Anti-tumor activity of functionalized biomimetic magnetite nanoparticles produced in the presence of MamC protein of Magnetococcus marinus MC-1

Magnetite Nanoparticles (MNPs) find many applications, including biotechnology, as they can be manipulated by an external magnetic field and functionalized with different molecules. Magnetotactic bacteria bio-mineralize magnetosomes (membrane-enveloped magnetites), which are the ideal magnetic particle. However, scaling-up magnetosome production is still challenging, so bio-mimetics, i.e. in vitro magnetite synthesis mediated by magnetosome-associated proteins is being explored. Our group is working with MamC from Magnetococcus marinus MC-1 that controls the morphology and size of the crystals, producing well faceted Biomimetic Magnetic Nanoparticles (BMNPs) of ~40 nm, which are paramagnetic at room and body temperature while having a large magnetic moment per particle under an external magnetic field. These BMNPs were cytocompatible and biocompatible in vivo. BMNPs were functionalized (isothermal adsorption) with a monoclonal antibody (mAb) recognizing the ectodomain of the human Met/HGF receptor (overexpressed in many cancers) and the chemotherapeutic Doxorubicin (DOXO). The functionalized BMNPs present hyperthermia and were stable at physiological pH, while releasing the adsorbed DOXO at acidic pH. mAb functionalization of BMNPs favored their interaction with cells expressing the Met/HGFR and cellular DOXO uptake and toxicity, which was enhanced upon cell exposition to a continuous magnetic field. Real-time cytotoxicity of the BMNPs showed that DOXO-mAb-BMNPs were significantly more toxic than DOXO-BMNPs on Met/HGFR expressing cells, while no differential toxicity was observed on cells not expressing this receptor. When DOXO-BMNPs were injected intravenously in tumor bearing mice and an external magnetic field was applied there, a higher amount of BMNPs accumulated in the tumor and tumor growth was decreased in comparison to mice in which no magnetic field was applied. These BMNPs could thus represent effective nano-carriers for targeted drug delivery and might be combined with hyperthermia to increase efficiency, resulting in a targeted local treatment of tumors with a decrease in the deleterious systemic side effects

Phase IV open-label study of the efficacy and safety of deferasirox after allogeneic stem cell transplantation

This is the first prospective study of deferasirox in adult allogeneic hematopoietic stem cell transplant recipients with transfusional iron overload in hematologic malignancies. Patients at least six months post transplant were treated with deferasirox at a starting dose of 10 mg/kg/day for 52 weeks or until serum ferritin was less than 400 ng/mL on two consecutive occasions. Thirty patients were enrolled and 22 completed the study. A significant reduction from baseline in median serum ferritin and in liver iron concentration at 52 weeks was observed in the overall population: from 1440 to 755.5 ng/mL (P=0.002) and from 14.5 to 4.6 mg Fe/g dw (P=0.0007), respectively. Reduction in serum ferritin in patients who did not discontinue deferasirox therapy was significantly greater than that found in those who prematurely discontinued the treatment (from 1541 to 581 ng/mL vs. from 1416 to 1486 ng/mL; P=0.008). Drug-related adverse events, reported in 17 patients (56.7%), were mostly mild to moderate in severity. There were no drug-related serious adverse events. Twelve patients (40.0%) showed an increase of over 33% in serum creatinine compared to baseline and greater than the upper limit of normal on two consecutive visits. Two patients (6.7%) with active graft-versus-host disease showed an increase in alanine aminotransferase exceeding 10 times upper limit of normal; both resolved. In this prospective study, deferasirox provided a significant reduction in serum ferritin and liver iron concentration over one year of treatment in allogeneic hematopoietic stem cell transplant recipients with iron overload. In addition, the majority of adverse events related to deferasirox were mild or moderate in severity. (clinicaltrials.gov identifier:01335035)

Fine particle pH and the partitioning of nitric acid during winter in the northeastern United States

Particle pH is a critical but poorly constrained quantity that affects many aerosol processes and properties, including aerosol composition, concentrations, and toxicity. We assess PM1 pH as a function of geographical location and altitude, focusing on the northeastern U.S., based on aircraft measurements from the Wintertime Investigation of Transport, Emissions, and Reactivity campaign (1 February to 15 March 2015). Particle pH and water were predicted with the ISORROPIA-II thermodynamic model and validated by comparing predicted to observed partitioning of inorganic nitrate between the gas and particle phases. Good agreement was found for relative humidity (RH) above 40%; at lower RH observed particle nitrate was higher than predicted, possibly due to organic-inorganic phase separations or nitrate measurement uncertainties associated with low concentrations (nitrate \u3c 1 µg m−3). Including refractory ions in the pH calculations did not improve model predictions, suggesting they were externally mixed with PM1 sulfate, nitrate, and ammonium. Sample line volatilization artifacts were found to be minimal. Overall, particle pH for altitudes up to 5000 m ranged between −0.51 and 1.9 (10th and 90th percentiles) with a study mean of 0.77 ± 0.96, similar to those reported for the southeastern U.S. and eastern Mediterranean. This expansive aircraft data set is used to investigate causes in variability in pH and pH-dependent aerosol components, such as PM1 nitrate, over a wide range of temperatures (−21 to 19°C), RH (20 to 95%), inorganic gas, and particle concentrations and also provides further evidence that particles with low pH are ubiquitous

Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality

Objective: Higher serum melatonin levels have previously been found in patients with severe sepsis who died within 30 days of diagnosis than in survivors. The objective of our study were to determine whether serum melatonin levels during the first seven days of severe sepsis diagnosis could be associated with sepsis severity and mortality. Methods: Multicentre study in eight Spanish Intensive Care Units which enrolled 308 patients with severe sepsis. We determined serum levels of melatonin, malondialdehyde (as biomarker of lipid peroxidation) and tumor necrosis factor-alpha at days 1, 4 and 8 of severe sepsis diagnosis. The study's primary endpoint was 30-day mortality. Results: A total of 103 patients had died and 205 survived at 30 days of severe sepsis diagnosis, with the non-survivors presenting higher serum melatonin levels at days 1 (p<0.001), 4 (p<0.001) and 8 (p<0.001) of severe sepsis diagnosis than the survivor patient group. The multiple logistic regression analysis found that serum melatonin levels at days 1, 4 and 8 of severe sepsis diagnosis (p<0.001, p = 0.01 and p = 0.001, respectively) were associated with mortality adjusted for age, serum lactic acid, SOFA score and diabetes mellitus. Conclusions: The novel and more interesting findings of our study were that serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality. (C) 2017 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades lnfecciosas y Microbiologia Clinica

In vitro and in vivo anti-Trypanosoma cruzi activity of new arylamine Mannich base-type derivatives

Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity and with a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7 and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high anti-parasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent

Determination of radiation hardness of silicon diodes

In this paper, we describe an experiment aimed to measure the physical observables, which can be used for the assessment of the radiation hardness of commercially available silicon photo diodes commonly used as nuclear detectors in particle accelerator laboratories. The experiment adopted the methodology developed during the International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP No. F11016) “Utilization of Ion Accelerators for Studying and Modelling Ion Induced Radiation Defects in Semiconductors and Insulators”. This methodology is based on the selective irradiation of micrometer-sized regions with different fluences of MeV ions using an ion microbeam and on the measurement of the charge collection efficiency (CCE) degradation by Ion Beam Induced Charge (IBIC) microscopy performed in full depletion condition, using different probing ions. The IBIC results are analyzed through a theoretical approach based on the Shockley-Read-Hall model for the free carrier recombination in the presence of ion-induced deep traps. This interpretative model allows the evaluation of the material radiation hardness in terms of recombination parameters for both electrons and holes. The device under study in this experiment was a commercial p-i-n photodiode, which was initially characterized by i) standard electronic characterization techniques to determine its doping and ii) the Angle-Resolved IBIC to evaluate its effective entrance window. Nine regions of (100 × 100) µm2 were irradiated with 11.25 MeV He ions up to a maximum fluence of 3·1012 ions/cm2. The CCE degradation was measured by the IBIC technique using 11.25 MeV He and 1.4 MeV He as probing ions. The model presented here proved to be effective for fitting the experimental data. The fitting parameters correspond to the recombination coefficients, which are the key parameters for the characterization of the effects of radiation damage in semiconductors.</p

Spectroscopic Observations of Convective Patterns in the Atmospheres of Metal-Poor Stars

Convective line asymmetries in the optical spectrum of two metal-poor stars, Gmb1830 and HD140283, are compared to those observed for solar metallicity stars. The line bisectors of the most metal-poor star, the subgiant HD140283, show a significantly larger velocity span that the expectations for a solar-metallicity star of the same spectral type and luminosity class. The enhanced line asymmetries are interpreted as the signature of the lower metal content, and therefore opacity, in the convective photospheric patterns. These findings point out the importance of three-dimensional convective velocity fields in the interpretation of the observed line asymmetries in metal-poor stars, and in particular, urge for caution when deriving isotopic ratios from observed line shapes and shifts using one-dimensional model atmospheres. The mean line bisector of the photospheric atomic lines is compared with those measured for the strong Mg I b1 and b2 features. The upper part of the bisectors are similar, and assuming they overlap, the bottom end of the stronger lines, which are formed higher in the atmosphere, goes much further to the red. This is in agreement with the expected decreasing of the convective blue-shifts in upper atmospheric layers, and compatible with the high velocity redshifts observed in the chromosphere, transition region, and corona of late-type stars.Comment: 27 pages, LaTeX; 10 Figures (14 PostScript files); to be published in The Astrophysical Journa

Psychotic Alzheimer\u27s disease is associated with gender-specific tau phosphorylation abnormalities

Converging evidence suggests that psychotic Alzheimer\u27s disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of alpha-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration. (C) 2014 Elsevier Inc. All rights reserved