Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production

The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for INa inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity

Analysis of dynamic mechanical response in torsion

We investigate the dynamic response of industrial rubbers (styrene-butadiene random copolymers, SBR) in torsion and compare against common small amplitude oscillatory shear measurements by using a torsion rectangular fixture, a modified torsion cylindrical fixture, and a conventional parallel plate fixture, respectively, in two different rheometers (ARES 2kFRTN1 from TA Instruments, USA and MCR 702 from Anton Paar-Physica, Austria). The effects of specimen geometry (length-to-width aspect ratio) on storage modulus and level of clamping are investigated. For cylindrical specimens undergoing torsional deformation, we find that geometry and clamping barely affect the shear moduli, and the measurements essentially coincide with those using parallel plates. In contrast, a clear dependence of the storage modulus on the aspect ratio is detected for specimens having rectangular cross section. The empirical correction used routinely in this test is based on geometrical factors and can account for clamping effects, but works only for aspect ratios above a threshold value of 1.4. By employing a finite element analysis, we perform a parametric study of the effects of the aspect ratio in the cross-sectional stress distribution and the linear viscoelastic torsional response. We propose a new, improved empirical equation for obtaining accurate moduli values in torsion at different aspect ratios, whose general validity is demonstrated in both rheometers. These results should provide a guideline for measurements with different elastomers, for which comparison with dynamic oscillatory tests may not be possible due to wall slip issues

Effect of organic treatments on soil carbon and nitrogen dynamics in vineyard

The work aims to investigate the effects of different soil management strategies on carbon sequestration and total nitrogen in areas of vineyards suffering from loss of soil functionality. Treatments, selected for inter-row management, to re-install soil functionality were based on compost or other organic amendments (COMP), green manure (GM), and dry mulching (DM) strategies using winter legumes and cereals. Cover crops were seeded in fall and mown in late spring, leaved in the ground for mulching in DM or incorporated into the uppermost soil layers in GM. Such approaches were investigated in six vineyards in Italy, six in France, and two vineyards in Slovenia and Turkey. The results showed that COMP significantly increased total organic carbon (TOC) and total nitrogen (Ntot) in the topsoil after one year of application. Also DM tends to increase significantly TOC in the topsoil, but only after two years. Modelling 20-year carbon stock dynamics in Italy vineyards, the average increase resulted 0.49, 0.34, 0.21 and 0.03 Mg C ha-1 yr-1 for COMP, DM, GM and control, respectively

Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production

The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for INa inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity

Monitoring and mapping soil functionality in degraded areas of organic European vineyards

Soil malfunctioning, caused by an improper land preparation before vine plantation and/or management, is a common problem in European vineyards. Soil malfunctioning can include: reduced contribution of the soil fauna, poor organic matter content, imbalance nutritional status, altered pH, water deficiency, soil compaction and/or scarce oxygenation. To address these problems, ReSolVe, a transnational European research project, aimed at testing the effects of selected agronomic strategies for restoring optimal soil functionality in degraded areas within organic vineyard. The project involves 8 research groups in 6 different EU countries (Italy, Spain, France, Sweden, Slovenia, and Turkey) with experts from several disciplines including soil science, ecology, microbiology, grapevine physiology, viticulture, and biometry. The experimental vineyards are situated in Italy (Chianti hills and Maremma plain, Tuscany), Spain (La Rioja), France (Bordeaux and Languedoc), and Slovenia (Primorska) for winegrapes, and in Turkey (Adana and Mersin) for tablegrapes. Three different restoring strategies have been implemented: (i) compost, (ii) green manure with winter legumes, and (iii) dry mulching with cover crops. These strategies have being tested according to their efficiency to improve i) plant and root growth; and ii) grape yield and quality; optimize iii) the quality of soil ecosystem services; and iv) the terroir effect. The first activity of the project was characterizing and mapping the degraded areas within experimental vineyards. In the work we used non-invasive technologies to characterize soil and plant status. In Spanish and Italian vineyards, the delineation of degraded areas was performed by gamma-ray spectroscopy for topsoil, RGB machine vision for canopy status and thermography for plant water status. Gamma-ray spectroscopy measured continuously the natural gamma-ray emitted from the first 30-40 cm of soil, calculating the contribution of the main radionuclides (40K, 232Th, and 238U). The spectra of gamma-ray were able to provide information about mineralogy, texture, surficial stoniness and carbonates. RGB and thermal cameras were used to assess canopy porosity, leaf area exposure and vine water status of both degraded and non-degraded areas. All soil, canopy and water status parameters were mapped

