Tailoring the tools to study prostate cancer metastasis

The work included in this thesis is aimed at developing novel tools to advance our understanding of prostate cancer. The clinical problem of prostate cancer is presented and discussed in the wider context of the current clinical knowledge, highlighting the genetic mechanisms at its base. A dedicated chapter focuses on bone metastases, highly morbid feature of advanced prostate cancer, discussing the known mechanisms and the available models to study it in translational research. Then, moving from the molecular analysis of clinical specimens of bone metastasis, a biochemical pathway is identified and further studied in vitro, ex vivo and in vivo, validating the initial findings. A novel, early-stage prostate cancer patient-derived xenograft is presented and extensively characterized and implemented in a drug screening. This allowed to screen the effect of over 70 known drugs on prostate cancer models, using three-dimensional cultures and a semi-automated platform. As all research builds on previously established findings, a bibliometric analysis tool is presented, to assist in the generation of a knowledge network arranged by topic and impact of research. All these aspects and findings are then discussed in the context of the current direction of prostate cancer research, its emerging tools and its long-known challenges.</table

Performance evaluation of Attribute-Based Encryption on constrained IoT devices

The Internet of Things (IoT) is enabling a new generation of innovative services based on the seamless integration of smart objects into information systems. This raises new security and privacy challenges that require novel cryptographic methods. Attribute-Based Encryption (ABE) is a type of public-key encryption that enforces a fine-grained access control on encrypted data based on flexible access policies. The feasibility of ABE adoption in fully-fledged computing systems, i.e., smartphones or embedded systems, has been demonstrated in recent works. In this paper, we consider IoT devices characterized by strong limitations in terms of computing, storage, and power. Specifically, we assess the performance of ABE in typical IoT constrained devices. We evaluate the performance of three representative ABE schemes configured considering the worst-case scenario on two popular IoT platforms, namely ESP32 and RE-Mote. Our results show that, if we assume to employ up to 10 attributes in ciphertexts and to leverage hardware cryptographic acceleration, then ABE can indeed be adopted on devices with very limited memory and computing power, while obtaining a satisfactory battery lifetime. In our experiments, as also performed in other works in the literature, we consider only the worst-case configuration, which, however, might not be completely representative of the real working conditions of sensors employing ABE. For this reason, we complete our evaluation by proposing a novel benchmark method that we used to complement the experiments by evaluating the average performance. We show that by always considering the worst case, the current literature significantly overestimates the processing time and the energy consumption

Study of a high spatial resolution 10B-based thermal neutron detector for application in neutron reflectometry: the Multi-Blade prototype

Although for large area detectors it is crucial to find an alternative to detect thermal neutrons because of the 3He shortage, this is not the case for small area detectors. Neutron scattering science is still growing its instruments' power and the neutron flux a detector must tolerate is increasing. For small area detectors the main effort is to expand the detectors' performances. At Institut Laue-Langevin (ILL) we developed the Multi-Blade detector which wants to increase the spatial resolution of 3He-based detectors for high flux applications. We developed a high spatial resolution prototype suitable for neutron reflectometry instruments. It exploits solid 10B-films employed in a proportional gas chamber. Two prototypes have been constructed at ILL and the results obtained on our monochromatic test beam line are presented here

Renal Toxicities in Cancer Patients Receiving Immune-Checkpoint Inhibitors: A Meta-Analysis

Aim: We performed a meta-analysis of the available clinical trials of immune-checkpoint inhibitors to assess risk differences and relative risks of renal toxicity. Methods: 17 randomized phase III studies were selected, including 10,252 patients. Results: The administration of immune-checkpoint inhibitors resulted in an overall low-grade, high-grade and all-grade renal toxicity Risk Difference of: 0.746% (95% CI 0.629% to 1.15%, p &lt; 0.001—random), 0.61% (95% CI, 0.292–0.929%, p &lt; 0.001—fixed) and 1.2% (95% CI, 0.601–1.85%—random), respectively. The pooled Relative Risk of low-grade, high-grade and all-grade renal toxicity was: 2.185 (95% CI 1.515–3.152—fixed), 2.610 (95% CI, 1.409–4.833, p = 0.002—fixed) and 2.473 (95% CI, 1.782–3.431, p &lt; 0.001—fixed), respectively. An increased risk of renal toxicity was evident in some subgroups more than others. Conclusion: Immune-checkpoint inhibitors are associated with an increased risk of renal toxicity

