bluuebunny/crossref_metadata_2025_split huggingface dataset:
Core requirements for successful data linkage: an example of a triangulation method
Authors: Hopf Y M , Francis J , Helms P J , Haughney J , Bond C 
Published: October 2016

ObjectivesThe aim was to explore the views of professional stakeholders and healthcare professionals (HCPs) on the linkage of UK National Health Service (NHS) data for paediatric pharmacovigilance purposes and to make recommendations for such a system.MethodsA mixed methods approach including a literature review, interviews, focus groups and a three-round Delphi survey with HCPs in Scotland was followed by a triangulation process using a systematic protocol. The survey was structured using the Theoretical Domains Framework of behaviour change. Items retained after applying the matrix-based triangulation process were thematically coded. Ethical approval was granted by the North of Scotland Research Ethics Service.ResultsResults from 18 papers, 23 interviewees, 23 participants of focus groups and 61 completed questionnaires in the Delphi survey contributed to the triangulation process. A total of 25 key findings from all four studies were identified during triangulation. There was good convergence; 21 key findings were agreed and remained to inform recommendations. The items were coded as practical/technical (eg, decision about the unique patient identifier to use), mandatory (eg, governed by statute), essential (consistently mentioned in all studies and therefore needed to ensure professional support) or preferable.ConclusionsThe development of a paediatric linked database has support from professional stakeholders and HCPs in Scotland. The triangulation identified three sets of core requirements for a new system of data linkage. An additional fourth set of ‘preferable’ requirements might increase engagement of HCPs and their support for the new system.
The Environmental footprint of morphine: a life cycle assessment from opium poppy farming to the packaged drug
Authors: McAlister Scott , Ou Yanjun , Neff Elise , Hapgood Karen , Story David , Mealey Philip , McGain Forbes 
Published: October 2016

ObjectiveTo examine the environmental life cycle from poppy farming through to production of 100 mg in 100 mL of intravenous morphine (standard infusion bag).Design‘Cradle-to-grave’ process-based life cycle assessment (observational).SettingsAustralian opium poppy farms, and facilities for pelletising, manufacturing morphine, and sterilising and packaging bags of morphine.Main outcome measuresThe environmental effects (eg, CO2equivalent (‘CO2e’) emissions and water use) of producing 100 mg of morphine. All aspects of morphine production from poppy farming, pelletising, bulk morphine manufacture through to final formulation. Industry-sourced and inventory-sourced databases were used for most inputs.ResultsMorphine sulfate (100 mg in 100 mL) had a climate change effect of 204 g CO2e (95% CI 189 to 280 g CO2e), approximating the CO2e emissions of driving an average car 1 km. Water use was 7.8 L (95% CI 6.7– to 9.0 L), primarily stemming from farming (6.7 L). All other environmental effects were minor and several orders of magnitude less than CO2e emissions and water use. Almost 90% of CO2e emissions occurred during the final stages of 100 mg of morphine manufacture. Morphine's packaging contributed 95 g CO2e, which accounted for 46% of the total CO2e (95% CI 82 to 155 g CO2e). Mixing, filling and sterilisation of 100 mg morphine bags added a further 86 g CO2e, which accounted for 42% (95% CI 80 to 92 g CO2e). Poppy farming (6 g CO2e, 3%), pelletising and manufacturing (18 g CO2e, 9%) made smaller contributions to CO2emissions.ConclusionsThe environmental effects of growing opium poppies and manufacturing bulk morphine were small. The final stages of morphine production, particularly sterilisation and packaging, contributed to almost 90% of morphine's carbon footprint. Focused measures to improve the energy efficiency and sources for drugsterilisationandpackagingcould be explored as these are relevant toall drugs. Comparisons of the environmental effects of the production of other drugs and between oral and intravenous preparations are required.
Effect of simple, targeted diet in pregnant women with metabolic risk factors on maternal and fetal outcomes (ESTEEM): study protocol for a pragmatic multicentre randomised trial
Authors: Al Wattar Bassel H , Dodds Julie , Placzek Anna , Spyreli Eleni , Moore Amanda , Hooper Richard , Beresford Lee , Roseboom Tessa J , Bes-Rastrollo Maira , Hitman Graham , Khan Khalid S , Thangaratinam Shakila 
Published: October 2016

