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Innovative therapeutic approaches for neurodegenerative disorders: drug repurposing and cell therapy
No full textNeurodegenerative diseases (NDs) are a group of heterogeneous disorders characterized by progressive dysfunction and loss of neurons that encompass many different entities. Due to a neuron’s impossibility of renewing itself, this loss is irreversible and is usually followed by the collapse of the structure and function of neural networks, triggering the breakdown of the core communicative circuitry. Involvement of functional systems differs between disorders and is associated with a broad spectrum of clinical presentations.
At present, the management of neurodegenerative disorders is often disease-specific, and research into therapy mainly focuses on classical pharmacological approaches and advanced therapies (cell and gene therapy). Several pharmacological therapies are currently accepted, which either target the disease pathogenesis or try to improve the symptoms experienced. Current treatments cannot prevent or completely arrest the progression of NDs; thus, with time, the efficacy of these treatments may be reduced. Hence, the detection of new targets for drug action is a priority. Drug repurposing, the application of an existing therapeutic to a new disease indication, is a recent and valuable strategy that overcomes several shortcomings of the de novo development of new drugs; indeed, it holds the promise of rapid clinical impact at a lower cost, by accelerating the discovery of new candidate molecules while reducing its economic impact and increasing the chances of clinical development and testing phases. This strategy has various advantages and has opened new scenarios, particularly in the context of rare diseases, such as mitochondrial or neurodegenerative diseases. Finding new indications can rapidly benefit patients for either approved or failed drugs for which safety has already been established.
An engaging alternative therapeutical option is cell therapy, which involves the transplantation of stem cells for the regeneration of neural tissue, the stabilization of the neuronal networks, and the provision of neurotrophic support. Cell therapy aims to improve the repair response of dysfunctional and damaged tissue; however, restoring neuronal connectivity, both local and long-range, remains a substantial problem. Recently, 3D organoid technology has emerged as the latest frontier in regenerative medicine for treating CNS disorders. Most of the research on cell-based therapy for neurodegenerative diseases has been conducted preclinically in animal models, in which there are positive signs that, despite disrupted organization, connections with host cells can improve functionality. However, significant challenges remain regarding whether and how promising preclinical findings can be translated into clinical trials. Developing innovative approaches to treat neurodegenerative disorders.
My PhD is focused on testing two different strategies to treat neurodegenerative disorders:
(1) a drug-repurposing strategy for neurodegenerative disorders caused by OXPHOS-related defects
and (2) the regeneration of brain damage by tissue graft.
For the first aim, we demonstrated that neuronal progenitor cells derived from patients who carry different homoplasmic mutations in the ATP6 gene all present constant biochemical and phenotypic traits that are independent of the pathogenic variant, confirming their suitability as tools for phenotypic drug screening. Sildenafil was able to ameliorate the abnormalities in all patient-derived cell lines. Our data strongly suggest that the therapeutic effect is being carried out through the activation of the cGMP cascade. We were also able to demonstrate that dopaminergic neurons derived from patient-NPCs exhibited a branching defect and that this phenotype was positively affected by treatment with Sildenafil. Overall, these data point to Sildenafil being a good candidate for managing Leigh Syndrome.
For the second aim, we focused on the self-repair process of dysfunctional brain circuits with the use of transplantable brain tissue, in the context of Temporal Lobe Epilepsy, which presents several symptoms mainly affecting the hippocampus, and is often resistant to anti-epileptic drugs. As a starting point we derived rat-brain organoids and evaluated their growth, morphology, cellular composition, differentiation, maturation, and functionality. As a second step, we started to set up a protocol for brain organoid transplantation in a rat model. Preliminary results showed that after transplantation, organoids can differentiate within the host brain, highlighting the potential for integration with the host networks and further boosting the potential use of organoids for brain regeneration
An efficient solution for GPUs to the ST-connectivity problem on dynamic graphs
No full textST-connectivity poses a decision problem, determining whether, for vertices s and t within a graph, t is reachable from s. The challenge arises in the context of dynamic real-world graphs that undergo rapid evolution over time. In these scenarios, repeatedly solving the s-t connectivity problem from the beginning after each graph modification becomes impractical. Although parallel solutions, especially designed for GPUs, have been introduced to tackle the size complexity of static graphs, none have specifically addressed the concern of work efficiency in dynamic graphs. We propose an efficient solution for GPUs to the st-connectivity problem that can handle concurrent processing of batches of graph updates. We use batch information strategically to reduce the overall workload needed for updating the connectivity result. We provide experimental results based on standard datasets and with graphs of different characteristics and batch sizes to evaluate the proposed solutions efficiency
The ARCH-COMP Friendly Verification Competition for Continuous and Hybrid Systems
No full textThe workshop on Applied Verification for Continuous and Hybrid Systems (ARCH) is an annual venue for researchers and practitioners working on automated analysis and verification of hybrid systems. ARCH-COMP is a friendly competition held with the ARCH event. The competition was established in 2017 and aims to explore, document, and push forward the state of the art in the field. It evaluates and compares methods and tools for automated hybrid systems analysis and verification on predefined benchmark problems. It is supported by an active community around several categories of problems, including linear and nonlinear systems, simulation-based and analytic methods, and models from many application domains, such as automotive systems or neural networks. This paper describes the format of the competition and its organization. It documents the experiences and decisions from the current and past editions of the competition and presents reflections and lessons learned
