bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Exacerbation and Respiratory InfectionS in COPD (AERIS): protocol for a prospective, observational cohort study
Authors: Bourne Simon , Cohet Catherine , Kim Viktoriya , Barton Anna , Tuck Andy , Aris Emmanuel , Mesia-Vela Sonia , Devaster Jeanne-Marie , Ballou W Ripley , Clarke Stuart , Wilkinson Tom 
Published: March 2014

IntroductionThe aetiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) remains incompletely understood and strategies for treatment and prevention have not altered significantly for many years. Improved understanding of the role of respiratory pathogens in acute exacerbations of COPD (AECOPD) is required and the use of molecular microbiological techniques may lead to insights into host–pathogen interactions and the development of more targeted therapeutic approaches.Methods and analysesAcute Exacerbation and Respiratory InfectionS in COPD (AERIS) is a longitudinal epidemiological study to assess how changes in the COPD airway microbiome contribute to the incidence and severity of AECOPD. Patients with COPD aged 40–85 are followed monthly for 2 years, and reviewed within 72 h of onset of symptoms of AECOPD. Exacerbations are detected using daily electronic diary cards. Blood, sputum, nasopharyngeal and urine samples are collected at prespecified timepoints. Molecular diagnostic and typing techniques are used to describe the dynamics of airway infection during AECOPD and stable disease, and associations with clinical outcome. This study aims to refine the case definition of AECOPD to reflect the possible microbiological aetiology. AERIS will assess the impact of AECOPD on health-related quality of life and healthcare resource utilisation, and the possible interactions between nutritional status, infection and immune responses.Ethics and disseminationAERIS is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and has been approved by the institutional ethics and review board. All participants must provide written informed consent. The results obtained will be disseminated at international medical conferences and in peer-reviewed publications.DiscussionFew other studies have addressed the complexity of the microbiological and systemic components of COPD or employed real-time electronic tracking of symptoms to identify AECOPD and potential aetiological triggers.ResultsResults of AERIS will increase our understanding of the contribution of pathogens to AECOPD, potentially leading to new targeted therapeutic and preventative interventions.Trial registration numberClinicalTrials.govNCT01360398.
Protocol for the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) retrospective study of coronary catheterisation and percutaneous coronary intervention
Authors: Li Jing , Dharmarajan Kumar , Li Xi , Lin Zhenqiu , Normand Sharon-Lise T , Krumholz Harlan M , Jiang Lixin ,   for the China PEACE Collaborative Group
Published: March 2014

IntroductionDuring the past decade, the volume of percutaneous coronary intervention (PCI) in China has risen by more than 20-fold. Yet little is known about patterns of care and outcomes across hospitals, regions and time during this period of rising cardiovascular disease and dynamic change in the Chinese healthcare system.Methods and analysisUsing the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) research network, the Retrospective Study of Coronary Catheterisation and Percutaneous Coronary Intervention (China PEACE-Retrospective CathPCI Study) will examine a nationally representative sample of 11 900 patients who underwent coronary catheterisation or PCI at 55 Chinese hospitals during 2001, 2006 and 2011. We selected patients and study sites using a two-stage cluster sampling design with simple random sampling stratified within economical-geographical strata. A central coordinating centre will monitor data quality at the stages of case ascertainment, medical record abstraction and data management. We will examine patient characteristics, diagnostic testing patterns, procedural treatments and in-hospital outcomes, including death, complications of treatment and costs of hospitalisation. We will additionally characterise variation in treatments and outcomes by patient characteristics, hospital, region and study year.Ethics and disseminationThe China PEACE collaboration is designed to translate research into improved care for patients. The study protocol was approved by the central ethics committee at the China National Center for Cardiovascular Diseases (NCCD) and collaborating hospitals. Findings will be shared with participating hospitals, policymakers and the academic community to promote quality monitoring, quality improvement and the efficient allocation and use of coronary catheterisation and PCI in China.Registration detailshttp://www.clinicaltrials.gov(NCT01624896).
Contribution of hospital mortality variations to socioeconomic disparities in in-hospital mortality
Authors: Kim Yoon , Oh Juhwan , Jha Ashish 
Published: March 2014

BackgroundWhile disparities in hospital care outcomes based on ethnicity or socioeconomic status have been documented in some nations, it is unclear to what extent this phenomenon occurs in high-income countries like Korea with relatively low income inequality.MethodsWe examined in-hospital mortality rates for wealthy and poor patients in South Korea for five common medical conditions. We measured in-hospital mortality rates and examined within-hospital differences (wealthy and poor patients receive different care at the same institution) as well as between-hospital differences (wealthy and poor patients receiving care at different institutions) across socioeconomic status. We built multivariable models that adjusted for risk and further adjusted our analyses for hospital characteristics including a hospital's overall mortality ranking.ResultsThere were 127 438 patients with one of the five conditions examined nested in 66 Korean hospitals. We found moderate differences in mortality rates between wealthy and poor patients across four of the five conditions. These mortality differences were largely attributable to differences in mortality rates for wealthy patients compared with those for poor patients within the same hospital (within-hospital variation) while a relatively small portion of these disparities were attributable to mortality difference between hospitals where wealthy and poor patients seek care (between-hospital variation). For example, we estimate that improving care for poor patients in the same hospital can eliminate 86% of the disparities for acute myocardial infarction outcomes, while ensuring equal access to low mortality hospitals would reduce only 16% of the disparities in outcomes.ConclusionsThis study suggests that to reduce socioeconomic disparities in hospital mortality, interventions that target within-hospital effects may be more effective than interventions targeting between hospital effects.
WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma
Authors: Rauscher Julian , Beschorner Rudi , Gierke Midea , Bisdas Sotirios , Braun Christian , Ebner Florian H , Schittenhelm Jens 
Published: March 2014

AimsThe zinc finger transcription factor WT1 is expressed in astrocytic neoplasms and therefore is a potential target of immunotherapy in brain tumours. Our aim was to further elucidate the role of WT1 as a diagnostic and prognostic marker in neuropathology, particularly as to the differentiation of astrocytoma from oligodendroglioma as well as to the dependency of WT1 expression on clinically relevant parameters.Methods829 evaluable brain tumour samples were investigated by WT1 immunohistochemistry on full tissue routine slides, consisting of 442 glioblastomas, 303 astrocytomas, 41 oligodendrogliomas and 43 oligoastrocytomas. In addition public WT1 gene expression data of 351 gliomas were analysed.ResultsOur data show that WT1 expression in diffuse astrocytic tumours increases with WHO tumour grade and is associated with older age, absence of IDH1 mutation but not related to O(6)- methyl guanine methyl transferase (MGMT) promoter methylation status. Univariable, but not multivariable survival analysis indicates that WT1 expression is associated with worse outcome in patients with diffuse astrocytoma but not glioblastoma.ConclusionsThe significant WT1 expression differences between diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas, which are also present in the Repository for Molecular Brain Neoplasia Data, National Cancer Institute (REMBRANDT, 2005, http://rembrandt.nci.nih.gov) gene database set, provide a rationale for use of WT1 as part of a routine immunohistochemistry panel.
Immunohistochemical analysis of molecular drivers in melanoma identifies p16 as an independent prognostic biomarker
Authors: Lade-Keller Johanne , Riber-Hansen Rikke , Guldberg Per , Schmidt Henrik , Hamilton-Dutoit Stephen Jacques , Steiniche Torben 
Published: March 2014

AimsTo perform immunohistochemical (IHC) analysis of molecular drivers related to the development and maintenance of melanoma and to assess their value as diagnostic and prognostic melanoma biomarkers in routine clinical practice.MethodsTissue microarrays constructed from a cohort of primary melanomas (n=355), benign naevi (n=37) and melanoma metastases (n=14) were evaluated for IHC expression of c-KIT, BRAFV600E, MITF, p16, p53 and PTEN, as well as for pERK, a surrogate marker for mitogen-activated protein kinase pathway activation. The results were correlated with clinicopathological parameters and clinical outcome.ResultsAbsent p16 expression and reduced MITF expression were both associated with the adverse prognostic markers ulceration (p=0.009 and p<0.0001, respectively), advanced tumour stage (p<0.0001 and p=0.001, respectively) and higher Breslow thickness (both p<0.0001), as well as with an adverse overall relapse-free survival (p<0.0001 and p=0.003, respectively). Absence of p16 expression predicted overall relapse-free (p=0.02) and distant metastasis-free (p=0.04) survival, independently of Breslow thickness, ulceration and tumour stage.ConclusionsIHC determined p16 expression is an independent prognostic biomarker of potential value in routine melanoma diagnostic practice.
EBS behaviour immediately after repository closure in a clay host rock: HE-E experiment (Mont Terri URL)
Authors: Gaus I. , Wieczorek K. , Schuster K. , Garitte B. , Senger R. , Vasconcelos R. , Mayor J. C. 
Published: March 2014

