27 research outputs found

    The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer

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    © The Author 2015.Background: The management of NSCLC has been transformed by stratified medicine. The National Lung Matrix Trial (NLMT) is a UK-wide study exploring the activity of rationally selected biomarker/targeted therapy combinations. Patients and methods: The Cancer Research UK (CRUK) Stratified Medicine Programme 2 is undertaking the large volume national molecular pre-screening which integrates with the NLMT. At study initiation, there are eight drugs being used to target 18 molecular cohorts. The aim is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. A Bayesian adaptive design that gives a more realistic approach to decision making and flexibility to make conclusions without fixing the sample size was chosen. The screening platform is an adaptable 28-gene Nextera next-generation sequencing platform designed by Illumina, covering the range of molecular abnormalities being targeted. The adaptive design allows new biomarker-drug combination cohorts to be incorporated by substantial amendment. The pre-clinical justification for each biomarker-drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Discrete routes of pathway activation or inactivation determined by cancer genome aberrations are treated as separate cohorts. Key translational analyses include the deep genomic analysis of pre- and post-treatment biopsies, the establishment of patient-derived xenograft models and longitudinal ctDNA collection, in order to define predictive biomarkers, mechanisms of resistance and early markers of response and relapse. Conclusion: The SMP2 platform will provide large scale genetic screening to inform entry into the NLMT, a trial explicitly aimed at discovering novel actionable cohorts in NSCLC

    Crop Updates 2003 - Geraldton

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    This session covers twenty eight papers from different authors Seasonal Outlook: What is in store for 2003, David Stephens, Department of Agriculture Examining The Management Options For Wheat Crops In The Coming Season, James Fisher, Department of Agriculture GMO’s – what do they offer? Ian Edwards, Grain Bio Tech Australia Pty Ltd The Big Gamble – Wheat prices for 2003, Dennis Wise, Profarmer Market outlook for other grains, Andrew Young, General Manager Agricorp Stripe rust – where to now for the WA wheat industry? Robert Loughman, Ciara Beard and Greg Shea, Department of Agriculture Baudin and Hamlin – new generation of malting barley developed in Western Australia, Blakely Paynter, Roslyn Jettner and Kevin Young, Department of Agriculture DBM in Canola, Kevin Walden, Department of Agriculture The latest on Lupin diseases, Geoff Thomas, Department of Agriculture Wheat variety performance in 2002 compared to the long term, Robin Wilson, Iain Barclay, Robyn McLean, Robert Loughman, Jenny Garlinge, Bill Lambe, Neil Venn and Peter Clarke, Department of Agriculture Do wide rows drought proof lupins on red loam? Martin Harries, Bob French, Wayne Parker and Murray Blyth, Department of Agriculture Do wide rows drought proof lupins on a sandy loam? Martin Harries, Bob French, Wayne Parker and Murray Blyth, Department of Agriculture Profit Proving Precision Agriculture, Peter Norris, Agronomy For Profit, Greg Lyle, CSIRO Land and Water, Yuna Farm Improvement Group Annual ryegrass seedbanks: the good, the bad, and the ugly, Kathryn Steadman, University of Western Australia, Amander Ellery, CSIRO Plant Industry, Sally C Peltzer, Department of Agriculture Wheat management packages for low rainfall areas, Kari-Lee Falconer, Department of Agriculture Ground water 1. Atrazine, Russell Speed, Department of Agriculture Groundwater 2. Current Trends, Russell Speed, Department of Agriculture Herbicide tolerance of wheat, lupins and pastures, Terry Piper and Harmohinder Dhammu, Department of Agriculture Farming with Tramlines, Bindi Webb, Paul Blackwell, Department of Agriculture, Phil Logue, Binnu, Nigel Moffat, Geraldton, Rohan Ford, Binnu, Miles Obst, Mingenew, The role of green manure crops in renovating poor performing paddocks: What’s it worth? Frances Hoyle, Leanne Schulz and Judith Devenish Department of Agriculture The looming threat of wild radish, Peter Newman, Department of Agriculture Does one ‘size’ fit all? Grant Morrow, Syngenta Crop Protection Climate Forecasts on the Internet, Ian Foster and David Stephens, Department of Agriculture Moisture delving = more reliable lupin establishment, Paul Blackwell, and Wayne Parker, Department of Agriculture Tramline Designs for better Weed control and Wheat value from non-spraying tramlines in a dry season, Paul Blackwell, Bindi Webb and Darshan Sharma, Department of Agriculture Biserrula Grazing Trial, Marnie Thomas, Department of Agriculture Performance of IT and TT canola varieties in the medium and high rainfall agzones of W.A., 2001-02, Graham Walton, Hasan Zaheer and Paul Carmody, Department of Agriculture Rapid Catchment Appraisal in Northern Agricultural Region, Mike Clarke, Paul Raper, Department of Agricultur

    Towards a Personal Health Large Language Model

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    In health, most large language model (LLM) research has focused on clinical tasks. However, mobile and wearable devices, which are rarely integrated into such tasks, provide rich, longitudinal data for personal health monitoring. Here we present Personal Health Large Language Model (PH-LLM), fine-tuned from Gemini for understanding and reasoning over numerical time-series personal health data. We created and curated three datasets that test 1) production of personalized insights and recommendations from sleep patterns, physical activity, and physiological responses, 2) expert domain knowledge, and 3) prediction of self-reported sleep outcomes. For the first task we designed 857 case studies in collaboration with domain experts to assess real-world scenarios in sleep and fitness. Through comprehensive evaluation of domain-specific rubrics, we observed that Gemini Ultra 1.0 and PH-LLM are not statistically different from expert performance in fitness and, while experts remain superior for sleep, fine-tuning PH-LLM provided significant improvements in using relevant domain knowledge and personalizing information for sleep insights. We evaluated PH-LLM domain knowledge using multiple choice sleep medicine and fitness examinations. PH-LLM achieved 79% on sleep and 88% on fitness, exceeding average scores from a sample of human experts. Finally, we trained PH-LLM to predict self-reported sleep quality outcomes from textual and multimodal encoding representations of wearable data, and demonstrate that multimodal encoding is required to match performance of specialized discriminative models. Although further development and evaluation are necessary in the safety-critical personal health domain, these results demonstrate both the broad knowledge and capabilities of Gemini models and the benefit of contextualizing physiological data for personal health applications as done with PH-LLM.Comment: 72 page

    Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

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    Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

    Medieval Activity at Mill Lane, Leeming, North Yorkshire

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    Event-Related Potentials and Emotion Dysregulation

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    Emotion dysregulation is a common feature of many psychological disorders. To date, however, most research evaluating emotion regulation has been limited to self-report assessments. Event-related potentials (ERPs) are well suited to disentangle discrete aspects of emotional processing that are critical to understanding both healthy and aberrant emotional functioning. This chapter focuses on a particular ERP component, the late positive potential (LPP), and reviews evidence that the LPP is modulated by emotional content and is sensitive to various emotion regulation strategies. Next, studies leveraging the LPP to examine individual differences in emotional processing in the context of psychopathology are reviewed. Finally, this chapter discusses methodological limitations of past research and current gaps in our understanding, including suggestions for future research using ERPs to study emotion dysregulation.</p

    The Effects of Functional Groups and Missing Linkers on the Adsorption Capacity of Aromatic Hydrocarbons in UiO-66 Thin Films

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    The adsorption of benzene, toluene, ethylbenzene, and xylene isomers, also known as BTEX, from the gas phase into porous thin films of the metal–organic framework UiO-66-X, where X = H, NH2, and NO2, was measured to quantify adsorption capacity. The thin films were grown by a vapor-conversion method onto Au-coated quartz microbalance crystals. The MOF thin films were characterized by IR and Raman spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and scanning electron microscopy. The thin films were activated by heating under high vacuum and exposed to each gas to calculate the Henry’s constant. The results demonstrate that the functional groups in the organic linker and missing-linkers both play important roles in the adsorption capacity. Several trends can be observed in the data. First, all the compounds in the BTEX family have lower Henry’s constants in the UiO-66-H films compared to the UiO-66-NH2 and UiO-66-NO2 films, which can largely be attributed to the absence of a functional group on the linker. Second, at 25 °C, the Henry’s constants for all the BTEX compounds in UiO-66-NO2 films are larger than UiO-66-NH2 films. Third, the role of missing linkers is addressed by comparing the measured adsorption capacity to ideal pore filling. The results show that the UiO-66-H films are the most defect-free and the UiO-66-NO2 films have the most missing linker defects.</jats:p
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