Mycobacterium tuberculosis Drives Expansion of Low-Density Neutrophils Equipped With Regulatory Activities

In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-density (NDNs) subsets in patients with active TB disease, in terms of frequency, phenotype, functional features, and gene expression signature. Full-blood counts from Healthy Donors (H.D.), Latent TB infected, active TB, and cured TB patients were performed. Frequency, phenotype, burst activity, and suppressor T cell activity of the two different subsets were assessed by flow cytometry while NETosis and phagocytosis were evaluated by confocal microscopy. Expression analysis was performed by using the semi-quantitative RT-PCR array technology. Elevated numbers of total neutrophils and a high neutrophil/lymphocyte ratio distinguished patients with active TB from all the other groups. PBMCs of patients with active TB disease contained elevated percentages of LDNs compared with those of H.D., with an increased expression of CD66b, CD33, CD15, and CD16 compared to NDNs. Transcriptomic analysis of LDNs and NDNs purified from the peripheral blood of TB patients identified 12 genes differentially expressed: CCL5, CCR5, CD4, IL10, LYZ, and STAT4 were upregulated, while CXCL8, IFNAR1, NFKB1A, STAT1, TICAM1, and TNF were downregulated in LDNs, as compared to NDNs. Differently than NDNs, LDNs failed to phagocyte live Mycobacterium tuberculosis (M. tuberculosis) bacilli, to make oxidative burst and NETosis, but caused significant suppression of antigen-specific and polyclonal T cell proliferation which was partially mediated by IL-10. These insights add a little dowel of knowledge in understanding the pathogenesis of human TB

Immune response to tick-borne hemoparasites: Host adaptive immune response mechanisms as potential targets for therapies and vaccines

Tick-transmitted pathogens cause infectious diseases in both humans and animals. Different types of adaptive immune mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen antigens or indirectly through soluble factors, such as cytokines and/or chemokines, secreted by host cells as response. Adaptive immunity effectors, such as antibody secretion and cytotoxic and/or T helper cell responses, are mainly involved in the late and long-lasting protective immune response. Proteins and/or epitopes derived from pathogens and tick vectors have been isolated and characterized for the immune response induced in different hosts. This review was focused on the interactions between tick-borne pathogenic hemoparasites and different host effector mechanisms of T-and/or B cell-mediated adaptive immunity, describing the efforts to define immunodominant proteins or epitopes for vaccine development and/or immunotherapeutic purposes. A better understanding of these mechanisms of host immunity could lead to the assessment of possible new immunotherapies for these pathogens as well as to the prediction of possible new candidate vaccine antigens

Multidisciplinarity in Transition Pathways for Patients With Kidney Disease: The Current State of Play

In the field of medical care, successful transition from pediatric-centered to adult-oriented healthcare can provide a sense of continuity in the development of youth, and prepare them to accept responsibility for and manage their own chronic kidney condition in complete autonomy. The so-called transition process requires the presence of some basic aspects: a multidisciplinary team, which acts as a bridge between child and adult services; a comprehensive clinical, cognitive, psychological, and social change for the young people; the involvement of family and caregivers. Within the framework of transition and chronicity during the developmental age, we selected international papers explaining models which agreed on some important steps in the transition process, although many differences can be observed between different countries. In fact, in Europe, the situation appears to be heterogeneous as regards certain aspects: the written transition plan, the educational programmes, the timing of transfer to adult services, the presence of a transition coordinator, a dedicated off-site transition clinic. We then analyzed some studies focusing on patients with renal diseases, including the first to contain a standardized protocol for transition which was launched recently in the USA, and which seems to have already achieved important positive, although limited, results. In Italy, the issue of transition is still in its infancy, however important efforts in the management of chronic kidney disease have already been initiated in some regions, including Emila Romagna, which gives us hope for the future of many young people

Vitamin D effects on bone homeostasis and cardiovascular system in patients with chronic kidney disease and renal transplant recipients

