Developmental Context Determines Latency of MYC-Induced Tumorigenesis

One of the enigmas in tumor biology is that different types of cancers are prevalent in different age groups. One possible explanation is that the ability of a specific oncogene to cause tumorigenesis in a particular cell type depends on epigenetic parameters such as the developmental context. To address this hypothesis, we have used the tetracycline regulatory system to generate transgenic mice in which the expression of a c-MYC human transgene can be conditionally regulated in murine hepatocytes. MYC's ability to induce tumorigenesis was dependent upon developmental context. In embryonic and neonatal mice, MYC overexpression in the liver induced marked cell proliferation and immediate onset of neoplasia. In contrast, in adult mice MYC overexpression induced cell growth and DNA replication without mitotic cell division, and mice succumbed to neoplasia only after a prolonged latency. In adult hepatocytes, MYC activation failed to induce cell division, which was at least in part mediated through the activation of p53. Surprisingly, apoptosis is not a barrier to MYC inducing tumorigenesis. The ability of oncogenes to induce tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult somatic cells have evolved mechanisms to prevent individual oncogenes from initiating cellular growth, DNA replication, and mitotic cellular division alone, thereby preventing any single genetic event from inducing tumorigenesis

Realising the Ambition - Being Me : National Practice Guidance for Early Years in Scotland

Since 2013 there has been a determined focus by the Scottish Government to work towards realising the ambition for Scotland to be the best place for children to grow up in and learn. Changes to the Children and Young People (Scotland) Act 2014, have resulted in our youngest children, particularly those from birth to starting school, being at the heart of significant new developments. In 2014 Scottish Government started to increase the number of hours of funded provision to 600 hours for 3 and 4 year olds and some two year olds. The national practice guidance, “Building the Ambition” was commissioned at this time to complement the new policy developments and to support practitioners. The further expansion of funded Early Learning and Childcare (ELC) to 1140 hours per year for all 3 and 4 year olds, and for around a quarter of 2 year olds will be available from August 2020. This expansion to 1140 hours seeks not only to extend funded places, but to also improve the quality of our ELC provision across Scotland. We know that the earliest years of life are crucial for every child. Evidence tells us that, if our early learning and childcare offer is to help children fulfil their potential and contribute to closing the poverty related gap in children’s outcomes, it has to be high quality. To support the expansion it was decided to refresh the original Building the Ambition, incorporating and updating relevant aspects of the Pre-Birth to Three guidance and extending across the child’s learning journey into the early years of primary school. This new guidance, Realising the Ambition: Being Me, reflects the original principles and philosophy of Building the Ambition and complements the current policy direction of ELC and early primary education. It aspires to support practitioners in delivering what babies and young children need most and how we can most effectively deliver this in Scotland to give children the best start in life. The practice guidance aims to support anyone who works with and for babies and young children across all areas of Scotland. It has been designed to: build confidence and capability of those who work with children and families from pre-birth to starting school and beyond; make links between practice, theory and policy guidance to reinforce aspects of high quality provision and the critical role practitioners play; clarify some aspects of current practice and provide a reference which practitioners can easily use; support improvement and quality by encouraging discussion, self reflection and questioning about relevant practice in each setting, and; provide advice on achieving the highest quality of ELC and early primary provision that will enable young children to experience and to play their own part in Scotland being the best place in the world to grow up

Predicting outcome in acute stroke with large vessel occlusion:application and validation of MR PREDICTS in the ESCAPE-NA1 population

Background: Predicting outcome after endovascular treatment for acute ischemic stroke is challenging. We aim to investigate differences between predicted and observed outcomes in patients with acute ischemic stroke treated with endovascular treatment and to evaluate the performance of a validated outcome prediction score. Patients and methods: MR PREDICTS is an outcome prediction tool based on a logistic regression model designed to predict the treatment benefit of endovascular treatment based on the MR CLEAN and HERMES populations. ESCAPE-NA1 is a randomized trial of nerinetide vs. placebo in patients with acute stroke and large vessel occlusion. We applied MR PREDICTS to patients in the control arm of ESCAPE-NA1. Model performance was assessed by calculating its discriminative ability and calibration. Results: Overall, 556/1105 patients (50.3%) in the ESCAPE-NA1-trial were randomized to the control arm, 435/556 (78.2%) were treated within 6 h of symptom onset. Good outcome (modified Rankin scale 0–2) at 3 months was achieved in 275/435 patients (63.2%), the predicted probability of good outcome was 52.5%. Baseline characteristics were similar in the study and model derivation cohort except for age (ESCAPE-NA1: mean: 70 y vs. HERMES: 66 y), hypertension (72% vs. 57%), and collaterals (good collaterals, 15% vs. 44%). Compared to HERMES we observed higher rates of successful reperfusion (TICI 2b-3, ESCAPE-NA1: 87% vs. HERMES: 71%) and faster times from symptom onset to reperfusion (median: 201 min vs. 286 min). Model performance was good, indicated by a c-statistic of 0.76 (95%confidence interval: 0.71–0.81). Conclusion: Outcome-prediction using models created from HERMES data, based on information available in the emergency department underestimated the actual outcome in patients with acute ischemic stroke and large vessel occlusion receiving endovascular treatment despite overall good model performance, which might be explained by differences in quality of and time to reperfusion. These findings underline the importance of timely and successful reperfusion for functional outcomes in acute stroke patients.</p

