The multikinase inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo.

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15% of all pediatric cancer-related deaths. New therapies are needed to improve outcomes for children with high-risk and relapsed tumors. Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, suggesting that combined inhibition may have increased efficacy. RXDX-105 is a small molecule inhibitor of multiple kinases, including the RET and BRAF kinases. We found that treatment of neuroblastoma cells with RXDX-105 resulted in a significant decrease in cell viability and proliferation in vitro and in tumor growth and tumor vascularity in vivo. Treatment with RXDX-105 inhibited RET phosphorylation and phosphorylation of the MEK and ERK kinases in neuroblastoma cells and xenograft tumors, and RXDX-105 treatment induced both apoptosis and cell cycle arrest. RXDX-105 also showed enhanced efficacy in combination with 13-cis-retinoic acid, which is currently a component of maintenance therapy for children with high-risk neuroblastoma. Our results demonstrate that RXDX-105 shows promise as a novel therapeutic agent for children with high-risk and relapsed neuroblastoma

Modeling the Population Effects of Hypoxia on Atlantic Croaker (Micropogonias undulatus) in the Northwestern Gulf of Mexico: Part 2—Realistic Hypoxia and Eutrophication

Quantifying the population-level effects of hypoxia on coastal fish species has been challenging. In the companion paper (part 1), we described an individual-based population model (IBM) for Atlantic croaker in the northwestern Gulf of Mexico (NWGOM) designed to quantify the long-term population responses to low dissolved oxygen (DO) concentrations during the summer. Here in part 2, we replace the idealized hypoxia conditions with realistic DO concentrations generated from a 3-dimensional water quality model. Three years were used and randomly arranged into a time series based on the historical occurrence of mild, intermediate, and severe hypoxia year types.We also used another water quality model to generate multipliers of the chlorophyll concentrations to reflect that croaker food can be correlated to the severity of hypoxia. Simulations used 100 years under normoxia and hypoxia conditions to examine croaker population responses to the following: (1) hypoxia with food uncoupled and coupled to the severity of hypoxia, (2) hypoxia reducing benthos due to direct mortality, (3) how much hypoxia would need to be reduced to offset decreased croaker food expected under 25 and 50% reduction in nutrient loadings, and (4) key assumptions about avoidance movement. Direct mortality on benthos had no effect on long-term simulated croaker abundance, and the effect of hypoxia (about a 25% reduction in abundance) was consistent whether chlorophyll (food) varied with hypoxia or not. Reductions in hypoxia needed with a 25% reduction in nutrient loadings to result in minimal loss of croaker is feasible, and the croaker population will likely do as well as possible (approach abundance under normoxia) under the 50% reduction in nutrient loadings. We conclude with a discussion of why we consider our simulation-based estimates of hypoxia causing a 25% reduction the long-term population abundance of croaker in the NWGOM to be realistic and robust

Scalable Synthesis of 5,11-diethynylated Indeno[1,2-\u3cem\u3eb\u3c/em\u3e]fluorene-6,12-diones and Exploration of Their Solid State Packing

We report a new synthetic route to 5,11-disubstituted indeno[1,2-b]fluorene-6,12-diones that is amenable to larger scale reactions, allowing for the preparation of gram amounts of material. With this new methodology, we explored the effects on crystal packing morphology for the indeno[1,2-b]fluorene-6,12-diones by varying the substituents on the silylethynyl groups

Crop Updates 2009 - Farming Systems

This session covers nineteen papers from different authors: Decision support technology 1. The use of high resolution imagery in broad acre cropping, Derk Bakker and Grey Poulish, Department of Agriculture and Food 2. Spraywise decisions – online spray applicatiors planning tool, Steve Lacy, Nufarm Australia Ltd 3. Testing for redlegged earthmite resistance in Western Australia, Svetlana Micic, Peter Mangano, Tony Dore and Alan Lord, Department of Agriculture and Food 4. Screening cereal, canola and pasture cultivars for Root Lesion Nematode (Pratylenchus neglectus), Vivien Vanstone, Helen Hunter and Sean Kelly,Department of Agriculture and Food Farming Systems Research 5. Lessons from five years of cropping systems research, WK Anderson, Department of Agriculture and Food 6. Facey Group rotations for profit: Five years on and where to next? Gary Lang and David McCarthy, Facey Group, Wickepin, WA Mixed Farming 7. Saline groundwater use by Lucerne and its biomass production in relation to groundwater salinity, Ruhi Ferdowsian, Ian Roseand Andrew Van Burgel, Department of Agriculture and Food 8. Autumn cleaning yellow serradella pastures with broad spectrum herbicides – a novel weed control strategy that exploits delayed germination, Dr David Ferris, Department of Agriculture and Food 9. Decimating weed seed banks within non-crop phases for the benefit of subsequent crops, Dr David Ferris, Department of Agriculture and Food 10. Making seasonal variability easier to deal with in a mixed farming enterprise! Rob Grima,Department of Agriculture and Food 11. How widely have new annual legume pastures been adopted in the low to medium rainfall zones of Western Australia? Natalie Hogg, Department of Agriculture and Food, John Davis, Institute for Sustainability and Technology Policy, Murdoch University 12. Economic evaluation of dual purpose cereal in the Central wheatbelt of Western Australia, Jarrad Martin, Pippa Michael and Robert Belford, School of Agriculture and Environment, CurtinUniversity of Technology, Muresk Campus 13. A system for improving the fit of annual pasture legumes under Western Australian farming systems, Kawsar P Salam1,2, Roy Murray-Prior1, David Bowran2and Moin U. Salam2, 1Curtin University of Technology; 2Department of Agriculture and Food 14. Perception versus reality: why we should measure our pasture, Tim Scanlon, Department of Agriculture and Food, Len Wade, Charles Sturt University, Megan Ryan, University of Western Australia Modelling 15. Potential impact of climate changes on the profitability of cropping systems in the medium and high rainfall areas of the northern wheatbelt, Megan Abrahams, Chad Reynolds, Caroline Peek, Dennis van Gool, Kari-Lee Falconer and Daniel Gardiner, Department of Agriculture and Food 16. Prediction of wheat grain yield using Yield Prophet®, Geoff Anderson and Siva Sivapalan, Department of Agriculture and Food 17. Using Yield Prophet® to determine the likely impacts of climate change on wheat production, Tim McClelland1, James Hunt1, Zvi Hochman2, Bill Long3, Dean Holzworth4, Anthony Whitbread5, Stephen van Rees1and Peter DeVoil6 1 Birchip Cropping Group, Birchip, Vic, 2Agricultural Production Systems Research Unit (APSRU), CSIRO Sustainable Ecosystems, Climate Adaptation Flagship, Qld, 3 AgConsulting, SA 4 Agricultural Production Systems Research Unit (APSRU), CSIRO Sustainable Ecosystems, Toowoomba Qld, 5 CSIRO Sustainable Ecosystems, SA, 6 Agricultural Production Systems Research Unit (APSRU), Department of Agriculture and Fisheries, Queensland 18. Simple methods to predict yield potential: Improvements to the French and Schultz formula to account for soil type and within-season rainfall, Yvette Oliver, Michael Robertson and Peter Stone, CSIRO Sustainable Ecosystems 19. Ability of various yield forecasting models to estimate soil water at the start of the growing season, Siva Sivapalan, Kari-Lee Falconer and Geoff Anderson, Department of Agriculture and Foo

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy

BackgroundThough metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT.Patients and methodsWe assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases.ResultsA database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and > 1 (0, 1, and 2); 0, 1, and > 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung).ConclusionThis pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis.

BACKGROUND: There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO2) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO2, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO2 in context with a meta-analysis of published estimates of the association. METHODS AND FINDINGS: Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9-10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV1 in CHASE to estimate the prevalence of children with abnormal lung function (FEV1<80% of predicted value) expected under different scenarios of NO2 exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 μg/m3 increase in NO2 was associated with an 8 ml lower FEV1 (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 μg/m3 increase in NO2 level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function. CONCLUSIONS: Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function

Maine Won\u27t Wait One-Year Progress Report, 2021

This document, an “Maine Climate Science Update 2021”, is an interim communication to the Maine Climate Council and the public about the ongoing work of the scientific community and recent events associated with climate change. It is divided into three sections: (1) current events that reflect the acceleration of extreme weather events in Maine and elsewhere with possible connections to climate change; (2) noteworthy scientific reports with national and international scope released in 2021; and (3) examples of recent peer-reviewed publications from the ongoing work of the scientific community to understand climate change in Maine

Cognition in males and females with autism: similarities and differences

The male bias in autism spectrum conditions (ASC) has led to females with ASC being under-researched. This lack of attention to females could hide variability due to sex that may explain some of the heterogeneity within ASC. In this study we investigate four key cognitive domains (mentalizing and emotion perception, executive function, perceptual attention to detail, and motor function) in ASC, to test for similarities and differences between males and females with and without ASC (n = 128 adults; n = 32 per group). In the mentalizing and facial emotion perception domain, males and females with ASC showed similar deficits compared to neurotypical controls. However, in attention to detail and dexterity involving executive function, although males with ASC showed poorer performance relative to neurotypical males, females with ASC performed comparably to neurotypical females. We conclude that performance in the social-cognitive domain is equally impaired in male and female adults with ASC. However, in specific non-social cognitive domains, performance within ASC depends on sex. This suggests that in specific domains, cognitive profiles in ASC are modulated by sex

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently