Biological activity of anti-miR-221 Peptide Nucleic Acids and relative building blocks

The study of new molecules able to selectively and stably interact with DNA and RNA is a field of great interest in consideration all the possible applications in medicine. Our study is related to the biomedical applications of the final product of PNA synthesis (the PNA itself) and the intermediate molecules obtained during the synthetic activity. In all the chemical synthesis approach of any pharmaceutical laboratory several molecules are produced, which are usually not considered for biological assays and technology transfer. We screened a set of C(5) uracil derivatives monomers, that were employed during the PNA synthesis, for activity on differentiated functions in K562 cells. We found that the highest antiproliferative effect and erythroid induction ability was exhibited by compound 9, a thymine derivative bearing a n-octyl chain on nitrogen N(1), whereas thymine (compound 2) did not show any effect, suggesting the importance of the linear alkil chain in N(1) position. Compound 9, furthermore, exhibits induce erythroid terminal differentiation without activation of apoptotic pathway. The interest in the context on anti-tumor differentiation therapy is related to the fact that, when compared to known erythroid differentiation antitumor inducers (such as for instance cytosine arabinoside, mithramycin, resveratrol), the lead compound we were able to identify is the most active agent. Therefore these molecules in our opinion deserves further research activity in order to define its possible application, for instance in the control of proliferation/differentiation of CML primary cells resistance to the commonly employed Imatinib (Gleevec®) therapy. As far as the final product of the synthetic strategy (a PNA recognizing miR- 221 and able to be internalized in target tumor cells thanking to a linked Arg-8 peptide), the results here presented allows to conclude that (a) it is internalized at high efficiency into target tumor cells; (b) inhibits the miR-221 hybridization availability and (c) has important effects on biological functions regulated by miR-221 (i.e. expression of the p27Kip1 mRNA/protein). These results are in our opinion of interest, considering on one hand the role of miR-221 in cancer and, on the other hand, the role of p27Kip1. As far as miR-221, it was found to be up-regulated in several tumors; in breast cancer miR-221 is up-regulated in breast cancer cell line (such as MDA-MB-231) and in metastatic tumors. In the contest of breast cancer, it was identified p27kip1 mRNA as possible target of miR-221. The cyclin-kinase inhibitor p27kip1 is a tumorsuppressor protein, involved in the control of cell cycle during the G0/G1 check-point transition: the loss or decrease of p27kip1, together with others, is one of contributory causes of the “proliferating state” of invasive cancer, which remains in this growth phase without arrive to differentiation. It is of great interest since it was found to be down-regulated in several type of tumors. The studies presented in this PhD Thesis teach that even intermediate synthetic molecules deserve attention in respect to possible biological effects on cells relevant to human pathologies. Moreover, we have identify two reagents of possible interest for the development of anti-cancer protocols: N(1)-octyl-thymine for the treatment of CML cells and Rpep-PNA-a221 for possible use in the treatment of breast cancer cells

Mechanical Plantar Foot Stimulation in Parkinson's Disease: A Scoping Review

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in older individuals. Neurorehabilitation-based interventions such as those improving gait are crucial for a holistic approach and to limit falls. Several studies have recently shown that mechanical plantar foot stimulation is a beneficial intervention for improving gait impairment in PD patients. The objective of this scoping review is to evaluate the beneficial effects of this stimulation on gait parameters, and to analyse protocols of foot stimulation and other effects in non-motor symptoms. Relevant articles were searched in the Medline database using Pubmed and Scopus, using the primary search terms 'foot stimulation' OR 'plantar stimulation' AND 'Parkinson's disease*'. Several protocols have been used for mechanical plantar foot stimulation (ranging from medical devices to textured insoles). The gait parameters that have been shown to be improved are stride length and walking speed. The beneficial effects are achieved after both acute and repeated plantar foot stimulation. Beneficial effects are observed in other organs and systems, such as muscle activation, brain connectivity, cardiovascular control in the central nervous system, and the release of brain-derived neurotrophic factor and cortisol in blood added evidence about this intervention's impact on brain function. Mechanical plantar foot stimulation is a safe and effective add-on treatment able for improving gait impairments in PD patients during the L-dopa off state. Randomized and controlled clinical trials to study its eventual potentiating effect with different pharmacotherapy regimens are warranted