Poor vitamin D status is common in patients with impaired renal function and represents one main component of the complex scenario of chronic kidney disease–mineral and bone disorder (CKD–MBD). Therapeutic and dietary efforts to limit the consequences of uremia-associated vitamin D deficiency are a current hot topic for researchers and clinicians in the nephrology area. Evidence indicates that the low levels of vitamin D in patients with CKD stage above 4 (GFR &lt; 15 mL/min) have a multifactorial origin, mainly related to uremic malnutrition, namely impaired gastrointestinal absorption, dietary restrictions (low-protein and low-phosphate diets), and proteinuria. This condi-tion is further worsened by the compromised response of CKD patients to high-dose cholecalciferol supplementation due to the defective activation of renal hydroxylation of vitamin D. Currently, the literature lacks large and interventional studies on the so-called non-calcemic activities of vitamin D and, above all, the modulation of renal and cardiovascular functions and immune response. Here, we review the current state of the art of the benefits of supplementation with native vitamin D in various clinical settings of nephrological interest: CKD, dialysis, and renal transplant, with a special focus on the effects on bone homeostasis and cardiovascular outcomes

La messa in sicurezza dell'area industriale di Priolo-Augusta rispetto ai rischi da terremoto e maremoto

I recenti forti terremoti che hanno interessato zone particolarmente industrializzate in Turchia ed in India (terremoto del 17.8.1999, Kocaeli, Turchia, Mw = 7.4; e terremoto di Guyarat, India, del 26.01.2001, Mw =7.7) hanno messo in evidenza che al danno prodotto dal terremoto si pu\uf2 aggiungere quello dovuto alle conseguenze di incidenti e/o rotture negli impianti, cosiddetti, \u201ca rischio di incidente rilevante\u201d. Il rischio totale nell\u2019area pu\uf2 quindi assumere valori estremamente elevati in termini economici, ambientali, e talvolta con perdita di vite umane. Ad esempio, nel caso del terremoto turco, il danneggiamento della raffineria Tupras di IZMIT ha provocato l\u2019incendio della stessa e la fuoriuscita di una quantit\ue0 rilevante di olio (Foto 1). Sulla base di quanto sopra e di quanto conosciuto, il presente studio si propone come elemento di base per l\u2019impostazione di interventi strutturali sugli impianti e sul territorio con l\u2019obiettivo di mettere il tutto in condizioni di sicurezza a fronte del terremoto (ed eventuale maremoto associato) atteso nell\u2019area. A questo scopo \ue8 stata realizzata un\u2019analisi per mettere in evidenza l\u2019entit\ue0 e la frequenza dei fenomeni naturali (terremoti e maremoti) che possono determinare significativi impatti sia sull\u2019ambiente fisico che su quello antropizzato (infrastrutture) nell\u2019area di Priolo-Augusta. Il progetto ha avuto come obiettivo iniziale la valutazione dei carichi dovuti a fenomeni naturali che, trasformati in termini ingegneristici, devono essere utilizzati per la verifica della idoneit\ue0 progettuale degli impianti industriali presenti nelle aree studiate. In particolare \ue8 stato valutato, dapprima, il terremoto di riferimento per la progettazione, in termini di picco massimo di accelerazione e spettro di risposta associato. In tale fase si \ue8 anche provveduto alla costruzione di scenari associati ad un eventuale maremoto. I siti prescelti sono esposti ad un elevato rischio sismico la cui definizione ha richiesto l\u2019adozione delle metodologie pi\uf9 avanzate disponibili. A tale scopo sono stati applicati diversi approcci innovativi sia di tipo sismologico che ingegneristico

Short Term and Long Term Bioacoustic Monitoring of the Marine Environment. Results from NEMO ONDE Experiment and Way Ahead.

The INFN NEMO-OνDE (Ocean Noise Detection Experiment) station, deployed on the seafloor at 2000 m depth 25 km offshore Catania (Sicily, Italy) in year 2005, was designed to continuously transmit broad-band acoustic data through optical cables to the INFN lab located in the port of Catania. It was operational until November 2006, when it was replaced by other experimental equipment. During the operational period, 5 minutes of recording (4 hydrophones, 45 kHz bandwidth, 96 kHz sampling rate at 24 bits resolution) were taken every hour. The experiment provided long-term data on the underwater noise and an unique opportunity to study the acoustic emissions of marine mammals living in, or transiting through the area east of Sicily. The recordings revealed a more frequent and consistent presence of sperm whales than previously believed