bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mode of delivery at birth and the metabolic syndrome in midlife: the role of the birth environment in a prospective birth cohort study
Authors: Bouhanick Béatrice , Ehlinger Virginie , Delpierre Cyrille , Chamontin Bernard , Lang Thierry , Kelly-Irving Michelle 
Published: May 2014

ObjectivesThe aim of this study is to examine the hypothesis that mode of delivery at birth may be associated with metabolic disorders in adult midlife.SettingPopulation cohort studyParticipantsThe National Child Development Study consists of individuals born during 1 week in 1958 in Great Britain. Respondents with biomedical data on the metabolic syndrome at age 45 were included.Outcome measureThe metabolic syndrome was defined based on the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III classification.Results7156 were born naturally; among the caesarean births, 106 were non-elective and 85 were elective caesareans. The metabolic syndrome is present in 37.7% of those born by non-elective caesareans, 25.9% of those born by elective caesarean and 27.5% of those born by vaginal delivery. In a multivariate logistic regression model adjusted for antenatal factors, birth history, mother's characteristics and the socioeconomic environment at birth, only birth by non-elective caesarean remained associated with the metabolic syndrome in adulthood compared with vaginal delivery (OR 1.51, 95% CI 1.00 to 2.30). Mother's obesity (OR 1.61, 95% CI 1.12 to 2.34) and low maternal education level (OR 1.47, 95% CI 1.30 to 1.67) were also independently associated with midlife metabolic syndrome.ConclusionsBirth by non-elective caesarean in 1958 may be associated with metabolic syndrome in adulthood after adjusting for prior confounding factors. We suggest that the birth context of emergency caesareans in 1958 is suggestive of a ‘fetal stress’ mechanism affecting health across the lifecourse.
Doing challenging research studies in a patient-centred way: a qualitative study to inform a randomised controlled trial in the paediatric emergency care setting
Authors: Woolfall Kerry , Young Bridget , Frith Lucy , Appleton Richard , Iyer Anand , Messahel Shrouk , Hickey Helen , Gamble Carrol 
Published: May 2014

ObjectiveTo inform the design of a randomised controlled trial (called EcLiPSE) to improve the treatment of children with convulsive status epilepticus (CSE). EcLiPSE requires the use of a controversial deferred consent process.DesignQualitative interview and focus group study.Setting8 UK support groups for parents of children who have chronic or acute health conditions and experience of paediatric emergency care.Participants17 parents, of whom 11 participated in telephone interviews (10 mothers, 1 father) and 6 in a focus group (5 mothers, 1 father). 6 parents (35%) were bereaved and 7 (41%) had children who had experienced seizures, including CSE.ResultsMost parents had not heard of deferred consent, yet they supported its use to enable the progress of emergency care research providing a child's safety was not compromised by the research. Parents were reassured by tailored explanation, which focused their attention on aspects of EcLiPSE that addressed their priorities and concerns. These aspects included the safety of the interventions under investigation and how both EcLiPSE interventions are used in routine clinical practice. Parents made recommendations about the appropriate timing of a recruitment discussion, the need to individualise approaches to recruiting bereaved parents and the use of clear written information.ConclusionsOur study provided information to help ensure that a challenging trial was patient centred in its design. We will use our findings to help EcLiPSE practitioners to: discuss potentially threatening trial safety information with parents, use open-ended questions and prompts to identify their priorities and concerns and clarify related aspects of written trial information to assist understanding and decision-making.
Patient Reporting of Safety experiences in Organisational Care Transfers (PRoSOCT): a feasibility study of a patient reporting tool as a proactive approach to identifying latent conditions within healthcare systems
Authors: Scott Jason , Waring Justin , Heavey Emily , Dawson Pamela 
Published: May 2014

