bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system
Authors: Rajendran Pradeep S. , Nakamura Keijiro , Ajijola Olujimi A. , Vaseghi Marmar , Armour J. Andrew , Ardell Jeffrey L. , Shivkumar Kalyanam 
Published: November 2015

Key points
Intrinsic cardiac (IC) neurons undergo differential morphological and phenotypic remodelling that reflects the site of myocardial infarction (MI).
Afferent neural signals from the infarcted region to IC neurons are attenuated, while those from border and remote regions are preserved post‐MI, giving rise to a ‘neural sensory border zone’.
Convergent IC local circuit (processing) neurons have enhanced transduction capacity following MI.
Functional network connectivity within the intrinsic cardiac nervous system is reduced post‐MI.
MI reduces the response and alters the characteristics of IC neurons to ventricular pacing.
AbstractAutonomic dysregulation following myocardial infarction (MI) is an important pathogenic event. The intrinsic cardiac nervous system (ICNS) is a neural network located on the heart that is critically involved in autonomic regulation. The aims of this study were to characterize structural and functional remodelling of the ICNS post‐MI in a porcine model (control (n = 16) vs. healed anteroapical MI (n = 16)). In vivo microelectrode recordings of basal activity, as well as responses to afferent and efferent stimuli, were recorded from intrinsic cardiac neurons. From control 118 neurons and from MI animals 102 neurons were functionally classified as afferent, efferent, or convergent (receiving both afferent and efferent inputs). In control and MI, convergent neurons represented the largest subpopulation (47% and 48%, respectively) and had enhanced transduction capacity following MI. Efferent inputs to neurons were maintained post‐MI. Afferent inputs were attenuated from the infarcted region (19% in control vs. 7% in MI; P = 0.03), creating a ‘neural sensory border zone’, or heterogeneity in afferent information. MI reduced transduction of changes in preload (54% in control vs. 41% in MI; P = 0.05). The overall functional network connectivity, or the ability of neurons to respond to independent pairs of stimuli, within the ICNS was reduced following MI. The neuronal response was differentially decreased to ventricular vs. atrial pacing post‐MI (63% in control vs. 44% in MI to ventricular pacing; P < 0.01). MI induced morphological and phenotypic changes within the ICNS. The alteration of afferent neural signals, and remodelling of convergent neurons, represents a ‘neural signature’ of ischaemic heart disease.
Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia
Authors: Turner Mark J. , Saint‐Criq Vinciane , Patel Waseema , Ibrahim Salam H. , Verdon Bernard , Ward Christopher , Garnett James P. , Tarran Robert , Cann Martin J. , Gray Michael A. 
Published: November 2015

Key points
Raised arterial blood CO2 (hypercapnia) is a feature of many lung diseases.
CO2 has been shown to act as a cell signalling molecule in human cells, notably by influencing the levels of cell signalling second messengers: cAMP and Ca2+.
Hypercapnia reduced cAMP‐stimulated cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid transport in Calu‐3 cells and primary human airway epithelia but did not affect cAMP‐regulated HCO3− transport via pendrin or Na+/HCO3− cotransporters.
These results further support the role of CO2 as a cell signalling molecule and suggests CO2‐induced reductions in airway anion and fluid transport may impair innate defence mechanisms of the lungs.
AbstractHypercapnia is clinically defined as an arterial blood partial pressure of CO2 of above 40 mmHg and is a feature of chronic lung disease. In previous studies we have demonstrated that hypercapnia modulates agonist‐stimulated cAMP levels through effects on transmembrane adenylyl cyclase activity. In the airways, cAMP is known to regulate cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated anion and fluid secretion, which contributes to airway surface liquid homeostasis. The aim of the current work was to investigate if hypercapnia could modulate cAMP‐regulated ion and fluid transport in human airway epithelial cells. We found that acute exposure to hypercapnia significantly reduced forskolin‐stimulated elevations in intracellular cAMP as well as both adenosine‐ and forskolin‐stimulated increases in CFTR‐dependent transepithelial short‐circuit current, in polarised cultures of Calu‐3 human airway cells. This CO2‐induced reduction in anion secretion was not due to a decrease in HCO3− transport given that neither a change in CFTR‐dependent HCO3− efflux nor Na+/HCO3− cotransporter‐dependent HCO3− influx were CO2‐sensitive. Hypercapnia also reduced the volume of forskolin‐stimulated fluid secretion over 24 h, yet had no effect on the HCO3− content of the secreted fluid. Our data reveal that hypercapnia reduces CFTR‐dependent, electrogenic Cl− and fluid secretion, but not CFTR‐dependent HCO3− secretion, which highlights a differential sensitivity of Cl− and HCO3− transporters to raised CO2 in Calu‐3 cells. Hypercapnia also reduced forskolin‐stimulated CFTR‐dependent anion secretion in primary human airway epithelia. Based on current models of airways biology, a reduction in fluid secretion, associated with hypercapnia, would be predicted to have important consequences for airways hydration and the innate defence mechanisms of the lungs.
Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study
Authors: Carlsten Chris , Blomberg Anders , Pui Mandy , Sandstrom Thomas , Wong Sze Wing , Alexis Neil , Hirota Jeremy 
Published: November 2015

RationaleTraffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood.ObjectiveTo test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects.Methods18 blinded atopic volunteers were exposed to filtered air or 300 µg PM2.5/m3 of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points.ResultsDiesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells.ConclusionInhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust.Trial registration numberNCT01792232.
An Exploratory Study on Outcomes of Social Enterprises in South Africa
Authors: Urban Boris 
Published: November 2015

This article investigates social enterprises in terms of their outcomes. Few studies focus on social entrepreneurs that incorporate an impact assessment of their social enterprises. The article responds to calls where it has been noted that the rapidly expanding social enterprise sector of the economy is evolving without effective evaluation tools that can provide reliable measurement and impact assessment.The study is conducted in two major cities in South Africa, where social entrepreneurship has unequivocal application, considering that traditional government initiatives are unable to satisfy the entire social deficit, and where challenges to non-profit accountability are acute. Social outcomes are measured in terms of the following dimensions: impact/reach, innovativeness of solution, replicability/expandability and sustainability. A survey is used to collect data from 165 social enterprises and is interpreted using descriptive statistics.Results on sample characteristics indicate that a diverse group of individuals are involved in a wide range of social enterprise activities. Descriptive statistics across the dimensions reflect above-average mean scores suggesting favourable perceptions of social outcomes.By providing an elementary measuring tool for social outcomes, researchers can test its validity across different contexts. Social enterprises need to demonstrate solid impact and reach of their outcomes, so they can replicate interventions, build partnerships, and remain sustainable by meeting the needs of groups who have been failed by previous government attempts in social redress.The article provides a much needed account of the evaluation of social enterprise outcomes in an emerging market context.
Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-κB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer
Authors: Peng Jin , Hamanishi Junzo , Matsumura Noriomi , Abiko Kaoru , Murat Kumuruz , Baba Tsukasa , Yamaguchi Ken , Horikawa Naoki , Hosoe Yuko , Murphy Susan K. , Konishi Ikuo , Mandai Masaki 
Published: November 2015

Abstract
Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD-L1) in a NF-κB–dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8+ T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-κB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-κB–mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer. Cancer Res; 75(23); 5034–45. ©2015 AACR.
Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells
Authors: Lerner Robin G. , Grossauer Stefan , Kadkhodaei Banafsheh , Meyers Ian , Sidorov Maxim , Koeck Katharina , Hashizume Rintaro , Ozawa Tomoko , Phillips Joanna J. , Berger Mitchel S. , Nicolaides Theodore , James C. David , Petritsch Claudia K. 
Published: November 2015

Abstract
The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133+ tumor-propagating cells isolated from primary GBM cell lines. We show that CD133+ cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133− cells. Furthermore, CD133+ cells exhibited an extended G2–M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133+ cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P &lt; 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133+ cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment. Cancer Res; 75(24); 5355–66. ©2015 AACR.
Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages
Authors: Liu Yueying , Metzinger Matthew N. , Lewellen Kyle A. , Cripps Stephanie N. , Carey Kyle D. , Harper Elizabeth I. , Shi Zonggao , Tarwater Laura , Grisoli Annie , Lee Eric , Slusarz Ania , Yang Jing , Loughran Elizabeth A. , Conley Kaitlyn , Johnson Jeff J. , Klymenko Yuliya , Bruney Lana , Liang Zhong , Dovichi Norman J. , Cheatham Bentley , Leevy W. Matthew , Stack M. Sharon 
Published: November 2015

AbstractEpithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro, ex vivo, and in vivo studies to test the hypothesis that obesity contributes to ovarian cancer metastatic success. Initial in vitro studies using three-dimensional mesomimetic cultures showed enhanced cell–cell adhesion to the lipid-loaded mesothelium. Furthermore, in an ex vivo colonization assay, ovarian cancer cells exhibited increased adhesion to mesothelial explants excised from mice modeling diet-induced obesity (DIO), in which they were fed a “Western” diet. Examination of mesothelial ultrastructure revealed a substantial increase in the density of microvilli in DIO mice. Moreover, enhanced intraperitoneal tumor burden was observed in overweight or obese animals in three distinct in vivo models. Further histologic analyses suggested that alterations in lipid regulatory factors, enhanced vascularity, and decreased M1/M2 macrophage ratios may account for the enhanced tumorigenicity. Together, these findings show that obesity potently affects ovarian cancer metastatic success, which likely contributes to the negative correlation between obesity and ovarian cancer survival. Cancer Res; 75(23); 5046–57. ©2015 AACR.
An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy
Authors: Tavaré Richard , Escuin-Ordinas Helena , Mok Stephen , McCracken Melissa N. , Zettlitz Kirstin A. , Salazar Felix B. , Witte Owen N. , Ribas Antoni , Wu Anna M. 
Published: November 2015

Abstract
The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8+ T cells and other immune cell subsets. In this study, we describe the generation of 89Zr-desferrioxamine–labeled anti-CD8 cys-diabody (89Zr-malDFO-169 cDb) for noninvasive immuno-PET tracking of endogenous CD8+ T cells. We demonstrate that anti-CD8 immuno-PET is a sensitive tool for detecting changes in systemic and tumor-infiltrating CD8 expression in preclinical syngeneic tumor immunotherapy models including antigen-specific adoptive T-cell transfer, agonistic antibody therapy (anti-CD137/4-1BB), and checkpoint blockade antibody therapy (anti–PD-L1). The ability of anti-CD8 immuno-PET to provide whole body information regarding therapy-induced alterations of this dynamic T-cell population provides new opportunities to evaluate antitumor immune responses of immunotherapies currently being evaluated in the clinic. Cancer Res; 76(1); 73–82. ©2015 AACR.
Educação básica, Biblioteca e Espírito científico: circunstâncias e oportunidades
Authors: Garcez Eliane Fioravante 
Published: November 2015

<span style="font-family: 'Times New Roman'; font-size: 10pt; mso-fareast-font-family: PMingLiU; mso-fareast-language: PT-BR; mso-ansi-language: PT-BR; mso-bidi-language: AR-SA;">Discorre sobre a escola e os reflexos das mudanças sociais nela e a partir dela. Aborda a questão da re-produção do conhecimento e sua repercussão no social. Sucintamente, apresenta dados sobre a avaliação do ensino brasileiro através do Censo Escolar de 2010 e do Relatório Pisa/OECD de 2009, estreitando a relação entre a Política Nacional de Educação e as perspectivas de desenvolvimento do país. Trata sobre a questão da pesquisa científica, a partir do seu nascedouro, a escola de Educação Básica. A prática de trabalhos-cópia tem revelado sério problema nesse ensino, que repercute nos demais níveis educacionais. Vislumbra a possibilidade de uma reorganização curricular onde o aluno tenha oportunidade de exercitar-se autor. Essa premissa atende as perspectivas da construção do conhecimento, do desenvolvimento da autonomia, e de se avançar em ciência e em tecnologia. Garantir recursos, pessoas qualificadas e um currículo que ilumine o caminho transcorrido pelo aluno durante as etapas da pesquisa escolar são entendidos como prioritários na construção do espírito científico a partir da Educação Básica.<span style="mso-spacerun: yes;"> </span>Aborda a necessidade da ampliação de número de escolas com bibliotecas e laboratórios de ciências (química, física, biologia e matemática), e de profissionais qualificados para melhor orientar os alunos no uso desses recursos na escola.</span>
Depressive Symptoms and Risk of Cardiovascular Events in Blacks
Authors: O’Brien Emily C. , Greiner Melissa A. , Sims Mario , Hardy Natalie Chantelle , Wang Wei , Shahar Eyal , Hernandez Adrian F. , Curtis Lesley H. 
Published: November 2015

Background—
Most studies of depression and cardiovascular risk have been conducted in white populations. We investigated this association in a community-based cohort of blacks.

Methods and Results—

We used data from the Jackson Heart Study to investigate associations of baseline depressive symptoms between 2000 and 2004 with incident stroke and coronary heart disease (CHD) during 10 years. We used Kaplan–Meier estimates and Cox proportional hazards models to assess cardiovascular event risk using 3 exposure variables: any depressive symptoms (Center for Epidemiological Studies Depression score ≥16); none (score <16), minor (score 16 to <21), and major depression (score≥21); and Center for Epidemiological Studies Depression score per 1-SD increase. Models were adjusted for a stroke or CHD risk score and behavioral risk factors. Of 3309 participants with no stroke history, 738 (22.3%) had baseline depressive symptoms. A similar proportion with no previous CHD had baseline depressive symptoms (21.8%). The unadjusted 10-year risk of stroke was similar among participants with any compared with no depressive symptoms (3.7% versus 2.6%;
P
=0.12). Unadjusted CHD rates were higher among participants with depressive symptoms (5.6% versus 3.6%;
P
=0.03), and differences persisted after adjustment for clinical and behavioral risk factors but not after adjustment for coping strategies. In adjusted models comparing major versus no depressive symptoms, patients with major depressive symptoms had a 2-fold greater hazard of stroke (hazard ratio, 1.95; 95% confidence interval, 1.02–3.71;
P
=0.04). In continuous models, a 1-SD increase in Center for Epidemiological Studies Depression score was associated with a 30% increase in adjusted incident stroke risk (
P
=0.04). Similar associations were observed for incident CHD in models adjusted for clinical and behavioral risk factors, but associations were not significant after adjustment for coping strategies.

Conclusions—
In a community-based cohort of blacks, major depressive symptoms were associated with greater risks of incident stroke and CHD after adjustment for clinical and behavioral risk factors.
The Utility of Therapeutic Hypothermia for Post–Cardiac Arrest Syndrome Patients With an Initial Nonshockable Rhythm
Authors: Perman Sarah M. , Grossestreuer Anne V. , Wiebe Douglas J. , Carr Brendan G. , Abella Benjamin S. , Gaieski David F. 
Published: November 2015

Background—
Therapeutic hypothermia (TH) attenuates reperfusion injury in comatose survivors of cardiac arrest. The utility of TH in patients with nonshockable initial rhythms has not been widely accepted. We sought to determine whether TH improved neurological outcome and survival in postarrest patients with nonshockable rhythms.

Methods and Results—

We identified 519 patients after in- and out-of-hospital cardiac arrest with nonshockable initial rhythms from the Penn Alliance for Therapeutic Hypothermia (PATH) registry between 2000 and 2013. Propensity score matching was used. Patient and arrest characteristics used to estimate the propensity to receive TH were age, sex, location of arrest, witnessed arrest, and duration of arrest. To determine the association between TH and outcomes, we created 2 multivariable logistic models controlling for confounders. Of 201 propensity score–matched pairs, mean age was 63±17 years, 51% were male, and 60% had an initial rhythm of pulseless electric activity. Survival to hospital discharge was greater in patients who received TH (17.6% versus 28.9%;
P
<0.01), as was a discharge Cerebral Performance Category of 1 to 2 (13.7% versus 21.4%;
P
=0.04). In adjusted analyses, patients who received TH were more likely to survive (odds ratio, 2.8; 95% confidence interval, 1.6–4.7) and to have better neurological outcome (odds ratio, 3.5; 95% confidence interval, 1.8–6.6) than those that did not receive TH.

Conclusions—
Using propensity score matching, we found that patients with nonshockable initial rhythms treated with TH had better survival and neurological outcome at hospital discharge than those who did not receive TH. Our findings further support the use of TH in patients with initial nonshockable arrest rhythms.