Publications by authors named "A Wright"

4,900 Publications

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SERUM PROTEOMICS AND PLASMA FIBULIN-3 IN DIFFERENTIATION OF MESOTHELIOMA FROM ASBESTOS-EXPOSED CONTROLS AND PATIENTS WITH OTHER PLEURAL DISEASES.

J Thorac Oncol 2021 Jun 8. Epub 2021 Jun 8.

Cancer Research UK Beatson Institute, Glasgow, UK.

Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan® proteomics and Fibulin-3 appeared highly accurate, but SOMAscan® has not been validated prospectively and subsequent Fibulin-3 data have been contradictory.

Methods: A multi-centre prospective observational study was performed in 22 centres, generating a large intention-to-diagnose cohort. Blood sampling, processing and diagnostic assessment were standardised, including 1-year follow-up. Plasma Fibulin-3 was measured using two enzyme-linked immunosorbent assays (ELISAs: CloudClone (used in previous studies) and BosterBio). Serum proteomics were measured using the SOMAscan® assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve (AUC)) was benchmarked against serum Mesothelin (Mesomark®). Biomarkers were correlated against primary tumour volume, inflammatory markers and asbestos exposure.

Results: 638 patients with suspected pleural malignancy (SPM) and 110 asbestos exposed controls (AECs) were recruited. SOMAscan® reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in differentiating non-MPM SPM patients. Fibulin-3 (by BosterBio following failed CloudClone validation) demonstrated 7.4% and 11.9% sensitivity at 95% specificity in MPM v. non-MPM SPM and AECs respectively (associated AUCs 0.611 (0.557-0.664), p=0.0015) and 0.516 (0.443-0.589), p=0.671), both inferior to Mesothelin. SOMAscan® proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumour volume.

Conclusions: SOMAscan® may prove useful as a future screening test for MPM in asbestos exposed persons. Neither Fibulin-3 nor SOMAscan® should be used for diagnosis or pathway stratification.
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http://dx.doi.org/10.1016/j.jtho.2021.05.018DOI Listing
June 2021

Intrinsic 5-lipoxygenase activity regulates migration and adherence of mantle cell lymphoma cells.

Prostaglandins Other Lipid Mediat 2021 Jun 8:106575. Epub 2021 Jun 8.

Department of Medicine Solna, Division of Hematology, Karolinska University Hospital and Institutet, Stockholm, Sweden. Electronic address:

Human B-lymphocytes express 5-lipoxygenase (5-LOX) and 5-LOX activating protein (FLAP) and can convert arachidonic acid to leukotriene B. Mantle cell lymphoma (MCL) cells contain similar amounts of 5-LOX as human neutrophils but the function and mechanism of activation of 5-LOX in MCL cells, and in normal B-lymphocytes, are unclear. Here we show that the intrinsic 5-LOX pathway in the MCL cell line JeKo-1 has an essential role in migration and adherence of the cells, which are important pathophysiological characteristics of B-cell lymphoma. Incubation of JeKo-1 with the FLAP inhibitor GSK2190915 or the 5-LOX inhibitor zileuton, at a concentration below 1 μM, prior to stimulation with the chemotactic agent CXCL12, led to a significant reduction of migration. CRISPR/Cas9 mediated deletion of ALOX5 gene in JeKo-1 cells also led to a significantly decreased migration of the cells. Furthermore, 5-LOX and FLAP inhibitors markedly decreased the adherence of JeKo-1 cells to stromal cells. In comparison, these drugs had a similar effect on adherence of JeKo-1 cells as the Bruton tyrosine kinase inhibitor ibrutinib, which has a proven anti-tumour effect. These results indicate that inhibition of 5-LOX may be a novel treatment for MCL and certain other B-cell lymphomas.
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http://dx.doi.org/10.1016/j.prostaglandins.2021.106575DOI Listing
June 2021

Apple consumption reduces markers of postprandial inflammation following a high fat meal in overweight and obese adults: A randomized, crossover trial.

Food Funct 2021 Jun 8. Epub 2021 Jun 8.

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2 W1, Canada.

High fat meal-induced postprandial inflammation is exacerbated in overweight and obesity and may contribute to cardiovascular disease (CVD) risk. This study aimed to determine the effects of apples, rich in anti-inflammatory polyphenols, on biomarkers of postprandial inflammation in individuals with overweight and obesity. A randomized, crossover trial was conducted with n = 26 participants (17 female/9 male; mean age 45.5 ± 3.12 years; mean BMI 34.1 ± 1.18 kg m-2) to assess the effects of 3 whole Gala apples (∼200 g) on the 2, 4 and 6 h postprandial response to a high fat meal providing 1 g fat per kg body weight. Changes in plasma biomarkers of inflammation (as the primary outcome) and endotoxin exposure, non-esterified fatty acids (NEFA) and total antioxidant capacity (TAC) were measured. Fasting (0 h) and 4 h peripheral blood mononuclear cells (PBMC) were also isolated from whole blood and stimulated with or without a physiological dose (10 ng mL-1) of lipopolysaccharide (LPS) to measure secreted cytokines. Apples modulated postprandial plasma IFN-γ and reduced its peak concentration (-12.8%), and increased both 4 h (14.4%) and peak (10.5%) TAC (P < 0.05). In unstimulated and LPS-stimulated PBMC, apples reduced secreted IL-6 (-49.3% and -17.1%) and TNF-α (-43.3% and -14.7%) and increased IL-4 (93.1% and 15.8%) in both the unstimulated and LPS-stimulated conditions, as well as decreased GM-CSF (-26.0%) and IL-17 (-47.9%) in unstimulated PBMC and G-CSF (-19.8%) in LPS-stimulated PBMC (P < 0.05). These data suggest acute whole Gala apple consumption may be an effective dietary strategy to mitigate high fat meal-induced postprandial inflammation that exacerbates CVD risk in overweight and obesity. This study was registered at clinicaltrials.gov, NCT03523403, The Apple Study: Investigating the Effects of Whole Apple Consumption on Risk Factors for Chronic Metabolic Diseases in Overweight and Obese Adults.
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http://dx.doi.org/10.1039/d1fo00392eDOI Listing
June 2021