IntroductionWomen with metabolic risk factors are at higher risk of adverse pregnancy outcomes. Mediterranean-based dietary interventions have the potential to minimise these risks. We aim to evaluate the effectiveness of a simple, targeted intervention modelled on Mediterranean diet in preventing maternal and fetal complications in pregnant women with metabolic risk factors.Methods and analysisPregnant women with a singleton pregnancy <18 weeks gestation, and without pre-existing diabetes, chronic renal disease and autoimmune diseases will be recruited. Women with metabolic risk factors will be randomised to receive a dietary intervention based on a Mediterranean pattern, supplemented with extra virgin olive oil and mixed nuts until delivery. The intervention will be delivered through a series of one to one and group sessions. The primary outcome is a composite maternal outcome of pre-eclampsia or gestational diabetes and a composite fetal outcome of stillbirth, small for gestational age fetus or admission to the neonatal intensive care unit. Secondary outcomes include maternal, fetal, dietary and laboratory outcomes. We aim to randomise 1230 eligible women with metabolic risk factors. We will also compare the outcomes in women with and without these risk factors. The sample size will provide us with 80% power at 5% significance, assuming a 20% loss to follow-up to detect a 30% reduction in maternal and fetal complications.Ethics and disseminationThe ESTEEM trial is designed to provide a definitive estimate of the effects of Mediterranean dietary pattern in pregnancy on maternal and fetal outcomes. The pragmatic nature of ESTEEM ensures the applicability of its findings into clinical practice. The findings of the study will be published in peer-reviewed journals and presented at national and international scientific meetings and congresses. Ethical approval was granted by the NHS Research Ethics Committees (14/EE/1048).Trial registration numberNCT02218931; Pre-results.
IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
Authors: Mace Thomas A , Shakya Reena , Pitarresi Jason R , Swanson Benjamin , McQuinn Christopher W , Loftus Shannon , Nordquist Emily , Cruz-Monserrate Zobeida , Yu Lianbo , Young Gregory , Zhong Xiaoling , Zimmers Teresa A , Ostrowski Michael C , Ludwig Thomas , Bloomston Mark , Bekaii-Saab Tanios , Lesinski Gregory B 
Published: October 2016

ObjectiveLimited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy.DesignTranscription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL−G12D, Trp53LSL−R270H, Pdx1-cre, Brca2F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis.ResultsPSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L−CD44−). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012).ConclusionsThese preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.
Theoretical study of some electrical parameters of graphene
Authors: Das D. K. , Roy S. , Sahoo S. 
Published: October 2016

Graphene, due to its numerous unique properties, is addressed as miraculous material by Novoselov et al. [Nature 490 (2012) 192]. It has ultrahigh heat and thermal conductivity. Several researchers over the globe are working on electrical properties of graphene like electrical resistance, electrical conductivity etc. In this paper, we estimate electrical resistivity, electrical conductivity and Lorenz number for graphene within the temperature range from 300 K to 500 K. Variation of these parameters with respect to temperature and sample size is also reported.
Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation
Authors: Omiya Shigemiki , Omori Yosuke , Taneike Manabu , Protti Andrea , Yamaguchi Osamu , Akira Shizuo , Shah Ajay M. , Nishida Kazuhiko , Otsu Kinya 
Published: October 2016

We have reported that the Toll-like receptor 9 (TLR9) signaling pathway plays an important role in the development of pressure overload-induced inflammatory responses and heart failure. However, its role in cardiac remodeling after myocardial infarction has not been elucidated. TLR9-deficient and control C57Bl/6 wild-type mice were subjected to left coronary artery ligation. The survival rate 14 days postoperation was significantly lower in TLR9-deficient mice than that in wild-type mice with evidence of cardiac rupture in all dead mice. Cardiac magnetic resonance imaging showed no difference in infarct size and left ventricular wall thickness and function between TLR9-deficient and wild-type mice. There were no differences in the number of infiltrating inflammatory cells and the levels of inflammatory cytokine mRNA in infarct hearts between TLR9-deficient and wild-type mice. The number of α-smooth muscle actin (αSMA)-positive myofibroblasts and αSMA/Ki67-double-positive proliferative myofibroblasts was increased in the infarct and border areas in infarct hearts compared with those in sham-operated hearts in wild-type mice, but not in TLR9-deficient mice. The class B CpG oligonucleotide increased the phosphorylation level of NF-κB and the number of αSMA-positive and αSMA/Ki67-double-positive cells and these increases were attenuated by BAY1-7082, an NF-κB inhibitor, in cardiac fibroblasts isolated from wild-type hearts. The CpG oligonucleotide showed no effect on NF-κB activation or the number of αSMA-positive and αSMA/Ki67-double-positive cells in cardiac fibroblasts from TLR9-deficient hearts. Although the TLR9 signaling pathway is not involved in the acute inflammatory response in infarct hearts, it ameliorates cardiac rupture possibly by promoting proliferation and differentiation of cardiac fibroblasts.Listen to this article’s corresponding podcast @ http://ajpheart.podbean.com/e/tlr9-in-post-infarct-cardiac-rupture/ .
Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in α- and β-myosin heavy chain fibers
Authors: Mickelson Alexis V. , Gollapudi Sampath K. , Chandra Murali 
Published: October 2016

The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation A28V in cardiac troponin T (TnT). The A28V mutation is located within the NH2terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how α- and β-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH2terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by α- and β-MHC isoforms. Recombinant wild-type mouse TnT (TnTWT) and the mouse equivalent of the human A28V mutation (TnTA30V) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (α-MHC) and transgenic (β-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnTA30Vdecreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges ( ER) by 30% in α-MHC fibers. In sharp contrast, TnTA30Vincreased ERby 55% in β-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in ERin TnTA30V+ α-MHC and TnTA30V+ β-MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnTA30V-mediated effects on Ca2+-activated maximal tension and instantaneous muscle fiber stiffness ( ED) were also divergently affected by α- and β-MHC. Our study demonstrates that TnTA30V+ α-MHC and TnTA30V+ β-MHC fibers show contrasting contractile phenotypes; however, only the observations from β-MHC fibers are consistent with the clinical data for A28V in humans.NEW & NOTEWORTHY The differential impact of α- and β-myosin heavy chain (MHC) on contractile dynamics causes a mutant cardiac troponin T (TnTA30V) to differently modulate cardiac contractile function. TnTA30Vattenuated Ca2+-activated maximal tension and length-mediated cross-bridge recruitment against α-MHC but augmented these parameters against β-MHC, suggesting divergent contractile phenotypes.
Left and right ventricular hemodynamic forces in healthy volunteers and elite athletes assessed with 4D flow magnetic resonance imaging
Authors: Arvidsson Per M. , Töger Johannes , Carlsson Marcus , Steding-Ehrenborg Katarina , Pedrizzetti Gianni , Heiberg Einar , Arheden Håkan 
Published: October 2016

Intracardiac blood flow is driven by hemodynamic forces that are exchanged between the blood and myocardium. Previous studies have been limited to 2D measurements or investigated only left ventricular (LV) forces. Right ventricular (RV) forces and their mechanistic contribution to asymmetric redirection of flow in the RV have not been measured. We therefore aimed to quantify 3D hemodynamic forces in both ventricles in a cohort of healthy subjects, using magnetic resonance imaging 4D flow measurements. Twenty five controls, 14 elite endurance athletes, and 2 patients with LV dyssynchrony were included. 4D flow data were used as input for the Navier-Stokes equations to compute hemodynamic forces over the entire cardiac cycle. Hemodynamic forces were found in a qualitatively consistent pattern in all healthy subjects, with variations in amplitude. LV forces were mainly aligned along the apical-basal longitudinal axis, with an additional component aimed toward the aortic valve during systole. Conversely, RV forces were found in both longitudinal and short-axis planes, with a systolic force component driving a slingshot-like acceleration that explains the mechanism behind the redirection of blood flow toward the pulmonary valve. No differences were found between controls and athletes when indexing forces to ventricular volumes, indicating that cardiac force expenditures are tuned to accelerate blood similarly in small and large hearts. Patients’ forces differed from controls in both timing and amplitude. Normal cardiac pumping is associated with specific force patterns for both ventricles, and deviation from these forces may be a sensitive marker of ventricular dysfunction. Reference values are provided for future studies.NEW & NOTEWORTHY Biventricular hemodynamic forces were quantified for the first time in healthy controls and elite athletes (n = 39). Hemodynamic forces constitute a slingshot-like mechanism in the right ventricle, redirecting blood flow toward the pulmonary circulation. Force patterns were similar between healthy subjects and athletes, indicating potential utility as a cardiac function biomarker.
Evaluation of Buccal Cell Samples for Studies of Oral Microbiota
Authors: Yu Guoqin , Phillips Steve , Gail Mitchell H. , Goedert James J. , Humphrys Michael , Ravel Jacques , Ren Yanfang , Caporaso Neil E. 
Published: October 2016

