bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between psychological distress and mortality: the case of Israel
Authors: Ponizovsky Alexander Michael , Haklai Ziona , Goldberger Nehama 
Published: March 2018

BackgroundPrevious studies have demonstrated the association between psychological distress (measured by the 12-item General Health Questionnaire, GHQ-12) and risks of all-cause mortality and deaths from cardiovascular, cancer and other causes. We hypothesised that in the Israeli population permanently exposed to war/terror stressors, this relationship is absent.MethodsWe performed an analysis of data from participants in the Israel National Health Survey conducted in 2003–2004, who died during the follow-up decade. Subjects were assigned to groups based on GHQ-12 score: 0–10 (asymptomatic), 11–14 (subclinically symptomatic), 15–19 (symptomatic) and 20–36 (highly symptomatic). Data were weighted to the total population.ResultsWe analysed data from 4843 individuals, median age 40.5 (IQR 28–54); 473 participants died during the follow-up. We found a significant increase in total mortality, cardiovascular and other causes of mortality (but not cancer deaths) with increase in GHQ-12 score (P for linear trend of ungrouped GHQ scores <0.0001, 0.0015 and <0.0001, respectively). The age–sex-adjusted HR for the highest GHQ-12 compared with the lowest asymptomatic category was 2.1 (95% CI 1.6 to 2.7) for all-cause deaths, 2.3 (95% CI 1.3 to 4.1) for cardiovascular disease deaths and 2.7 (95% CI 1.9 to 3.9) for other deaths. The HR remained significant after adjustment for education, smoking, alcohol consumption and diabetes. The HR even increased after excluding participants with baseline cardiovascular diseases and cancer.ConclusionContrary to our hypothesis, psychological distress was associated with all-cause and cardiovascular but not cancer mortality. The absence of reverse causality provides evidence for the direct deleterious effects of psychological distress on mortality outcomes.
Incident CTS in a large pooled cohort study: associations obtained by a Job Exposure Matrix versus associations obtained from observed exposures
Authors: Dale Ann Marie , Ekenga Christine C , Buckner-Petty Skye , Merlino Linda , Thiese Matthew S , Bao Stephen , Meyers Alysha Rose , Harris-Adamson Carisa , Kapellusch Jay , Eisen Ellen A , Gerr Fred , Hegmann Kurt T , Silverstein Barbara , Garg Arun , Rempel David , Zeringue Angelique , Evanoff Bradley A 
Published: March 2018

BackgroundThere is growing use of a job exposure matrix (JEM) to provide exposure estimates in studies of work-related musculoskeletal disorders; few studies have examined the validity of such estimates, nor did compare associations obtained with a JEM with those obtained using other exposures.ObjectiveThis study estimated upper extremity exposures using a JEM derived from a publicly available data set (Occupational Network, O*NET), and compared exposure-disease associations for incident carpal tunnel syndrome (CTS) with those obtained using observed physical exposure measures in a large prospective study.Methods2393 workers from several industries were followed for up to 2.8 years (5.5 person-years). Standard Occupational Classification (SOC) codes were assigned to the job at enrolment. SOC codes linked to physical exposures for forceful hand exertion and repetitive activities were extracted from O*NET. We used multivariable Cox proportional hazards regression models to describe exposure-disease associations for incident CTS for individually observed physical exposures and JEM exposures from O*NET.ResultsBoth exposure methods found associations between incident CTS and exposures of force and repetition, with evidence of dose–response. Observed associations were similar across the two methods, with somewhat wider CIs for HRs calculated using the JEM method.ConclusionExposures estimated using a JEM provided similar exposure-disease associations for CTS when compared with associations obtained using the ‘gold standard’ method of individual observation. While JEMs have a number of limitations, in some studies they can provide useful exposure estimates in the absence of individual-level observed exposures.
Quantitative compositional mapping of mineral phases by electron probe micro-analyser
Authors: Lanari Pierre , Vho Alice , Bovay Thomas , Airaghi Laura , Centrella Stephen 
Published: March 2018

Abstract
Compositional mapping has greatly impacted mineralogical and petrological studies over the past half-century with increasing use of the electron probe micro-analyser. Many technical and analytical developments have benefited from the synergies of physicists and geologists and they have greatly contributed to the success of this analytical technique. Large-area compositional mapping has become routine practice in many laboratories worldwide, improving our ability to measure the compositional variability of minerals in natural geological samples and reducing the operator bias as to where to locate single spot analyses. This chapter aims to provide an overview of existing quantitative techniques for the evaluation of rock and mineral compositions and to present various examples of applications. A new advanced method for compositional map standardization that relies on internal standards and accurately corrects the X-ray intensities for continuum background is also presented. This technique has been implemented into the computer software XMapTools. The improved workflow defines the appropriate practice of accurate standardization and provides data-reporting standards to help improve petrological interpretations.
Clostridium difficile toxins A and B decrease intestinal SLC26A3 protein expression
Authors: Coffing Hayley , Priyamvada Shubha , Anbazhagan Arivarasu N. , Salibay Christine , Engevik Melinda , Versalovic James , Yacyshyn Mary Beth , Yacyshyn Bruce , Tyagi Sangeeta , Saksena Seema , Gill Ravinder K. , Alrefai Waddah A. , Dudeja Pradeep K. 
Published: March 2018

