A Strategy for Imidazotetrazine Prodrugs with Anti-cancer Activity Independent of MGMT and MMR

The imidazotetrazine ring is an acid-stable precursor and prodrug of highly-reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and have antitumor activity independent of the O6-methylguanine-DNA methyltransferase and DNA mismatch repair constraints that limit the use of temozolomide

Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from Hypotaurine

Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis, from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part this is due to the incorrect assignment, in 1962, of the enzyme as an NAD-dependent hypotaurine dehydrogenase. For more than 55 years the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase 1 (FMO1). Metabolite analysis of the urine of Fmo1-null mice by 1H NMR spectroscopy revealed a build-up of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that human FMO1 catalyzes the conversion of hypotaurine to taurine utilizing either NADPH or NADH as co-factor. FMO1 has a wide substrate range and is best known as a xenobiotic- or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1-catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biological processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, anti-oxidant and anti-inflammatory functions, and the pathogenesis of obesity and skeletal muscle disorders

Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumors. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in G1 supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies

Exciton localization mechanisms in wurtzite/zinc-blende GaAs nanowires

We investigate the emission properties of excitons in GaAs nanowires containing quantum disks formed by structural alternation between the zinc-blende and wurtzite phases, by means of temperature-dependent photoluminescence. At 10 K the emission from an ensemble of disks is distributed in a band of full width at half maximum ∼30 meV, whereas the emission linewidth for a single disk is 700 μeV. While the disk ensemble emission exhibits an S-shaped temperature dependence, the emission from single quantum disks follows the temperature dependence of the band gap over the whole temperature range. This indicates that intradisk exciton localization on impurities is negligible and that increasing the temperature induces a transfer of excitons from narrow to thick disks along the length of the wires. Our observations of the emission linewidth for single crystal-phase quantum disks show a scattering rate of excitons with acoustic phonons eight times larger than the values usually reported for (Al,Ga)As/GaAs quantum wells. This large scattering rate demonstrates that the electron effective mass in wurtzite GaAs is much heavier than in zinc-blende GaAs and is evidence of coupling between the Γ7 and Γ8 conduction bands of wurtzite GaAs.We acknowledge financial support from the Poynton Cambridge Australia Scholarship and from the European Union Seventh Framework Program under grant agreement No. 265073. A.F.iM. and E.U. acknowledge funding through the Marie Curie Excellence grant SENFED. S.C.B. thanks S.N.F. for funding through the Marie-Heim Vögtlin scheme

From the artificial atom to the Kondo-Anderson model: Orientation-dependent magnetophotoluminescence of charged excitons in InAs quantum dots

We present a magnetophotoluminescence study on neutral and charged excitons confined to InAs/GaAs quantum dots. Our investigation relies on a confocal microscope that allows arbitrary tuning of the angle between the applied magnetic field and the sample growth axis. First, from experiments on neutral excitons and trions, we extract the in-plane and on-axis components of the Landé tensor for electrons and holes in the s shell. Then, based on the doubly negatively charged exciton magnetophotoluminescence, we show that the p-electron wave function spreads significantly into the GaAs barriers. We also demonstrate that the p-electron g factor depends on the presence of a hole in the s shell. The magnetic field dependence of triply negatively charged excitons photoluminescence exhibits several anticrossings, as a result of coupling between the quantum dot electronic states and the wetting layer. Finally, we discuss how the system evolves from a Kondo-Anderson exciton description to the artificial atom model when the orientation of the magnetic field goes from Faraday to Voigt geometry.We acknowledge funding from the EPSRC. B.V.H. also thanks the Hitachi Cambridge Laboratory for additional fund- ing. P.C. acknowledges financial support from the European Union Seventh Framework Programme under Grant agreement No. 265073

Temperature-dependence of exciton radiative recombination in (Al,Ga)N/GaN quantum wells grown on a-plane GaN substrates

This article presents the dynamics of excitons in a-plane (Al,Ga)N/GaN single quantum wells of various thicknesses grown on bulk GaN substrates. For all quantum well samples, recombination is observed to be predominantly radiative in the low-temperature range. At higher temperatures, the escape of charge carriers from the quantum well to the (Al,Ga)N barriers is accompanied by a reduction in internal quantum efficiency. Based on the temperature-dependence of time-resolved photoluminescence experiments, we also show how the local disorder affects the exciton radiative lifetime at low temperature and the exciton non-radiative lifetime at high temperature.We acknowledge financial support from the Swiss National Science Foundation through Project No. 129715 and from the Polish National Science Center (Project DEC-2011/ 03/B/ST3/02647). The work was partially supported by the European Union within European Regional Development Fund through Innovative Economy Grant No. POIG.01.01.02-00-008/08. P.C. also acknowledges financing from the European Union Seventh Framework Program under grant agreement No. 265073

Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

BACKGROUND: The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. METHODS: CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. RESULTS: Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. CONCLUSION: In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC50 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 lM compared to 28.1 and 19.2 lM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml-1, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity

Insights from Australians with respiratory disease living in the community with experience of self-managing through an emergency department 'near miss' for breathlessness: A strengths-based qualitative study

© 2017 Article author(s). Objectives: Breathlessness 'crises' in people with chronic respiratory conditions are a common precipitant for emergency department (ED) presentations, many of which might be avoided through improved self-management and support. This study sought insights from people with experience of ED 'near misses' where they considered going to the ED but successfully self-managed instead. Design and methods: A qualitative approach was used with a phenomenological orientation. Participants: were eligible if they reported breathlessness on most days from a diagnosed respiratory condition and experience of ≥1 ED near miss. Recruitment was through respiratory support groups and pulmonary rehabilitation clinics. Semistructured interviews were conducted with each participant via telephone or face-to-face. Questions focused on ED-related decision-making, information finding, breathlessness management and support. This analysis used an integrative approach and independent coding by two researchers. Lazarus and Cohen's Transactional Model of Stress and Coping informed interpretive themes. Results: Interviews were conducted with 20 participants, 15 of whom had chronic obstructive pulmonary disease. Nineteen interviews were conducted via telephone. Analysis identified important factors in avoiding ED presentation to include perceived control over breathlessness, self-efficacy in coping with a crisis and desire not to be hospitalised. Effective coping strategies included: taking a project management approach that involved goal setting, monitoring and risk management; managing the affective dimension of breathlessness separately from the sensory perceptual and building three-way partnerships with primary care and respiratory services. Conclusions: In addition to teaching non-pharmacological and pharmacological management of breathlessness, interventions should aim to develop patients' generic self-management skills. Interventions to improve self-efficacy should ensure this is substantiated by transfer of skills and support, including knowledge about when ED presentation is necessary. Complementary initiatives are needed to improve coordinated, person-centred care. Future research should seek ways to break the cyclical relationship between affective and sensory-perceptual dimensions of breathlessness

Reversals in nature and the nature of reversals

The asymmetric shape of reversals of the Earth's magnetic field indicates a possible connection with relaxation oscillations as they were early discussed by van der Pol. A simple mean-field dynamo model with a spherically symmetric $\alpha$ coefficient is analysed with view on this similarity, and a comparison of the time series and the phase space trajectories with those of paleomagnetic measurements is carried out. For highly supercritical dynamos a very good agreement with the data is achieved. Deviations of numerical reversal sequences from Poisson statistics are analysed and compared with paleomagnetic data. The role of the inner core is discussed in a spectral theoretical context and arguments and numerical evidence is compiled that the growth of the inner core might be important for the long term changes of the reversal rate and the occurrence of superchrons.Comment: 24 pages, 12 figure