organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment

Abstract Selenium(Se)-containing compounds have attracted a growing interest as anticancer agents over recent decades, with mounting reports demonstrating their high efficacy and selectivity against cancer cells. Typically, Se compounds exert their cytotoxic effects by acting as pro-oxidants that alter cellular redox homeostasis. However, the precise intracellular targets, signalling pathways affected and mechanisms of cell death engaged following treatment vary with the chemical properties of the selenocompound and its metabolites, as well as the cancer model that is used. Naturally occurring organic Se compounds, besides encompassing a significant antitumor activity with an apparent ability to prevent metastasis, also seem to have fewer side effects and less systemic effects as reported for many inorganic Se compounds. On this basis, many novel organoselenium compounds have also been synthesized and examined as potential chemotherapeutic agents. This review aims to summarize the most well studied natural and synthetic organoselenium compounds and provide the most recent developments in our understanding of the molecular mechanisms that underlie their potential anticancer effects

Large scale copy number variation (CNV) at 14q12 is associated with the presence of genomic abnormalities in neoplasia

BACKGROUND: Advances made in the area of microarray comparative genomic hybridization (aCGH) have enabled the interrogation of the entire genome at a previously unattainable resolution. This has lead to the discovery of a novel class of alternative entities called large-scale copy number variations (CNVs). These CNVs are often found in regions of closely linked sequence homology called duplicons that are thought to facilitate genomic rearrangements in some classes of neoplasia. Recently, it was proposed that duplicons located near the recurrent translocation break points on chromosomes 9 and 22 in chronic myeloid leukemia (CML) may facilitate this tumor-specific translocation. Furthermore, ~15–20% of CML patients also carry a microdeletion on the derivative 9 chromosome (der(9)) and these patients have a poor prognosis. It has been hypothesised that der(9) deletion patients have increased levels of chromosomal instability. RESULTS: In this study aCGH was performed and identified a CNV (RP11-125A5, hereafter called CNV14q12) that was present as a genomic gain or loss in 10% of control DNA samples derived from cytogenetically normal individuals. CNV14q12 was the same clone identified by Iafrate et al. as a CNV. Real-time polymerase chain reaction (Q-PCR) was used to determine the relative frequency of this CNV in DNA from a series of 16 CML patients (both with and without a der(9) deletion) together with DNA derived from 36 paediatric solid tumors in comparison to the incidence of CNV in control DNA. CNV14q12 was present in ~50% of both tumor and CML DNA, but was found in 72% of CML bearing a der(9) microdeletion. Chi square analysis found a statistically significant difference (p ≤ 0.001) between the incidence of this CNV in cancer and normal DNA and a slightly increased incidence in CML with deletions in comparison to those CML without a detectable deletion. CONCLUSION: The increased incidence of CNV14q12 in tumor samples suggests that either acquired or inherited genomic variation of this new class of variation may be associated with onset or progression of neoplasia

FR II radio galaxies at low frequencies I : morphology, magnetic field strength and energetics

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. ©: 2016 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.Due to their steep spectra, low-frequency observations of FR II radio galaxies potentially provide key insights in to the morphology, energetics and spectrum of these powerful radio sources. However, limitations imposed by the previous generation of radio interferometers at metre wavelengths has meant that this region of parameter space remains largely unexplored. In this paper, the first in a series examining FR IIs at low frequencies, we use LOFAR observations between 50 and 160 MHz, along with complementary archival radio and X-ray data, to explore the properties of two FR II sources, 3C452 and 3C223. We find that the morphology of 3C452 is that of a standard FR II rather than of a double-double radio galaxy as had previously been suggested, with no remnant emission being observed beyond the active lobes. We find that the low-frequency integrated spectra of both sources are much steeper than expected based on traditional assumptions and, using synchrotron/inverse-Compton model fitting, show that the total energy content of the lobes is greater than previous estimates by a factor of around 5 for 3C452 and 2 for 3C223. We go on to discuss possible causes of these steeper than expected spectra and provide revised estimates of the internal pressures and magnetic field strengths for the intrinsically steep case. We find that the ratio between the equipartition magnetic field strengths and those derived through synchrotron/inverse-Compton model fitting remains consistent with previous findings and show that the observed departure from equipartition may in some cases provide a solution to the spectral versus dynamical age disparity.Peer reviewe

Organic Selenium Compounds as Oxidants in Cancer Therapy

Organic Selenium Compounds as Oxidants in Cancer Therap

Deletion of \u3ci\u3eShank1\u3c/i\u3e Has Minimal Effects on the Molecular Composition and Function of Glutamatergic Afferent Postsynapses in the Mouse Inner Ear

Abstract Shank proteins (1-3) are considered the master organizers of glutamatergic postsynaptic densities in the central nervous system, and the genetic deletion of either Shank1, 2, or 3 results in altered composition, form, and strength of glutamatergic postsynapses. To investigate the contribution of Shank proteins to glutamatergic afferent synapses of the inner ear and especially cochlea, we used immunofluorescence and quantitative real time PCR to determine the expression of Shank1, 2, and 3 in the cochlea. Because we found evidence for expression of Shank1 but not 2 and 3, we investigated the morphology, composition, and function of afferent postsynaptic densities from defined tonotopic regions in the cochlea of Shank1(-/-) mice. Using immunofluorescence, we identified subtle changes in the morphology and composition (but not number and localization) of cochlear afferent postsynaptic densities at the lower frequency region (8 kHz) in Shank1(-/-) mice compared to Shank1(+/+) littermates. However, we detected no differences in auditory brainstem responses at matching or higher frequencies. We also identified Shank1 in the vestibular afferent postsynaptic densities, but detected no differences in vestibular sensory evoked potentials in Shank1(-/-) mice compared to Shank1(+/+) littermates. This work suggests that Shank proteins play a different role in the development and maintenance of glutamatergic afferent synapses in the inner ear compared to the central nervous system

Chromosomal Localization of DNA Amplifications in Neuroblastoma Tumors Using cDNA Microarray Comparative Genomic Hybridization

Conventional comparative genomic hybridization (CGH) profiling of neuroblastomas has identified many genomic aberrations, although the limited resolution has precluded a precise localization of sequences of interest within amplicons. To map high copy number genomic gains in clinically matched stage IV neuroblastomas, CGH analysis using a 19,200-feature cDNA microarray was used. A dedicated (freely available) algorithm was developed for rapid in silico determination of chromosomal localizations of microarray cDNA targets, and for generation of an ideogram-type profile of copy number changes. Using these methodologies, novel gene amplifications undetectable by chromosome CGH were identified, and larger MYCN amplicon sizes (in one tumor up to 6 Mb) than those previously reported in neuroblastoma were identified. The genes HPCAL1, LPIN1/KIAA0188, NAG, and NSE1/LOC151354 were found to be coamplified with MYCN. To determine whether stage IV primary tumors could be further subclassified based on their genomic copy number profiles, hierarchical clustering was performed. Cluster analysis of microarray CGH data identified three groups: 1) no amplifications evident, 2) a small MYCN amplicon as the only detectable imbalance, and 3) a large MYCN amplicon with additional gene amplifications. Application of CGH to cDNA microarray targets will help to determine both the variation of amplicon size and help better define amplification-dependent and independent pathways of progression in neuroblastoma

Activation of BK and SK channels by efferent synapses on outer hair cells in high-frequency regions of the rodent cochlea

Cholinergic neurons of the brainstem olivary complex project to and inhibit outer hair cells (OHCs), refining acoustic sensitivity of the mammalian cochlea. In all vertebrate hair cells studied to date, cholinergic inhibition results from the combined action of ionotropic acetylcholine receptors and associated calcium-activated potassium channels. Although inhibition was thought to involve exclusively small conductance (SK potassium channels), recent findings have shown that BK channels also contribute to inhibition in basal, high-frequency OHCs after the onset of hearing. Here we show that the waveform of randomly timed IPSCs (evoked by high extracellular potassium) in high-frequency OHCs is altered by blockade of either SK or BK channels, with BK channels supporting faster synaptic waveforms and SK channels supporting slower synaptic waveforms. Consistent with these findings, IPSCs recorded from high-frequency OHCs that express BK channels are briefer than IPSCs recorded from low-frequency (apical) OHCs that do not express BK channels and from immature high-frequency OHCs before the developmental onset of BK channel expression. Likewise, OHCs of BKα(-/-) mice lacking the pore-forming α-subunit of BK channels have longer IPSCs than do the OHCs of BKα(+/+) littermates. Furthermore, serial reconstruction of electron micrographs showed that postsynaptic cisterns of BKα(-/-) OHCs were smaller than those of BKα(+/+) OHCs, and immunofluorescent quantification showed that efferent presynaptic terminals of BKα(-/-) OHCs were smaller than those of BKα(+/+) OHCs. Together, these findings indicate that BK channels contribute to postsynaptic function, and influence the structural maturation of efferent-OHC synapses

DNA binding, cleavage and cytotoxicity of a novel dimetallic Fe(III) triaza-cyclononane complex

A novel bimetallic Fe(III) complex with the bis(triaza-cyclononane) ligand 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol (bcmp) is reported. [Fe2{bcmp(-H)}(μ-OH)Cl2]Cl2 (2) contains two octahedral Fe(III) centers bound to the two triaza-cyclononane rings of bcmp. The coordination sphere is completed by one chlorine, one bridging phenolate oxygen and one bridging hydroxide group. The complex has been characterized by elemental analysis, Mössbauer spectroscopy, UV–Vis spectroscopy, pH potentiometric titration, ESI mass spectrometry and cyclic voltammetry. The complex hydrolyzes the DNA model bis(2,4-dinitrophenyl) phosphate (BDNPP) with a maximum activity a pH 7. Michaelis–Menten behavior is observed with kcat = 3.56 × 10−4 s−1 and Km = 0.56 mM (pH 7.0, 40 °C). The interaction of 2 with CT DNA was studied by electronic absorption spectroscopy and gel electrophoresis. Notably, the complex relaxes supercoiled pUC19 DNA into the nicked form at low micromolar concentration (10 μM) in the presence of an external reducing agent (ascorbic acid). Finally, the in vitro antiproliferative activity of 2 was assessed on a panel of human cancer cell lines and results revealed that the complex exhibited a significant cytotoxic effects in particular versus colon LoVo cancer cells, wih IC50 value 2.5 times lower than that shown by the reference metallodrug cisplatin (3.54 versus 8.53 μM)