bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Accessible Proteogenomics Informatics Resource for Cancer Researchers
Authors: Chambers Matthew C. , Jagtap Pratik D. , Johnson James E. , McGowan Thomas , Kumar Praveen , Onsongo Getiria , Guerrero Candace R. , Barsnes Harald , Vaudel Marc , Martens Lennart , Grüning Björn , Cooke Ira R. , Heydarian Mohammad , Reddy Karen L. , Griffin Timothy J. 
Published: November 2017

Abstract
Proteogenomics has emerged as a valuable approach in cancer research, which integrates genomic and transcriptomic data with mass spectrometry–based proteomics data to directly identify expressed, variant protein sequences that may have functional roles in cancer. This approach is computationally intensive, requiring integration of disparate software tools into sophisticated workflows, challenging its adoption by nonexpert, bench scientists. To address this need, we have developed an extensible, Galaxy-based resource aimed at providing more researchers access to, and training in, proteogenomic informatics. Our resource brings together software from several leading research groups to address two foundational aspects of proteogenomics: (i) generation of customized, annotated protein sequence databases from RNA-Seq data; and (ii) accurate matching of tandem mass spectrometry data to putative variants, followed by filtering to confirm their novelty. Directions for accessing software tools and workflows, along with instructional documentation, can be found at z.umn.edu/canresgithub. Cancer Res; 77(21); e43–46. ©2017 AACR.
LesionTracker: Extensible Open-Source Zero-Footprint Web Viewer for Cancer Imaging Research and Clinical Trials
Authors: Urban Trinity , Ziegler Erik , Lewis Rob , Hafey Chris , Sadow Cheryl , Van den Abbeele Annick D. , Harris Gordon J. 
Published: November 2017

Abstract
Oncology clinical trials have become increasingly dependent upon image-based surrogate endpoints for determining patient eligibility and treatment efficacy. As therapeutics have evolved and multiplied in number, the tumor metrics criteria used to characterize therapeutic response have become progressively more varied and complex. The growing intricacies of image-based response evaluation, together with rising expectations for rapid and consistent results reporting, make it difficult for site radiologists to adequately address local and multicenter imaging demands. These challenges demonstrate the need for advanced cancer imaging informatics tools that can help ensure protocol-compliant image evaluation while simultaneously promoting reviewer efficiency. LesionTracker is a quantitative imaging package optimized for oncology clinical trial workflows. The goal of the project is to create an open source zero-footprint viewer for image analysis that is designed to be extensible as well as capable of being integrated into third-party systems for advanced imaging tools and clinical trials informatics platforms. Cancer Res; 77(21); e119–22. ©2017 AACR.
The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized—A New Paradigm in Large-Scale Computational Research
Authors: Lau Jessica W. , Lehnert Erik , Sethi Anurag , Malhotra Raunaq , Kaushik Gaurav , Onder Zeynep , Groves-Kirkby Nick , Mihajlovic Aleksandar , DiGiovanna Jack , Srdic Mladen , Bajcic Dragan , Radenkovic Jelena , Mladenovic Vladimir , Krstanovic Damir , Arsenijevic Vladan , Klisic Djordje , Mitrovic Milan , Bogicevic Igor , Kural Deniz , Davis-Dusenbery Brandi 
Published: November 2017

Abstract
The Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org) enables researchers to rapidly access and collaborate on massive public cancer genomic datasets, including The Cancer Genome Atlas. It provides secure on-demand access to data, analysis tools, and computing resources. Researchers from diverse backgrounds can easily visualize, query, and explore cancer genomic datasets visually or programmatically. Data of interest can be immediately analyzed in the cloud using more than 200 preinstalled, curated bioinformatics tools and workflows. Researchers can also extend the functionality of the platform by adding their own data and tools via an intuitive software development kit. By colocalizing these resources in the cloud, the CGC enables scalable, reproducible analyses. Researchers worldwide can use the CGC to investigate key questions in cancer genomics. Cancer Res; 77(21); e3–6. ©2017 AACR.
The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer
Authors: Krupke Debra M. , Begley Dale A. , Sundberg John P. , Richardson Joel E. , Neuhauser Steven B. , Bult Carol J. 
Published: November 2017