Soil functionality assessment in degraded plots of vineyards

Land transformation to adapt fields to mechanization in perennial crop farming is a common practice which includes land levelling, deep ploughing, stone-breakage and clearing, application of fertilizers and amendments. Manipulation of the natural soil profile along its entire depth can severely disturb the naturally existing chemical physical,biological and hydrological equilibrium (Costantini and Barbetti, 2008; Costantini et al., 2013). The most common effects of the land transformation are mixing of soil horizons and soil truncation, which result in reduction of soil depth and available water, organic matter depletion, enrichment of calcium carbonate content in the topsoil,imbalance of some element ratio, and decline in the activity and diversity of soil biological communities involved in nutrient cycles. A decline in the capacity of soil to accommodate the soil-dwelling organisms causes a strong impact on several ecosystem services, in particular, the growth of the vine, the quality and quantity of the grapes,the production costs and the risk of erosion. These negative effects of a pre-planting mismanagement can occur simultaneously and interact to decrease soil fertility and grapevine performance (Lanyon et al., 2004; Tagliavini and Rombolà, 2001; Martínez-Casasnovas and Ramos, 2009).Since soil spatial variability is usually high, soil manipulations frequently result into reduced soil functionality and decline of soil ecosystem services in defined plots of the vineyards. Sometimes soil degradation in these areas is very high and compromises not only vine performance and crop yield, but also disease resistance of plants to diseases and their survival. The impact of improper soil manipulations in vineyards may be of particular concern, because vineyards are frequently located on marginal hillsides, which are sensitive to soil erosion and characterized by shallow soil depth (Ramos, 2006). This paper wants to show the assessment of soil functionality in degraded areas within two farms in Tuscany. This work reports the results of the first activities in Italian sites of the ReSolVe Core-organic+ project, aimed at restoring optimal Soil functionality in degraded areas within organic European vineyards

Effects of Lattice and Molecular Phonons on Photoinduced Neutral-to-Ionic Transition Dynamics in Tetrathiafulvalene-pp-Chloranil

For electronic states and photoinduced charge dynamics near the neutral-ionic transition in the mixed-stack charge-transfer complex tetrathiafulvalene-$p$-chloranil (TTF-CA), we review the effects of Peierls coupling to lattice phonons modulating transfer integrals and Holstein couplings to molecular vibrations modulating site energies. The former stabilizes the ionic phase and reduces discontinuities in the phase transition, while the latter stabilizes the neutral phase and enhances the discontinuities. To reproduce the experimentally observed ionicity, optical conductivity and photoinduced charge dynamics, both couplings are quantitatively important. In particular, strong Holstein couplings to form the highly-stabilized neutral phase are necessary for the ionic phase to be a Mott insulator with large ionicity. A comparison with the observed photoinduced charge dynamics indicates the presence of strings of lattice dimerization in the neutral phase above the transition temperature.Comment: 9 pages, 7 figures, accepted for publication in J. Phys. Soc. Jp

Abstracts of the Giornate di Coniglicoltura ASIC 2007

(2008). Abstracts of the Giornate di Coniglicoltura ASIC 2007. World Rabbit Science. 16(2). doi:10.4995/wrs.2008.634SWORD16

Nanoparticles synthesis in wet-operating stirred media: Preliminary investigation with DEM simulations

The growing demand of nanomaterials is pushing towards the development of alternative strategies for the safe and sustainable production of nanoparticles. At the same time, to ensure high performances, a fine control over the product specifications is required. We focused on a bottom-up method combined with a mechanical disaggregation technique using a wet bead-stirring process, since it provides numerous advantages over other approaches, including the minimization of the nanoparticles air dispersion and a greater control over the final product. However, given the broad variability of the parameters involved in both the setup and operation of the process, it is essential to combine the experiments with a theoretical-simulative study to optimize the design. The present activity consists in the preliminary simulation of the interactions among the grinding beads, modelled through the discrete element method (DEM), and the magnetic stirrer. This approach, providing information regarding the frequency and energy of collisions, which can be related to the properties of the produced nanoparticles, allows a fine tuning of the process parameters

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability