bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trading quality for relevance: non-health decision-makers’ use of evidence on the social determinants of health
Authors: McGill Elizabeth , Egan Matt , Petticrew Mark , Mountford Lesley , Milton Sarah , Whitehead Margaret , Lock Karen 
Published: April 2015

ObjectivesLocal government services and policies affect health determinants across many sectors such as planning, transportation, housing and leisure. Researchers and policymakers have argued that decisions affecting wider determinants of health, well-being and inequalities should be informed by evidence. This study explores how information and evidence are defined, assessed and utilised by local professionals situated beyond the health sector, but whose decisions potentially affect health: in this case, practitioners working in design, planning and maintenance of the built environment.DesignA qualitative study using three focus groups. A thematic analysis was undertaken.SettingThe focus groups were held in UK localities and involved local practitioners working in two UK regions, as well as in Brazil, USA and Canada.ParticipantsUK and international practitioners working in the design and management of the built environment at a local government level.ResultsParticipants described a range of data and information that constitutes evidence, of which academic research is only one part. Built environment decision-makers value empirical evidence, but also emphasise the legitimacy and relevance of less empirical ways of thinking through narratives that associate their work to art and philosophy. Participants prioritised evidence on the acceptability, deliverability and sustainability of interventions over evidence of longer term outcomes (including many health outcomes). Participants generally privileged local information, including personal experiences and local data, but were less willing to accept evidence from contexts perceived to be different from their own.ConclusionsLocal-level built environment practitioners utilise evidence to make decisions, but their view of ‘best evidence’ appears to prioritise local relevance over academic rigour. Academics can facilitate evidence-informed local decisions affecting social determinants of health by working with relevant practitioners to improve the quality of local data and evaluations, and by advancing approaches to improve the external validity of academic research.
EXPERTS 1—experiences of long-term life-limiting conditions among patients and carers: protocol for a qualitative meta-synthesis and conceptual modelling study
Authors: May Carl R , Masters Jayne , Welch Lindsay , Hunt Katherine , Pope Catherine , Myall Michelle , Griffiths Peter , Roderick Paul , Glanville Julie , Richardson Alison 
Published: April 2015

IntroductionIncreasing numbers of the population are living with long-term life-limiting conditions with a significant proportion characterised by multimorbidity. Patients with these conditions often experience high volumes of clinical interaction involving them, their caregivers and healthcare providers in complex patterns of organising, coordinating, negotiating and managing care. A better understanding of the sources of experienced complexity and multimorbidity, from the patient perspective is paramount to improve capacity and manage workload to promote improved experience of illness, more effective healthcare utilisation and improved healthcare outcomes. To better understand the sources of complexity we will undertake an evidence synthesis of qualitative studies of patient and informal carer experiences of three common long-term life-limiting conditions. We will investigate what is known about these diseases at different stages in disease progression, treatment regimens and places of care.Method and analysisWe will include qualitative studies of patients’ and carers’ (aged >18) accounts of their experiences of healthcare provision in a range of settings and healthcare systems. We will conduct an extensive electronic database search of publications in English between 2000 and 2014. Results and discussions sections of the papers will be regarded as formal data using the constant comparison method of qualitative analysis. From the meta-synthesis results, we will build a conceptual model of mechanisms and processes that shape patients’ journeys towards end of life to suggest where in the patient journey new interventions to improve patient and carer experience can be developed and delivered. The study is being conducted between 1 December 2014 and 31 December 2015.Ethics and disseminationNo human subjects or personal data are involved and no ethical issues are anticipated. An important element of dissemination is informing user communities about the practical implications of the work through workshops, meetings and social media. Scientific results will be published in peer reviewed journals and disseminated through conferences.Trial registration numberPROSPERO CRD42014014547.
Efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide added to insulin therapy in poorly regulated patients with type 1 diabetes—a protocol for a randomised, double-blind, placebo-controlled study: The Lira-1 study
Authors: Dejgaard Thomas Fremming , Knop Filip Krag , Tarnow Lise , Frandsen Christian Seerup , Hansen Tanja Stenbæk , Almdal Thomas , Holst Jens Juul , Madsbad Sten , Andersen Henrik Ullits 
Published: April 2015