BackgroundIt is increasingly recognised that patients can play a role in reporting safety incidents. Studies have tended to focus on patients within hospital settings, and on the reporting of patient safety incidents as defined within a medical model of safety. This study aims to determine the feasibility of collecting and using patient experiences of safety as a proactive approach to identifying latent conditions of safety as patients undergo organisational care transfers.Methods and analysisThe study comprises three components: (1) patients’ experiences of safety relating to a care transfer, (2) patients’ receptiveness to reporting experiences of safety, (3) quality improvement using patient experiences of safety. (1) A safety survey and evaluation form will be distributed to patients discharged from 15 wards across four clinical areas (cardiac, care of older people, orthopaedics and stroke) over 1 year. Healthcare professionals involved in the care transfer will be provided with a regular summary of patient feedback. (2) Patients (n=36) who return an evaluation form will be sampled representatively based on the four clinical areas and interviewed about their experiences of healthcare and safety and completing the survey. (3) Healthcare professionals (n=75) will be invited to participate in semistructured interviews and focus groups to discuss their experiences with and perceptions of receiving and using patient feedback. Data analysis will explore the relationship between patient experiences of safety and other indicators and measures of quality and safety. Interview and focus group data will be thematically analysed and triangulated with all other data sources using a convergence coding matrix.Ethics and disseminationThe study has been granted National Health Service (NHS) Research Ethics Committee approval. Patient experiences of safety will be disseminated to healthcare teams for the purpose of organisational development and quality improvement. Results will be disseminated to study participants as well as through peer-reviewed outputs.
The OxVALVE population cohort study (OxVALVE-PCS)—population screening for undiagnosed valvular heart disease in the elderly: study design and objectives
Authors: Coffey Sean , d'Arcy Joanna L , Loudon Margaret A , Mant David , Farmer Andrew J , Prendergast Bernard D ,   for the OxVALVE-PCS group
Published: May 2014

IntroductionValvular heart disease (VHD) is an increasingly important cardiac condition, driven by an ageing population and lack of progress in the development of medical therapies. There is a dearth of accurate information to guide decision-makers in the development of strategies to combat VHD, and no population-based study has been performed specifically to investigate its contemporary epidemiology. This document describes the design and methodology of the OxVALVE population cohort study (OxVALVE-PCS), which was conceived to address this need.Methods and analysisParticipants aged 65 years and older attending a participating general practice in Oxfordshire, UK, are invited to attend a screening examination. Exclusion criteria include previously diagnosed VHD, inability to provide consent, terminal illness or excessive frailty. Demographics, a focused cardiovascular history and vital signs are recorded at the initial screening examination, accompanied by an echocardiogram. Any finding of significant VHD triggers a separate, more formal echocardiographic assessment (including acquisition of a three-dimensional dataset) and collection of blood samples for future genetic and biomarker analysis. Participants provide consent for longitudinal follow-up and enrolment in future cohort substudies. We also assess the acceptability of community-based echocardiographic examination and compare self-assessed quality of life between those with and without VHD.ConclusionsOxVALVE-PCS will provide contemporary epidemiological data concerning the community prevalence of undiagnosed VHD, facilitate accurate deployment of scarce resources to meet the anticipated increase in demand for VHD-associated healthcare and create a series of subcohorts with carefully defined genotypes and echocardiographic phenotypes for long overdue clinical studies.Ethics and disseminationThis study was approved by the local research ethics committee (Southampton, UK; REC Ref: 09/H0502/58).ResultsResults will be submitted for publication in peer-reviewed scientific journals.
The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors
Authors: Izumchenko Evgeny , Chang Xiaofei , Michailidi Christina , Kagohara Luciane , Ravi Rajani , Paz Keren , Brait Mariana , Hoque Mohammad O. , Ling Shizhang , Bedi Atul , Sidransky David 
Published: May 2014

AbstractAlthough specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKI), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial–mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here, we show that during transforming growth factor β (TGFβ)–mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of the mitogen-inducible gene 6 (MIG6), a negative regulator of EGFR. The MIG6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of MIG6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild-type EGFR showed that the tumor MIG6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ–miR200–MIG6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of MIG6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs. Cancer Res; 74(14); 3995–4005. ©2014 AACR.
Pooling Prospective Studies to Investigate the Etiology of Second Cancers
Authors: Black Amanda , Gibson Todd M. , Shiels Meredith S. , Park Yikyung , Robien Kim , Albanes Demetrius , Weinstein Stephanie J. , Freeman Laura E. Beane , Andreotti Gabriella , Purdue Mark P. , Fraumeni Joseph F. , Hartge Patricia , Tucker Margaret A. , Hoover Robert N. , Cerhan James R. , Zeleniuch-Jacquotte Anne , Curtis Rochelle E. , Elena Joanne , Sampson Joshua N. , de Gonzalez Amy Berrington , Morton Lindsay M. 
Published: May 2014

