Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Africa and the global carbon cycle

The African continent has a large and growing role in the global carbon cycle, with potentially important climate change implications. However, the sparse observation network in and around the African continent means that Africa is one of the weakest links in our understanding of the global carbon cycle. Here, we combine data from regional and global inventories as well as forward and inverse model analyses to appraise what is known about Africa's continental-scale carbon dynamics. With low fossil emissions and productivity that largely compensates respiration, land conversion is Africa's primary net carbon release, much of it through burning of forests. Savanna fire emissions, though large, represent a short-term source that is offset by ensuing regrowth. While current data suggest a near zero decadal-scale carbon balance, interannual climate fluctuations (especially drought) induce sizeable variability in net ecosystem productivity and savanna fire emissions such that Africa is a major source of interannual variability in global atmospheric CO(2). Considering the continent's sizeable carbon stocks, their seemingly high vulnerability to anticipated climate and land use change, as well as growing populations and industrialization, Africa's carbon emissions and their interannual variability are likely to undergo substantial increases through the 21st century

Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer

To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies. The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was studied over a range of doses against 12 pediatric tumor xenograft models. Pharmacokinetic, pharmacodynamic, and genomic studies were undertaken. In vitro neuroblastoma cell lines were generally more sensitive to MLN8237 than Ewing sarcoma lines. MLN8237 demonstrated significant activity in vivo against solid tumor models at the maximum tolerated dose (MTD); however, only 2 of 6 neuroblastoma models had objective responses at 0.25MTD. In contrast, MLN8237 induced objective responses at its MTD and at 0.5MTD in three ALL models and in two out of three at 0.25MTD. Pharmacokinetic studies at 0.5MTD demonstrated a T (max) of 0.5 h, C (max) of 24.8 mu M, AUC((0-24)) of 60.3 mu M h, and 12 h trough level of 1.2 mu M. Mitotic indices increased 6-12 h after MLN8237 administration. AURKA copy number variation was frequent in xenografts, and expression was highly correlated with copy number. Objective responses were more frequent in tumors with decreased AURKA copy number (5/8) compared to those with increased gene copy number (2/14). This report confirms the significant activity against both solid tumor and ALL xenografts at the MTD, with a steep dose response. These data support clinical development of MLN8237 in childhood cancer. Because of the steep dose-response relationship, such studies should target achieving trough levels of 1 mu M or higher for sustained periods of treatment

Assessing inter-sectoral climate change risks: the role of ISIMIP

The aims of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) are to provide a framework for the intercomparison of global and regional-scale risk models within and across multiple sectors and to enable coordinated multi-sectoral assessments of different risks and their aggregated effects. The overarching goal is to use the knowledge gained to support adaptation and mitigation decisions that require regional or global perspectives within the context of facilitating transformations to enable sustainable development, despite inevitable climate shifts and disruptions. ISIMIP uses community-agreed sets of scenarios with standardized climate variables and socio-economic projections as inputs for projecting future risks and associated uncertainties, within and across sectors. The results are consistent multi-model assessments of sectoral risks and opportunities that enable studies that integrate across sectors, providing support for implementation of the Paris Agreement under the United Nations Framework Convention on Climate Change

Insights into the evaluation and management of dyspepsia: recent developments and new guidelines

Dyspepsia is a very common gastrointestinal (GI) condition worldwide. We critically examine the recommendations of recently published guidelines for the management of dyspepsia, including those produced jointly by the American College of Gastroenterology and the Canadian Association of Gastroenterology, and those published by the UK National Institute for Health and Care Excellence. Dyspepsia is a symptom complex, characterized by a range of upper GI symptoms including epigastric pain or burning, early satiety, and post-prandial fullness. Although alarm features are used to help prioritize access to upper GI endoscopy, they are of limited utility in predicting endoscopic findings, and the majority of patients with dyspepsia will have no organic pathology identified at upper GI endoscopy. These patients are labelled as having functional dyspepsia (FD). The Rome IV criteria, which are used to define FD, further subclassify patients with FD as having either epigastric pain syndrome or post-prandial distress syndrome, depending on their predominant symptoms. Unfortunately, the Rome criteria perform poorly at identifying FD without the need for upper GI endoscopy. This has led to the investigation of alternative diagnostic approaches, including whether a capsaicin pill or combined serum biomarkers can accurately identify patients with FD. However, there is insufficient evidence to support either of these approaches at the present time. Patients with FD should be tested for H. pylori infection and be prescribed eradication therapy if they test positive. If they continue to have symptoms following this, then a trial of treatment with a proton pump inhibitor (PPI) should be given for up to 8 weeks. In cases where symptoms fail to adequately respond to PPI treatment, a tricyclic antidepressant may be of benefit, and should be continued for 6 to 12 months in patients who respond. Prokinetics demonstrate limited efficacy for treating FD, but could be considered if other strategies have failed. However, there are practical difficulties due to their limited availability in some countries and the risk of serious side effects. Patients with FD who fail to respond to drug treatments should be offered psychological therapy, where available. Overall, with the exception of recommendations relating to H. pylori testing and the prescription of PPIs, which are made on the basis of high-quality evidence, the evidence underpinning other elements of dyspepsia management is largely of low-quality. Consequently, there are still many aspects of the evaluation and management of dyspepsia that require further research

