Enhancement of Cytotoxicity by Combining Pyrenyl-Dendrimers and Arene Ruthenium Metallacages

Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyrGn) or alcohol (pyrGn-OH) (n = 1–3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, [Ru6(p-cymene) 6 (OO∩OO)3(tpt)2]6+ (OO∩OO = 5,8-dioxydo- 1,4-naphtaquinonato (donq) [1]6+ and 6,11-dioxydo-5,12- naphtacenedionato (dotq) [2]6+; tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host–guest properties of [guestC1]6+ and [guestC2]6+ were studied in solution by NMR and UV–vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water- soluble host–guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells

Precious metal carborane polymer nanoparticles: characterisation of micellar formulations and anticancer activity

YesWe report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] (1 and 2) in Pluronic® triblock copolymer P123 core–shell micelles. The spherical nanoparticles RuMs and OsMs, dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively). Complexes 1 and 2 were highly active towards A2780 human ovarian cancer cells (IC50 0.17 and 2.50 μM, respectively) and the encapsulated complexes, as RuMs and OsMs nanoparticles, were less potent (IC50 6.69 μM and 117.5 μM, respectively), but more selective towards cancer cells compared to normal cells.We thank the Leverhulme Trust (Early Career Fellowship no. ECF-2013-414 to NPEB), the University of Warwick (Grant no. RDF 2013-14 to NPEB), the Swiss National Science Foundation (Grant no. PA00P2_145308 to NPEB and PBNEP2_142949 to APB), the ERC (Grant no. 247450 to PJS), EPSRC (EP/G004897/ 1 to APB, and EP/F034210/1 to PJS), Institute of Advanced Study (IAS) – University of Warwick (Fellowship to JJSB), and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (055663/Z/98/Z) for funding to the Electron Microscopy Facility, School of Life Sciences, University of Warwick

Synthesis and controlled growth of osmium nanoparticles by electron irradiation

YesWe have synthesised osmium nanoparticles of defined size (1.5–50 nm) on a B- and S-doped turbostratic graphitic structure by electron-beam irradiation of an organometallic osmium complex encapsulated in self-spreading polymer micelles, and characterised them by transmission electron microscopy (TEM), high-resolution TEM (HRTEM), and atomic force microscopy (AFM) on the same grid. Oxidation of the osmium nanoparticles after exposure to air was detected by X-ray photoelectron spectroscopy (XPS).We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RD14102 to NPEB), the ERC (Grant No. 247450 to PJS), and the EPSRC (EP/F034210/1 to PJS). L.M.A.P., J.L., and G.C. acknowledge financial support from the EU through the ERC Consolidator Grant “VISUAL-MS”

Arene ruthenium dithiolato-carborane complexes for boron neutron capture theory (BNCT)

YesWe report the effect of low-energy thermal neutron irradiation on the antiproliferative activities of a highly hydrophobic organometallic arene ruthenium dithiolatoecarborane complex [Ru(p-cymene) (1,2- dicarba-closo-dodecarborane-1,2-dithiolato)] (1), and of its formulation in Pluronic® triblock copolymer P123 coreeshell micelles (RuMs). Complex 1 was highly active, with and without neutron irradiation, towards human ovarian cancer cells (A2780; IC50 0.14 mM and 0.17 mM, respectively) and cisplatinresistant human ovarian cancer cells (A2780cisR; IC50 0.05 and 0.13 mM, respectively). Complex 1 was particularly sensitive to neutron irradiation in A2780cisR cells (2.6 more potent after irradiation compared to non-irradiation). Although less potent, the encapsulated complex 1 as RuMs nanoparticles resulted in higher cellular accumulation (2.5 ), and was sensitive to neutron irradiation in A2780 cells (1.4 more potent upon irradiation compared to non-irradiation).We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RD14102 to NPEB), the University of Birmingham/EPSRC Follow-on- Fund (Grant No UOBFOF026 to BP), the ERC (Grant No. 247450 to PJS), EPSRC (EP/F034210/1 to PJS)

Online security assessment with load and renewable generation uncertainty: The iTesla project approach