Abstract
Background: The human microbiota is postulated to affect cancer risk, but collecting microbiota specimens with prospective follow-up for diseases will take time. Buccal cell samples have been obtained from mouthwash for the study of human genomic DNA in many cohort studies. Here, we evaluate the feasibility of using buccal cell samples to examine associations of human microbiota and disease risk.
Methods: We obtained buccal cells from mouthwash in 41 healthy participants using a protocol that is widely employed to obtain buccal cells for the study of human DNA. We compared oral microbiota from buccal cells with that from eight other oral sample types collected by following the protocols of the Human Microbiome Project. Microbiota profiles were determined by sequencing 16S rRNA gene V3–V4 region.
Results: Compared with each of the eight other oral samples, the buccal cell samples had significantly more observed species (P &lt; 0.002) and higher alpha diversity (Shannon index, P &lt; 0.02). The microbial communities were more similar (smaller beta diversity) among buccal cells samples than in the other samples (P &lt; 0.001 for 12 of 16 weighted and unweighted UniFrac distance comparisons). Buccal cell microbial profiles closely resembled saliva but were distinct from dental plaque and tongue dorsum.
Conclusions: Stored buccal cell samples in prospective cohort studies are a promising resource to study associations of oral microbiota with disease.
Impact: The feasibility of using existing buccal cell collections in large prospective cohorts allows investigations of the role of oral microbiota in chronic disease etiology in large population studies possible today. Cancer Epidemiol Biomarkers Prev; 26(2); 249–53. ©2016 AACR.
Abstract A36: Resistance to IGF-1R targeted therapy by insulin-like growth factor 2-mediated tumor microenvironment network
Authors: Lee Ji-Sun , Lee Ho-Young 
Published: October 2016

Abstract
Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumor microenvironment (TME) to innate resistance to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R mAb that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumor infiltration of stromal cells and metastatic tumor growth and, ultimately, decreases overall survival of mice. Cixutumumab treatment stimulates recruitment of macrophages and fibroblasts via STAT3-dependent transcriptional up-regulation of IGF2 in cancer cells and paracrine IGF2/IGF-2R activation, resulting in the stroma-derived CXCL8 production and thus angiogenic and metastatic environment. Silencing IGF2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and angiogenic activities of vascular endothelial cells. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signaling network may overcome the adverse consequences of anti-IGF-1R mAb-based therapies.
Citation Format: Ji-Sun Lee, Ho-Young Lee. Resistance to IGF-1R targeted therapy by insulin-like growth factor 2-mediated tumor microenvironment network. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A36.
Abstract B21: Exostosin 1 regulates cancer cell stemness in breast cancer cells
Authors: Manandhar Sarala , Kim Chang-gu , Oh Su Young , Lee Sun-Hee , Seok Jiyoon , Jung Yuk-Dong , Lee Hye-Eun , Choi Young-Sun , Lee You Mie* 
Published: October 2016

Abstract
Cancer stem cells (CSCs), a group of cancer cells, are associated with resistance to radiation and chemotherapy and are implicated in recurrent of cancer. Exostosin 1 (EXT1) gene is widely reported as tumor suppressor and its indispensable role in elongation of heparan sulfate (HS) can speculate probable role as tumor promotor. In recent years, a number of tumors are reported to over express EXT1. Here, we investigated the role of EXT1 in the maintenance of cancer cell stemness. MCF7/ADR cells developed by exposing MCF7, breast cancer cells, to doxorubicin for several months in culture, showed high resistance to doxorubicin compared to MCF7, parental cell line. Doxorubicin resistant MCF7/ADR cells have enhanced P-glycoprotein (P-gp) expression. In FACs analysis, MCF7/ADR cells were accounted for high number of CSC population; they possessed large number of ALDH+ and CD44+/CD24- population compared to MCF7. CSC marker, CD44, was found overexpressed in MCF7/ADR compared to MCF7. Besides that, in mammosphere culture, MCF7/ADR cells formed large number of mammospheres in contrast to MCF7. In microarray data analysis, several genes were found upregulated in MCF7/ADR cells and EXT1 was selected as a candidate gene. Overexpressed EXT1 in MCF7/ADR cells was confirmed by real time PCR. The critical role of EXT1 in maintaining cancer cell stemness was confirmed by siRNA mediated knockdown of EXT1. Knockdown of EXT1 repressed CSC markers, reduced population of ALDH+ and CD44+/CD24-, and suppressed expression of CD44. As a molecular mechanism, we detected suppressed expression of heparan sulfate, syndecan1(SDC1) with siEXT1. With these results, we can suggest that EXT1 level might be a determining factor for doxorubicin sensitive breast cancer cells and enhanced expression of EXT1 can take part in development of CSC phenotype on exposure to anthracycline based therapy through upregulation of SDC1.
Citation Format: Sarala Manandhar, Chang-gu Kim, Su Young Oh, Sun-Hee Lee, Jiyoon Seok, Yuk-Dong Jung, Hye-Eun Lee, Young-Sun Choi, You Mie Lee*. Exostosin 1 regulates cancer cell stemness in breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B21.