The soft skills required in HR. An investigation into some companies in the province of Vicenza.

openIl lavoro svolto in questa tesi dal titolo "Le soft skills richieste in HR. Un'indagine su alcune aziende della provincia di Vicenza", presenta una ricerca sulle soft skills richieste nel territorio vicentino nell'area HR. Questo perché, negli ultimi anni, c'è stato un riconoscimento dell'importanza di queste abilità nella scelta di un candidato. Il mio interesse è centrato sulla provincia in cui vivo, cioè Vicenza e per vedere se queste richieste sono in linea con la letteratura più recentemente esaminata. Il primo capitolo si concentra sul dare una definizione di soft skills che, come si vedrà, non è univoca. Continua con la descrizione delle tre soft skill più richieste dalle aziende per il 2023 e l'importanza che hanno. Nel secondo capitolo si analizzail contesto organizzativo e i tipi di culture che possono essere presenti/caratterizzare un'azienda. Vengono presentati anche costrutti come i valori aziendali, la vision e la mission aziendale. Il terzo capitolo spiega il reparto HR, i suoi compiti, le competenze trasversali che i suoi dipendenti devono svolgere e come queste abilità sono generate dalle varie attività di formazione. Il quarto capitolo è la ricerca. Ho creato un'intervista con domande relative alla letteratura e l'obiettivo della ricerca. Ho intervistato 15 responsabili HR di grandi aziende della provincia di Vicenza e poi ho analizzato i dati e tratto le conclusioni.The work done in this thesis titled "The soft skills required in HR. An investigation into some companies in the province of Vicenza", presents a research on the soft skills required in the territory of Vicenza in the HR department. This is because, in recent years, there has been a recognition of the importance these skills have in choosing a candidate. My interest is centered on the province in which I live, namely Vicenza and to see if these requests are in line with the most recently examined literature. The first chapter focuses on giving a definition of soft skills that, as you will see, is not unique. It continues with the description of the three most requested soft skills by companies for 2023 and the importance they have. In the second chapter we analyze the organizational context and the types of cultures that can be present/characterize a company. Constructs such as company values, vision and corporate mission are also presented. The third chapter explains the HR department, its tasks, the soft skills that its employees must have to perform and how these skills are generated by the various training activities. The fourth chapter is research. I created an interview with questions related to literature and the goal of research. I interviewed 15 HR managers from large companies in the province of Vicenza and then analyzed the data and drew conclusions

