Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM

Fighting Putin and the Kremlin’s grip in neo-authoritarian Russia: the experience of liberal journalists

Slavtcheva-Petkova, V. (2017). Fighting Putin and the Kremlin’s grip in neo-authoritarian Russia: the experience of liberal journalists. Journalism. Copyright © [2017]. Reprinted by permission of SAGE Publications.Russia is one of the most dangerous countries for journalists and the conflict with Ukraine and Russia’s involvement in Syria present even further challenges for the future of Russian journalism. In addition to the financial pressures, physical attacks, abductions and harassment, liberal journalists now face an increasing threat to the democratising role they see themselves as playing. President Vladimir Putin’s soaring popularity and the elaborate range of tactics used to suppress press freedom are forcing liberal media to rethink their mission(s) and identity(ies). This paper presents empirical evidence on the range of tactics used by Russian authorities as well as the coping strategies adopted by journalists. The study shows that some Russian media and journalists demonstrate a great degree of resilience in their efforts to expose wrongdoings and hold the powerful to account. The article questions the applicability of Western-centric normative media system theories because it shows that the breadth, depth, and mechanisms of control in modern-day Russia are very different from the ones used during Soviet times, and yet, Russian media and society do not appear to be on a linear journey from authoritarianism to democracy. The article presents the findings of a semi-ethnographic study of some of Russia’s most influential liberal news outlets – Novaya Gazeta, Radio Echo of Moscow and Radio Free Europe/Liberty. The study was conducted in May 2014 in the midst of the conflict with Ukraine. It involved observations of editorial meetings, documentary analysis and interviews with editors, deputy editors and journalists

Identification of Spt5 Target Genes in Zebrafish Development Reveals Its Dual Activity In Vivo

Spt5 is a conserved essential protein that represses or stimulates transcription elongation in vitro. Immunolocalization studies on Drosophila polytene chromosomes suggest that Spt5 is associated with many loci throughout the genome. However, little is known about the prevalence and identity of Spt5 target genes in vivo during development. Here, we identify direct target genes of Spt5 using fogsk8 zebrafish mutant, which disrupts the foggy/spt5 gene. We identified that fogsk8 and their wildtype siblings differentially express less than 5% of genes examined. These genes participate in diverse biological processes from stress response to cell fate specification. Up-regulated genes exhibit shorter overall gene length compared to all genes examined. Through chromatin immunoprecipitation in zebrafish embryos, we identified a subset of developmentally critical genes that are bound by both Spt5 and RNA polymerase II. The protein occupancy patterns on these genes are characteristic of both repressive and stimulatory elongation regulation. Together our findings establish Spt5 as a dual regulator of transcription elongation in vivo and identify a small but diverse set of target genes critically dependent on Spt5 during development

Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs

Inductively coupled plasma mass spectrometry hyphenated to capillary gas chromatography as a detection system for the speciation analysis of organolead compounds in environmental water

The application of an inductively coupled plasma mass spectrometry detection system to the speciation of organolead compounds in environmental waters is described. Derivatization was carried out by propylation with a Grignard reagent after extraction of the organolead compounds into hexane as their diethyldithiocarbamate complexes. This was followed by separation and detection with capillary gas chromatography and inductively coupled plasma mass spectrometry. Detection limits ranging from 10 fg (0.05 ng l(-1)) (as Pb) for trimethyllead to 16 fg (0.08 ng l(-1)) (as Ph) for diethyllead were achieved. The accuracy of the method was confirmed by additional analysis of the water samples with capillary gas chromatography coupled to microwave-induced plasma atomic emission spectrometry and by the analysis of a reference material from the Standards, Measurements & Testing Programme of the European Union