Predicting outcome in acute stroke with large vessel occlusion:application and validation of MR PREDICTS in the ESCAPE-NA1 population

Background: Predicting outcome after endovascular treatment for acute ischemic stroke is challenging. We aim to investigate differences between predicted and observed outcomes in patients with acute ischemic stroke treated with endovascular treatment and to evaluate the performance of a validated outcome prediction score. Patients and methods: MR PREDICTS is an outcome prediction tool based on a logistic regression model designed to predict the treatment benefit of endovascular treatment based on the MR CLEAN and HERMES populations. ESCAPE-NA1 is a randomized trial of nerinetide vs. placebo in patients with acute stroke and large vessel occlusion. We applied MR PREDICTS to patients in the control arm of ESCAPE-NA1. Model performance was assessed by calculating its discriminative ability and calibration. Results: Overall, 556/1105 patients (50.3%) in the ESCAPE-NA1-trial were randomized to the control arm, 435/556 (78.2%) were treated within 6 h of symptom onset. Good outcome (modified Rankin scale 0–2) at 3 months was achieved in 275/435 patients (63.2%), the predicted probability of good outcome was 52.5%. Baseline characteristics were similar in the study and model derivation cohort except for age (ESCAPE-NA1: mean: 70 y vs. HERMES: 66 y), hypertension (72% vs. 57%), and collaterals (good collaterals, 15% vs. 44%). Compared to HERMES we observed higher rates of successful reperfusion (TICI 2b-3, ESCAPE-NA1: 87% vs. HERMES: 71%) and faster times from symptom onset to reperfusion (median: 201 min vs. 286 min). Model performance was good, indicated by a c-statistic of 0.76 (95%confidence interval: 0.71–0.81). Conclusion: Outcome-prediction using models created from HERMES data, based on information available in the emergency department underestimated the actual outcome in patients with acute ischemic stroke and large vessel occlusion receiving endovascular treatment despite overall good model performance, which might be explained by differences in quality of and time to reperfusion. These findings underline the importance of timely and successful reperfusion for functional outcomes in acute stroke patients.</p

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Crop Updates 2008 - Farming Systems

This session covers thirty nine papers from different authors: PLENARY 1. Developments in grain end use, Dr John de Majnik, New Grain Products, GRDC, Mr Paul Meibusch, New Farm Products and Services, GRDC, Mr Vince Logan, New Products Executive Manager, GRDC PRESENTATIONS 2. Global warming potential of wheat production in Western Australia: A life cycle assessment, Louise Barton1, Wahid Biswas2 and Daniel Carter3, 1School of Earth & Geographical Sciences, The University of Western Australia, 2Centre of Excellence in Cleaner Production, Division of Science and Engineering, Curtin University of Technology, 3Department of Agriculture and Food 3. How much fuel does your farm use for different farm operations? Nicolyn Short1, Jodie Bowling1, Glen Riethmuller1, James Fisher2 and Moin Salam1, 1Department of Agriculture and Food, 2Muresk Institute, Curtin University of Technology 4. Poor soil water storage and soil constraints are common in WA cropping soils, Stephen Davies, Jim Dixon, Dennis Van Gool and Alison Slade, Department of Agriculture and Food, Bob Gilkes, School of Earth and Geographical Sciences, University of Western Australia 5. Developing potential adaptations to climate change for low rainfall farming system using economic analysis tool. STEP, Megan Abrahams, Caroline Peek, Dennis Van Gool, Daniel Gardiner and Kari-Lee Falconer, Department of Agriculture and Food 6. What soil limitations affect the profitability of claying on non-wetting sandplain soils? David Hall1, Jeremy Lemon1, Harvey Jones1, Yvette Oliver2 and Tania Butler1, 1Department of Agriculture and Food, 2CSIRO Div Sustainable Ecology, Perth 7. Farming systems adapting to a variable climate; Two case studies, Kari-Lee Falconer, Department of Agriculture and Food 8. Importance of accounting for variation in crop yield potential when making fertiliser decisions, Michael Robertson and Yvette Oliver, CSIRO Sustainable Ecosystems, Floreat 9. Soil acidity is a widespread problem across the Avon River Basin, Stephen Carr1, Chris Gazey2, David York1 and Joel Andrew1, 1Precision SoilTech, 2Department of Agriculture and Food 10. The use of soil testing kits and ion-selective electrodes for the analysis of plant available nutrients in Western Australian soils, Michael Simeoni and Bob Gilkes School of Earth and Geographical Sciences, University of Western Australia 11. Redlegged earth mite resistance and integrated strategies for their control in Western Australia, Mangano G. Peter and Micic Svetlana, Department of Agriculture and Food 12. The economics of treating soil pH (liming), Chris Gazey, Steve Davies, Dave Gartner and Adam Clune, Department of Agriculture and Food, 13. Health benefits – A future differentiator for high value grains, Matthew Morell, Theme Leader, CSIRO Food Futures Flagship 14. Carbon in Sustralian cropping soils – We need to be realistic, Alan Umbers (M Rur Sc), GRDC/DAFF Sustainable Industries Initiative Project 15. AGWEST® Bartolo bladder clover (Trifolium spumosum) − a low cost annual pasture legume for the wheat/sheep zone, Angelo Loi, Brad Nutt and Clinton Revell, Department of Agriculture and Food 16. Maximising the value of point based soil sampling: Monitering trends in soil pH through time, Joel Andrew1, David York1, Stephen Carr1 and Chris Gazey2, 1Precision SoilTech, 2Department of Agriculture and Food 17. Improved crop root growth and productivity with deep ripping and deep placed lime, Stephen Davies1, Geoff Kew2*, Chris Gazey1, David Gartner1 and Adam Clune1, 1Department of Agriculture and Food, 2School of Earth and Geographical Sciences University of Western Australia, *Presenting author 18. The role of pastures in hosting Root Lesion Nematode (RLN, Pratylenchus neglectus), Vivien Vanstone, Ali Bhatti and Ming Pei You, Department of Agriculture and Food 19. To rip or not to rip. When does it pay? Imma Farre, Bill Bowden and Stephen Davies, Department of Agriculture and Food 20. Can yield be predicted from remotely sensed data, Henry Smolinski, Jane Speijers and John Bruce, Department of Agriculture and Food 21. Rotations for profit, David McCarthy and Gary Lang, Facey Group, Wickepin, WA 22. Rewriting rules for the new cropping economics, David Rees, Consultant, Albany 23. Reducing business risk in Binnu! – A case study, Rob Grima, Department of Agriculture and Food 24. Does improved ewe management offer grain farmers much extra profit? John Young, Farming Systems Analysis Service, Ross Kingwell, Department of Agriculture and Food, and UWA, Chris Oldham, Department of Agriculture and Food RESEARCH HIGHLIGHTS 25. Crop establishment and productivity with improved root zone drainage, Dr Derk Bakker, Research Officer, Department of Agriculture and Food 26. Will wheat production in Western Australia be more risky in the future? Imma Farre and Ian Foster, Department of Agriculture and Food PAPERS 27. Building farmers’ adaptive capacity to manage seasonal variability and climate change, David Beard, Department of Agriculture and Food 28. Precision placement increases crop phosphorus uptake under variable rainfall: Simulation studies, Wen Chen1 2, Richard Bell1, Bill Bowden2, Ross Brennan2, Art Diggle2 and Reg Lunt2, 1School of Environmental Science, Murdoch University, 2Department of Agriculture and Food 29. What is the role of grain legumes on red soil farms? Rob Grima, Department of Agriculture and Food 30. Fertiliser placement influences plant growth and seed yield of grain crops at different locations of WA, Qifu Ma1, Zed Rengel1, Bill Bowden2, Ross Brennan2, Reg Lunt2 and Tim Hilder2, 1Soil Science & Plant Nutrition, University of Western Australia, 2Department of Agriculture and Food 31. A review of pest and disease occurrences for 2007, Peter Mangano and Dusty Severtson, Department of Agriculture and Food 32. Effect of stocking rates on grain yield and quality of wheat in Western Australia in 2007, Shahajahan Miyan, Sam Clune, Barb Sage and Tenielle Martin, Department of Agriculture and Food 33. Storing grain is not ‘set and forget’ management, Chris Newman, Department of Agriculture and Food 34. Improving understanding of soil plant available water capacity (PAWC): The WA soil water database (APSoil), Yvette Oliver, Neal Dalgliesh and Michael Robertson, CSIRO Sustainable Ecosystems 35. The impact of management decisions in drought on a low rainfall northern wheatbelt farm, Caroline Peek and Andrew Blake, Department of Agriculture and Food 37. Cullen – A native pasture legume shows promise for the low-medium rainfall cropping zone, Megan Ryan, Richard Bennett, Tim Colmer, Daniel Real, Jiayin Pang, Lori Kroiss, Dion Nicol and Tammy Edmonds-Tibbett, School of Plant Biology, The University of Western Australia and Future Farm Industries CRC 38. Climate risk management tools – useful, or just another gadget? Lisa Sherriff, Kari-Lee Falconer, Daniel Gardiner and Ron McTaggart Department of Agriculture and Food 39. Benefits of crop rotation for management of Root Lesion Nematode (RLN, Pratylenchus neglectus), Vivien Vanstone, Sean Kelly and Helen Hunter, Department of Agriculture and Foo

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation