A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin

Ruthenium complexes are considered as potential replacements for platinum compounds in oncotherapy. Their clinical development is handicapped by a lack of consensus on their mode of action. In this study, we identify three histones (H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium compound (RDC11). Using purified histones, we confirmed an interaction between the ruthenium complex and histones that impacted on histone complex formation. A comparative study of the ruthenium complex versus cisplatin showed differential epigenetic modifications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modifications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures specific for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to specificities distinguishing the ruthenium complex from cisplatin. For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways. To further understand the role of HDACs in these regulations, we used suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin cytotoxicity while antagonizing the ruthenium complex activity. This study provides critical information for the characterization of signaling pathways differentiating both compounds, in particular, by the identification of a non-DNA direct target for an organoruthenium complex

Three cities – Lyon, Munich, Vienna – will be SMARTER TOGETHER

In September 2015, the cities of Lyon, Munich and Vienna and 28 partners from research and industry were awarded funding for a joint project proposal within the European „Smart City and Communities“ intiative. Under the headline „SMARTER TOGETHER“, the consortium applied for a volume of 25 Mio. EUR for the implementation of „smart“ and innovative actions in the three partner cities and for cooperation with three so called follower cities – Santiago de Compostela, Sofia und Venice. The requested funding is available as part of the EU-framework programme for research and innovation „Horizon 2020“. The funding is provided to support the implementation and testing of innovative Smart City solutions for low energy districts on a large scale and in an integrated way: Extensive energetic renewal of existing housing stock with (in Lyon and Munich) multi-faceted ownership structures, user-centered sustainable mobility solutions, innovative business models, generation of renewable energy and multiple use of infrastructure through the use of information- and communication technology (ICT). The overall aim is to improve the quality of life in neighbourhoods and to create more sustainable and user-friendly living environments. A particular focus will be on „smart“ and active forms of participation of citizens. The timeframe for the project roll-out is three years (2016-2018) followed by two years of monitoring and evaluation (2019-2020). Thereafter, successful solutions and findings are to be replicated in other districts and cities for further added value. Here, the follower cities Santiago de Compostela, Sofia and Venice as well as the European city network Energy Cities will play an important role. The projects will be implemented in close cooperation between industry, small and medium-sized enterprises, municipal companies, citizens and other interested stakeholders. The EU commission lauded the right balance between innovative technologies and the social dimension of the project: smart and integrated solutions shall improve the quality of life of citizens. The main challenge of Smarter Together is related to the so-called co-creation approach. All involved cities, research institutes and industrial partners as well as external stakeholders seek to jointly create solutions and methodologies for innovative and replicable city development, based on lessons learned and strong knowledge exchange. Therefore the project defrined a complex iterative peer-to-peer process, allowing for a constant knowledge exchange among all affected stakeholders

A retinoscopic survey of 333 horses and ponies in the UK

Introduction: Ophthalmic examination in the horse is generally limited to crude assessment of vision and screening for ocular lesions. The refractive state of equine eyes and the potential impact on vision and performance requires further investigation. Objective: To assess the refractive state of a large, mixed breed sample of horses and ponies in the United Kingdom (UK). Procedure: The refractive state of both eyes of 333 horses and ponies was determined by streak retinoscopy and the effect of age, height, gender, breed and management regime on the refractive state assessed. Results: The majority of eyes tested were emmetropic (83.63%), with 68.5% of horses having refractive errors of ≤ -0.50D or ≥ +0.50D. Refractive errors of greater than 1.50D (in either direction) were found in 2.7% of the eyes tested. Ametropic eyes included hyperopia (54%) and myopia (46%). Anisometropia was found in 30.3% of horses and ponies. Breed of horse/pony was the only factor that affected refractive state (in the left eye only, p<0.05) with 2 Thoroughbred crosses having a tendency towards myopia and Warmbloods / Shires towards hyperopia. Discussion / Conclusion: The retinoscopic survey found emmetropia to be the predominant refractive state of the equine eye with no evidence of an overall trend towards myopia or hyperopia. However, individual and breed related differences were found. Such factors should be considered in the selection of horses for sport and leisure, and when evaluating their performance potential. More comprehensive visual testing would be valuable in identifying underlying causes of behavioural problems

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors

Homology between p63 and p53 has suggested that these proteins might function similarly. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63+/- mice in both WT and p53-compromised backgrounds. We found that p63+/- mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53+/- mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53+/- mice. Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53

Holographic Traction Force Microscopy

Traction Force Microscopy (TFM) computes the forces exerted at the surface of an elastic material by measuring induced deformations in volume. It is used to determine the pattern of the adhesion forces exerted by cells or by cellular assemblies grown onto a soft deformable substrate. Typically, colloidal particles are dispersed in the substrate and their displacement is monitored by fluorescent microscopy. As with any other fluorescent techniques, the accuracy in measuring a particule’s position is ultimately limited by the number of evaluated fluorescent photons. Here, we present a TFM technique based on the detection of probe particle displacements by holographic tracking microscopy. We show that nanometer scale resolutions of the particle displacements can be obtained and determine the maximum volume fraction of markers in the substrate. We demonstrate the feasibility of the technique experimentally and measure the three-dimensional force fields exerted by colorectal cancer cells cultivated onto a polyacrylamide gel substrate

Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis

We have compiled the p73-mediated cell cycle arrest and apoptosis pathways. p73 is a member of the p53 family, consisting of p53, p63 and p73. p73 exists in several isoforms, presenting different domain structures. p73 functions not only as a tumor suppressor in apoptosis but also as differentiator in embryo development. p53 mutations are responsible for half of the human cancers; p73 can partially substitute mutant p53 as tumor suppressor. The pathways we assembled create a p73-centered network consisting of 53 proteins and 176 interactions. We clustered our network into five functional categories: Upregulation, Activation, Suppression, Transcriptional Activity and Degradation. Our literature searches led to discovering proteins (c-Jun and pRb) with apparent opposing functional effects; these indicate either currently missing proteins and interactions or experimental misidentification or functional annotation. For convenience, here we present the p73 network using the molecular interaction map (MIM) notation. The p73 MIM is unique amongst MIMs, since it further implements detailed domain features. We highlight shared pathways between p53 and p73. We expect that the compiled and organized network would be useful to p53 family-based studies