bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy
Authors: Clémenson Céline , Chargari Cyrus , Liu Winchygn , Mondini Michele , Ferté Charles , Burbridge Mike F. , Cattan Valérie , Jacquet-Bescond Anne , Deutsch Eric 
Published: June 2017

Abstract
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non–small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo. In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107–19. ©2017 AACR.
Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity
Authors: Zhang Xiuli , Kim Samuel , Hundal Jasreet , Herndon John M. , Li Shunqiang , Petti Allegra A. , Soysal Savas D. , Li Lijin , McLellan Mike D. , Hoog Jeremy , Primeau Tina , Myers Nancy , Vickery Tammi L. , Sturmoski Mark , Hagemann Ian S. , Miller Chris A. , Ellis Matthew J. , Mardis Elaine R. , Hansen Ted , Fleming Timothy P. , Goedegebuure S. Peter , Gillanders William E. 
Published: June 2017

Abstract
Next-generation sequencing technologies have provided insights into the biology and mutational landscape of cancer. Here, we evaluate the relevance of cancer neoantigens in human breast cancers. Using patient-derived xenografts from three patients with advanced breast cancer (xenografts were designated as WHIM30, WHIM35, and WHIM37), we sequenced exomes of tumor and patient-matched normal cells. We identified 2,091 (WHIM30), 354 (WHIM35), and 235 (WHIM37) nonsynonymous somatic mutations. A computational analysis identified and prioritized HLA class I–restricted candidate neoantigens expressed in the dominant tumor clone. Each candidate neoantigen was evaluated using peptide-binding assays, T-cell cultures that measure the ability of CD8+ T cells to recognize candidate neoantigens, and preclinical models in which we measured antitumor immunity. Our results demonstrate that breast cancer neoantigens can be recognized by the immune system, and that human CD8+ T cells enriched for prioritized breast cancer neoantigens were able to protect mice from tumor challenge with autologous patient-derived xenografts. We conclude that next-generation sequencing and epitope-prediction strategies can identify and prioritize candidate neoantigens for immune targeting in breast cancer. Cancer Immunol Res; 5(7); 516–23. ©2017 AACR.
Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension
Authors: Tojais Nancy F. , Cao Aiqin , Lai Ying-Ju , Wang Lingli , Chen Pin-I , Alcazar Miguel A. Alejandre , de Jesus Perez Vinicio A. , Hopper Rachel K. , Rhodes Christopher J. , Bill Matthew A. , Sakai Lynn Y. , Rabinovitch Marlene 
Published: June 2017

Objective—
We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.

Approach and Results—

Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with
Bmpr2/1a
compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a
BMPR2
mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in
BMPR2
mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In
Bmpr2/1a
heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension.

Conclusions—
Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.
Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study
Authors: Seyednasrollah Fatemeh , Mäkelä Johanna , Pitkänen Niina , Juonala Markus , Hutri-Kähönen Nina , Lehtimäki Terho , Viikari Jorma , Kelly Tanika , Li Changwei , Bazzano Lydia , Elo Laura L. , Raitakari Olli T. 
Published: June 2017

Background—
Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods.

Methods and Results—

A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3–18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744,
P
<0.0001) and validation data (AUC=0.769 versus AUC=0.747,
P
=0.026). WGRS97 improved the accuracy in training (AUC=0.782 versus AUC=0.744,
P
<0.0001) but not in validation data (AUC=0.749 versus AUC=0.747,
P
=0.785). Higher WGRS19 associated with higher body mass index at 9 years and WGRS97 at 6 years. Replication in BHS confirmed our findings that WGRS19 and WGRS97 are associated with body mass index.

Conclusions—
WGRS19 improves prediction of adulthood obesity. Predictive accuracy is highest among young children (3–6 years), whereas among older children (9–18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity.
Referral to Cardiac Rehabilitation After Percutaneous Coronary Intervention, Coronary Artery Bypass Surgery, and Valve Surgery
Authors: Beatty Alexis L. , Bradley Steven M. , Maynard Charles , McCabe James M. 
Published: June 2017

Background—
Despite guideline recommendations that patients undergoing percutaneous coronary intervention (PCI), coronary artery bypass surgery, or valve surgery be referred to cardiac rehabilitation, cardiac rehabilitation is underused. The objective of this study was to examine hospital-level variation in cardiac rehabilitation referral after PCI, coronary artery bypass surgery, and valve surgery.