Abstract
Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology.
Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements.
Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers.
Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention.
Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.
NADPH Oxidases as Therapeutic Targets in Chronic Myelogenous Leukemia
Authors: Sánchez-Sánchez Beatriz , Gutiérrez-Herrero Sara , López-Ruano Guillermo , Prieto-Bermejo Rodrigo , Romo-González Marta , Llanillo Marcial , Pandiella Atanasio , Guerrero Carmen , Miguel Jesús F. San , Sánchez-Guijo Fermín , del Cañizo Consuelo , Hernández-Hernández Angel 
Published: May 2014

Abstract
Purpose: Cancer cells show higher levels of reactive oxygen species (ROS) than normal cells and increasing intracellular ROS levels are becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myelogenous leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here, we assessed NADPH oxidases as therapeutic targets in CML.
Experimental Design: We have analyzed the effect of different NADPH oxidase inhibitors, either alone or in combination with BCR-ABL inhibitors, in CML cells and in two different animal models for CML.
Results: NADPH oxidase inhibition dramatically impaired the proliferation and viability of BCR-ABL–expressing cells due to the attenuation of BCR-ABL signaling and a pronounced cell-cycle arrest. Moreover, the combination of NADPH oxidase inhibitors with BCR-ABL inhibitors was highly synergistic. Two different animal models underscore the effectiveness of NADPH oxidase inhibitors and their combination with BCR-ABL inhibitors for CML targeting in vivo.
Conclusion: Our results offer further therapeutic opportunities for CML, by targeting NADPH oxidases. In the future, it would be worthwhile conducting further experiments to ascertain the feasibility of translating such therapies to clinical practice. Clin Cancer Res; 20(15); 4014–25. ©2014 AACR.
Neural Autoantibody Clusters Aid Diagnosis of Cancer
Authors: Horta Erika S. , Lennon Vanda A. , Lachance Daniel H. , Jenkins Sarah M. , Smith Carin Y. , McKeon Andrew , Klein Christopher , Pittock Sean J. 
Published: May 2014

Abstract
Purpose: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer.
Patients and Methods: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil).
Results: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P &lt; 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies).
Conclusions: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type. Clin Cancer Res; 20(14); 3862–9. ©2014 AACR.
Rescue of Notch-1 Signaling in Antigen-Specific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer
Authors: Sierra Rosa A. , Thevenot Paul , Raber Patrick L. , Cui Yan , Parsons Chris , Ochoa Augusto C. , Trillo-Tinoco Jimena , Valle Luis Del , Rodriguez Paulo C. 
Published: May 2014

Abstract
An impaired antitumor immunity is found in patients with cancer and represents a major obstacle in the successful development of different forms of immunotherapy. Signaling through Notch receptors regulates the differentiation and function of many cell types, including immune cells. However, the effect of Notch in CD8+ T-cell responses in tumors remains unclear. Thus, we aimed to determine the role of Notch signaling in CD8+ T cells in the induction of tumor-induced suppression. Our results using conditional knockout mice show that Notch-1 and Notch-2 were critical for the proliferation and IFNγ production of activated CD8+ T cells and were significantly decreased in tumor-infiltrating T cells. Conditional transgenic expression of Notch-1 intracellular domain (N1IC) in antigen-specific CD8+ T cells did not affect activation or proliferation of CD8+ T cells, but induced a central memory phenotype and increased cytotoxicity effects and granzyme B levels. Consequently, a higher antitumor response and resistance to tumor-induced tolerance were found after adoptive transfer of N1IC-transgenic CD8+ T cells into tumor-bearing mice. Additional results showed that myeloid-derived suppressor cells (MDSC) blocked the expression of Notch-1 and Notch-2 in T cells through nitric oxide–dependent mechanisms. Interestingly, N1IC overexpression rendered CD8+ T cells resistant to the tolerogenic effect induced by MDSC in vivo. Together, the results suggest the key role of Notch in the suppression of CD8+ T-cell responses in tumors and the therapeutic potential of N1IC in antigen-specific CD8+ T cells to reverse T-cell suppression and increase the efficacy of T cell–based immunotherapies in cancer. Cancer Immunol Res; 2(8); 800–11. ©2014 AACR.
Risk Factor Differences in Calcified and Noncalcified Aortic Plaque
Authors: Chuang Michael L. , Gona Philimon , Oyama-Manabe Noriko , Manders Emily S. , Salton Carol J. , Hoffmann Udo , Manning Warren J. , O’Donnell Christopher J. 
Published: May 2014

Objective—
The objective of this study was to determine the prevalence and risk factor (RF) correlates of aortic plaque (AP) detected by cardiovascular magnetic resonance (CMR), which mainly shows noncalcified plaques, and by noncontrast computed tomography (CT), which best depicts calcified plaques, in community-dwelling adults.

Approach and Results—

A total of 1016 Framingham Heart Study Offspring cohort members (64±9 years; 474 men) underwent CMR and CT of the aorta. Potential RFs for AP (age; sex; body mass index; blood pressure; low-density lipoprotein and high-density lipoprotein cholesterol; fasting glucose; C-reactive protein; prevalent hypertension, diabetes mellitus, smoking; use of antihypertensive, diabetes mellitus, or lipid-lowering drugs) were compared between participants, with zero versus nonzero AP by CMR and by CT. Candidate RFs attaining
P
<0.05 for difference with either imaging modality were entered into multivariable logistic regression models adjusting for age, sex, and other RFs. Odds ratios were calculated for modality-specific prevalence of AP. Associations between RFs and continuous measures of AP were assessed using Tobit regression. Prevalence of CMR and CT AP was 49% and 82%, respectively. AP burdens by CMR and CT were correlated,
r
=0.28,
P
<0.0001. Increasing age and smoking were associated with prevalent AP by both CMR and CT. Additionally, prevalent AP by CMR was associated with female sex and fasting glucose and prevalent AP by CT with hypertension treatment and adverse lipid profile.

Conclusions—
AP by CMR and CT are both associated with smoking and increasing age, but other RFs differ between calcified and noncalcified AP. The relative predictive value of AP detected by CMR versus by CT for incident cardiovascular events remains to be determined.
Transcriptional Regulation of Endothelial Arginase 2 by Histone Deacetylase 2
Authors: Pandey Deepesh , Sikka Gautam , Bergman Yehudit , Kim Jae Hyung , Ryoo Sungwoo , Romer Lewis , Berkowitz Dan 
Published: May 2014

Objective—
Arginase 2 (Arg2) is a critical target in atherosclerosis because it controls endothelial nitric oxide, proliferation, fibrosis, and inflammation. Regulators of Arg2 transcription in the endothelium have not been characterized. The goal of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial Arg2 transcription and endothelial function.

Approach and Results—
The HDAC inhibitor trichostatin A increased levels of Arg2 mRNA, protein, and activity in both human aortic endothelial cells and mouse aortic rings. These changes occurred in both time- and dose-dependent patterns and resulted in Arg2-dependent endothelial dysfunction. Trichostatin A and the atherogenic stimulus oxidized low-density lipoprotein enhanced the activity of common promoter regions of Arg2. HDAC inhibition with trichostatin A also decreased endothelial nitric oxide, and these effects were blunted by arginase inhibition. Nonselective class I HDAC inhibitors enhanced Arg2 expression, whereas the only selective inhibitor that increased Arg2 expression was mocetinostat, a selective inhibitor of HDACs 1 and 2. Additionally, mouse aortic rings preincubated with mocetinostat exhibited dysfunctional relaxation. Overexpression of HDAC2 (but not HDAC 1, 3, or 8) cDNA in human aortic endothelial cells suppressed Arg2 expression in a concentration-dependent manner, and siRNA knockdown of HDAC2 enhanced Arg2 expression. Chromatin immunoprecipitation indicated direct binding of HDAC2 to the Arg2 promoter, and HDAC2 overexpression in human aortic endothelial cells blocked oxidized low-density lipoprotein–mediated activation of the Arg2 promoter. Finally, overexpression of HDAC2 blocked oxidized low-density lipoprotein–mediated vascular dysfunction.

Conclusions—
HDAC2 is a critical regulator of Arg2 expression and thereby endothelial nitric oxide and endothelial function. Overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis.