Biological Activity of Natural and Synthetic Compounds

A drug discovery program starts when a disease or clinical condition has no suitable drugs. In response, the pharmaceutical industry and academic research groups can follow different processes aimed at identifying new molecules with drug-like properties that efficiently modulate the desired biological target. These new chemical entities can be isolated from natural sources or obtained by chemical synthesis, as demonstrated by the articles and review papers reported in this Special Issue

Implementazione di un sistema di monitoraggio sui fattori di qualità dell'handling aeroportuale

Il presente lavoro di tesi nasce dall'esigenza SAT di implementare un sistema di monitoraggio sulla qualità dell'handling aeroportuale. Il problema è stato suddiviso in tre sotto-obiettivi: -controllo del processo; -verifica degli obiettivi dichiarati; - segmentazione ed analisi dati. Lo studio dei sotto-obiettivi ha avviato una collaborazione con la società di gestione aeroportuale, sezione Quality Management, oltre a richiedere la presenza in pista per un mese. Le attività necessarie per il conseguimento degli obiettivi sono articolate come descritto di seguito. •Controllo del processo Si compone di due aspetti: mappatura del processo e individuazione delle responsabilità. Per valutare le possibili inefficienze o criticità è necessario conoscere la sequenzialità delle operazioni per lo sbarco dei passeggeri e la riconsegna merci. In particolare è richiesto di capire quali siano le unità coinvolte e i legami direttivi. Per l'assistenza alle compagnie aeree, airside, sono interessate quattro aree caratteristiche. Comprendere la struttura del processo produttivo ha permesso di individuare, laddove esistano, le criticità che impediscono di completare i servizi in tempi rapidi. Le attività svolte all'interno del terminal o landside (check-in, sicurezza, biglietteria e controllo passaporti) sono operazioni di front line che si svolgono all'interno di un'unica area strategica e non richiedono la mappa del processo. •Verifica degli obiettivi dichiarati In riferimento alle sessioni di rilevamento condotte nel corso dell'anno 2003, misurazioni messe a disposizione dal gestore SAT, le informazioni sono state elaborate mediante l'applicazione della metodologia ENAC per valutare la loro rispondenza agli obiettivi dichiarati. La procedura seguita ha utilizzato sia i dati temporali sia i sondaggi svolti nello stesso anno. La comparazione contestuale di misure oggettive e di misure soggettive ha avvalorato l'analisi svolta e le decisioni correttive assunte dal gestore per l'anno successivo. •Segmentazione ed analisi dati Le due sessioni di bassa stagione nel biennio 2004-2005 sono state impiegate per valutare l'evoluzione delle prestazioni mediante una segmentazione ulteriore dei campioni, qualora la numerosità del dato lo consentisse. Il gestore aeroportuale, a partire dal 2004, ha deciso di impiegare per finalità interne le misurazioni necessarie per redigere la Carta dei Servizi. Tali indicatori sono stati affiancati da altri per ampliare la conoscenza del processo di erogazione. Nell'area dei servizi aeroportuali la fase del prodotto non pare riscontrabile in alcun tipo di business, in quanto i servizi che vengono forniti sia dal lato dell'airside sia da quello del landside non consentono l'acquisizione di vantaggi concorrenziali derivanti dal processo di know-how particolari ed esclusivi. Invece diviene sempre più importante la tecnologia di processo, nella quale gli aspetti critici si spostano sulle modalità di attuazione e di organizzazione del processo di produzione. In tale contesto, il punto di distinzione rispetto alla concorrenza non può che essere rappresentato dalla modalità di svolgimento del servizio e quindi dal livello di qualità. Le segmentazioni (giorno e fasce orarie) sono impiegate allo scopo di valutare l'allocazione delle risorse e la capacità di rispondere alle fluttuazioni di traffico. L'ulteriore distinzione del campione, basata sulla tipologia di aeromobile, è indirizzata a valutare le diverse prestazioni delle aerolinee. Di particolare interesse, in un primo momento, il confronto tra i vettori IATA e successivamente il confronto con i low cost. Gli operatori low cost richiedono garanzie di rapidità delle stesse operazioni di assistenza a terra per assicurare un'elevata rotazione quotidiana del velivolo

Il "complesso" rapporto tra le organizzazioni non profit ed il sistema finanziario. Un'indagine empirica.