The Impact of Acoustic Wave Therapy on Viability and Differentiation Capacity of Human Adipose Stem Cells
Get PDFBackground: Acoustic Wave Therapy (AWT) is a particular shock wave treatment that combines focused and radial shock waves, resulting in particular efficiency in the body's superficial layers. Its application before fat grafting has the potential to enhance it, favoring a better result of the graft. Aims: The aim of this study was to analyze the effects of AWT on fat tissue. Methods: Histological analysis of fat harvested from the abdomen of 40 subjects was evaluated. Twenty subjects had been pre-treated with AWT, while 20 had not. Extraction and characterization of adipose-derived stem cells (ADSCs) were performed for all. The multilineage differentiation capacity of extracted ADSCs and exosome extracellular vesicles' production from the fat samples were analyzed in both groups of specimens. Results: All 40 specimens presented both preservation of the structure of the tissue and of the cells, particularly of adipocytes. The cell growth resulted higher for pre-treated samples. All ADSCs from all the samples were able to differentiate along adipogenic, chondrogenic, and osteogenic lineages. In particular, for pre-treated samples, in the adipogenic lineage, a more advanced maturation phase was observed, and in the chondrogenic lineage, a chondroid matrix was evident around chondrocyte aggregates. All the samples reacted with exosome extracellular vesicles' production to stress. Conclusions: The results highlighted that AWT aligns with the in-force minimal manipulation regulations, as the tissue and cells' structure and functionality were preserved. The types of differentiation observed permitted us to speculate about possible new applications in aesthetic and regenerative medicine
Development of Artificial Intelligence-Based Real-Time Automatic Fusion of Multiparametric Magnetic Resonance Imaging and Transrectal Ultrasonography of the Prostate
No full textObjectives: To report the development of artificial intelligence (AI)-based software to allow for the autonomous fusion of transrectal ultrasound and multiparametric magnetic resonance images of the prostate to be used during transperineal prostate biopsies. Materials and methods: This study was approved by the Institutional Review Board (protocol ID3167CESC). The automatic software development for fusion biopsy involved three steps: 1) Developing an AI component to segment the prostate during ultrasound; 2) Developing the component to segment anatomical structures in magnetic resonance images using labeled datasets from the Cancer Imaging Archive and in-house scans; 3) Developing the fusion component to register segmented ultrasound and magnetic resonance images using a three-step process: pre-alignment, rigid alignment, and elastic fusion, validated by measuring the lesion distance between modalities. Statistical analysis included descriptive statistics and the Mann-Whitney U test, evaluating outcomes with Dice scores and average precision metrics. Results: The ultrasound component showed a Dice score of 0.87 with a test set of 75,357 images and 28,946 annotations. The magnetic resonance component achieved a Dice score of 0.85 on a test set of 2,494 images and annotations. It also demonstrated a mean Average Precision of 0.80 for bounding boxes and 0.88 for segmented objects, both measured at a 50% intersection over union threshold. The fusion AI component reduced the median magnetic resonance-ultrasound lesion distance from 8 mm (IQR 6-9) after rigid fusion to 4 mm (IQR 3-5) after elastic fusion (p<0.001). Conclusion: A data processing pipeline and AI were created to allow for the autonomous fusion of ultrasound and magnetic resonance images to be ideally used during transperineal prostate biopsies
Evaluating high power laser therapy (HPLT) as treatment for chemotherapy‐induced oral mucositis in paediatric patients with oncohematological diseases‐ Dr Jin
No full textN.A
Single-Cell RNA Sequencing Analysis Reveals Exercise-Induced Transcriptional Dynamics in Half-Marathon Runners
Get PDFPrevious studies in sports science suggested that regular exercise has a positive impact on human health. However, the effects of endurance sports and their underlying mechanisms are still not completely understood. One of the main debates regards the modulation of immune dynamics in high-intensity exercise. As part of the "Run 4 Science" project in Verona, Italy, we conducted a single-cell RNA sequencing analysis on half-marathon amateur runners to investigate the transcriptional dynamics of peripheral blood mononuclear cells following endurance exercise. Blood samples were collected from four participants before and after running a half-marathon to carry out a comprehensive transcriptomic analysis of immune cells at the single-cell level. Our analysis revealed significant alterations in the transcriptional profiles following endurance physical exercise. Modulations in myeloid cells suggested the activation of stress response (6 related pathways, p < 0.04) and pathways related to viral processes (4 related pathways, p < 0.03), while in lymphoid cells they hinted to a shift towards immune activation (24 related pathways, p < 0.01). Additionally, transcriptional changes in platelets point to an activation of the coagulation process (5 related pathways, p < 0.005). Single-cell data was also analyzed following a pseudo-bulk approach (i.e., simulating a bulk RNAseq experiment) to gain further biological insights. Our findings suggest that a pseudo-bulk analysis could offer complementary findings to classical single-cell analysis methods and demonstrate that endurance physical exercise, such as running a half-marathon, induces substantial changes in the transcriptional dynamics of immune cells. These insights contribute to a better understanding of the immune modulation mediated by endurance exercise and may inform future training routines or nutritional guidelines based on individual gene expression levels
Analisi genetica dei cambiamenti del microbiota orale indotti dal probiotico Curasept Prevent dopo l’estrazione dei terzi molari mandibolari (studio pilota)
No full textIntroduzione: questo studio pilota clinico ha come obiettivo quello di valutare le differenze del microbiota orale in pazienti sottoposti a estrazione chirurgica degli ottavi inferiori inclusi o semi-inclusi prima e dopo la somministrazione di probiotico.