IntroductionIntensive insulin therapy is recommended for the treatment of type 1 diabetes (T1D). Hypoglycaemia and weight gain are the common side effects of insulin treatment and may reduce compliance. In patients with insulin-treated type 2 diabetes, the addition of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy has proven effective in reducing weight gain and insulin dose. The present publication describes a protocol for a study evaluating the efficacy and safety of adding a GLP-1RA to insulin treatment in overweight patients with T1D in a randomised, double-blinded, controlled design.Methods and analysisIn total, 100 patients with type 1 diabetes, poor glycaemic control (glycated haemoglobin (HbA1c) >8%) and overweight (body mass index >25 kg/m2) will be randomised to either liraglutide 1.8 mg once daily or placebo as an add-on to intensive insulin therapy in this investigator initiated, double-blinded, placebo-controlled parallel study. The primary end point is glycaemic control as measured by changes in HbA1c. Secondary end points include changes in the insulin dose, hypoglyacemic events, body weight, lean body mass, fat mass, food preferences and adverse events. Glycaemic excursions, postprandial glucagon levels and gastric emptying rate during a standardised liquid meal test will also be studied.Ethics and disseminationThe study is approved by the Danish Medicines Authority, the Regional Scientific-Ethical Committee of the Capital Region of Denmark and the Data Protection Agency. The study will be carried out under the surveillance and guidance of the good clinical practice (GCP) unit at Copenhagen University Hospital Bispebjerg in accordance with the ICH-GCP guidelines and the Helsinki Declaration.Trial registration numberNCT01612468.
Structural and stratigraphic evolution of the Iberia–Newfoundland hyper-extended rifted margin: a quantitative modelling approach
Authors: Mohn Geoffroy , Karner Garry D. , Manatschal Gianreto , Johnson Christopher A. 
Published: April 2015

Abstract
We investigate the evolution of the Iberia–Newfoundland margin from Permian post-orogenic extension to Early Cretaceous break-up. We used a Quantitative Basin Analysis approach to integrate seismic stratigraphic interpretations and drill-hole data of two representative sections across the Iberia–Newfoundland margin with kinematic models for lithospheric thinning and subsequent flexural readjustment. We model the distribution of extension and thinning, palaeobathymetry, crustal structure, and subsidence and uplift history as functions of space and time. We start our modelling following post-orogenic extension, magmatic underplating and thermal re-equilibration of the Permian lithosphere. During the Late Triassic–Early Jurassic, broadly distributed, depth-independent lithospheric extension evolved into Late Jurassic–Early Cretaceous depth-dependent thinning as crustal extension progressed from distributed to focused deformation. During this time, palaeobathymetries rapidly deepened across the margin. Modelling of the southern and northern profiles highlighted the rapid development of crustal deformation from south to north over a 5–10 myr period, which accounts for the rapid change in Tithonian–Valanginian, deep- to shallow-water sedimentary facies between the Abyssal Plain and the adjacent Galicia Bank, respectively. Late-stage deformation of both margins was characterized by brittle deformation of the remaining continental crust, which led to exhumation of subcontinental mantle and, eventually, continental break-up and seafloor spreading.
Performance Measurement and Analysis of High-Availability Clusters
Authors: Kaur Arvinder , Verma Shraddha 
Published: April 2015