Methods and Results—
We analyzed data from the Clinical Outcomes Assessment Program, a registry of all nonfederal hospitals performing PCI and cardiac surgery in Washington State. We included eligible PCI, coronary artery bypass surgery, and valve surgery patients from 2010 to 2015. We analyzed PCI and cardiac surgery separately by performing multivariable hierarchical logistic regression for the outcome of cardiac rehabilitation referral at discharge, clustered by hospital. Patient-level covariates included age, sex, race/ethnicity, comorbidities, and procedure indication/status. Cardiac rehabilitation referral was reported in 48% (34 047/71 556) of PCI patients and 91% (21 831/23 972) of cardiac surgery patients. The hospital performing the procedure was a stronger predictor of referral than any individual patient characteristic for PCI (hospital referral range 3%–97%; median odds ratio, 5.94; 95% confidence interval, 4.10–9.49) and cardiac surgery (range 54%–100%; median odds ratio, 7.09; 95% confidence interval, 3.79–17.80). Hospitals having an outpatient cardiac rehabilitation program explained only 10% of PCI variation and 0% of cardiac surgery variation.

Conclusions—
Cardiac rehabilitation referral at discharge was less prevalent after PCI than cardiac surgery. The strongest predictor of cardiac rehabilitation referral was the hospital performing the procedure. Efforts to improve cardiac rehabilitation referral should focus on increasing referral after PCI, especially in low referral hospitals.
Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling
Authors: Chaanine Antoine H. , Sreekumaran Nair K , Bergen Robert H. , Klaus Katherine , Guenzel Adam J. , Hajjar Roger J. , Redfield Margaret M. 
Published: June 2017

Background

Following pressure overload, compensatory concentric left ventricular remodeling (
CR
) variably transitions to eccentric remodeling (
ER
) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from
CR
to
ER
, before overt systolic dysfunction.

Methods and Results

Sprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed
CR
(left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent
CR
, mild
ER
, and moderate
ER
with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham,
CR
and mild
ER
phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (
BNIP
3 and Bax/Bcl‐2).

Conclusions

After pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory
CR
. The transition to mild
ER
is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate
ER
is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.
Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy
Authors: Robinson Thompson G. , Wang Xia , Arima Hisatomi , Bath Philip M. , Billot Laurent , Broderick Joseph P. , Demchuk Andrew M. , Donnan Geoffery A. , Kim Jong S. , Lavados Pablo M. , Lee Tsong-Hai , Lindley Richard I. , Martins Sheila C. O. , Olavarria Veronica V. , Pandian Jeyaraj D. , Parsons Mark W. , Pontes-Neto Octavio M. , Ricci Stefano , Sato Shoichiro , Sharma Vijay K. , Nguyen Thang H. , Wang Ji-Guang , Woodward Mark , Chalmers John , Anderson Craig S. 
Published: June 2017

Background and Purpose—
Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study).

Methods—
Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2–6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria.

Results—

There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81–1.26;
P
=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75–1.20;
P
=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87–1.21;
P
=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00–3.30;
P
=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (
P
-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2–6; OR, 0.84; 95% CI, 0.62–1.12 versus OR, 1.16; 95% CI, 0.99–1.36).

Conclusions—
Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01422616.
Discussion Interrupted: The Destruction and Protection of Cultural Property under International Law and Islamic Law - the Case of Prosecutor v. Al Mahdi
Authors: Badar Mohamed Elewa , Higgins Noelle 
Published: June 2017

Al Mahdi was the first case before the International Criminal Court (icc), which focused on the destruction of cultural property, and indeed, the first case before an international criminal tribunal which had the destruction of cultural property as the sole charge against a jihadist. This case note first addresses the international legal framework on the protection of cultural property in Section 2. Section 3 then assesses the concept of hisbah and its operation, including the reasons why the Hisbah in Mali destroyed cultural property. The next section considers the facts of the Al Mahdi case. Section 5 highlights the shortfalls in the Trial Chamber’s consideration of the rationales for the protection and destruction of cultural property, before the note concludes in Section 6.
Reservoir Evaporation in the Western United States: Current Science, Challenges, and Future Needs
Authors: Friedrich Katja , Grossman Robert L. , Huntington Justin , Blanken Peter D. , Lenters John , Holman Kathleen D. , Gochis David , Livneh Ben , Prairie James , Skeie Erik , Healey Nathan C. , Dahm Katharine , Pearson Christopher , Finnessey Taryn , Hook Simon J. , Kowalski Ted 
Published: June 2017

AbstractOne way to adapt to and mitigate current and future water scarcity is to manage and store water more efficiently. Reservoirs act as critical buffers to ensure agricultural and municipal water deliveries, mitigate flooding, and generate hydroelectric power, yet they often lose significant amounts of water through evaporation, especially in arid and semiarid regions. Despite this fact, reservoir evaporation has been an inconsistently and inaccurately estimated component of the water cycle within the water resource infrastructure of the arid and semiarid western United States. This paper highlights the increasing importance and challenges of correctly estimating and forecasting reservoir evaporation in the current and future climate, as well as the need to bring new ideas and state-of-the-art practices for the estimation of reservoir evaporation into operational use for modern water resource managers. New ideas and practices include i) improving the estimation of reservoir evaporation using up-to-date knowledge, state-of-the-art instrumentation and numerical models, and innovative experimental designs to diagnose processes and accurately forecast evaporation; ii) improving our understanding of spatial and temporal variations in evaporative water loss from existing reservoirs and transferring this knowledge when expanding reservoirs or siting new ones; and iii) implementing an adaptive management plan that incorporates new knowledge, observations, and forecasts of reservoir evaporation to improve water resource management.
Building the Sun4Cast System: Improvements in Solar Power Forecasting
Authors: Haupt Sue Ellen , Kosović Branko , Jensen Tara , Lazo Jeffrey K. , Lee Jared A. , Jiménez Pedro A. , Cowie James , Wiener Gerry , McCandless Tyler C. , Rogers Matthew , Miller Steven , Sengupta Manajit , Xie Yu , Hinkelman Laura , Kalb Paul , Heiser John 
Published: June 2017

AbstractAs integration of solar power into the national electric grid rapidly increases, it becomes imperative to improve forecasting of this highly variable renewable resource. Thus, a team of researchers from the public, private, and academic sectors partnered to develop and assess a new solar power forecasting system, Sun4Cast. The partnership focused on improving decision-making for utilities and independent system operators, ultimately resulting in improved grid stability and cost savings for consumers. The project followed a value chain approach to determine key research and technology needs to reach desired results.Sun4Cast integrates various forecasting technologies across a spectrum of temporal and spatial scales to predict surface solar irradiance. Anchoring the system is WRF-Solar, a version of the Weather Research and Forecasting (WRF) numerical weather prediction (NWP) model optimized for solar irradiance prediction. Forecasts from multiple NWP models are blended via the Dynamic Integrated Forecast (DICast) System, which forms the basis of the system beyond about 6 h. For short-range (0–6 h) forecasts, Sun4Cast leverages several observation-based nowcasting technologies. These technologies are blended via the Nowcasting Expert System Integrator (NESI). The NESI and DICast systems are subsequently blended to produce short- to midterm irradiance forecasts for solar array locations. The irradiance forecasts are translated into power with uncertainties quantified using an analog ensemble approach and are provided to the industry partners for real-time decision-making. The Sun4Cast system ran operationally throughout 2015 and results were assessed.This paper analyzes the collaborative design process, discusses the project results, and provides recommendations for best-practice solar forecasting.
The Dynamical Influence of the Atlantic Multidecadal Oscillation on Continental Climate
Authors: O’Reilly Christopher H. , Woollings Tim , Zanna Laure 
Published: June 2017

Abstract
The Atlantic multidecadal oscillation (AMO) in sea surface temperature (SST) has been shown to influence the climate of the surrounding continents. However, it is unclear to what extent the observed impact of the AMO is related to the thermodynamical influence of the SST variability or the changes in large-scale atmospheric circulation. Here, an analog method is used to decompose the observed impact of the AMO into dynamical and residual components of surface air temperature (SAT) and precipitation over the adjacent continents. Over Europe the influence of the AMO is clearest during the summer, when the warm SAT anomalies are interpreted to be primarily thermodynamically driven by warm upstream SST anomalies but also amplified by the anomalous atmospheric circulation. The overall precipitation response to the AMO in summer is generally less significant than the SAT but is mostly dynamically driven. The decomposition is also applied to the North American summer and the Sahel rainy season. Both dynamical and residual influences on the anomalous precipitation over the Sahel are substantial, with the former dominating over the western Sahel region and the latter being largest over the eastern Sahel region. The results have potential implications for understanding the spread in AMO variability in coupled climate models and decadal prediction systems.
Fish and Meat Are Often Withheld From the Diets of Infants 6 to 12 Months in Fish-Farming Households in Rural Bangladesh
Authors: Thorne-Lyman Andrew L. , Valpiani Natalie , Akter Rumana , Baten Md Abdul , Genschick Sven , Karim Manjurul , Thilsted Shakuntala H. 
Published: June 2017

Background: Fish is a widely available animal-source food in Bangladesh and a rich source of nutrients, yet little is known about practices related to incorporating fish into the diets of infants and young children. Objective: Use dietary diversity data to explore consumption patterns of fish and high-quality food items within the household and examine factors associated with delayed introduction of fish to infants and young children. Methods: Cross-sectional survey of 496 households with children <36 months participating in the Aquaculture for Income and Nutrition project in Bangladesh. Data collected included household characteristics, women’s dietary diversity score, and minimum dietary diversity score along with data on Infant and Young Child Feeding practices. Results: Most children (63.4%) met the threshold for minimum dietary diversity. Despite having received extensive nutrition education related to including fish in complementary foods, only half of the caretakers introduced fish at 6 months and the mean age of introduction of small fish was 8.7 months. Meat and fish were not common in infant diets but increased with child age. Concerns about bones were a major barrier to incorporating fish into infant diets. Conclusion: Given its nutrient profile and widespread availability in certain contexts, fish could be an underutilized opportunity to improve nutrition and health outcomes of infants and young children. Further research, including utilizing food processing technologies, is needed to develop appropriate responses to overcome these barriers.