Materiali e Metodi: sono stati arruolati 20 pazienti (tra i 16 e i 35 anni) che necessitavano dell’estrazione chirurgica di un terzo molare inferiore. A seguito dell’intervento, tutti i pazienti sono stati sottoposti a terapia antibiotica, clorexidina e probiotici a base di Bifidobacterium lactis HN019 e Kluyveromyces marxianus fragilis B0399. È stata effettuata un’analisi della flora orale tramite il sequenziamento NGS (Next Generation Sequencing) di parte del gene batterico16S rRNA (regione V3-V4) attraverso il prelievo di 3 tamponi orali prima dell’intervento (T0), a 10 giorni (T1) dopo terapia con antibiotico e clorexidina e dopo 28 giorni (T2) di terapia con probiotici.
Risultati: dall’analisi longitudinale della diversità batterica (dell’alfa e della beta diversity) è stato possibile verificare una differenza statisticamente significativa tra T0 e T1 dopo terapia con antibiotici e clorexidina con una riduzione della ricchezza e della variabilità della flora orale. Tra T1 e T2 c’è stata una differenza statisticamente significativa dopo il trattamento con il probiotico normalizzando la flora ai livelli del T0.
Conclusione: l’utilizzo del probiotico a seguito della terapia antibiotica e antisettica è in grado di agevolare il riequilibrio delle specie microbiche, andando nello specifico a favorire l’eubiosi precedentemente presente nei pazienti trattati
Sustainability in Energy Companies Under the Lens of Cultural Pressures: When Do We Talk of Greenwashing?
Get PDFListed companies allocate resources to various renewable energy and green innovation initiatives driven by economic and environmental, social, and governance (ESG) objectives. Corporations experience increased pressure from stakeholders, potentially hindering the concurrent achievement of economic and ESG goals and leading to phenomena such as greenwashing. This study examines whether these investments and practices represent an authentic transformation in corporate strategy or a mere rebranding attempt. Moreover, it investigates whether cultural dimensions can serve as predictors of greenwashing. The investigation progresses through three stages. First, a homogenous dataset of 59 companies listed in EU countries between 2011 and 2022 is identified. Second, the data envelopment analysis methodology is employed in the second stage to determine the energy companies' efficiency. An effective energy enterprise must simultaneously achieve social, environmental, and economic objectives. The study calculates a greenwashing proxy, creating a binary variable assigning a value of 1 to energy companies not impacted by greenwashing and 0 to those that are. Finally, logistic regression is utilized to investigate the correlation between the variable that denotes energy companies subjected to greenwashing and Hofstede's cultural dimensions. The study reveals that firms operating in countries with high levels of masculinity are more likely to participate in deceptive environmental practices known as “greenwashing.” This outcome has implications for academic and practical purposes, notably regarding stakeholder involvement and the re-evaluation of strategic and decision-making procedures impacted by the interplay of cultural values and green technology. To the best of our knowledge, this study represents the sole investigation that applies this approach to examining non-financial reporting, focusing on the interplay between cultural values, ESG, and their interaction effects
Mortality trends for colorectal cancer during the COVID-19 pandemic in the US
No full textThe results of our analysis show that the early phase of the COVID-19 pandemic has likely had a negative impact on early mortality from colorectal cancer in the US, as shown by the significant increase in the age-adjusted death rate recorded in 2021, reversing the otherwise favorable downward trend of the previous three years. A further, although not yet statistically significant, increase was recorded between the years 2022 and 2023, which needs to be monitored closely as it may reflect a second peak of later colorectal cancer mortality due to delayed management of a number of patients with curable disease