Abstract
The evolution of the clay-based engineered barrier system (EBS) of geological repositories for radioactive waste has been the subject of many research programmes during the last decade. The early post-closure thermal behaviour is elucidated by the HE-E experiment, a 1:2 scale heating experiment (at the Mont Terri Rock Laboratory), which was implemented in the first semester of 2011, with the initiation of the heating phase in June 2011. A maximum temperature of 140 °C was reached in June 2012. After 15 months of heating, the temperature evolution in the EBS and the Opalinus Clay reflects the design calculations, and thermally induced porewater overpressures are being measured at a few metres’ distance in the Opalinus Clay. Seismic methods proved to be a sensitive tool for the continuous characterization of changes of EBS and Opalinus Clay properties. Design modelling and predictive modelling based on the as-built parameter dataset with established coupled codes (TOUGH, CODE_BRIGHT; using various geometries) are described. The results indicate that the models are generally in agreement with the observations and capable of capturing the evolution of the experiment.
JNK Signaling Mediates EPHA2-Dependent Tumor Cell Proliferation, Motility, and Cancer Stem Cell–like Properties in Non–Small Cell Lung Cancer
Authors: Song Wenqiang , Ma Yufang , Wang Jialiang , Brantley-Sieders Dana , Chen Jin 
Published: March 2014

Abstract
Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non–small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here, we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a c-JUN-NH2-kinase (JNK) inhibitor, recapitulated defects in EPHA2-deficient tumor cells, whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem–like cells (CSC). RNA interference-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH+ cancer stem–like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH+ populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung CSCs. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in CSC function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC. Cancer Res; 74(9); 2444–54. ©2014 AACR.
Identification of miR-133b and RB1CC1 as Independent Predictors for Biochemical Recurrence and Potential Therapeutic Targets for Prostate Cancer
Authors: Li Xia , Wan Xuechao , Chen Hongbing , Yang Shu , Liu Yiyang , Mo Wenjuan , Meng Delong , Du Wenting , Huang Yan , Wu Hai , Wang Jingqiang , Li Tao , Li Yao 
Published: March 2014

AbstractObjective: We aimed to investigate the contribution of microRNA-133b (miR-133b) in prostate cancer cell proliferation, cell cycle, and apoptosis. We also examined expression of miR-133b in prostate cancer tissues, and evaluated the prognostic significance of miR-133b, as well as its target gene RB1CC1 in patients with prostate cancer after radical prostatectomy.Experimental Design: miR-133b mimics (miR-133bm) and anti–miR-133b were transfected into LNCaP and PC-3 cells. CCK-8 was used to look at cell proliferation, flow cytometric analysis was carried out to study cell cycle, and apoptosis was determined by caspase-3 activity. miR-133b expression was assessed by real-time reverse transcription PCR and in situ hybridization in prostatic cell lines and 178 prostate tissue samples, respectively. The protein level of RB1CC1 was examined by Western blot and immunohistochemistry in prostatic cell lines and prostate tissue samples, respectively.Results: Overexpression of miR-133b in LNCaP cells boosted cell proliferation and cell-cycle progression, but inhibited apoptosis; in contrast, miR-133bm promoted cell apoptosis, but suppressed cell proliferation and cell-cycle progression in PC-3 cells. In LNCaP cells, silencing of RB1CC1, a target of miR-133b, inhibited cell apoptosis, and promoted cell-cycle progression. Moreover, miR-133b expression was significantly inversely correlated with RB1CC1 expression in prostate cancer tissues. Multivariate Cox analysis indicated that miR-133b and RB1CC1 might be two independent prognostic factors of biochemical recurrence.Conclusions: miR-133b might enhance tumor-promoting properties in less aggressive LNCaP cells, whereas this miR may act as a tumor suppressor in more aggressive PC-3 cells. miR-133b and RB1CC1 were independent prognostic indicators for prostate cancer. Clin Cancer Res; 20(9); 2312–25. ©2014 AACR.
Selective JAK2 Inhibition Specifically Decreases Hodgkin Lymphoma and Mediastinal Large B-cell Lymphoma Growth In Vitro and In Vivo
Authors: Hao Yansheng , Chapuy Bjoern , Monti Stefano , Sun Heather H. , Rodig Scott J. , Shipp Margaret A. 
Published: March 2014

