A mechanistic study on the phototoxicity of atorvastatin: singlet oxygen generation by a phenanthrene-like photoproduct

Atorvastatin calcium (ATV) is one of the most frequently prescribed drugs worldwide. Among the adverse effects observed for this lipid-lowering agent, clinical cases of cutaneous adverse reactions have been reported and associated with photosensitivity disorders. Previous work dealing with ATV photochemistry has shown that exposure to natural sunlight in aqueous solution leads to photoproducts resulting from oxidation of the pyrrole ring and from cyclization to a phenanthrene derivative. Laser flash photolysis of ATV, at both 266 and 308 nm, led to a transient spectrum with two maxima at λ ) 360 and λ ) 580 nm (τ ) 41 μs), which was assigned to the primary intermediate of the stilbene-like photocyclization. On the basis of the absence of a triplet-triplet absorption, the role of the parent drug as singlet oxygen photosensitizer can be discarded. By contrast, a stable phenanthrene-like photoproduct would be a good candidate to play this role. Laser flash photolysis of this compound showed a triplet-triplet transient absorption at λmax ) 460 nm with a lifetime of 26 μs, which was efficiently quenched by oxygen (kq ) 3 ((0.2) × 109 M-1 s-1). Its potential to photosensitize formation of singlet oxygen was confirmed by spin trapping experiments, through conversion of TEMP to the stable free radical TEMPO. The photoreactivity of the phenanthrene-like photoproduct was investigated using Trp as a marker. The disappearance of the amino acid fluorescence (λmax ) 340 nm) after increasing irradiation times at 355 nm was taken as a measurement of photodynamic oxidation. To confirm the involvement of a type II mechanism, the same experiment was also performed in D2O; this resulted in a significant enhancement of the reaction rate. On the basis of the obtained photophysical and photochemical results, the phototoxicity of atorvastatin can be attributed to singlet oxygen formation with the phenanthrene-like photoproduct as a photosensitizer

Mode Confinement in Photonic Quasi-Crystal Point-Defect Cavities for Particle Accelerators

In this Letter, we present a study of the confinement properties of point-defect resonators in finite-size photonic-bandgap structures composed of aperiodic arrangements of dielectric rods, with special emphasis on their use for the design of cavities for particle accelerators. Specifically, for representative geometries, we study the properties of the fundamental mode (as a function of the filling fraction, structure size, and losses) via 2-D and 3-D full-wave numerical simulations, as well as microwave measurements at room temperature. Results indicate that, for reduced-size structures, aperiodic geometries exhibit superior confinement properties by comparison with periodic ones.Comment: 4 pages, 4 figures, accepted for publication in Applied Physics Letter

Reduced expression of THRβ in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression

Purpose Down-regulation of thyroid hormone receptor beta (THRβ) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRβ mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical–biological features. Methods Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRβ gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRβ. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. Results THRβ transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRβ expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. Conclusions Our results demonstrate that down-regulation of THRβ is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis

HYDRAULIC RISK ASSESSMENT IN ARCHAEOLOGICAL SITES SUPPORTED BY AN INTEGRATED DIGITAL SURVEY – CFD (COMPUTATIONAL FLUID DYNAMICS) MONITORING APPROACH

Abstract. This paper presents a methodological approach for analysing and evaluating hydraulic risks in complex archaeological areas, and thereby substantially improve general preservation and conservation efforts involving cultural heritage.The hypogeum of Calaforno (province of Ragusa, Sicily) represents a unique sample of rock-cut architecture in terms of size and architectural features, and an ideal candidate for the case study due to its high historical, archaeological and cultural significance, as well as its intrinsic fragility and criticality associated with hydrogeological and seismic factors.The interdisciplinary research approach involved archaeological and engineering contributions towards the development of numerical models for the assessment of hydraulic risks threatening archaeological heritage. The morphological characteristics of the site rendered the use of a Laser Scanner necessary for three-dimensional survey.The prehistoric structures currently undergoing excavation outside the main entrance of the monument have raised concerns regarding the impact of the Manna stream, which flows a few meters from the main entrance to the hypogeum, which has seen periodic flooding in some of its rooms. Simulations of these flooding events were performed in order to attain better understanding of the hydraulic phenomena influencing the site, especially regarding the dynamics associated with surface runoff.The interdisciplinary approach to this research, combining in-depth archaeological expertise with digital 3D surveying and modelling technologies, has proven fundamental to the effective monitoring of this morphologically complex site, and should perhaps be considered integral to any preventive assessment and risk management initiative involving cultural heritage

The role of endocannabinoids in gonadal function and fertility along the evolutionary axis.

Endocannabinoids are natural lipids able to bind to cannabinoid and vanilloid receptors. Their biological actions at the central and peripheral level are under the tight control of the proteins responsible for their synthesis, transport and degradation. In the last few years, several reports have pointed out these lipid mediators as critical signals, together with sex hormones and cytokines, in various aspects of animal and human reproduction. The identification of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in reproductive cells and tissues of invertebrates, vertebrates and mammals highlights the key role played by these endogenous compounds along the evolutionary axis. Here, we review the main actions of endocannabinoids on female and male reproductive events, and discuss the interplay between them, steroid hormones and cytokines in regulating fertility. In addition, we discuss the involvement of endocannabinoid signalling in ensuring a correct chromatin remodeling, and hence a good DNA quality, in sperm cells

Italian Health Care System: Methodology Suggestion for the Financial Equilibrium and Essential Level of Care

Italian Regions are the accountable entities for healthcare policies: their activity is not limited to policymaking but includes also management and financing of the Healthcare Public Utilities and services. A first step will be the creation of a dataset of revenues and expenditures of the Healthcare sector. Second, the cofinancing policy will be analyzed using comparative grids of in/out-flows of each Region. Third, it will be taken into account the regional fiscal coverage of the balance deficit. The sample is composed by the Italian Regions. Last the analysis between our theoretical approach based on law and the real economic balance. Furthermore it will be analyzed the National and Regional Healthcare System financing (in)-stability, highlighting current cash flows, sources and investments using the \u201cseparation\u201d of the Healthcare accounting items in the Balance Sheet. Through chi-square test analysis and method of OLS the group of study look a possible relation be-tween balance and respect of lea without finding a relationship. Latter, it will be represented an analysis of the National Health Fund allocation to the Regions. It will be also conducted a critical analysis of the current allocation formula and it will be proposed a simplified criterion of allocation

Catalytic oxygen production mediated by smart capsules to modulate elastic turbulence under a laminar flow regime

none11Liquid flow in microchannels is completely laminar and uniaxial, with a very low Reynolds number regime and long mixing lengths. To increase fluid mixing and solubility of reactants, as well as to reduce reaction time, complex three-dimensional networks inducing chaotic advection have to be designed. Alternatively, turbulence in the liquid can be generated by active mixing methods (magnetic, acoustic waves, etc.) or adding small quantities of elastic materials to the working liquid. Here, polyelectrolyte multilayer capsules embodying a catalytic polyoxometalate complex have been suspended in an aqueous solution and used to create elastic turbulence and to propel fluids inside microchannels as an alternative to viscoelastic polymers. The overall effect is enhanced and controlled by feeding the polyoxometalate-modified capsules with hydrogen peroxide, H2O2, thus triggering an on-demand propulsion due to oxygen evolution resulting from H2O2 decomposition. The quantification of the process is done by analysing some structural parameters of motion such as speed, pressure, viscosity, and Reynolds and Weissenberg numbers, directly obtained from the capillary dynamics of the aqueous mixtures with different concentrations of H2O2. The increases in fluid speed as well as the capsule-induced turbulence effects are proportional to the H2O2 added and therefore dependent on the kinetics of H2O2 dismutation.Zizzari A.; Bianco M.; Miglietta R.; del Mercato L. L.; Carraro M.; Soraru A.; Bonchio M.; Gigli G.; Rinaldi R.; Viola I.; Arima, V.Zizzari, A.; Bianco, M.; Miglietta, R.; del Mercato, L. L.; Carraro, M.; Soraru, A.; Bonchio, M.; Gigli, Giuseppe; Rinaldi, Rosaria; Viola, I.; Arima, V

Safety and activity of trastuzumab-containing therapies for the treatment of metastatic breast cancer: our long-term clinical experience (GOIM study).

Background: Trastuzumab is widely used as the treatment of choice for HER2-positive metastatic breast cancer (MBC). Patients and methods: Seventy patients, median age 57 years and range 31–81 years, were included in our retrospective analysis with the aim to evaluate safety and activity of trastuzumab-containing therapies. Results: We observed for first-line treatment response rate (RR) 41%, stable disease (SD) 47% and time to progression (TTP) 8 months (range 1–44). Corresponding numbers for second line were RR 23%, SD 62% and (TTP) 9 months (range 3–23) and beyond second line RR 22%, SD 78% and (TTP) 9 months (range 4–19). Overall survival was 19.2 months (3–62 months). The median cumulative dose of trastuzumab administrated was 5286 mg (464–17 940 mg). Trastuzumab was well tolerated. Median left ventricular ejection function (LVEF) at baseline was 62% and at the end of treatment was 59%. The more relevant adverse events consisted of an asymptomatic decrease in LVEF to 40% (baseline 60%) and a grade 3 symptomatic increase in bilirubin. Conclusion: Trastuzumab-containing therapies in MBC show a good safety and toxicity profile and a remarkable activity even in heavily pretreated women. Patients should benefit from continued trastuzumab therapy, as shown by the maintenance of (TTP) even beyond second-line treatment

Lapatinib/Paclitaxel polyelectrolyte nanocapsules for overcoming multidrug resistance in ovarian cancer.

The sonication-assisted layer-by-layer (SLBL) technology was developed to combine necessary factors for an efficient drug-delivery system: (i) control of nanocolloid size within 100 - 300 nm, (ii) high drug content (70% wt), (iii) shell biocompatibility and biodegradability, (iv) sustained controlled release, and (v) multidrug-loaded system. Stable nanocolloids of Paclitaxel (PTX) and lapatinib were prepared by the SLBL method. In a multidrug-resistant (MDR) ovarian cancer cell line, OVCAR-3, lapatinib/PTX nanocolloids mediated an enhanced cell growth inhibition in comparison with the PTX-only treatment. A series of in vitro cell assays were used to test the efficacy of these formulations. The small size and functional versatility of these nanoparticles, combined with their ability to incorporate various drugs, indicates that lapatinib/PTX nanocolloids may have in vivo therapeutic applications

Controle genético da reação do feijoeiro comum ao vírus do mosaico dourado.

O objetivo deste trabalho foi obter informações básicas sobre o controle genético da reação do feijoeiro comum ao VMDF que ocorre no Brasil. Foram realizados cinco cruzamentos entre linhagens/cultivares de feijoeiro comum envolvendo sempre um genitor como fonte de tolerância ao VMDF, previamente identificada, e outro, suscetível, como fonte de adaptação, e com características comerciais desejáveis.bitstream/CNPAF/23531/1/bolpesq_15.pd