Clostridium difficile infection (CDI) is the primary cause of nosocomial diarrhea in the United States. Although C. difficile toxins A and B are the primary mediators of CDI, the overall pathophysiology underlying C. difficile-associated diarrhea remains poorly understood. Studies have shown that a decrease in both NHE3 (Na+/H+ exchanger) and DRA (downregulated in adenoma, Cl−/[Formula: see text] exchanger), resulting in decreased electrolyte absorption, is implicated in infectious and inflammatory diarrhea. Furthermore, studies have shown that NHE3 is depleted at the apical surface of intestinal epithelial cells and downregulated in patients with CDI, but the role of DRA in CDI remains unknown. In the current studies, we examined the effects of C. difficile toxins TcdA and TcdB on DRA protein and mRNA levels in intestinal epithelial cells (IECs). Our data demonstrated that DRA protein levels were significantly reduced in response to TcdA and TcdB in IECs in culture. This effect was also specific to DRA, as NHE3 and PAT-1 (putative anion transporter 1) protein levels were unaffected by TcdA and TcdB. Additionally, purified TcdA and TcdA + TcdB, but not TcdB, resulted in a decrease in colonic DRA protein levels in a toxigenic mouse model of CDI. Finally, patients with recurrent CDI also exhibited significantly reduced expression of colonic DRA protein. Together, these findings indicate that C. difficile toxins markedly downregulate intestinal expression of DRA which may contribute to the diarrheal phenotype of CDI. NEW & NOTEWORTHY Our studies demonstrate, for the first time, that C. difficile toxins reduce DRA protein, but not mRNA, levels in intestinal epithelial cells. These findings suggest that a downregulation of DRA may be a critical factor in C. difficile infection-associated diarrhea.
Lower tendon stiffness in very old compared with old individuals is unaffected by short-term resistance training of skeletal muscle
Authors: Eriksen Christian Skou , Henkel Cecilie , Svensson Rene B. , Agergaard Anne-Sofie , Couppé Christian , Kjaer Michael , Magnusson S. Peter 
Published: March 2018

Aging negatively affects collagen-rich tissue, like tendons, but in vivo tendon mechanical properties and the influence of physical activity after the 8th decade of life remain to be determined. This study aimed to compare in vivo patellar tendon mechanical properties in moderately old (old) and very old adults and the effect of short-term resistance training. Twenty old (9 women, 11 men, >65 yr) and 30 very old (11 women, 19 men, >83 yr) adults were randomly allocated to heavy resistance training (HRT) or no training (CON) and underwent testing of in vivo patellar tendon (PT) mechanical properties and PT dimensions before and after a 3-mo intervention. Previous measurements of muscle properties, blood parameters, and physical activity level were included in the analysis. Data from 9 old HRT, 10 old CON, 14 very old CON, and 12 old HRT adults were analyzed. In addition to lower quadriceps muscle strength and cross-sectional area (CSA), we found lower PT stiffness and Young’s modulus ( P < 0.001) and a trend toward the lower mid-portion PT-CSA ( P = 0.09) in very old compared with old subjects. Daily step count was also lower in very old subjects ( P < 0.001). Resistance training improved muscle strength and cross-sectional area equally in old and very old subjects ( P < 0.05) but did not affect PT mechanical properties or dimension. We conclude that PT material properties are reduced in very old age, and this may likely be explained by reduced physical activity. Three months of resistance training however, could not alter PT mechanical properties in very old individuals. NEW & NOTEWORTHY This research is the first to quantify in vivo tendon mechanical properties in a group of very old adults in their eighties. Patellar tendon stiffness was lower in very old (87 yr on average) compared with moderately old (68 yr on average) individuals. Reduced physical activity with aging may explain some of the loss in tendon stiffness, but regular heavy resistance training for 3 mo was not sufficient to change tendon mechanical properties.
Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine
Authors: Olver T. Dylan , Edwards Jenna C. , Ferguson Brian S. , Hiemstra Jessica A. , Thorne Pamela K. , Hill Michael A. , Laughlin M. Harold , Emter Craig A. 
Published: March 2018

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.
Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the α-Ketoglutarate Signaling Pathway
Authors: Tseng Chien-Wei , Kuo Wen-Hung , Chan Shih-Hsuan , Chan Hong-Lin , Chang King-Jen , Wang Lu-Hai 
Published: March 2018

Abstract
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (αKG) enhanced the levels of tumor suppressors succinate dehydrogenase and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy.
Significance: These findings uncover the clinical significance of TKT in breast cancer progression and metastasis and demonstrate effective therapy by inhibiting TKT or by adding αKG. Cancer Res; 78(11); 2799–812. ©2018 AACR.
CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti–PD-1 Treatment
Authors: Edwards Jarem , Wilmott James S. , Madore Jason , Gide Tuba Nur , Quek Camelia , Tasker Annie , Ferguson Angela , Chen Jinbiao , Hewavisenti Rehana , Hersey Peter , Gebhardt Thomas , Weninger Wolfgang , Britton Warwick J. , Saw Robyn P.M. , Thompson John F. , Menzies Alexander M. , Long Georgina V. , Scolyer Richard A. , Palendira Umaimainthan 
Published: March 2018