Abstract
Purpose: Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers.
Experimental Design: We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number.
Results: Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number–dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition.
Conclusions: In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted. Clin Cancer Res; 20(10); 2674–83. ©2014 AACR.
Autophagy Is a Survival Mechanism of Acute Myelogenous Leukemia Precursors during Dual mTORC2/mTORC1 Targeting
Authors: Altman Jessica K. , Szilard Amy , Goussetis Dennis J. , Sassano Antonella , Colamonici Marco , Gounaris Elias , Frankfurt Olga , Giles Francis J. , Eklund Elizabeth A. , Beauchamp Elspeth M. , Platanias Leonidas C. 
Published: March 2014

Abstract
Purpose: To examine whether induction of autophagy is a mechanism of leukemic cell resistance to dual mTORC1/mTORC2 inhibitors in acute myelogenous leukemia (AML) leukemic progenitors.
Experimental Design: Combinations of different experimental approaches were used to assess induction of autophagy, including immunoblotting to detect effects on LC3II and p62/SQTM1 expression and on ULK1 phosphorylation, immunofluorescence, and electron microscopy. Functional responses were assessed using cell viability and apoptosis assays, and clonogenic leukemic progenitor assays in methylcellulose.
Results: We provide evidence that treatment of AML cells with catalytic mTOR inhibitors results in induction of autophagy, which acts as a regulatory mechanism to promote leukemic cell survival. Such induction of autophagy by dual mTORC1/mTORC2 inhibitors partially protects primitive leukemic precursors from the inhibitory effects of such agents and limits their activities. Simultaneous blockade of the autophagic process using chloroquine or by knockdown of ULK1 results in enhanced antileukemic responses.
Conclusions: Dual targeting of mTORC2 and mTORC1 results in induction of autophagy in AML cells. Combinations of catalytic mTOR targeting agents and autophagy inhibitors may provide a unique approach to target primitive leukemic precursors in AML. Clin Cancer Res; 20(9); 2400–9. ©2014 AACR.
Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer
Authors: Meric-Bernstam Funda , Frampton Garrett M. , Ferrer-Lozano Jaime , Yelensky Roman , Pérez-Fidalgo Jose A. , Wang Ying , Palmer Gary A. , Ross Jeffrey S. , Miller Vincent A. , Su Xiaoping , Eroles Pilar , Barrera Juan Antonio , Burgues Octavio , Lluch Ana M. , Zheng Xiaofeng , Sahin Aysegul , Stephens Philip J. , Mills Gordon B. , Cronin Maureen T. , Gonzalez-Angulo Ana M. 
Published: March 2014

AbstractThere is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1–12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed. Mol Cancer Ther; 13(5); 1382–9. ©2014 AACR.
High Birth Weight Is Associated With Obesity and Increased Carotid Wall Thickness in Young Adults
Authors: Skilton Michael R. , Siitonen Niina , Würtz Peter , Viikari Jorma S.A. , Juonala Markus , Seppälä Ilkka , Laitinen Tomi , Lehtimäki Terho , Taittonen Leena , Kähönen Mika , Celermajer David S. , Raitakari Olli T. 
Published: March 2014

Objective—
There is some evidence that people born with high birth weight may be at increased risk of cardiovascular disease in adulthood. Details of the underlying mechanisms remain unknown. We sought to determine whether people born large for gestational age have poor arterial health, increased adiposity, and a poor cardiovascular risk factor profile.

Approach and Results—

Carotid intima-media thickness, brachial flow–mediated dilatation, and cardiovascular risk factors were compared between young adults (24–45 years) born at term who were large for gestational age (birth weight >90th percentile; n=171), and a control group with normal birth weight (50–75th percentile; n=525), in the Cardiovascular Risk in Young Finns Study. Those born large for gestational age had higher body mass index throughout childhood, adolescence, and as young adults (26.4 kg/m
2
[SD 4.9], versus normal birth weight 25.1 kg/m
2
[SD 4.6];
P
=0.002), and 2-fold greater risk of obesity. Other cardiovascular risk factors and arterial function did not differ; however, carotid intima-media thickness was increased in people born large for gestational age (0.60 mm [SD 0.09], versus normal birth weight 0.57 mm [SD 0.09];
P
=0.003), independent of cardiovascular risk factors (
P
=0.001 after adjustment). Both obesity and high birth weight were independently associated with carotid intima-media thickness in a graded and additive fashion.

Conclusions—
Young adults born large for gestational age are more likely to be obese, yet have an otherwise healthy cardiovascular risk profile. Nonetheless, they have increased carotid intima-media thickness, a marker of subclinical atherosclerosis, consistent with an increased risk of cardiovascular disease.