Creazione di un percorso integrato di cura del piede diabetico a Bologna

Il diabete mellito è una malattia cronica complessa, molto diffusa e in grande espansione in tutte le aree del mondo. Fra le svariate complicanze una delle più invalidanti è rappresentata dalla patologia denominata “piede diabetico” vero e proprio, marker di mortalità. Si stima, a livello mondiale, che circa 246 milioni di persone abbiano il diabete (5,9% della popolazione) e che ogni 30 secondi un arto inferiore viene amputato a causa del diabete. Rispetto ai pazienti senza ulcere, il costo di assistenza alle persone diabetiche con ulcera del piede è di 5,4 volte superiore per l’anno dopo il primo episodio di ulcera e 2,8 volte più alta nel secondo anno. Non si parla dunque di un problema clinico, ma anche di un problema socio-economico di rilevanti proporzioni per gli elevati costi di gestione. Numerosi sono gli studi che dimostrano una riduzione percentuale significativa delle amputazioni grazie alle cure podologiche: Lavery et al. affermano come un team che includa un podologo possa dopo 2 anni ridurre del 47% le amputazioni, del 38% i ricoveri in ospedale e del 70% i ricoveri in strutture specializzate, Gibson dimostra come cure podologiche tempestive riducano del 36% la probabilità di subire un’amputazione ed infine La Società Italiana Diabetologi afferma nell’operazione “guarda prima i piedi” come le ulcere siano facilmente evitabili con interventi di screening e che ciò potenzialmente determinerebbe un risparmio di oltre 50 milioni di euro. Ho quindi creato, in collaborazione con il personale medico dell’Unità Operativa di Diabetologia del Policlinico S’Orsola-Malpighi, questo percorso assistenziale che rispetti i cardini della prevenzione, garantendo sia le cure mediche per la patologia acuta, sia per la prevenzione primaria ed educazione sanitaria. Questa integrazione rispetta le attuali linee guida e garantisce a tutti i pazienti un esame completo del piede almeno una volta all’anno, fino a una volta al mese in base al rischio. Con questo modello organizzativo anche a Bologna, dove fino ad oggi non era prevista la figura del podologo, si può parlare di intervento multidisciplinare, continuità assistenziale, valutazione globale del paziente, educazione sanitaria del paziente e dei familiari e assistenza omogenea e capillare. Il percorso da me ideato ha garantito in un anno di attività a 46 pazienti diabetici le cure podologiche essenziali secondo le linee guida amd-sid. Questi pazienti sono stati inseriti in un programma di screening, riabilitativo e preventivo in sinergia con il medico curante e il medico diabetologo. Molto ancora c’è da fare per migliorare questo “modello locale” nato per tamponare una situazione di emergenza sul territorio. La speranza è quindi di vedere concesse, anche alla luce di iniziative propositive come questa, ai pazienti diabetici le cure podologiche preventive e curative

Personalised and precision medicine: 3D printed sensorized orthoses as a tool for quantitative diagnosis and monitoring movement

Obiettivo di questa tesi di dottorato è di mostrare un metodo sperimentale e innovativo attraverso il quale è possibile realizzare una calzatura personalizzata e sensorizzata mediante un processo di fabbricazione additiva di Fused Deposition Modelling (FDM). I recenti progressi tecnologici e lo sviluppo di nuovi approcci nella realizzazione di dispositivi su misura, come la prototipazione rapida a mezzo di scansione laser e la stampa additiva, hanno evidenziato la potenzialità di un miglioramento significativo della produzione di questi dispositivi in termini di riproducibilità, qualità del prodotto e abbattimento dei costi. La riproducibilità del processo e la validazione del dispositivo si sono basate sull’interazione di diverse competenze: cliniche, biomeccaniche, di scienza dei materiali e di design. In seguito ad uno studio sulle proprietà meccaniche dei materiali esistenti e al perfezionamento del processo di design della protesi personalizzata è stato ideato un sistema per creare all’interno delle ortesi uno spazio dedicato alla sensoristica. Queste protesi dotate di dispositivi tecnologici come i sensori inerziali, gravimetrici, GPS e sistemi di trasmissione wireless potranno essere utili non solo per migliorare l’assetto del piede, organo sensoriale e motorio di centrale importanza per il sistema biomeccanico e posturale-propriocettivo del corpo umano, ma anche come strumento di diagnosi quantitativa e qualitativa nonché come sistema di monitoraggio dei risultati clinici in ambito neurologico, ortopedico e riabilitativo.The aim of this doctoral thesis is to demonstrate an innovative method that achieves a customized and sensorized shoe using an additive manufacturing process of Fused Deposition Modelling (FDM). The recent technological advances and the development of new approaches in the creation of custom-made devices, such as rapid prototyping by means of laser scanning and additive printing, have highlighted the potential for a significant improvement in the production of these devices in terms of reproducibility, quality of the product and cost reduction. The reproducibility of the process and the validation of the device were based on the interaction of different competencies: clinical, biomechanical, material and design science. Following a study on the mechanical properties of existing materials and the improvement of the process for designing the customized prosthesis, a system was devised to create a space dedicated to sensors inside the orthoses. These prostheses, fitted with technological devices such as inertial, gravimetric, GPS and wireless transmission sensors, will be useful not only for improving the position of the foot (a sensory and motor organ of central importance for the biomechanical and postural-proprioceptive system of the human body) but will lead also as a quantitative and qualitative diagnostic tool, as well as a system for monitoring clinical results in the neurological, orthopaedic and rehabilitation fields

Mithramycin encapsulated in polymeric micelles by microfluidic technology as novel therapeutic protocol for beta-thalassemia

This report shows that the DNA-binding drug, mithramycin, can be efficiently encapsulated in polymeric micelles (PM-MTH), based on Pluronic® block copolymers, by a new microfluidic approach. The effect of different production parameters has been investigated for their effect on PM-MTH characteristics. The compared analysis of PM-MTH produced by microfluidic and conventional bulk mixing procedures revealed that microfluidics provides a useful platform for the production of PM-MTH with improved controllability, reproducibility, smaller size, and polydispersity. Finally, an investigation of the effects of PM-MTH, produced by microfluidic and conventional bulk mixing procedures, on the erythroid differentiation of both human erythroleukemia and human erythroid precursor cells is reported. It is demonstrated that PM-MTH exhibited a slightly lower toxicity and more pronounced differentiative activity when compared to the free drug. In addition, PM-MTH were able to upregulate preferentially ?-globin messenger ribonucleic acid production and to increase fetal hemoglobin (HbF) accumulation, the percentage of HbF-containing cells, and their HbF content without stimulating ?-globin gene expression, which is responsible for the clinical symptoms of ß-thalassemia. These results represent an important first step toward a potential clinical application, since an increase in HbF could alleviate the symptoms underlying ß-thalassemia and sickle cell anemia. In conclusion, this report suggests that PM-MTH produced by microfluidic approach warrants further evaluation as a potential therapeutic protocol for ß-thalassemia.<br/

Non-operative treatment of morton's interdigital neuroma with a foot orthosis

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The role of incoherent twin boundaries on the plasticity of Cu micropillars

The role of a ∑3{1 1 2} incoherent twin boundary (ITB) on the shear stress of Cu at the micron scale has been investigated through microcompression of bi-crystalline pillars containing ITB, as well as single-crystalline pillars, in two different compression directions. The Cu sample containing ITBs was synthesized using magnetron sputtering on a sapphire substrate. Firstly, pillars along [1 1 1] compression direction were milled on the film surface. As multiple slip systems were activated upon loading, the dislocation-ITB interaction in this direction was dominated by the dislocation–dislocation interactions. Another set of pillars was milled from the side of the film (in the thickness of the film) in a nominally [13] compression direction. Compression in this direction activated a single slip in each grain, which facilitated the investigation of the interaction between dislocations and ITBs. Post-mortem images showed that slip traces were not distinctly connected at the boundary unlike ideal slip transmission in pillars containing a coherent twin boundary. Moreover, bi-crystalline pillars in the single slip direction are stronger than single-crystalline pillars. The observations indicate that ITBs are not impenetrable for dislocations, but the boundary demonstrates some resistance to transmission

The Association between Cognitive Impairment and Diabetic Foot Care : Role of Neuropathy and Glycated Hemoglobin

Diabetes mellitus is associated with impairment in cognitive functions which can complicate adherence to self-care behaviors. We evaluated the incidence of cognitive impairment in patients with diabetes mellitus to determine the strength of the association between diabetic foot (a complication that occurs in about 10% of diabetic patients), adherence to the clinician's recommendations, glycemic control, and cognitive function. A prospective study was carried out in a probabilistic sample of older patients with diabetic foot living in three nursing homes. Cognitive functions were evaluated by the MMSE (Mini-Mental State Examination), the Trail Making test (TMT), and the Michigan neuropathy screening instrument (MNSI). There were no significant associations between cognitive function and neuropathy or foot alterations, although glycated hemoglobin (HB1Ac > 7%) significantly (p 7%) and a neuropathy score of 5.5 in the MNSI are the best-cut off points to discriminate poor adherence to the clinician's recommendations for self-care behaviors in people with diabetic foot complication. In this study, we observed that foot disorders were associated with impaired global cognitive function in elderly patients (aged ≥ 65). Podiatrists and physicians should consider cognitive dysfunction as an important chronic complication in the management of diabetic foot