High-availability clusters are groups of servers that provide a reliable framework for applications to achieve a minimum downtime and quick recovery time without any human intervention and yet are completely opaque to the users. Almost all industries are continuously pursuing the goal to minimize their critical application downtimes by using various techniques such as fault tolerance, redundancy, mirroring and clustering. During downtime, applications become unavailable to end users, which can lead to financial, reputation and regulatory business impacts. High-availability clusters provide a mechanism to migrate complete applications or services from one server to another seamlessly without any human intervention at the time of failure of any critical component or the complete server. Hence, an application would start on a healthy server, without end users realizing this failover.
In this work, key features and aspects of two cluster products, 'Symantec Veritas Cluster Suite' and 'Red Hat Cluster' were compared against each other based on various parameters. A simulated environment was created to perform a comprehensive analysis of performances of both products. In this work, measurement of average failover time was taken and compared as the key reliability and serviceability attribute. Thus, based on this experimental work, it is concluded that in a controlled test environment running a simple web-server application, Red Hat cluster gives a better failover performance as compared to Veritas Cluster Suite. However, in a large-scale environment, if we consider factors like operating system compatibility, supported applications, compatibility with volume managers, hardware compatibility, reliability, fault tolerance, predictive failure, self-healing etc., then the Veritas Cluster Suite comes out as the winner.
Accuracy of Molecular Data Generated with FFPE Biospecimens: Lessons from the Literature
Authors: Greytak Sarah R. , Engel Kelly B. , Bass B. Paige , Moore Helen M. 
Published: April 2015

Abstract
Formalin-fixed and paraffin-embedded (FFPE) tissue biospecimens are a valuable resource for molecular cancer research. Although much can be gained from their use, it remains unclear whether the genomic and expression profiles obtained from FFPE biospecimens accurately reflect the physiologic condition of the patient from which they were procured, or if such profiles are confounded by biologic effects from formalin fixation and processing. To assess the physiologic accuracy of genomic and expression data generated with FFPE specimens, we surveyed the literature for articles investigating genomic and expression endpoints in case-matched FFPE and fresh or frozen human biospecimens using the National Cancer Institute's Biospecimen Research Database (http://biospecimens.cancer.gov/brd). Results of the survey revealed that the level of concordance between differentially preserved biospecimens varied among analytical parameters and platforms but also among reports, genes/transcripts of interest, and tumor status. The identified analytical techniques and parameters that resulted in strong correlations between FFPE and frozen biospecimens may provide guidance when optimizing molecular protocols for FFPE use; however, discrepancies reported for similar assays also illustrate the importance of validating protocols optimized for use with FFPE specimens with a case-matched fresh or frozen cohort for each platform, gene or transcript, and FFPE processing regime. On the basis of evidence published to date, validation of analytical parameters with a properly handled frozen cohort is necessary to ensure a high degree of concordance and confidence in the results obtained with FFPE biospecimens. Cancer Res; 75(8); 1541–7. ©2015 AACR.
Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer
Authors: Khan Sheema , Ebeling Mara C. , Chauhan Neeraj , Thompson Paul A. , Gara Rishi K. , Ganju Aditya , Yallapu Murali M. , Behrman Stephen W. , Zhao Haotian , Zafar Nadeem , Singh Man Mohan , Jaggi Meena , Chauhan Subhash C. 
Published: April 2015

Abstract
The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine. Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene, has potent anticancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ormeloxifene inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ormeloxifene with gemcitabine at the molecular level. Ormeloxifene caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NF-κB, p-AKT, and cyclin D1. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice. Furthermore, ormeloxifene depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ormeloxifene in combination with gemcitabine restored the tumor-suppressor miR-132 and inhibited stromal cell infiltration into the tumor tissues. In addition, invasiveness of tumor cells cocultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ormeloxifene treatment alone or in combination with gemcitabine. We propose that ormeloxifene has high therapeutic index and in a combination therapy with gemcitabine, it possesses great promise as a treatment of choice for PDAC/pancreatic cancer. Cancer Res; 75(11); 2292–304. ©2015 AACR.
Mesoscopic and Macroscopic Optoacoustic Imaging of Cancer
Authors: Taruttis Adrian , van Dam Gooitzen M. , Ntziachristos Vasilis 
Published: April 2015