Natural climate solutions for the United States

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Science Advances 4 (2018): eaat1869, doi:10.1126/sciadv.aat1869.Limiting climate warming to <2°C requires increased mitigation efforts, including land stewardship, whose potential in the United States is poorly understood. We quantified the potential of natural climate solutions (NCS)—21 conservation, restoration, and improved land management interventions on natural and agricultural lands—to increase carbon storage and avoid greenhouse gas emissions in the United States. We found a maximum potential of 1.2 (0.9 to 1.6) Pg CO2e year−1, the equivalent of 21% of current net annual emissions of the United States. At current carbon market prices (USD 10 per Mg CO2e), 299 Tg CO2e year−1 could be achieved. NCS would also provide air and water filtration, flood control, soil health, wildlife habitat, and climate resilience benefits.This study was made possible by funding from the Doris Duke Charitable Foundation. C.A.W. and H.G. acknowledge financial support from NASA’s Carbon Monitoring System program (NNH14ZDA001N-CMS) under award NNX14AR39G. S.D.B. acknowledges support from the DOE’s Office of Biological and Environmental Research Program under the award DE-SC0014416. J.W.F. acknowledges financial support from the Florida Coastal Everglades Long-Term Ecological Research program under National Science Foundation grant no. DEB-1237517

Exploring subtle land use and land cover changes: a framework for future landscape studies

UMR AMAP, équipe 3International audienceLand cover and land use changes can have a wide variety of ecological effects, including significant impacts on soils and water quality. In rural areas, even subtle changes in farming practices can affect landscape features and functions, and consequently the environment. Fine-scale analyses have to be performed to better understand the land cover change processes. At the same time, models of land cover change have to be developed in order to anticipate where changes are more likely to occur next. Such predictive information is essential to propose and implement sustainable and efficient environmental policies. Future landscape studies can provide a framework to forecast how land use and land cover changes is likely to react differently to subtle changes. This paper proposes a four step framework to forecast landscape futures at fine scales by coupling scenarios and landscape modelling approaches. This methodology has been tested on two contrasting agricultural landscapes located in the United States and France, to identify possible landscape changes based on forecasting and backcasting agriculture intensification scenarios. Both examples demonstrate that relatively subtle land cover and land use changes can have a large impact on future landscapes. Results highlight how such subtle changes have to be considered in term of quantity, location, and frequency of land use and land cover to appropriately assess environmental impacts on water pollution (France) and soil erosion (US). The results highlight opportunities for improvements in landscape modelling

Effects of Elevated Temperature and Carbon Dioxide on the Growth and Survival of Larvae and Juveniles of Three Species of Northwest Atlantic Bivalves

Rising CO2 concentrations and water temperatures this century are likely to have transformative effects on many coastal marine organisms. Here, we compared the responses of two life history stages (larval, juvenile) of three species of calcifying bivalves (Mercenaria mercenaria, Crassostrea virginica, and Argopecten irradians) to temperatures (24 and 28°C) and CO2 concentrations (∼250, 390, and 750 ppm) representative of past, present, and future summer conditions in temperate estuaries. Results demonstrated that increases in temperature and CO2 each significantly depressed survival, development, growth, and lipid synthesis of M. mercenaria and A. irradians larvae and that the effects were additive. Juvenile M. mercenaria and A. irradians were negatively impacted by higher temperatures while C. virginica juveniles were not. C. virginica and A. irradians juveniles were negatively affected by higher CO2 concentrations, while M. mercenaria was not. Larvae were substantially more vulnerable to elevated CO2 than juvenile stages. These findings suggest that current and future increases in temperature and CO2 are likely to have negative consequences for coastal bivalve populations

The E-ELT first light spectrograph HARMONI: capabilities and modes

Trabajo presentado en SPIE Astronomical Telescopes, celebrado en San Diego (California), del 26 de junio al 1 de julio de 2016HARMONI is the E-ELT's first light visible and near-infrared integral field spectrograph. It will provide four different spatial scales, ranging from coarse spaxels of 60 × 30 mas best suited for seeing limited observations, to 4 mas spaxels that Nyquist sample the diffraction limited point spread function of the E-ELT at near-infrared wavelengths. Each spaxel scale may be combined with eleven spectral settings, that provide a range of spectral resolving powers (R 3500, 7500 and 20000) and instantaneous wavelength coverage spanning the 0.5 - 2.4 ¿m wavelength range of the instrument. In autumn 2015, the HARMONI project started the Preliminary Design Phase, following signature of the contract to design, build, test and commission the instrument, signed between the European Southern Observatory and the UK Science and Technology Facilities Council. Crucially, the contract also includes the preliminary design of the HARMONI Laser Tomographic Adaptive Optics system. The instrument's technical specifications were finalized in the period leading up to contract signature. In this paper, we report on the first activity carried out during preliminary design, defining the baseline architecture for the system, and the trade-off studies leading up to the choice of baseline