The Synthesis and Biological Evaluation of Multifunctionalised Derivatives of Noscapine as Cytotoxic Agents

Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well‐known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6′, 9′, 1 and 7‐positions, is described. In a previous study, replacement of the naturally occurring N‐methyl group in the 6′‐position with an N‐ethylaminocarbonyl was shown to promote cell‐cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9′‐position, regioselective O‐demethylation to reveal a free phenol in the 7‐position, and reduction of the lactone to the corresponding cyclic ether in the 1‐position. The incorporation of new aryl substituents in the 9′‐position was also investigated. The study identified interesting new compounds able to induce G2/M cell‐cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF‐7, and the human pancreatic epithelioid carcinoma cell line PANC‐1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6′‐ethylaminocarbonyl along with 9′‐chloro, 7‐hydroxy and lactone moieties exhibited the most promising biological activities, with EC₅₀ values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.     

New chlorinated amphetamine-type-stimulants disinfection-by-products formed during drinking water treatment

Previous studies have demonstrated high removal rates of amphetamine-type-stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3-dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L.     

A ticket to ride: Education and migration from lagging areas

National policies may have heterogeneous effects at the regional level. When coming to programmes aimed at increasing human capital, worker mobility from poorer to richer regions can reduce the benefits of the policy for the former areas. We focus on Italy and estimate the impact of education on the probability of migrating from a lagging area to a leading one. Endogeneity is addressed by exploiting an increase in the minimum school-leaving age in an instrumental variable framework. We find that one additional year of education increases the probability to migrate by 1.7 percentage points (9% of the average migration rate).     

On the elimination of quadrature subcells for discontinuous functions in the eXtended Finite‐Element Method

The introduction of discontinuous/non‐differentiable functions in the eXtended Finite‐Element Method allows to model discontinuities independent of the mesh structure. However, to compute the stiffness matrix of the elements intersected by the discontinuity, a subdivision of the elements into quadrature subcells aligned with the discontinuity line is commonly adopted. In the paper, it is shown how standard Gauss quadrature can be used in the elements containing the discontinuity without splitting the elements into subcells or introducing any additional approximation. The technique is illustrated and developed in one, two and three dimensions for crack and material discontinuity problems. Copyright © 2005 John Wiley & Sons, Ltd.     

Improved in vitro anti-tumoral activity, intracellular uptake and apoptotic induction of gemcitabine-loaded pegylated unilamellar liposomes

Anaplastic thyroid carcinoma is one of the most aggressive and lethal solid carcinomas affecting humans. A major limit of the chemotherapeutic agents is represented by their low therapeutic index. In this work, we investigated the possibility of improving the anti-tumoral activity of gemcitabine by using pegylated unilamellar liposomes. Liposomes were made up of 1,2-dipalmitoyl-sn-glycero-3-phospocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio) and they were prepared with a pH gradient to improve the gemcitabine loading capacity. The anti-tumoral efficacy of the liposomal formulation was tested in vitro on human anaplastic thyroid carcinoma cells (ARO) in culture, comparing the effects with those of the free drug. Gemcitabine-loaded unilamellar liposomes had a mean size approximately 200 nm with a zeta potential approximately -2 mV. The liposomal carrier noticeably improved the anti-tumoral activity of gemcitabine against ARO cells in terms of both dose-dependent cytotoxic effect and of drug exposition effect. Namely, gemcitabine-loaded liposomes showed a cytotoxic effect (58.2% increase of cell mortality at 1 microM with respect to free drug) after 12 h incubation, while the free drug showed a significant activity only after 72 h incubation. Moreover, a significant effect on the cell mortality appeared at 0.1 microM and 100% mortality was detected at a concentration of 1 microM of gemcitabine-loaded liposomes, while the free drug elicited the same effect at a concentration of 100 microM. The improved anti-tumoral activity of gemcitabine determined by the liposomal carrier was due to a greater intracellular uptake. The intracellular gemcitabine levels as a function of time showed a sinusoidal profile with peaks after 2 h, 6 h and 11 h, related to the cellular cycle of ARO. PARP cleavage and DNA fragmentation analysis provided clear evidence of the apoptosis induction in ARO cells by treatment with liposomally entrapped gemcitabine after 72 h incubation. Thus, gemcitabine-loaded liposomes may have a potential therapeutic relevance for the treatment of anaplastic thyroid carcinoma.     

Study of Nanostructured Array of Antidots Using Pulsed Magnetic Fields

The absence of the superparamagnetic limit in nanostructured antidots makes them strong candidates for ultra-high density recording media. In this work, nanoporous alumina templates (NpATs), with average pore diameters ～35 nm and separation ～100 nm, were grown using a two-step anodization method. A Ni₈₀Fe₂₀ thin film of 6.5 nm was then sputtered on top of such NpATs, building an antidot network. A detailed study of the magnetoresistance (MR) (fields up to 25 T and temperatures down to 77 K) was performed. The antidot network sample revealed an anomalous MR and R(T) behaviour at T _M ～250 K arising from a spin-flip transition occurring in a thin iron oxide layer.     

A crash-prediction model for road tunnels

Considerable research has been carried out into open roads to establish relationships between crashes and traffic flow, geometry of infrastructure and environmental factors, whereas crash-prediction models for road tunnels, have rarely been investigated. In addition different results have been sometimes obtained regarding the effects of traffic and geometry on crashes in road tunnels. However, most research has focused on tunnels where traffic and geometric conditions, as well as driving behaviour, differ from those in Italy. Thus, in this paper crash prediction-models that had not yet been proposed for Italian road tunnels have been developed. For the purpose, a 4-year monitoring period extending from 2006 to 2009 was considered. The tunnels investigated are single-tube ones with unidirectional traffic. The Bivariate Negative Binomial regression model, jointly applied to non-severe crashes (accidents involving material-damage only) and severe crashes (fatal and injury accidents only), was used to model the frequency of accident occurrence. The year effect on severe crashes was also analyzed by the Random Effects Binomial regression model and the Negative Multinomial regression model. Regression parameters were estimated by the Maximum Likelihood Method. The Cumulative Residual Method was used to test the adequacy of the regression model through the range of annual average daily traffic per lane. The candidate set of variables was: tunnel length (L), annual average daily traffic per lane (AADT_L), percentage of trucks (%Tr), number of lanes (N_L), and the presence of a sidewalk. Both for non-severe crashes and severe crashes, prediction-models showed that significant variables are: L, AADT_L, %Tr, and N_L. A significant year effect consisting in a systematic reduction of severe crashes over time was also detected. The analysis developed in this paper appears to be useful for many applications such as the estimation of accident reductions due to improvement in existing tunnels and/or to modifications of traffic control systems, as well as for the prediction of accidents when different tunnel design options are compared.     

Structural and dielectric properties of (001) and (111)-oriented BaZr0.2Ti0.8O3 epitaxial thin films

We have grown and characterized BaZr_0.2Ti_0.8O₃ (BZT) epitaxial thin films deposited on (001) and (111)-oriented SrRuO₃-buffered SrTiO₃ substrates by pulsed laser deposition. Structural and morphological characterizations were performed using X-ray diffractometry and atomic force microscopy, respectively. A cube-on-cube epitaxial relationship was ascertained from the θ-2θ and φ diffractograms in both (001) and (111)-oriented films. The (001)-oriented films showed a smooth granular morphology, whereas the faceted pyramid-like crystallites of the (111)-oriented films led to a rough surface. The dielectric response of BZT at room temperature was measured along the growth direction. The films were found to be ferroelectric, although a well-saturated hysteresis loop was obtained only for the (001)-oriented films. High leakage currents were observed for the (111) orientation, likely associated to charge transport along the boundaries of its crystallites. The remanent polarization, coercive field, dielectric constant, and relative change of dielectric permittivity (tunability) of (111)-oriented BZT were higher than those of (001)-oriented BZT.     

Estimation of the thickness and the optical parameters of several stacked thin films using optimization

The reverse engineering problem addressed in the present research consists of estimating the thicknesses and the optical constants of two thin films deposited on a transparent substrate using only transmittance data through the whole stack. No functional dispersion relation assumptions are made on the complex refractive index. Instead, minimal physical constraints are employed, as in previous works of some of the authors where only one film was considered in the retrieval algorithm. To our knowledge this is the first report on the retrieval of the optical constants and the thickness of multiple film structures using only transmittance data that does not make use of dispersion relations. The same methodology may be used if the available data correspond to normal reflectance. The software used in this work is freely available through the PUMA Project web page (http://www.ime.usp.br/~egbirgin/puma/).