Abstract
Purpose: Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response.
Patients and Methods: We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti–PD-1 therapy.
Results: Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells were associated with improved melanoma-specific survival in immunotherapy-naïve melanoma patients. Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti–PD-1 immunotherapy.
Conclusions: Tumor-resident CD8+ T-cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti–PD-1 and anti–LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade. Clin Cancer Res; 24(13); 3036–45. ©2018 AACR.
Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
Authors: McCoach Caroline E. , Blakely Collin M. , Banks Kimberly C. , Levy Benjamin , Chue Ben M. , Raymond Victoria M. , Le Anh T. , Lee Christine E. , Diaz Joseph , Waqar Saiama N. , Purcell William T. , Aisner Dara L. , Davies Kurtis D. , Lanman Richard B. , Shaw Alice T. , Doebele Robert C. 
Published: March 2018

Abstract
Purpose: Patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a noninvasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy.
Patients and Methods: The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma.
Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK-positive patients had no history of targeted therapy (cohort 1), with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR-activating mutations, an ALK fusion was identified on progression (cohort 4; 4 STRN, 1 EML4; one both STRN and EML4); five harbored EGFR T790M.
Conclusions: In this cohort of cfDNA-detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression. Clin Cancer Res; 24(12); 2758–70. ©2018 AACR.
Switch in Laminin β2 to Laminin β1 Isoforms During Aging Controls Endothelial Cell Functions—Brief Report
Authors: Wagner Julian U.G. , Chavakis Emmanouil , Rogg Eva-Maria , Muhly-Reinholz Marion , Glaser Simone F. , Günther Stefan , John David , Bonini Francesca , Zeiher Andreas M. , Schaefer Liliana , Hannocks Melanie-Jane , Boon Reinier A. , Dimmeler Stefanie 
Published: March 2018

Objective—
Endothelial cells play important roles in tissue homeostasis and vascularization, a function that is impaired by aging. Here, we aim to decipher the role of the microenvironment underlying the impairment of endothelial cell functions by aging.

Approach and Results—

RNA sequencing of isolated cardiac endothelial cells derived from young and 18-month-old mouse hearts revealed that aging affects the endothelial expression of genes encoding extracellular matrix proteins, specifically the laminin β1 (
Lamb1
) and laminin β2 (
Lamb2
) chains. Whereas
Lamb1
was upregulated,
Lamb2
was decreased in endothelial cells in old mice compared with young controls. A similar change in expression patterns was observed after induction of acute myocardial infarction. Mimicking aging and injury conditions by plating endothelial cells on laminin β1–containing laminin 411 matrix impaired endothelial cell adhesion, migration, and tube formation and augmented endothelial-to-mesenchymal transition and endothelial detachment compared with laminin 421, which contains the laminin β2 chain. Because laminins can signal via integrin receptors, we determined the activation of ITGB1 (integrin β1). Laminin 421 coating induced a higher activation of ITGB1 compared with laminin 411. siRNA-mediated silencing of ITGB1 reduced laminin β2–dependent adhesion, suggesting that laminin β2 more efficiently activates ITGB1.

Conclusions—
Mimicking age-related modulation of laminin β1 versus β2 chain expression changes the functional properties and phenotype of endothelial cells. The dysregulation of the extracellular matrix during vascular aging may contribute to age-associated impairment of organ function and fibrosis.
Social networks: a tool for assessing the impact of perturbations on wildlife behaviour and implications for pathogen transmission
Authors: Jones K.L. , Thompson R.C.A. , Godfrey S.S. 
Published: March 2018

Abstract
Wildlife are increasingly subject to perturbations, which can impact pathogen transmission and lead to disease emergence. While a myriad of factors influence disease dynamics in wildlife, behaviour is emerging as a major influence. In this review, we examine how perturbations alter the behaviour of individuals and how, in turn, disease transmission may be impacted, with a focus on the use of network models as a powerful tool. There are emerging hypotheses as to how networks respond to different types of perturbations. The broad effects of perturbations make predicting potential outcomes and identifying mitigation opportunities for disease emergence critical; yet, the current paucity of data makes identification of underlying trends difficult. Social network analysis facilitates a mechanistic approach to how perturbation-induced behavioural changes result in shifts in pathogen transmission. However, the field is still developing, and future work should strive to address current deficits. There is particular need for empirical data to support modelling predictions and increased inclusion of pathogen monitoring in network studies.
Religious Women, Mystic Journeys and Agency in Early Modern Spain
Authors: Evangelisti Silvia 
Published: March 2018

Abstract
This article examines the narratives of female mystic journeys that were sometimes included in the biographies and the autobiographies of religious women printed in Spain between the mid-sixteenth century and the first half of the eighteenth century. By showing the ability of women to convert non-Christians in Asia, North Africa and America, and to defend the Catholic faith in Europe, the texts provide the opportunity to examine idealized models of female religious engagement from an unusual angle.