was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer
DNA Damage–Mediated Innate Immunity and Related Liquid Biopsybased Biomarkers Uncovering Novel Features of Immune-Responsiveness in Small Cell Lung Cancer
No full textSmall cell lung cancer (SCLC) remains one of the most aggressive types of lung cancer. Its poor prognosis is strictly related to rapid tumor growth, early dissemination, high molecular heterogeneity, and treatment adaptability due to subtype plasticity and immune evasion. Although SCLC accounts for approximately 15% of all lung cancers, it is responsible for a high number of lung cancer–related deaths, with five-year survival rates remaining poor despite recent advances obtained from the introduction of immunotherapy in clinical settings. Standard front-line therapy for extensive-stage SCLC (ES-SCLC) consists of four cycles of platinum-based chemotherapy combined with anti–PD-L1 immunotherapy, followed by maintenance with immunotherapy alone. However, patient response to this regimen is highly heterogeneous, with a significant fraction exhibiting primary resistance, and even in responding patients, the benefits are often not durable due to the subsequent acquisition of mechanisms of secondary resistance. This therapeutic gap underscores the urgent need for mechanistic studies to design novel therapeutic strategies to overcome both intrinsic and acquired resistance. A major challenge in SCLC is the absence of targetable oncogenic drivers and reliable predictive biomarkers. Moreover, although SCLC is often characterized by a high tumor mutational burden (TMB), it fails to consistently predict immunotherapy responsiveness, suggesting that immune evasion mechanisms extend beyond mutation-derived antigenicity, due to low antigen-presenting machinery. A recent transcriptomic characterization refined SCLC classification into four molecular subtypes (ASCL1+, NEUROD1+, POU2F3+, and YAP1+) proposing an additional “inflamed” subtype instead of YAP1+ subtype, characterized by high immune infiltration, particularly by cytotoxic T cells and natural killer (NK) cells. Even if this subtype is associated with better clinical responses to chemo-immunotherapy (as demonstrated in trials like Impower-133), the high heterogeneity and dynamic nature of ES-SCLC subtypes requires a deeper understanding of the underlying mechanisms to define why only a subset of patients benefits from immune-based therapies.
The present doctoral research aims to investigate the molecular and immunological pathways involved in treatment response/resistance in SCLC through the investigation of three main biological axis: the DNA damage response (DDR), epithelial–mesenchymal transition (EMT), and innate immune activation. The first part of this work focuses on studying the effect of DNA-damaging therapies (namely chemotherapy, radiotherapy or DDR inhibitors) as well as the transcriptional consequences of MYC amplification and MAX co-expression in engineered SCLC models. The results presented in this thesis demonstrates for the first time that sequential administration of a novel DDR inhibitor, specifically DNA-PKi, or radiotherapy following chemotherapy significantly enhanced innate immune signaling through cGAS–STING and MAVS pathways. DNA-PKi can induce a sustained immune response in SCLC through concomitant upregulation of multiple innate immune cytosolic dsDNA/RNA sensors, through the activation of a non-canonical STING-MAVS axis. Moreover, non-neuroendocrine (non-NE) subtypes displayed higher expression of immune markers and stronger responsiveness to combined treatment compared to neuroendocrine (NE) tumors. This subtype-dependent variability in immune activation suggests that the therapeutic response in SCLC is not only determined by tumor-intrinsic effects by genotoxic damages but also by the immune reactivity of the tumor. Transcriptomic profiling revealed a MYC-dependent reprogramming of DDR and immune signaling pathways. Functionally, MYC/MAX-overexpressing cells displayed higher sensitivity to DNA-damaging agents and showed enhanced activation of STING–IRF3 signaling following sequential DNA-PKi after cisplatin treatment. Therefore, MYC amplification primes SCLC cells for both increased DNA damage vulnerability and innate immune activation.
The translational part of this work focuses on correlation studies involving peripheral immune components of therapy response, looking for new non-invasive approaches for biomarkers identification. Specifically, ex vivo study of peripheral blood mononuclear cells (PBMCs) showed that cGAS–STING expression correlated with clinical response to anti–PD-L1 therapy. Rare germline variants analysis through whole exome sequencing of PBMCs revealed the presence of pathogenic DDR variants among best responders, suggesting that DDR machinery defects may modulate immunotherapy efficacy. In parallel, the isolation and characterization of exosomes derived from PBMCs (PBMC-EXs) from best responders showed an enrichment in immune sensors such as STING and MAVS. Functionally, these PBMC-EXs were able to reduce viability in SCLC cells in vitro, indicating that circulating immune-derived exosomes actively participate in tumor–immune communication. Finally, the characterization of NK cell heterogeneity and function in SCLC patients undergoing chemo-immunotherapy was performed. Results showed an enrichment of activated NK cells (NK1 and NK3 subsets) in best responders, characterized by upregulation of interferon-stimulated genes, granzyme B, and perforin. Conversely, non-responders exhibited exhausted NK cell profiles represented by NKint and NK2 subsets.
Collectively, the results presented in the present thesis establishes novel mechanistic and translational insights into how DDR activation, MYC signaling, and innate immune pathways intersect to determine treatment response in SCLC. It positions PBMC-based assays, exosomes, and NK cell phenotyping as practical tools for real-time monitoring of therapy response. Taken together, these findings suggest we need to change the way we think about SCLC. It is important to consider its immunological complexity and heterogeneity to design more effective, biomarker-informed combination therapies that can change immune-cold tumours into immune-responsive disease
Moving Beyond Inclusive Marketing and Unleashing the Power of Culturally Relevant Marketing Using Tolu Oke’s “DEI Pyramid.” A Conversation with Tolulope Oke
No full textThis work critically examines the cultural foundations of inclusive marketing,
highlighting how an effective strategy must address multiple levels and
types of barriers that can impede truly impactful DEI efforts, including
personal, systemic, and institutional obstacles. Only if they adopt a
systematic and “layer-by-layer” approach to Beliefs, Processes, and
Commitment can the organisations build credibility that leads to genuine,
sustainable progress in terms of social inclusion
Raphael seen through MA-XRF: understanding the master and his atelier by studying the Capodimonte collection
No full textRaphael’s paintings in the Capodimonte collection, ‘Museo e Real Bosco di Capodimonte’ in Naples, offer the opportunity to describe the master’s great career and technical evolution from the earliest production, as in the Baronci Panel, to the mature collaboration with his pupil and successor Giulio Romano for the Madonna of the Cat. At the same time, coeval and later copies describe the impressive favour Raphael gained, yet when he was alive and in the following centuries. Studying the materiality of Raphael’s paintings in the Capodimonte collection brings more extensive knowledge on his technique, but also gives a sense of how his pupils and followers imitated or distanced themselves from him, participating to the discussion on the role of copies in the fifteenth and sixteenth century. MA-XRF scanning of Raphael’s works in the collection, and the analysis of artworks attributed to his workshop or identified as later copies assisted in the redefinition of the master’s material peculiarities. Beyond offering insights into the conservation history of the paintings, chemical data chiefly allowed the description of: (1) the master’s early technique in the Baronci panel, (2) the master’s practice, his material experimentation and conceptual setting up in works attributed to his workshop
A TOPSIS-Based Approach to Evaluate Alternative Solutions for GDPR-Compliant Smart-City Services Implementation
No full textAdapting or designing a system which operates on personal data in EU is impacted by the privacy-by-design and privacy-by-default principles because of the prescriptions of the GDPR. In this paper we propose an approach to decision making which is based on TOPSIS (Technique for Order Preference by Similarity to Ideal Solution). The approach is applied to a GDPR system compliance design process, based on a case study about system performance evaluation by means of queuing networks, but is absolutely general with respect to analogous problems, in which cost issues should be balanced with technical performances and risk exposure
Clinical Features, Management and Prognosis of Hepatic Sarcoidosis: Insights From a Nationwide Italian Study
No full textBackground and Aims: Sarcoidosis is a rare systemic granulomatous disease involving the liver in up to 20% of cases. Data on hepatic sarcoidosis (HS) prevalence and management remain limited. This study aims to provide a comprehensive analysis of HS patients across Italy, focusing on diagnostic pathways, management strategies, and prognostic factors. Methods: This multicenter retrospective study, conducted from April 2022 to December 2023, includes data from 36 hepatology units, affiliated with the Italian Association for the Study of the Liver (AISF), invited to analyse consecutive cases of HS reported between 2003 and 2023. Results: A total of 78 patients with HS were identified, with complete data available for 58 (median age 53 years; 57% female; 81% Caucasian), prospectively followed for a median of 41 months. Pulmonary and lymphatic involvement were present in 45% and 34% of cases, respectively. Isolated hepatic involvement was seen in 10%. Liver biopsy revealed granulomas in all specimens. Histological cirrhosis and clinically significant portal hypertension (CSPH) were observed in 10% and 14% of patients, respectively. Patients with CSPH had a significantly higher body mass index (BMI) compared to those without (33 vs. 25, p = 0.002). Steroids and ursodeoxycholic acid were the first-line treatments for 80% and 28% of patients, respectively, while 29% required second-line therapies. One patient died from liver-related complications. Conclusions: This nationwide study underscores the variability in HS presentation and management across Italy. Liver biopsy remains essential for diagnosis and staging. While steroids are the primary treatment, many patients require second-line therapies. Our finding of a higher BMI in patients with CSPH suggests that metabolic factors may play a role in disease progression, warranting further investigation