La tesi tratta il rapporto tra il sistema finanziario e le organizzazioni non profit. In perticolare, analizza gli strumenti di finanza dedicata e di finanza etica vera e propria (Banca Popolare Etica e Mag).Infine il lavoro si conclude con un'indagine svolta da Respet sul territorio romano a cui ho collaborato

Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways

Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADþ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism

Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction

Direct targeting of energy metabolism to defeat cancer is not a recent strategy. Although quite a few drugs use cellular metabolism for their antitumor effect, no direct inhibitors of energy metabolism have been approved by the FDA. Currently, several inhibitors of lactate dehydrogenase A (LDH-A), a key player in glycolysis, are in development. Earlier, we demonstrated the efficacy of N-hydroxyindole-based LDH-A inhibitors in different cancer types. In this study we describe the efficacy of NHI-Glc-2, which is designed to dual target cancer cells, by exploiting a simultaneous enhanced glucose uptake by overexpressed glucose transporter 1 (GLUT1) and by inhibition of LDH-A. NHI-Glc-2 inhibits LDH-A enzyme activity, PANC-1 cell growth and disrupts spheroid integrity, with an overall effect that is more pronounced when combined with gemcitabine

Chronic Iliac Vein Occlusion and Painful Nonhealing Ulcer Induced by High Venous Pressures from an Arteriovenous Malformation

Chronic femoral vein compression (May-Thurner Syndrome) is a known rare cause of deep venous thrombosis. Subsequent angiogenesis and the development of arteriovenous malformation (AVM) in the setting of chronic venous thrombosis is by itself a rare and poorly understood phenomenon. We report a case in which elevated venous pressures resulting from such compression appear to have resulted in the development of a pelvic arteriovenous malformation, which was further complicated by chronic, nonhealing painful lower extremity ulcers, and the development of extensive subcutaneous venous collaterals. Following successful embolization of the pelvic AVM and ablation of veins under the ulcers with laser and sclerotherapy, the patient's ulcers healed and she became pain-free

Anticancer agents interacting with membrane glucose transporters

The altered metabolism observed in cancer cells generally consists of increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore, GLUTs are considered as suitable targets for treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents

An update on therapeutic opportunities offered by cancer glycolytic metabolism

AbstractAlmost all invasive cancers, regardless of tissue origin, are characterized by specific modifications of their cellular energy metabolism. In fact, a strong predominance of aerobic glycolysis over oxidative phosphorylation (Warburg effect) is usually associated with aggressive tumour phenotypes. This metabolic shift offers a survival advantage to cancer cells, since they may continue to produce energy and anabolites even when they are exposed to either transient or permanent hypoxic conditions. Moreover, it ensures a high production rate of glycolysis intermediates, useful as building blocks for fast cell proliferation of cancer cells. This peculiar metabolic profile may constitute an ideal target for therapeutic interventions that selectively hit cancer cells with minimal residual systemic toxicity. In this review we provide an update about some of the most recent advances in the discovery of new bioactive molecules that are able to interfere with cancer glycolysis

New agents against hypoxic tumours counteracting invasiveness and metabolism

My research activity concerns the design and the synthesis of heterocycles which are intended to act against tumour hypoxia. Unlike healthy cells, which are regularly vascularized, cancer tissues are often characterized by hypoxic regions, due to the rapid and uncontrolled cellular growth and the irregular vascular network. This condition brings to the overexpression of several proteins and, among them, two important novel antitumoural targets, that are lysyl oxidase (LOX) and lactate dehydrogenase A (LDH-A), constituted the main focuses of my research, because they are key enzymes involved in hypoxic tumour growth and invasiveness. In particular, LOX is an enzyme implicated in the remodeling of the extracellular matrix and in the promotion of the metastatic process, so it is deeply involved in the invasive ability of hypoxic tumours. This PhD thesis was aimed to design and synthesize hypoxia-activated nitroaromatic pro-drugs of beta-aminoproprionitrile (BAPN), which is a well-known LOX inhibitor that cannot be developed as a drug due to its many unwanted side effects. These prodrugs should be able to selectively delivery BAPN to hypoxic tumour sites in order to block LOX-induced promotion of invasiveness, reducing systemic side effects. The synthesized molecules were biologically evaluated in LOX inhibition and cell invasion assays, and some compounds proved to be promising LOX inhibitors. As for LDH-A, this enzyme is involved in the peculiar sugar metabolism that occurs in invasive cancers, consisting in a metabolic switch (called the “Warburg effect”) from oxidative phosphorylation to an increased anaerobic glycolysis. LDH-A constitutes a major checkpoint in the switch from aerobic to anaerobic glycolysis, by catalysing the reduction of pyruvate to lactate. The genetic or chemical inhibition of this enzyme proved to counteract tumour growth. Furthermore, LDH-A is also a safe target, causing myoglobinuria only during intense anaerobic exercise in people with an hereditary deficiency of this enzyme. In this PhD project, a new class of LDH-A inhibitors based on COOH-substituted N-hydroxyindole structure (NHIs) was designed and synthesized. Enzymatic assays and cellular-based experiments led to the discovery of new promising and selective inhibitors of LDH-A