Selenium supplementation acting through the induction of thioredoxin reductase and glutathione peroxidase protects the human endothelial cell line EAhy926 from damage by lipid hydroperoxides

AbstractThe human endothelial cell line EAhy926 was used to determine the importance of selenium in preventing oxidative damage induced by tert-butyl hydroperoxide (tert-BuOOH) or oxidised low density lipoprotein (LDLox). In cells grown in a low selenium medium, tert-BuOOH and LDLox killed cells in a dose-dependent manner. At 555 mg/l LDLox or 300 μM tert-BuOOH, >80% of cells were killed after 20 h. No significant cell kill was achieved by these agents if cells were pre-incubated for 48 h with 40 nM sodium selenite, a concentration that maximally induced the activities of cytoplasmic glutathione peroxidase (cyGPX; 5.1-fold), phospholipid hydroperoxide glutathione peroxidase (PHGPX;1.9-fold) and thioredoxin reductase (TR; 3.1-fold). Selenium-deficient cells pre-treated with 1 μM gold thioglucose (GTG) (a concentration that inhibited 25% of TR activity but had no inhibitory effect on cyGPX or PHGPX activity) were significantly (P<0.05) more susceptible to tert-BuOOH toxicity (LC50 110 μM) than selenium-deficient cells (LC50 175 μM). This was also the case for LDLox. In contrast, cells pre-treated with 40 nM selenite prior to exposure to GTG were significantly more resistant to damage from tert-BuOOH and LDLox than Se-deficient cells. Treatment with GTG or selenite had no significant effect on intracellular total glutathione concentrations. These results suggest that selenium supplementation, acting through induction of TR and GPX, has the potential to protect the human endothelium from oxidative damage

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

The Anti-social Behaviour, Crime and Policing Act 2014: implications for sex workers and their clients

© 2015 Taylor & Francis. The Anti-social Behaviour, Crime and Policing Act 2014 introduced new powers to deal with behaviour deemed to be ‘anti-social’. In this paper we consider how the new law could be used against sex workers and their clients and the impact this may have. Although the new powers were not intentionally designed to respond to prostitution, we suggest that they will be utilised to tackle it. We argue that the law will be used inconsistently in a way which will go directly against policy which seeks to ‘tackle demand’ and take a less punitive approach to dealing with sex workers. Despite a policy shift to see sex workers more as victims and less as offenders, we draw on existing evidence to demonstrate that the new anti-social behaviour order law will be utilised to exclude street sex workers from public spaces. We claim that a degree of ‘policy re-fraction’ will occur when the new laws are implemented by practitioners

STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

BACKGROUND: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. CONCLUSIONS: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

The Communist Party and the New Party

This is an Author's Accepted Manuscript of an article published in Contemporary British History, vol. 23(4), 2009, pp.477-491 copyright Taylor & Francis, available online at: http://www.tandfonline.com/doi/full/10.1080/13619460903198101The New Party was never at the centre of the concerns of the Communist Party of Great Britain (CPGB). However, the CPGB had to take a line on the new organisation when it was formed, and tried to use it to smear Labour and Independent Labour Party politicians as enemies of the working class. As the 1931 political crisis unfolded, the New Party became increasingly an irrelevance at the side of the much more tangible threat of the National government, although communists did campaign against Mosley in late 1931. Ultimately, the New Party was significant for the communists because it seemed to offer some vindication of the 'class against class' line; because it suggested that the CPGB was not always wrong in its analysis; because it led to increased attention to the party's youth movement; and because it led to the leading left-wing polemicist of the 1930s, John Strachey, working with the CPGB for almost a decade

Crop Updates 2002 - Lupins

This session covers twenty four papers from different authors: LUPIN INDUSTRY ISSUES AND RESEARCH DIRECTIONS ACKNOWLEDGMENTS Amelia McLarty LUPIN CONVENOR DEPARTMENT OF AGRICULTURE VARIETIES 1. Evaluation of lupinus mutabilis in Western Australia, Bob French, Laurie Wahlsten and Martin Harries, Department of Agriculture 2. Adaption of restricted-branching lupins in short-growing season environments, Bob French, Laurie Wahlsten, Department of Agriculture ESTABLISHMENT 3. Moisture delving for better lupin establishment, Dr Paul Blackwell, Department of Agriculture 4. Lupins, tramlines, 600mm rows, rolling and shield spraying … a good result in a dry season! Paul Blackwell and Mike Collins, Department of Agriculture 5. Lupin wider row spacing data and observations, Bill CrabtreeA, Geoff FosberyB, Angie RoeB, Mike CollinsCand Matt BeckettA,AWANTFA, BFarm Focus Consultants and CDepartment of Agriculture NUTRITION 6. Lupin genotypes respond differently to potash, Bob French and Laurie Wahlsten, Department of Agriculture 7. Consequence of radish competition on lupin nutrients in a wheat-lupin rotation, Abul Hashem and Nerys Wilkins, Department of Agriculture 8. Consequence of ryegrass competition on lupin nutrients in a wheat-lupin rotation, Abul Hashem and Nerys Wilkins, Department of Agriculture PESTS AND DISEASES 9. Fungicide sprays for control of lupin anthracnose, Geoff Thomas and Ken Adcock, Department of Agriculture 10. Estimated yield losses in lupin varieties from sowing anthracnose infected seed, Geoff Thomas, Department of Agriculture 11. Effect of variety and environment (northern and southern wheatbelt) on yield losses in lupins due to anthracnose, Geoff Thomas and Ken Adcock, Department of Agriculture, 12. A decision support system for the control of aphids and CMV in lupin crops, Debbie Thackray, Jenny Hawkes and Roger Jones, Centre for Legumes in Mediterranean Agriculture and Department of Agriculture 13. Integrated management strategies for virus diseases of lupin, Roger Jones, Crop Improvement Institute, Department of Agriculture, and Centre for Legumes in Mediterranean Agriculture, University of WA 14. Quantifying yield losses caused by the non-necrotic strain of BYMV in lupin, Roger Jones and Brenda Coutts, Department of Agriculture, and Centre for Legumes in Mediterranean Agriculture 15. Screening for pod resistance to phomopsis in various lupin species, Manisha Shankar1, Mark Sweetingham1&2and Bevan Buirchell2 1Co-operative Research Centre for Legumes in Mediterranean Agriculture, The University of Western Australia, 2 Department of Agriculture 16. Lupin disease diagnostics, Nichole Burges and Dominie Wright, Department of Agriculture QUALITY AND MARKET DEVELOPMENT 17. To GM or not to GM pulses – that is the question, Dr Susan J. Barker, The University of Western Australia 18. Towards a management package for grain protein in lupins, Bob French, Senior Research Officer, Department of Agriculture 19. Yield and seed protein response to foliar application of N among lupin genotypes, Jairo A Palta1&2, Bob French2&3and Neil C Turner1&2 , 1 CSIRO Plant Industry, Floreat Park, 2 CLIMA, University of Western Australia,3Department of Agriculture 20. Foliar nitrogen application to improve protein content in narrow-leafed lupin, Martin Harries, Bob French, Laurie Wahlsten, Department of Agriculture, Matt Evans, CSBP 21. Effect of time of swathing of lupins on grain protein content, Martin Harries, Department of Agriculture 22. Putting a value on protein premiums for the animal feed industries: Aquaculture, Brett Glencross and John Curnow, Department of Fisheries, Wayne Hawkins, Department of Agriculture 23. Progress in selecting for reduced seed hull and pod wall in lupin, Jon C. Clements, CLIMA, University of Western Australia 24. Contact details for principal author