Redox control of multidrug resistance and Its possible modulation by antioxidants

Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed

The Ineludible non-Gaussianity of the Primordial Black Hole Abundance

We study the formation of primordial black holes when they are generated by the collapse of large overdensities in the early universe. Since the density contrast is related to the comoving curvature perturbation by a nonlinear relation, the overdensity statistics is unavoidably non-Gaussian. We show that the abundance of primordial black holes at formation may not be captured by a perturbative approach which retains the first few cumulants of the non-Gaussian probability distribution. We provide two techniques to calculate the non-Gaussian abundance of primordial black holes at formation, one based on peak theory and the other on threshold statistics. Our results show that the unavoidable non-Gaussian nature of the inhomogeneities in the energy density makes it harder to generate PBHs. We provide simple (semi-)analytical expressions to calculate the non-Gaussian abundances of the primordial black holes and show that for both narrow and broad power spectra the gaussian case from threshold statistics is reproduced by increasing the amplitude of the power spectrum by a factor ${\cal O}(2\div 3)$.Comment: 26 pages, 10 figures, matching published versio

Multi-wavelength observations of 3FGL J2039.6-5618: a candidate redback millisecond pulsar

We present multi-wavelength observations of the unassociated gamma-ray source 3FGL J2039.6-5618 detected by the Fermi Large Area Telescope. The source gamma-ray properties suggest that it is a pulsar, most likely a millisecond pulsar, for which neither radio nor $\gamma$-ray pulsations have been detected yet. We observed 3FGL J2039.6-5618 with XMM-Newton and discovered several candidate X-ray counterparts within/close to the gamma-ray error box. The brightest of these X-ray sources is variable with a period of 0.2245$\pm$0.0081 d. Its X-ray spectrum can be described by a power law with photon index $\Gamma_X =1.36\pm0.09$, and hydrogen column density $N_{\rm H} < 4 \times 10^{20}$ cm$^{-2}$, which gives an unabsorbed 0.3--10 keV X-ray flux of $1.02 \times 10^{-13}$ erg cm$^{-2}$ s$^{-1}$. Observations with the Gamma-Ray Burst Optical/Near-Infrared Detector (GROND) discovered an optical counterpart to this X-ray source, with a time-average magnitude $g'\sim 19.5$. The counterpart features a flux modulation with a period of 0.22748$\pm$0.00043 d that coincides, within the errors, with that of the X-ray source, confirming the association based on the positional coincidence. We interpret the observed X-ray/optical periodicity as the orbital period of a close binary system where one of the two members is a neutron star. The light curve profile of the companion star, with two asymmetric peaks, suggests that the optical emission comes from two regions at different temperatures on its tidally-distorted surface. Based upon its X-ray and optical properties, we consider this source as the most likely X-ray counterpart to 3FGL J2039.6-5618, which we propose to be a new redback system.Comment: 35 pages, 8 figures, accepted for publication on Astrophysical Journa

Insulin resistance and HCV virologic response to peg-interferons (Peg-IFN) with ribavirin (RBV) in HIV/HCV co-infected patients

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Covalency, double-counting and the metal-insulator phase diagram in transition metal oxides

Dynamical mean field theory calculations are used to show that for late transition-metal-oxides a critical variable for the Mott/charge-transfer transition is the number of d-electrons, which is determined by charge transfer from oxygen ions. Insulating behavior is found only for a narrow range of d-occupancy, irrespective of the size of the intra-d Coulomb repulsion. The result is useful in interpreting 'density functional +U' and 'density functional plus dynamical mean field' methods in which additional correlations are applied to a specific set of orbitals and an important role is played by the 'double counting correction' which dictates the occupancy of these correlated orbitals. General considerations are presented and are illustrated by calculations for two representative transition metal oxide systems: layered perovskite Cu-based "high-Tc" materials, an orbitally non-degenerate electronically quasi-two dimensional systems, and pseudocubic rare earch nickelates, an orbitally degenerate electronically three dimensional system. Density functional calculations yield d-occupancies very far from the Mott metal-insulator phase boundary in the nickelate materials, but closer to it in the cuprates, indicating the sensitivity of theoretical models of the cuprates to the choice of double counting correction and corroborating the critical role of lattice distortions in attaining the experimentally observed insulating phase in the nickelates.Comment: 10+ pages, 5 figure

Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing

Responding to Incorrect ISDS Decision-Making: Policy Options

Criticism of the quality of investor-State dispute settlement (ISDS) decision-making often focuses on inconsistency (comparing ISDS decisions), and less frequently, incorrectness (evaluating individual ISDS decisions on a standalone basis). This article situates incorrect ISDS decision-making within the broader context of public international law and develops potential policy responses, guided by three considerations. First, criticism of ISDS decision-making has been significant. Second, criticism of particular ISDS decisions, even when widespread and intense, does not necessarily establish their incorrectness. Finally, development of policy options should be informed by a broad understanding of ‘incorrectness’, to include instances of questionable legal analysis that cast doubt on the reliability of ISDS legal conclusions and outcomes; that approach can support not only the avoidance of incorrect ISDS decision-making in a strict sense, but also, more expansively, the achievement of correct ISDS decision-making, consisting of two core elements: correct identification and precise application of applicable law

Seasonal reproductive activity and innervation of vas deferens and accessory male genital glands in the water buffalo (Bubalus bubalis)

Autonomic nerves supplying mammalian male internal genital organs have an important role in the regulation of reproductive function. To find out the relationships between the neurochemical content of these nerves and the reproductive activity, we performed an immunohistochemical study in a species, the water buffalo, exhibiting a seasonal sexual behaviour. The distribution of noradrenergic and peptide-containing nerves was evaluated during the mating (autumn-winter) and non-mating (spring-summer) periods. During the mating period, a dense noradrenergic innervation was observed to supply the vas deferens as well as the accessory genital glands. Peptide-containing nerves were also observed but with a lower density. During the non-mating period noradrenergic nerves dramatically reduced. These results suggest that there is a neuro-endocrine interaction between androgen hormones and the autonomic nerve supply in the regulation of male water buffalo reproductive functions

Functional assessment of cancer therapy questionnaire for breast cancer (FACT-B+4): Italian version validation

BACKGROUND: Improvements in breast cancer diagnosis and treatment led to an increased incidence of survivors' rate. The healthcare system has to face new problems related not only to the treatment of the disease, but also to the management of the quality of life after the diagnosis. The aim of this study was to validate the Italian version of the Functional Assessment of Cancer Therapy - Breast (FACT-B+4) questionnaire and to evaluate its reliability. METHODS: The questionnaire was administered twice, with an interval of three days between each administration, to a cohort of women of the Breast Surgical Unit, PoliclincoUmberto I. Cronbach's alpha was used as a measure of the internal consistency of the Italian version. RESULTS: The Italian version of the tool was administered to 55 subjects. The Cronbach's alpha for most scores registered values >0.7, both at baseline and at the follow-up analysis, therefore the subscale showed good internal consistency. CONCLUSIONS: The Italian version of FACT-B+4 demonstrated acceptable reliability properties in the Breast Unit patients. The use of this questionnaire seemed to be effective and in line with the results derived from the English and Spanishversions. Internal consistency and validity had similar performance results

Additive manufacturing of Oxide Dispersion Strengthened (ODS) alloys

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