130 research outputs found
Effective combination of biocompatible zinc oxide nanocrystals and high-energy shock waves for the treatment of colorectal cancer
No full textAbstract Background Colorectal cancer (CRC) is the third most diagnosed tumor worldwide, with a very high mortality rate, second only to lung cancer. Current treatments, such as surgery, chemotherapy or radiotherapy, are not effective enough and show several limitations. Among the emerging strategies, nanomedicine offers very powerful tools in cancer treatment. Recently, the combination of nanoparticle antitumor effect with a triggering external stimulation was formulated to boost up the cytotoxic activity. Results In this work, we show the synergistic effect of oleic acid-capped zinc oxide nanocrystals (ZnO NCs) and mechanical high-energy shock waves (SW) in the treatment for CRC cells, in vitro. We tested two different types of ZnO NCs synthetized in our laboratory, the basal undoped ZnO NCs and the iron-doped ones (Fe:ZnO NCs). The presence of the oleic acid capping and the further amino-propyl functionalization guarantee a high colloidal stability to both NCs, while the iron doping confers to Fe:ZnO NCs interesting magnetic properties useful for imaging applications in a clinical perspective. Thus, the iron-doped ZnO NCs are very attractive as potentially theranostic nanoparticles, allowing both stimuli-responsive therapy and magnetic resonance imaging. Importantly, two colon adenocarcinoma cell lines, the HT-29 and the Dukes’ type C Colo 320DM cells were tested, both showing a good bio-tolerance and internalization rates of NCs. With the aim of eradicating the CRC cells, the possible synergism between the undoped/iron-doped ZnO NCs and an external physical stimulus, i.e., high-energy SW, was then here investigated in vitro. We demonstrated that the combined treatment resulted in an augmentation of the antitumor activity, especially for Colo 320DM cells, when compared to controls. Moreover, a repeated and sequenced SW treatment (three times/day, 3SW) after ZnO NCs exposure resulted in a further increased mortality of CRC cells. Conclusion Our work proposes the combination of the cytotoxic activity of ZnO NCs with the SW external stimulation to obtain a booster of the antitumor activity, which warrants further investigation in vivo on CRC as well as on other tumors. Graphical Abstrac
Convolutional Autoencoder for the Spatiotemporal Latent Representation of Turbulence
No full textTurbulence is characterised by chaotic dynamics and a high-dimensional state space, which make this phenomenon challenging to predict. However, turbulent flows are often characterised by coherent spatiotemporal structures, such as vortices or large-scale modes, which can help obtain a latent description of turbulent flows. However, current approaches are often limited by either the need to use some form of thresholding on quantities defining the isosurfaces to which the flow structures are associated or the linearity of traditional modal flow decomposition approaches, such as those based on proper orthogonal decomposition. This problem is exacerbated in flows that exhibit extreme events, which are rare and sudden changes in a turbulent state. The goal of this paper is to obtain an efficient and accurate reduced-order latent representation of a turbulent flow that exhibits extreme events. Specifically, we employ a three-dimensional multiscale convolutional autoencoder (CAE) to obtain such latent representation. We apply it to a three-dimensional turbulent flow. We show that the Multiscale CAE is efficient, requiring less than 10% degrees of freedom than proper orthogonal decomposition for compressing the data and is able to accurately reconstruct flow states related to extreme events. The proposed deep learning architecture opens opportunities for nonlinear reduced-order modeling of turbulent flows from data.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Aerodynamic
Anti-CD38 targeted nanotrojan horses stimulated by acoustic waves as therapeutic nanotools selectively against Burkitt’s lymphoma cells
No full textAbstract The horizon of nanomedicine research is moving toward the design of therapeutic tools able to be completely safe per se, and simultaneously be capable of becoming toxic when externally activated by stimuli of different nature. Among all the stimuli, ultrasounds come to the fore as an innovative approach to produce cytotoxicity on demand in presence of NPs, without invasiveness, with high biosafety and low cost. In this context, zinc oxide nanoparticles (NPs) are among the most promising metal oxide materials for theranostic application due to their optical and semi-conductor properties, high surface reactivity, and their response to ultrasound irradiation. Here, ZnO nanocrystals constitute the stimuli-responsive core with a customized biomimicking lipidic shielding, resembling the composition of natural extracellular vesicles. This core–shell hybrid structure provides