Abstract
Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67–70. ©2017 AACR.
The ISB Cancer Genomics Cloud: A Flexible Cloud-Based Platform for Cancer Genomics Research
Authors: Reynolds Sheila M. , Miller Michael , Lee Phyliss , Leinonen Kalle , Paquette Suzanne M. , Rodebaugh Zack , Hahn Abigail , Gibbs David L. , Slagel Joseph , Longabaugh William J. , Dhankani Varsha , Reyes Madelyn , Pihl Todd , Backus Mark , Bookman Matthew , Deflaux Nicole , Bingham Jonathan , Pot David , Shmulevich Ilya 
Published: November 2017

Abstract
The ISB Cancer Genomics Cloud (ISB-CGC) is one of three pilot projects funded by the National Cancer Institute to explore new approaches to computing on large cancer datasets in a cloud environment. With a focus on Data as a Service, the ISB-CGC offers multiple avenues for accessing and analyzing The Cancer Genome Atlas, TARGET, and other important references such as GENCODE and COSMIC using the Google Cloud Platform. The open approach allows researchers to choose approaches best suited to the task at hand: from analyzing terabytes of data using complex workflows to developing new analysis methods in common languages such as Python, R, and SQL; to using an interactive web application to create synthetic patient cohorts and to explore the wealth of available genomic data. Links to resources and documentation can be found at www.isb-cgc.org. Cancer Res; 77(21); e7–10. ©2017 AACR.
Novel SEC61G–EGFR Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens
Authors: Servidei Tiziana , Meco Daniela , Muto Valentina , Bruselles Alessandro , Ciolfi Andrea , Trivieri Nadia , Lucchini Matteo , Morosetti Roberta , Mirabella Massimiliano , Martini Maurizio , Caldarelli Massimo , Lasorella Anna , Tartaglia Marco , Riccardi Riccardo 
Published: November 2017

Abstract
The basis for molecular and cellular heterogeneity in ependymomas of the central nervous system is not understood. This study suggests a basis for this phenomenon in the selection for mitogen-independent (MI) stem-like cells with impaired proliferation but increased intracranial tumorigenicity. MI ependymoma cell lines created by selection for EGF/FGF2-independent proliferation exhibited constitutive activation of EGFR, AKT, and STAT3 and sensitization to the antiproliferative effects of EGFR tyrosine kinase inhibitors (TKI). One highly tumorigenic MI line harbored membrane-bound, constitutively active, truncated EGFR. Two EGFR mutants (ΔN566 and ΔN599) were identified as products of intrachromosomal rearrangements fusing the 3′ coding portion of the EGFR gene to the 5′-UTR of the SEC61G, yielding products lacking the entire extracellular ligand-binding domain of the receptor while retaining the transmembrane and tyrosine kinase domains. EGFR TKI efficiently targeted ΔN566/ΔN599-mutant–mediated signaling and prolonged the survival of mice bearing intracranial xenografts of MI cells harboring these mutations. RT-PCR sequencing of 16 childhood ependymoma samples identified SEC61G–EGFR chimeric mRNAs in one infratentorial ependymoma WHO III, arguing that this fusion occurs in a small proportion of these tumors. Our findings demonstrate how in vitro culture selections applied to genetically heterogeneous tumors can help identify focal mutations that are potentially pharmaceutically actionable in rare cancers. Cancer Res; 77(21); 5860–72. ©2017 AACR.
WebMeV: A Cloud Platform for Analyzing and Visualizing Cancer Genomic Data
Authors: Wang Yaoyu E. , Kutnetsov Lev , Partensky Antony , Farid Jalil , Quackenbush John 
Published: November 2017

Abstract
Although large, complex genomic datasets are increasingly easy to generate, and the number of publicly available datasets in cancer and other diseases is rapidly growing, the lack of intuitive, easy-to-use analysis tools has remained a barrier to the effective use of such data. WebMeV (http://mev.tm4.org) is an open-source, web-based tool that gives users access to sophisticated tools for analysis of RNA-Seq and other data in an interface designed to democratize data access. WebMeV combines cloud-based technologies with a simple user interface to allow users to access large public datasets, such as that from The Cancer Genome Atlas or to upload their own. The interface allows users to visualize data and to apply advanced data mining analysis methods to explore the data and draw biologically meaningful conclusions. We provide an overview of WebMeV and demonstrate two simple use cases that illustrate the value of putting data analysis in the hands of those looking to explore the underlying biology of the systems being studied. Cancer Res; 77(21); e11–14. ©2017 AACR.
miR-519d Promotes Melanoma Progression by Downregulating EphA4
Authors: Hua Kuo-Tai , Hong Jin-Bong , Sheen Yi-Shuan , Huang Hsin-Yi , Huang Yi-Ling , Chen Jau-Shiuh , Liao Yi-Hua 
Published: November 2017

AbstractIncreasing evidence suggests that there is a unique cell subpopulation in melanoma that can form nonadherent melanospheres in serum-free stem cell medium, mimicking aggressive malignancy. Using melanospheres as a model to investigate progression mechanisms, we found that miR-519d overexpression was sufficient to promote cell proliferation, migration, invasion, and adhesion in vitro and lung metastatic capability in vivo. The cell adhesion receptor EphA4 was determined to be a direct target of miR-519d. Forced expression of EphA4 reversed the effects of miR-519d overexpression, whereas silencing of EphA4 phenocopied the effect of miR-519d. Malignant progression phenotypes were also affected at the level of epithelial-to-mesenchymal transition and the ERK1/2 signaling pathway inversely affected by miR-519d or EphA4 expression. In clinical specimens of metastatic melanoma, we observed significant upregulation of miR-519d and downregulation of EphA4, in the latter case correlated inversely with overall survival. Taken together, our results suggest a significant functional role for miR-519d in determining EphA4 expression and melanoma progression.Significance: These results suggest a significant role for miR-519d in determining expression of a pivotal cell adhesion molecule that may impact risks of malignant progression in many cancers. Cancer Res; 78(1); 216–29. ©2017 AACR.
A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors
Authors: Evans Kurt W. , Yuca Erkan , Akcakanat Argun , Scott Stephen M. , Arango Natalia Paez , Zheng Xiaofeng , Chen Ken , Tapia Coya , Tarco Emily , Eterovic Agda K. , Black Dalliah M. , Litton Jennifer K. , Yap Timothy A. , Tripathy Debu , Mills Gordon B. , Meric-Bernstam Funda 
Published: November 2017

AbstractBackground: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy.Experimental Design: PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA) were performed. Phenotypic profiling was performed by determining efficacy of a panel of standard and investigational agents.Results: Twenty-six PDXs were developed from 25 patients. Twenty-two were generated from residual disease following neoadjuvant chemotherapy, and 24 were from triple-negative breast cancer (TNBC). These PDXs harbored a heterogeneous set of genomic alterations and represented all TNBC molecular subtypes. On RPPA, PDXs varied in extent of PI3K and MAPK activation. PDXs also varied in their sensitivity to chemotherapeutic agents. PI3K, mTOR, and MEK inhibitors repressed growth but did not cause tumor regression. The PARP inhibitor talazoparib caused dramatic regression in five of 12 PDXs. Notably, four of five talazoparib-sensitive models did not harbor germline BRCA1/2 mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations.Conclusions: PDXs capture the molecular and phenotypic heterogeneity of TNBC. Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes. These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers. Clin Cancer Res; 23(21); 6468–77. ©2017 AACR.
Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract
Authors: Worst Thomas Stefan , Daskalova Kristina , Steidler Annette , Berner-Leischner Karin , Röth Ralph , Niesler Beate , Kriegmair Maximilian C. , Erben Philipp , Pfalzgraf Daniel 
Published: November 2017

<b><i>Background:</i></b> Little is known about the role of WNT signalling in pathological processes involving the urinary tract stroma. Here the impact of WNT signalling on bladder wall fibroblasts (BWFs) was studied using integrated expression profiling. <b><i>Material and Methods:</i></b> WNT ligand and downstream WNT pathway component expression was profiled in human BWFs using qRT-PCR. Highly expressed <i>WNT2B</i> was knocked down using siRNA in BWFs. The expression of 730 mRNAs and 800 miRNAs was analyzed on the nCounter MAX platform in #<i>WNT2B</i> and control transfected BWFs. qRT-PCR was used for validation in vitro and in matched scar and healthy bladder wall tissue samples of 12 patients with vesico-urethral anastomotic stricture (VUAS). <b><i>Results:</i></b> Thirteen genes and 9 miRNAs showed differential expression in #<i>WNT2B</i> cells. Among these were <i>TNFSF10</i>, a key apoptosis inductor, (0.22fold, <i>p</i> = 0.011) and miR-1246 (36.2fold, <i>p</i> = 0.031). miRNA target prediction indicated <i>TNFSF10</i> to be regulated by miR-1246. qRT-PCR analysis confirmed differential expression of miR-1246 and <i>TNFSF10</i> in <i>#WNT2B</i> BWFs<i>.</i> Furthermore, <i>TNFSF10</i> was significantly underexpressed in VUAS tissue (<i>p</i> = 0.009). <b><i>Conclusion:</i></b> Perturbation of WNT signalling results in an altered expression of the apoptosis inductor <i>TNFSF10</i>. Similar changes are observed in VUAS. Further studies investigating the crosslink between WNT signalling and apoptosis regulation in the urinary tract stroma are warranted.
Prognostic Value of Cardiopulmonary Exercise Testing in Heart Failure With Reduced, Midrange, and Preserved Ejection Fraction
Authors: Nadruz Wilson , West Erin , Sengeløv Morten , Santos Mário , Groarke John D. , Forman Daniel E. , Claggett Brian , Skali Hicham , Shah Amil M. 
Published: November 2017

Background

This study aimed to compare the independent and incremental prognostic value of peak oxygen consumption (
VO
2
) and minute ventilation/carbon dioxide production (
VE
/
VCO
2
) in heart failure (
HF
) with preserved (
HF
p
EF
), midrange (
HF
m
EF
), and reduced (
HF
r
EF
) ejection fraction (
LVEF
).

Methods and Results

In 195
HF
p
EF
(
LVEF
≥50%), 144
HF
m
EF
(
LVEF
40–49%), and 630
HF
r
EF
(
LVEF
<40%) patients, we assessed the association of cardiopulmonary exercise testing variables with the composite outcome of death, left ventricular assist device implantation, or heart transplantation (256 events; median follow‐up of 4.2 years), and 2‐year incident
HF
hospitalization (244 events). In multivariable Cox regression analysis, greater association with outcomes in
HF
p
EF
than
HF
r
EF
were noted with peak
VO
2
(
HR
[95%
confidence interval
]: 0.76 [0.67–0.87] versus 0.87 [0.83–0.90] for the composite outcome,
P
interaction
=0.052; 0.77 [0.69–0.86] versus 0.92 [0.88–0.95], respectively for
HF
hospitalization,
P
interaction
=0.003) and
VE
/
VCO
2
slope (1.11 [1.06–1.17] versus 1.04 [1.03–1.06], respectively for the composite outcome,
P
interaction
=0.012; 1.10 [1.05–1.15] versus 1.04 [1.03–1.06], respectively for
HF
hospitalization,
P
interaction
=0.019). In
HF
m
EF
, peak
VO
2
and
VE
/
VCO
2
slope were associated with the composite outcome (0.79 [0.70–0.90] and 1.12 [1.05–1.19], respectively), while only peak
VO
2
was related to
HF
hospitalization (0.81 [0.72–0.92]). In
HF
p
EF
and
HF
r
EF
, peak
VO
2
and
VE
/
VCO
2
slope provided incremental prognostic value beyond clinical variables based on the C‐statistic, net reclassification improvement, and integrated diagnostic improvement, with models containing both measures demonstrating the greatest incremental value.

Conclusions

Both peak
VO
2
and
VE
/
VCO
2
slope provided incremental value beyond clinical characteristics and
LVEF
for predicting outcomes in
HF
p
EF
. Cardiopulmonary exercise testing variables provided greater risk discrimination in
HF
p
EF
than
HF
r
EF
.
Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y–Ca
2+
‐Activated Potassium Channel–Nitric Oxide Mediated Mechanism
Authors: Olver T. Dylan , Hiemstra Jessica A. , Edwards Jenna C. , Schachtman Todd R. , Heesch Cheryl M. , Fadel Paul J. , Laughlin M. Harold , Emter Craig A. 
Published: November 2017

Background

Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [
AB
]) and the loss of female sex hormones (ovariectomy [
OVX
]) impairs cerebrovascular control and spatial memory.

Methods and Results

Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2)
AB
, (3)
OVX
, and (4)
AB
‐
OVX
. Pigs underwent
OVX
and
AB
at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole‐board task) were lower in the
OVX
groups (
P
<0.05), with significant impairments in the
AB
‐
OVX
group (
P
<0.05). Resting carotid artery β stiffness and vascular resistance during central hypovolemia were increased in the
AB
‐
OVX
group (
P
<0.05), and blood flow recovery after central hypovolemia was reduced in both
OVX
groups (
P
<0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the
AB
‐
OVX
group (
P
<0.05), and vasodilation to the Ca
2+
‐activated potassium channel α‐subunit agonist
NS
‐1619 was impaired in both
AB
groups (
P
<0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca
2+
‐activated potassium channel α‐subunit protein was increased in
AB
groups (
P
<0.05).

Conclusions

Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y–induced vasoconstriction along with reduced vasodilation associated with decreased Ca
2+
‐activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.
Baroclinic Instability in the Presence of Convection
Authors: Callies Jörn , Ferrari Raffaele 
Published: November 2017

AbstractBaroclinic mixed-layer instabilities have recently been recognized as an important source of submesoscale energy in deep winter mixed layers. While the focus has so far been on the balanced dynamics of these instabilities, they occur in and depend on an environment shaped by atmospherically forced small-scale turbulence. In this study, idealized numerical simulations are presented that allow the development of both baroclinic instability and convective small-scale turbulence, with simple control over the relative strength. If the convection is only weakly forced, baroclinic instability restratifies the layer and shuts off convection, as expected. With increased forcing, however, it is found that baroclinic instabilities are remarkably resilient to the presence of convection. Even if the instability is too weak to restratify the layer and shut off convection, the instability still grows in the convecting environment and generates baroclinic eddies and fronts. This suggests that despite the vigorous atmospherically forced small-scale turbulence in winter mixed layers, baroclinic instabilities can persistently grow, generate balanced submesoscale turbulence, and modify the bulk properties of the upper ocean.
Falls From Agricultural Machinery: Risk Factors Related to Work Experience, Worked Hours, and Operators’ Behavior
Authors: Caffaro Federica , Roccato Michele , Micheletti Cremasco Margherita , Cavallo Eugenio 
Published: November 2017

Objective We investigated the risk factors for falls when egressing from agricultural tractors, analyzing the role played by worked hours, work experience, operators’ behavior, and near misses. Background Many accidents occur within the agricultural sector each year. Among them, falls while dismounting the tractor represent a major source of injuries. Previous studies pointed out frequent hazardous movements and incorrect behaviors adopted by operators to exit the tractor cab. However, less is known about the determinants of such behaviors. In addition, near misses are known to be important predictors of accidents, but they have been under-investigated in the agricultural sector in general and as concerns falls in particular. Method A questionnaire assessing dismounting behaviors, previous accidents and near misses, and participants’ relation with work was administered to a sample of Italian tractor operators ( n = 286). Results A mediated model showed that worked hours increase unsafe behaviors, whereas work experience decreases them. Unsafe behaviors in turn show a positive association with accidents, via the mediation of near misses. Conclusions We gave a novel contribution to the knowledge of the chain of events leading to fall accidents in the agricultural sector, which is one of the most hazardous industries. Applications Besides tractor design improvements, preventive training interventions may focus on the redesign of the actual working strategies and the adoption of engaging training methods in the use of machinery to optimize the learning of safety practices and safe behaviors.