Abstract
Optoacoustic imaging combines the rich contrast of optical methods with the resolution of ultrasound imaging. It can therefore deliver optical visualization of cancer far deeper in tissue than optical microscopy and other conventional optical imaging methods. Technological progress and novel contrast media have resulted in optoacoustic imaging being propagated to basic cancer research and in clinical translation projects. We briefly review recent technological advances, showcase the ability to resolve unique cancer biomarkers based on spectral features at different imaging scales, and highlight the imaging performance achieved in preclinical and clinical imaging applications. Cancer Res; 75(8); 1548–59. ©2015 AACR.
MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFκB Activation in Breast Cancer
Authors: Muñoz-Galván Sandra , Gutierrez Gabriel , Perez Marco , Carnero Amancio 
Published: April 2015

Abstract
MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na+-coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFκB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17-induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na+-coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFκB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug. Mol Cancer Ther; 14(6); 1454–65. ©2015 AACR.
Identification of Pathogenic Cardiac CD11c
+
Macrophages in Nod1-Mediated Acute Coronary Arteritis
Authors: Motomura Yoshitomo , Kanno Shunsuke , Asano Kenichi , Tanaka Masato , Hasegawa Yutaka , Katagiri Hideki , Saito Takashi , Hara Hiromitsu , Nishio Hisanori , Hara Toshiro , Yamasaki Sho 
Published: April 2015

Objective—
Nod1 is an intracellular pattern recognition receptor for bacterial peptidoglycan fragments. We previously reported that a synthetic Nod1 ligand, FK565, induced acute coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanisms underlying this characteristic inflammation have remained elusive.

Approach and Results—

We found that CD11c
+
MHC class II
+
cells accumulated in the heart of FK565-treated mice before arteritis development. Morphological features and gene expression signatures of the cardiac CD11c
+
MHC class II
+
cells suggested that this population is closely related to macrophages, and thus, we designated them cardiac CD11c
+
macrophages. Nod1 in nonhematopoietic cells, rather than hematopoietic cells, was required for the increase of cardiac CD11c
+
macrophages and arteritis development. Among nonhematopoietic cells, cardiac endothelial cells produced a large amount of chemokines in response to FK565. Endothelial cell–specific blockade of Nod1 signaling suppressed FK565-induced expression of these chemokines, accumulation of cardiac CD11c
+
macrophages, and subsequent coronary arteritis development. We also found that CCR2
+
Ly6C
hi
inflammatory monocytes in peripheral blood supplied precursors of cardiac CD11c
+
macrophages. CCR2-deficient mice or pertussis toxin–treated mice exhibited decreased numbers of cardiac CD11c
+
macrophages and reduced arteritis.

Conclusions—

These results suggest that Ly6C
hi
monocytes are recruited to FK565-activated endothelial cells to generate cardiac CD11c
+
macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis.
Loss of Interleukin-21 Receptor Activation in Hypoxic Endothelial Cells Impairs Perfusion Recovery After Hindlimb Ischemia
Authors: Wang Tao , Cunningham Alexis , Dokun Ayotunde O. , Hazarika Surovi , Houston Kevin , Chen Lingdan , Lye R. John , Spolski Rosanne , Leonard Warren J. , Annex Brian H. 
Published: April 2015

Objective—
Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease. We previously identified that the different phenotypic outcomes after HLI across inbred mouse strains is related to a region on the short arm of mouse chromosome 7. The gene coding the interleukin-21 receptor (IL-21R) lies at the peak of association in this region.

Approach and Results—

With quantitative real-time polymerase chain reaction, we found that a mouse strain with a greater ability to upregulate IL-21R after HLI had better perfusion recovery than a strain with no upregulation after HLI. Immunofluorescent staining of ischemic hindlimb tissue showed IL-21R expression on endothelial cells (ECs) from C57BL/6 mice. An EC-enriched fraction isolated from ischemic hindlimb muscle showed higher Il-21R levels than an EC-enriched fraction from nonischemic limbs. In vitro, human umbilical vein ECs showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In vivo, either knockout
Il21r
or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2–associated X protein ratio.

Conclusion—
Our data indicate that IL-21R upregulation and ligand activation in hypoxic ECs may help perfusion recovery by limiting/preventing apoptosis and favoring cell survival and angiogenesis through the signal transducer and activator of transcription 3 pathway.