Urodynamic characterization of giggle incontinence in children.

Neurourol Urodyn 2021 Jun 8. Epub 2021 Jun 8.

Department of Pediatric Urology, Evelina London Children's Hospital, London, UK.

Aims: Giggle incontinence is a rare condition resulting in excessive urinary incontinence with laughter, where bladder function is otherwise "normal." Urodynamic descriptions of the condition to date are limited. We believe that giggle incontinence has characteristic urodynamic findings. We tested this hypothesis.

Methods: We retrospectively reviewed the urodynamic investigations of patients with giggle incontinence managed in a tertiary regional bladder unit between February 2014 and November 2019.

Results: We identified the studies of seven patients, median age 13.5 years (10.4-15.7) of whom 6 were female. All had videourodynamics. Two went on to have further invasive investigation; one had urethral pressure profile and one had ambulatory urodynamics. Detrusor overactivity (DO) was observed in six. DO was asensate in all. In five DO was triggered by laughter and was associated with laughter induced incontinence in four. Six had DO that was not provoked by laugher. In one amplitude of DO was proportional to vigour of laughter. In three patients there was identification of sudden pelvic floor relaxation during laughter resulting in incontinence. Stress urinary incontinence was not observed in any.

Conclusions: Giggle incontinence is a complex phenomenon. Urodynamic diagnosis is challenging and is dependent on eliciting laughter. We present the first urodynamic demonstration that giggle incontinence is associated with laughter-induced, asensate DO and concurrent, momentary pelvic floor relaxation. We hope this will provide a more consistent basis for defining this condition in the future.
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http://dx.doi.org/10.1002/nau.24725DOI Listing
June 2021

Effects of Withdrawal from Cocaine Self-Administration on Rat Orbitofrontal Cortex Parvalbumin Neurons Expressing : Sex-Dependent Changes in Neuronal Function and Unaltered Serotonin Signaling.

eNeuro 2021 Jun 1. Epub 2021 Jun 1.

Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224

The orbitofrontal cortex (OFC) is a brain region involved in higher-order decision-making. Rodent studies show that cocaine self-administration (CSA) reduces OFC contribution to goal-directed behavior and behavioral strategies to avoid drug intake. This change in OFC function persists for many weeks after cocaine withdrawal, suggesting involvement in the process of addiction. The mechanisms underlying impaired OFC function by cocaine are not well-understood. However, studies implicate altered OFC serotonin (5-HT) function in disrupted cognitive processes during addiction and other psychiatric disorders. Thus, it is hypothesized that cocaine impairment of OFC function involves changes in 5-HT signaling, and previous work shows that 5-HT and 5-HT receptor-mediated effects on OFC pyramidal neurons (PyNs) are impaired weeks after cocaine withdrawal. However, 5-HT effects on other contributors to OFC circuit function have not been fully investigated, including the parvalbumin-containing, fast-spiking interneurons (OFC), whose function is essential to normal OFC-mediated behavior. Here, 5-HT function in naive rats and those withdrawn from CSA were evaluated using a novel rat transgenic line in which the rat parvalbumin promoter drives Cre-recombinase expression to permit identification of OFC cells by fluorescent reporter protein expression. We find that whereas CSA altered basal synaptic and membrane properties of the OFC neurons in a sex-dependent manner, the effects of 5-HT on these cells were unchanged by CSA. These data suggest that the behavioral effects of dysregulated OFC 5-HT function caused by cocaine experience are primarily mediated by changes in 5-HT signaling at PyNs, and not at OFC neurons.Cocaine addiction involves the inability to change behavior having negative consequences and to adopt beneficial behaviors. The orbitofrontal cortex (OFC) is a brain region involved in this behavioral flexibility, and OFC function is impaired after cocaine use. Moreover, signaling by the neurotransmitter serotonin (5-HT) is impaired in OFC pyramidal neurons (PyNs) after cocaine. However, whether other types of neurons are affected by cocaine is unknown, and we asked whether changes occur in another class of OFC cells known as parvalbumin interneurons. We report that cocaine changed the activity of parvalbumin interneurons in a sex-dependent manner but did not alter 5-HT effects. This suggests that the effects of cocaine on 5-HT function in OFC involves PyNs and not parvalbumin interneurons.
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http://dx.doi.org/10.1523/ENEURO.0017-21.2021DOI Listing
June 2021