high bio- and hemocompatibility towards healthy cells and is here proofed for the treatment of Burkitt’s Lymphoma. This is a very common haematological tumor, typically found in children, for which consolidated therapies are so far the combination of chemo-therapy drugs and targeted immunotherapy. In this work, the proposed safe-by-design antiCD38-targeted hybrid nanosystem exhibits an efficient selectivity toward cancerous cells, and an on-demand activation, leading to a significant killing efficacy due to the synergistic interaction between US and targeted hybrid NPs. Interestingly, this innovative treatment does not significantly affect healthy B lymphocytes nor a negative control cancer cell line, a CD38- acute myeloid leukemia, being thus highly specific and targeted. Different characterization and analyses confirmed indeed the effective formation of targeted hybrid ZnO NPs, their cellular internalization and the damages produced in Burkitt’s Lymphoma cells only with respect to the other cell lines. The presented work holds promises for future clinical applications, as well as translation to other tumor types. Graphical abstrac
Cardiogenic Pulmonary Edema in Emergency Medicine
No full textCardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung’s alveolar spaces due to an
elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the
left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause
barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading
to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of
procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species
(RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid
balance. Some studies claim that these patients may have higher levels of surfactant protein B in the
bloodstream. The correct approach to patients with CPE should include a detailed medical history
and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE
phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators
are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paperreviews the pathophysiology,
clinical presentation, and management of CPE
Eurozona e debito pubblico: gli eurobond come strumento di integrazione politico-istituzionale
No full textGli eurobond non sono un tema nuovo. Sono presenti nella letteratura economica, meno in quella giuridica, da oltre trent’anni, con denominazioni che spesso mutano a seconda delle formulazioni proposte. Rientrano in quella categoria di idee che hanno valore non solo sotto il profilo della tecnica finanziaria o della finanza pubblica, ma anche perché rappresentano un primo passo verso la realizzazione di un’unione politica dell’Europa. I favorevoli vedono in questo tipo di proposte non solo una risposta alla crisi attraverso il finanziamento degli investimenti pubblici, ma anche la costruzione di una politica fiscale europea da affiancare a quella monetaria della Banca centrale europea. Gli scettici pongono, invece, l’accento sui tempi troppo lunghi che tali proposte richiederebbero per essere attuate e sul consenso non unanime che esse riscuotono da parte dei Paesi dell’Eurozona. L’introduzione degli eurobond presenta, infatti, ostacoli legali e distributivi. Quelli legali hanno a che fare, in particolare, con l’articolo 125 del Trattato sul Funzionamento dell’Unione europea (TFUE), che dispone il divieto di salvataggio da parte dell’Unione a favore di un Paese membro in difficoltà e, in particolare, vieta a ciascuno Stato membro di rispondere o di subentrare nei debiti di altri Stati membri (cosiddetta “clausola di no bail out”). Gli ostacoli distributivi sono legati alle modalità di partecipazione dei Paesi membri alle emissioni congiunte dei titoli del debito europeo in termini di risorse finanziarie e ai timori dei Paesi virtuosi del Nord Europa di dover fornire un contributo maggiore rispetto ai Paesi meno virtuosi del Sud Europa.
La tesi affronta, innanzitutto, il tema della fragilità della costruzione europea, che dipende essenzialmente dall’aver creato – contrariamente a quanto avvenuto nella storia dei popoli – “una moneta senza Stato”. Questa circostanza ha condotto, alla fine del 2009, alla crisi dell’euro e dei debiti sovrani. Per rimediare a tale fragilità istituzionale, bisognerebbe por mano a una serie di riforme come il rafforzamento del ruolo della Banca centrale europea come prestatore di ultima istanza, il completamento dell’unione bancaria, l’approfondimento dell’unione del mercato dei capitali, l’allargamento del bilancio europeo e l’accentramento delle politiche fiscali nazionali. Tra queste riforme rientra anche quella di dar vita all’emissione congiunta di debito sovrano a livello di Eurozona, o, in alternativa, a schemi che non prevedono la mutualizzazione del debito. Al riguardo, la ricerca prende in esame l’esistenza di eventuali basi giuridiche per emettere un debito federale dell’Unione europea, distinto dal debito degli Stati membri o, in alternativa, per procedere alla mutualizzazione dei debiti degli Stati membri.
La tesi passa, poi, in rassegna le varie proposte avanzate in tema di eurobond, classificandole in due gruppi principali, a seconda che prevedano o meno la mutualizzazione del debito. Nell’ambito delle proposte che si basano sulla mutualizzazione del debito rientrano gli eurobond in senso stretto, gli union bond, gli stability bond, le obbligazioni blu e rosse. Tali proposte, in quanto fondate sulla mutualizzazione del debito, non sono compatibili con l’articolo 125 del TFUE e richiederebbero pertanto la sua modifica. Nel secondo gruppo di proposte – che non contemplano la mutualizzazione del debito e pertanto non richiedono la modifica del TFUE – rientrano il programma PADRE (Politically Acceptable Debt Restructuring in Europe), il Fondo di ammortamento del debito a livello europeo (European Redemption Fund), gli European Safe Bond - ESB (acronimo inglese di “Titoli europei sicuri”), i Sovereign Bond Backed Securities - SBBS (acronimo inglese di “Titoli garantiti da obbligazioni sovrane”).
La ricerca esplora i possibili approcci alla prosecuzione del progetto europeo: la via della riduzione del rischio (risk-reduction), la via della condivisione del rischio (risk-sharing), la via della sintesi tra riduzione e condivisione del rischio. Quest’ultima via appare a chi scrive come l’unica politicamente percorribile. La stessa unione monetaria si è realizzata come combinazione tra i due approcci: il processo di convergenza delle finanze pubbliche (risk reduction) ha condotto alla creazione di un’unica banca centrale con il compito di mettere in atto un’unica politica monetaria e del cambio (risk sharing). Vi è però la necessità per l’Italia di fare la propria parte invertendo la traiettoria del rapporto debito-Pil attraverso un serio e rigoroso piano pluriennale di rientro dal debito (risk reduction), per acquisire, agli occhi dei principali partner europei, quella credibilità necessaria per convincerli a dar vita a un vero e proprio debito federale europeo (risk sharing). Gli eurobond non sono l’unico mezzo per raggiungere la finalità di una unificazione politica dell’Europa ma hanno il pregio di mettere insieme l’approccio funzionalista dei passi graduali con quello federalista della meta finale. Analogamente a quanto avvenuto nella storia di alcuni popoli (in particolare negli Stati Uniti d’America) in cui il processo di unificazione dei debiti ha segnato la nascita dello Stato, anche nel vecchio continente l’europeizzazione del debito degli Stati membri, al di là della valenza in termini di finanza pubblica, potrebbe assurgere a un vero e proprio atto “costitutivo” di un futuro Stato federale europeo.
Sotto il profilo metodologico, la ricerca è stata condotta attraverso la strumentazione propria dell’analisi economica del diritto, nella consapevolezza che il mercato – vale a dire il meccanismo economico che orienta il comportamento di individui e gruppi – da solo non è sufficiente ma ha bisogno di regole per poter funzionare. Anzi, se ben regolato, il mercato può essere fattore di sviluppo e di benessere. Questo ragionamento vale anche per il mercato comune e per la moneta unica europea, che da soli non bastano più. Come si è tentato di mostrare in questo lavoro, anche l’Eurozona, per poter sopravvivere e progredire, ha bisogno di un adeguamento delle proprie istituzioni che passa anche attraverso l’emissione congiunta di debito sovrano. Coerentemente con tale impostazione, l’indagine cerca di avere un approccio critico al tema degli eurobond, tentando di analizzarne i singoli aspetti con indipendenza di giudizio. La stesura dei capitoli e dei singoli paragrafi è stata preceduta da un lavoro di documentazione e consultazione di testi, riviste specializzate e articoli. Le conoscenze teoriche acquisite e le idee maturate sono state verificate sul campo, grazie ad un confronto diretto con i dirigenti che, nell’ambito del Dipartimento del Tesoro del Ministero dell’Economia e delle Finanze, hanno la responsabilità dell’emissione e della gestione del debito pubblico italiano. Chi scrive lavora presso la direzione del Debito pubblico del Dipartimento del Tesoro; cionondimeno, le opinioni che qui esprime sono personali e non rappresentano o impegnano in alcun modo l’amministrazione di appartenenza.
Alla luce delle considerazioni svolte, si ritiene che davvero gli eurobond possano spingere l’Eurozona verso una maggiore integrazione politico-istituzionale. L’analisi economica e giuridica può dare il proprio contributo alla comprensione della questione, ma la scelta dei passi da compiere in concreto spetta alle leadership politiche europee in quanto investite del consenso popolare. Il ricercatore può esporre gli effetti che derivano dall'adozione di una particolare misura o di uno specifico strumento. Oltre non può andare.Eurobonds are not a new topic. They have been present in the economic literature, less in the legal literature, for thirty years, with denominations which change according to the proposed formulations. They are relevant not only in terms of financial economics or public finance, but also because they represent a first step towards the realization of a political union of Europe. Those in favor look at eurobonds not only as a response to the crisis through the financing of public investments, but also as a tool to build up a European fiscal policy in addition to the monetary policy of the European Central Bank. On the contrary, the skeptics underline the fact that such proposals would require too mach time to be implemented and the fact that they have short consent in the Eurozone countries. The introduction of eurobonds presents legal and distributive barriers. The legal barriers are linked to the Article 125 of the Treaty on the Functioning of the European Union (TFEU), which provides for so-colled “no bail out clause” (“A Member State shall not be liable for or assume the commitments of central governments, regional, local or other public authorities, other bodies governed by public law, or public under¬ takings of another Member State”). The distributive obstacles, on the other hand, are linked to the way in which Member States could participate in joint issuance of European debt securities. In particular, the virtuous countries of Northern Europe are afraid that they would pay a greater share than the less virtuous countries of the Southern Europe.
First of all, the thesis analyzes the fragility of the European institutions, which depends essentially on having created – contrary to what has happened in the history of peoples – “a currency without a State”. In the end of 2009, this fragility led Europe to the crisis of euro and sovereign debts. To face this fragility, some institutional reforms should be carried out, such as the strengthening of the role of the European Central Bank as a lender of last resort, the completion of the banking union, the deepening of the capital market, the enlargement of the European budget and the centralization of national fiscal policies. These reformes also include the joint issuance of sovereign debts of Eurozone Member States. In this regard, the research examines the existence of possible legal bases for issuing a federal debt of the European Union, different from the debt of the Member States or, alternatively, for joint issuing the debt securities of the Member States.
Secondly, the thesis examines the various proposals of eurobonds, classifying them in two main groups. The first group, based on the joint issuance of debt, includes eurobonds in the strict sense, union bonds, stability bonds, blue and red bonds. These proposals, being based on the joint issuance of debt, are contrary to Article 125 of the TFEU and therefore would require its modification. The second group of proposals – which do not contemplate the joint issuance of debt and therefore do not require the modification of the TFEU – include the PADRE program (Politically Acceptable Debt Restructuring in Europe), the European Redemption Debt Fund, the European Safe Bonds, the Sovereign Bond Backed Securities.
Thirdly, the research explores the possible approaches to the continuation of the European project: the risk-reduction path, the risk-sharing path, the synthesis between risk reduction and risk sharing. This third path seems to be the only politically feasible. As we know, also the monetary union was realized as a combination of the two approaches: the process of convergence of public finances (risk reduction) led to the creation of a single central bank with the task of managing a single monetary policy (risk sharing). However, Italy has to reverse the trend of the debt-to-GDP ratio through a serious and rigorous long-term debt reduction plan (risk reduction), in order to convince the main European partners to issue European federal debt (risk sharing). Eurobonds are not the only tool to achieve the goal of a political unification of Europe but they have the merit of putting together the functionalist approach based on the gradual steps with the federalist approach based on the final goal. Similarly to what has happened in the history of some peoples, such as the United States of America, where the process of unification of debt of the single States has marked the birth of the federal State, even in Europe the consolidation of debt of the Member States might be a constitutive act of the United States of Europe.
Methodologically, the research is based on the economic analysis of law. According to this view, market – the economic mechanism which guides the behavior of individuals and groups – is not enough but needs good regulation. Indeed, if it is well regulated, market may be a factor of development and welfare. This way of thinking is also valid for the European single market and for the euro, which are no longer enough. As we have tried to show in this work, also the Eurozone institutions need a deep reform – including the joint issuance of sovereign debt – for their surviving and progress.
This work tries to have a critical approach to the topic of eurobonds. The theoretical knowledge and ideas have been checked thanks to a direct dialogue with managers who, within the Treasury Department of the Ministry of the Economy and Finance, are responsible for issuance and management of the Italian public debt. The author of this research works in the Public Debt Directorate at Treasury Department; nevertheless his opinions are personal and do not represent the Treasury Department.
For these considerations, eurobonds might really push the Eurozone towards a greater political and institutional integration. The economic and legal analysis may give its contribution to the debate, but the actual choices are up to the European policy-makers
Human renal angiomyolipoma cells of male and female origin can migrate and are influenced by microenvironmental factors.
No full textBACKGROUND:Improving the knowledge of angiomyolipoma physiopathology might help in refining its pharmacological treatment. We investigated if angiomyolipoma cells have migratory properties, how their growth and motility can be influenced by the hormonal milieu, and if this can be related to a specific gender. METHODS:Primary cells were isolated from angiomyolipomas surgically resected for therapeutical reasons in a female and in a male patient. The genetic control demonstrated no TSC2 deletion. Bi- (wound healing) and three-dimensional (transwell assay) migration were analyzed in vitro in basal conditions and under the influence of 17- β-estradiol and SDF-1α. RESULTS:Treatment up to 72 hours with 17-β-estradiol (0.1-100 nM), tamoxifen (0.2-20 μM) or with both, does not modify angiomyolipoma cells proliferation. On the other hand, SDF-1α and 17-β-estradiol treatment induce a significant motility increase (both bi- and three-dimensional) which becomes evident already after 2 hours of incubation. Angiomyolipoma cells express mRNA coding for SDF-1α and 17-β-estradiol receptors and secrete both the metalloproteases principally involved in malignant phenotype acquisition, i.e. MMP-2 and MMP-9. CONCLUSION:Angiomyolipoma cells behave similarly, despite their different source. Primary angiomyolipoma cells migrate in response to hormonal milieu and soluble factors, and produce active metalloproteases, both aspects being consistent with the theory claiming they can migrate to the lungs (and/or other organs) and colonizing them. No main feature, among the aspects we analyzed, seems to be referable to the gender of origin
Pregnancy Arrhythmias: Management in the Emergency Department and Critical Care
No full textPregnancy is closely associated with an elevated risk of arrhythmias, constituting the predominant cardiovascular complication during this period. Pregnancy may induce the exacerbation of previously controlled arrhythmias and, in some instances, arrhythmias may present for the first time in pregnancy. The most important proarrhythmic mechanisms during pregnancy are the atrial and ventricular stretching, coupled with increased sympathetic activity. Notably, arrhythmias, particularly those originating in the ventricles, heighten the likelihood of syncope, increasing the potential for sudden cardiac death. The effective management of arrhythmias during the peripartum period requires a comprehensive, multidisciplinary approach from the prepartum to the postpartum period. The administration of antiarrhythmic drugs during pregnancy necessitates meticulous attention to potential alterations in pharmacokinetics attributable to maternal physiological changes, as well as the potential for fetal adverse effects. Electric cardioversion is a safe and effective intervention during pregnancy and should be performed immediately in patients with hemodynamic instability. This review discusses the pathophysiology of arrythmias in pregnancy and their management
ZnO nanocrystals shuttled by extracellular vesicles as effective Trojan nano-horses against cancer cells
No full textA comparative analysis of low intensity ultrasound effects on living cells: from simulation to experiments
No full textUltrasounds are already broadly exploited in clinical diagnostics and are now becoming a powerful and not harmful tool in antitumoral therapies, as they are able to produce damages towards cancer cells, thank to inertial cavitation and temperature increase. The use of US alone or combined to molecular compounds, microbubbles or solid-state nanoparticles is the focus of current research and clinical trials, like thermoablation, drug sonoporation or sonodynamic therapies. In the present work, we discuss on the non-thermal effects of ultrasound and the conditions which enable oxygen radical production and which
role they can have in provoking the death of different cancer cell lines. In this perspective, we set a mathematical model to
predict the pressure spatial distribution in a defined water sample volume and thus obtain a map of acoustic pressures and
acoustic intensities of the applied ultrasound at different input powers. We then validate and verify these numerical results
with direct acoustic measurements and by detecting the production of reactive oxygen species (ROS) by means of sonochemiluminescence (SCL) and electron paramagnetic resonance (EPR) spectroscopy, applied to the same water sample volume and using the same US input parameters adopted in the simulation. Finally, the various US conditions are applied to two different set of cancer cell lines, a cervical adenocarcinoma and a hematological cancer, Burkitt’s lymphoma. We hypothesize how the ROS generation can influence the recorded cell death. In a second set of experiments, the role of semiconductor metal oxide nanocrystals, i.e. zinc oxide, is also evaluated by adding them to the water and biological systems. In particular, the
role of ZnO in enhancing the ROS production is verified. Furthermore, the interplay among US and ZnO nanocrystals is
evaluated in provoking cancer cell death at specific conditions. This study demonstrates a useful correlation between numerical
simulation and experimental acoustic validation as well as with ROS measurement at both qualitative and quantitative levels during US irradiation of simple water solution. It further tries to translate the obtained results to justify one of the possible mechanisms responsible of cancer cell death. It thus aims to pave the way for the use of US in cancer therapy and a better understanding on the non-thermal effect that a specific set of US parameters can have on cancer cells cultured in vitro
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