The secure integration of renewable generation into modern power systems requires an appropriate assessment of the security of the system in real-time. The uncertainty associated with renewable power makes it impossible to tackle this problem via a brute-force approach, i.e. it is not possible to run detailed online static or dynamic simulations for all possible security problems and realizations of load and renewable power. Intelligent approaches for online security assessment with forecast uncertainty modeling are being sought to better handle contingency events. This paper reports the platform developed within the iTesla project for online static and dynamic security assessment. This innovative and open-source computational platform is composed of several modules such as detailed static and dynamic simulation, machine learning, forecast uncertainty representation and optimization tools to not only filter contingencies but also to provide the best control actions to avoid possible unsecure situations. Based on High Performance Computing (HPC), the iTesla platform was tested in the French network for a specific security problem: overload of transmission circuits. The results obtained show that forecast uncertainty representation is of the utmost importance, since from apparently secure forecast network states, it is possible to obtain unsecure situations that need to be tackled in advance by the system operator

Benchmarking and Validation of Cascading Failure Analysis Tools

Cascading failure in electric power systems is a complicated problem for which a variety of models, software tools, and analytical tools have been proposed but are difficult to verify. Benchmarking and validation are necessary to understand how closely a particular modeling method corresponds to reality, what engineering conclusions may be drawn from a particular tool, and what improvements need to be made to the tool in order to reach valid conclusions. The community needs to develop the test cases tailored to cascading that are central to practical benchmarking and validation. In this paper, the IEEE PES working group on cascading failure reviews and synthesizes how benchmarking and validation can be done for cascading failure analysis, summarizes and reviews the cascading test cases that are available to the international community, and makes recommendations for improving the state of the art

Fabrication of crystals from single metal atoms

YesMetal nanocrystals offer new concepts for the design of nanodevices with a range of potential applications. Currently the formation of metal nanocrystals cannot be controlled at the level of individual atoms. Here we describe a new general method for the fabrication of multi-heteroatom-doped graphitic matrices decorated with very small, ångström-sized, three-dimensional (3D)-metal crystals of defined size. We irradiate boron-rich precious-metal-encapsulated self-spreading polymer micelles with electrons and produce, in real time, a doped graphitic support on which individual osmium atoms hop and migrate to form 3D-nanocrystals, as small as 15 Å in diameter, within 1 h. Crystal growth can be observed, quantified and controlled in real time. We also synthesize the first examples of mixed ruthenium–osmium 3D-nanocrystals. This technology not only allows the production of ångström-sized homo- and hetero-crystals, but also provides new experimental insight into the dynamics of nanocrystals and pathways for their assembly from single atoms.We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RDF 2013-14 to NPEB), the Swiss National Science Foundation (Grant No. PA00P2_145308 to NPEB and PBNEP2_142949 to APB), the ERC (Grant No. 247450 to PJS), EPSRC (EP/G004897/1 to RKOR, and EP/F034210/1 to PJS) and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (Grant No. 055663/Z/98/Z) for funding the Electron Microscopy Facility, School of Life Sciences, University of Warwick. We also thank COST Action CM1105 for stimulating discussions, Thomas Wilks for supplying the micelle image for Figure 1, and the Australian Synchrotron and the University of Monash for allocation of time on the SAXS/ WAXS beamline and funding. The 2000FX Gatan Orius digital TEM camera used in this research was funded by Science City: Creating and Characterizing Next Generation Advanced Materials, with support from Advantage West Midlands and part funded by the European Regional Development Fund

Synthesis, characterisation, and in vitro anticancer activity of catalytically active indole-based half-sandwich complexes

YesThe synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD+ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes

Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) Complex

YesRuthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates.UF150295/Royal Society; University of Bradford; Government Department of Business, Energy and Industrial Strategy; SBF003\1170/British Heart Foundation Springboard Award; AMS_/Academy of Medical Sciences/United Kingdo

Perioperative mortality after hemiarthroplasty related to fixation method: A study based on the Australian Orthopaedic Association National Joint Replacement Registry

Background and purpose: The appropriate fixation method for hemiarthroplasty of the hip as it relates to implant survivorship and patient mortality is a matter of ongoing debate. We examined the influence of fixation method on revision rate and mortality.----- ----- Methods: We analyzed approximately 25,000 hemiarthroplasty cases from the AOA National Joint Replacement Registry. Deaths at 1 day, 1 week, 1 month, and 1 year were compared for all patients and among subgroups based on implant type.----- ----- Results: Patients treated with cemented monoblock hemiarthroplasty had a 1.7-times higher day-1 mortality compared to uncemented monoblock components (p < 0.001). This finding was reversed by 1 week, 1 month, and 1 year after surgery (p < 0.001). Modular hemiarthroplasties did not reveal a difference in mortality between fixation methods at any time point.----- ----- Interpretation: This study shows lower (or similar) overall mortality with cemented hemiarthroplasty of the hip