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

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

Póster presentado en el 11th International Terroir Congress, celebrado en Willamette Valley, Oregon (Estados Unidos) del 10 al 14 de julio de 2016.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.Peer Reviewe

On farm agronomic and first environmental evaluation of oil crops for sustainable bioenergy chains

Energy crops, and in particular oil crops, could be an important occasion for developing new non food production rows for a new multi-functional agriculture in Italy. In this view, the use of local biomass is a fundamental starting point for the development of a virtuous energy chain that should pursue not only agricultural profitability, but also chain sustainability and that is less dependent on the global market, characterized by instability in terms of biomass availability and price. From this perspective, particular attention must be paid to crop choice on the basis of its rusticity and of its adaptability to local growing conditions and to low input cropping systems. In this context, alike woody and herbaceous biomasses, oil crops such as sunflower and rapeseed should be able to support local agricultural bioenergy chain in Italy. In addition, in a local bioenergy chain, the role of the farmers should not be limited just to grain production; but also grain processing should be performed at farm or consortium level in oilseed extraction plants well proportioned to the cropped surface. In this way, by means of a simple power generator, farmer could thus produce its own thermal and electric energy from the oil, maximizing his profit. This objective could also be achieved through the exploitation of the total biomass, including crop residues and defatted seed meals, that may be considered as fundamental additional economic and/or environmental benefits of the chain. This paper reports some results of three-years on-farm experiments on oil crop chain carried out in the framework of "Bioenergie" project, that was focused to enhance farmers awareness of these criteria and to the feasibility at open field scale of low-input cultivation of rapeseed, sunflower and Brassica carinata in seven Italian regions. In several on-farm experiences, these crops produced more than 800 kg ha-1 of oil with good energy properties. Defatted seed meals could be interesting as organic fertilizers and, in the case of B. carinata, as a biofumigant amendment that could offer a total or partial alternative to some chemicals in agriculture. Furthermore, biomass soil incorporation could contribute to C sequestration, catching CO2 from atmosphere and sinking a part in soil as stable humus. Finally, four different open field experiences carried out again in the second year of the project, have been analysed in order to evaluate their energy and greenhouse gasses balance after cultivation phase

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Restoring soil functionality in degraded areas within vineyards by organic treatments: the experimental layout of the RESOLVE Core-organic+ project

Degraded areas are frequent in vineyards, even if managed by organic farming, mainly caused by soil truncation, soil erosion, or salts enrichment. Recovering strategies implemented in 19 degraded vineyards in 5 countries within the RESOLVE project concerned: (i) composted organic amendments, or seeding of cover crops (including legumes) for (ii) green manure or (iii) dry mulch. The relationships between vineyard management and pedo-climatic conditions are useful to better understand other contributions dealing with RESOLVE project reported in the present special issue. The results suggested that the nature of degradation requires optimum seedbed preparation to grow green manure crops. Whereas dry mulching plants needs less tillage operations (neither incorporation nor sowing, if self-reseeding plants), helping the recovery of soil functionality. The potential soil erosion by water was esteemed for the 38 plots, confirming that is a common agent of land degradation in vineyards

A novel fully human antitumor ImmunoRNase resistant to the RNase inhibitor.

The ErbB2 tyrosine kinase receptor is an attractive target for immunotherapy, as it is overexpressed in many carcinomas. ImmunoRNases, made up of a human anti-ErbB2 scFv (single chain antibody fragment) and human RNases, have been engineered to overcome the limits of immunotoxins, made up of mouse antibodies and plant or bacterial toxins, such as immunogenicity and non-specific toxicity. Here we describe the construction and characterization of a second-generation anti-ErbB2 immunoRNase, called ERB-HP-DDADD-RNase, obtained by fusing Erbicin, a human ErbB2-directed scFv, with an inhibitor-resistant variant of human pancreatic RNase (HP-DDADD-RNase). This novel immunoRNase retains both the enzymatic activity of human pancreatic RNase and the specific binding of the parental scFv to ErbB2-positive cells, showing an affinity comparable with that of the previously reported parental immunoRNase (ERB-HP-RNase). Moreover, the novel immunoRNase is endowed with an effective and selective in vitro antiproliferative action for ErbB2-positive tumor cells, which is more potent than that of the parental immunoRNase on tumor cells expressing low levels of ErbB2, due to its resistance to the RNase inhibitor. Thus, the novel immunoRNase could represent a valuable tool for ErbB2-positive cancer therapy. © 2012 © The Author 2012

EFFECT OF ORGANIC TREATMENTS ON SOIL CARBON AND NITROGEN DYNAMICS IN VINEYARD((+))

WOS: 000435853000001The 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

Effects of a second-generation human anti-ErbB2 ImmunoRNase on trastuzumab-resistant tumors and cardiac cells

The inhibition of ErbB2 by the use of human antibodies can be a valuable strategy for the treatment of breast and gastric cancer. Trastuzumab, a humanized anti-ErbB2 antibody in clinical use, is effective but can engender resistance as well as cardiotoxicity. ImmunoRNases, made up of a human anti-ErbB2 scFv and human pancreatic ribonucleases (HP-RNases), have been engineered to overcome the limits of other immunotoxins, such as immunogenicity and nonspecific toxicity. Here, we report that a novel anti-ErbB2 immunoRNase, called Erb-HPDDADD-RNase, obtained by fusing Erbicin, a human ErbB2-directed scFv, with an HP-RNase variant that resists the cytosolic inhibitor protein, binds with high affinity to a panel of ErbB2-positive gastric tumor cells and inhibits their growth more than does the parental immunoRNase, which is not resistant to the inhibitor. Moreover, Erb-HP-DDADD-RNase is endowed with antiproliferative activity for trastuzumab-resistant cancer cells both in vitro and in vivo that is more potent than that of the parental immunoRNase. Importantly, Erb-HP-DDADD-RNase does not show cardiotoxic effects in vitro on human cardiomyocytes and does not impair cardiac function in a mouse model. Thus, Erb-HP-DDADD-RNase could fulfil the therapeutic need of cancer patients ineligible for trastuzumab treatment due to primary or acquired trastuzumab resistance or to cardiac dysfunction

A new biobased liquid formulation with biofumigant and fertilising properties for drip irrigation distribution

As an evolution of the solid materials for soil biofumigation, a new liquid product suitable for drip irrigation has been defined. A specific biotechnological formulation has been developed and patented to activate the potential biofumigant properties of defatted Brassica carinata seed meal. Through this process, sinigrin, the main glucosinolate contained in B. carinata, was almost completely hydrolysed to allyl isothiocyanate in about 30. min and released from the meal to the liquid fraction. The formulation was then suitable for distribution by drip irrigation after a simple filtration to remove the solid phase.The effect of this new formulation was tested in glasshouse conditions against the root-knot nematode, Meloidogyne incognita, and on Folsomia candida, a non target soil dwelling microarthropod, observing statistically significant dose-effect correlations clearly linked to the release of allyl isothiocyanate. © 2012 Elsevier B.V