An exploration of the ability of tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model

<p>Abstract</p> <p>Background</p> <p>To study the ability of tepoxalin, a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX) and its active metabolite to reduce the catabolic response of cartilage to cytokine stimulation in an <it>in vitro </it>model of canine osteoarthritis (OA).</p> <p>Grossly normal cartilage was collected post-mortem from seven dogs that had no evidence of joint disease. Cartilage explants were cultured in media containing the recombinant canine interleukin-1<it>β </it>(IL-1<it>β</it>) at 100 ng/ml and recombinant human oncostatin-M (OSM) at 50 ng/ml. The effects of tepoxalin and its metabolite were studied at three concentrations (1 × 10^-5, 1 × 10^-6and 1 × 10^-7M). Total glycosaminoglycan (GAG) and collagen (hydroxyproline) release from cartilage explants were used as outcome measures of proteoglycan and collagen depletion respectively. PGE₂and LTB₄assays were performed to study the effects of the drug on COX and LOX activity.</p> <p>Results</p> <p>Treatment with IL-1<it>β </it>and OSM significantly upregulated both collagen (p = 0.004) and proteoglycan (p = 0.001) release from the explants. Tepoxalin at 10^-5M and 10^-6M caused a decrease in collagen release from the explants (p = 0.047 and p = 0.075). Drug treatment showed no effect on GAG release. PGE₂concentration in culture media at day 7 was significantly increased by IL-1<it>β </it>and OSM and treatment with both tepoxalin and its metabolite showed a trend towards dose-dependent reduction of PGE₂production. LTB₄concentrations were too low to be quantified. Cytotoxicity assays suggested that neither tepoxalin nor its metabolite had a toxic effect on the cartilage chondrocytes at the concentrations and used in this study.</p> <p>Conclusion</p> <p>This study provides evidence that tepoxalin exerts inhibition of COX and can reduce <it>in vitro </it>collagen loss from canine cartilage explants at a concentration of 10^-5M. We can conclude that, in this model, tepoxalin can partially inhibit the development of cartilage degeneration when it is available locally to the tissue.</p

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci

Data quality of Aeolus wind measurements

The European Space Agency (ESA)'s Earth Explorer Aeolus was launched in August 2018 carrying the world's first spaceborne wind lidar, the Atmospheric Laser Doppler Instrument (ALADIN). ALADIN uses a high spectral resolution Doppler wind lidar operating at 355nm to measure profiles of line-of-sight wind components in near-real-time (NRT). ALADIN samples the atmosphere from 30km altitude down to the Earth's surface or to the level where the lidar signal is attenuated by optically thick clouds. The global wind profiles provided by ALADIN help to improve weather forecasting and the understanding of atmospheric dynamics as they fill observational gaps in vertically resolved wind profiles mainly in the tropics, southern hemisphere, and over the northern hemisphere oceans. In January 2020, the European Centre for Medium-Range Weather Forecasts (ECMWF) became the first numerical weather prediction (NWP) centre to assimilate Aeolus observations for operational forecasting. A main prerequisite for beneficial impact is data of sufficient quality. Such high data quality has been achieved through close collaboration of all involved parties within the Aeolus Data Innovation and Science Cluster (DISC), which was established after launch to study and improve the data quality of Aeolus products. The tasks of the Aeolus DISC include the instrument and platform monitoring, calibration, characterization, retrieval algorithm refinement, processor evolution, quality monitoring, product validation, and impact assessment for NWP. The achievements of the Aeolus DISC for the NRT data quality and the current status of Aeolus wind measurements will be described and summarized. Further, an outlook on future improvements and the availability of reprocessed datasets with enhanced data quality will be provided

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Acknowledgments We thank Dr Stuart MacGregor for his input on the study proposal and review of prior versions of this manuscript. We also thank all patients and controls for participating in this study. The MD Anderson controls were drawn from dbGaP (study accession: phs000187.v1.p1). Genotyping of these controls were done through the University of Texas MD Anderson Cancer Center (UTMDACC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR). We acknowledge the principal investigators of this study: Christopher Amos, Qingyi Wei, and Jeffrey E. Lee. Controls from the Genome-Wide Association Study of Parkinson Disease were obtained from dbGaP (study accession: phs000196.v2.p1). This work, in part, used data from the National Institute of Neurological Disorders and Stroke (NINDS) dbGaP database from the CIDR: NeuroGenetics Research Consortium Parkinson’s disease study. We acknowledge the principal investigators and coinvestigators of this study: Haydeh Payami, John Nutt, Cyrus Zabetian, Stewart Factor, Eric Molho, and Donald Higgins. Controls from the Chronic Renal Insufficiency Cohort (CRIC) were drawn from dbGaP (study accession: phs000524.v1.p1). The CRIC study was done by the CRIC investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Data and samples from CRIC reported here were supplied by NIDDK Central Repositories. This report was not prepared in collaboration with investigators of the CRIC study and does not necessarily reflect the opinions or views of the CRIC study, the NIDDK Central Repositories, or the NIDDK. We acknowledge the principal investigators and the project officer of this study: Harold I Feldman, Raymond R Townsend, Lawrence J. Appel, Mahboob Rahman, Akinlolu Ojo, James P. Lash, Jiang He, Alan S Go, and John W. Kusek. The following UK hospitals participated in sample collection through the Stomach and Oesophageal Cancer Study (SOCS) collaboration network: Addenbrooke’s Hospital, University College London, Bedford Hinchingbrooke Hospital, Peterborough City Hospital, West Suffolk Norfolk and Norwich University Hospital, Churchill Hospital, John Hospital, Velindre Hospital, St Bartholomew’s Hospital, Queen’s Burton, Queen Elisabeth Hospital, Diana Princess of Wales, Scunthorpe General Hospital, Royal Devon & Exeter Hospital, New Cross Hospital, Belfast City Hospital, Good Hope Hospital, Heartlands Hospital, South Tyneside District General Hospital, Cumberland Infirmary, West Cumberland Hospital, Withybush General Hospital, Stoke Mandeville Hospital, Wycombe General Hospital, Wexham Park Hospital, Southend Hospital, Guy’s Hospital, Southampton General Hospital, Bronglais General Hospital, Aberdeen Royal Infirmary, Manor Hospital, Clatterbridge Centre for Oncology, Lincoln County Hospital, Pilgrim Hospital, Grantham & District Hospital, St Mary’s Hospital London, Croydon University Hospital, Whipps Cross University Hospital, Wansbeck General Hospital, Hillingdon Hospital, Milton Keynes General Hospital, Royal Gwent Hospital, Tameside General Hospital, Castle Hill Hospital, St Richard’s Hospital, Ipswich Hospital, St Helens Hospital, Whiston Hospital, Countess of Chester Hospital, St Mary’s Hospital IOW, Queen Alexandra Hospital, Glan Clwyd Hospital, Wrexham Maelor Hospital, Darent Valley Hospital, Royal Derby Hospital, Derbyshire Royal Infirmary, Scarborough General Hospital, Kettering General Hospital, Kidderminster General Hospital, Royal Lancaster Infirmary, Furness General Hospital, Westmorland General Hospital, James Cook University Hospital, Friarage Hospital, Stepping Hill Hospital, St George’s Hospital London, Doncaster Royal Infirmary, Maidstone Hospital, Tunbridge Hospital, Prince Charles Hospital, Hartlepool Hospital, University Hospital of North Tees, Ysbyty Gwynedd, St. Jame’s University Hospital, Leeds General Infirmary, North Hampshire Hospital, Royal Preston Hospital, Chorley and District General, Airedale General Hospital, Huddersfield Royal Infirmary, Calderdale Royal Hospital, Torbay District General Hospital, Leighton Hospital, Royal Albert Edward Infirmary, Royal Surrey County Hospital, Bradford Royal Infirmary, Burnley General Hospital, Royal Blackburn Hospital, Royal Sussex County Hospital, Freeman Hospital, Royal Victoria Infirmary, Victoria Hospital Blackpool, Weston Park Hospital, Royal Hampshire County Hospital, Conquest Hospital, Royal Bournemouth General Hospital, Mount Vernon Hospital, Lister Hospital, William Harvey Hospital, Kent and Canterbury Hospital, Great Western Hospital, Dumfries and Galloway Royal Infirmary, Poole General Hospital, St Hellier Hospital, North Devon District Hospital, Salisbury District Hospital, Weston General Hospital, University Hospital Coventry, Warwick Hospital, George Eliot Hospital, Alexandra Hospital, Nottingham University Hospital, Royal Chesterfield Hospital, Yeovil District Hospital, Darlington Memorial Hospital, University Hospital of North Durham, Bishop Auckland General Hospital, Musgrove Park Hospital, Rochdale Infirmary, North Manchester General, Altnagelvin Area Hospital, Dorset County Hospital, James Paget Hospital, Derriford Hospital, Newham General Hospital, Ealing Hospital, Pinderfields General Hospital, Clayton Hospital, Dewsbury & District Hospital, Pontefract General Infirmary, Worthing Hospital, Macclesfield Hospital, University Hospital of North Staffordshire, Salford Royal Hospital, Royal Shrewsbury Hospital, and Manchester Royal Infirmary. Conflict of interest The authors disclose no conflicts. Funding This work was primarily funded by the National Institutes of Health (NIH) (R01CA136725). The funders of the study had no role in the design, analysis, or interpretation of the data, nor in writing or publication decisions related to this article. Jing Dong was supported by a Research Training Grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RP160097) and the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin (AHW). Quinn T. Ostrom was supported by RP160097. Puya Gharahkhani was supported by a grant from National Health and Medical Research Council of Australia (1123248). Geoffrey Liu was supported by the Alan B. Brown Chair in Molecular Genomics and by the CCO Chair in Experimental Therapeutics and Population Studies. The University of Cambridge received salary support for Paul D. Pharoah from the NHS in the East of England through the Clinical Academic Reserve. Brian J. Reid was supported by a grant (P01CA91955) from the NIH/National Cancer Institute (NCI). Nicholas J. Shaheen was supported by a grant (P30 DK034987) from NIH. Thomas L. Vaughan was supported by NIH Established Investigator Award K05CA124911. Michael B. Cook was supported by the Intramural Research Program of the NCI, NIH, Department of Health and Human Services. Douglas A. Corley was supported by the NIH grants R03 KD 58294, R21DK077742, and RO1 DK63616 and NCI grant R01CA136725. Carlo Maj was supported by the BONFOR-program of the Medical Faculty, University of Bonn (O-147.0002). Jesper Lagergren was supported by the United European Gastroenterology (UEG) Research Prize. David C. Whiteman was supported by fellowships from the National Health and Medical Research Council of Australia (1058522, 1155413).Peer reviewedPostprin

A pervasive role for biomass burning in tropical high ozone/low water structures.

Air parcels with mixing ratios of high O3 and low H2O (HOLW) are common features in the tropical western Pacific (TWP) mid-troposphere (300-700 hPa). Here, using data collected during aircraft sampling of the TWP in winter 2014, we find strong, positive correlations of O3 with multiple biomass burning tracers in these HOLW structures. Ozone levels in these structures are about a factor of three larger than background. Models, satellite data and aircraft observations are used to show fires in tropical Africa and Southeast Asia are the dominant source of high O3 and that low H2O results from large-scale descent within the tropical troposphere. Previous explanations that attribute HOLW structures to transport from the stratosphere or mid-latitude troposphere are inconsistent with our observations. This study suggest a larger role for biomass burning in the radiative forcing of climate in the remote TWP than is commonly appreciated.We thank L. Pan for coordinating the CONTRAST flights and her constructive criticism of an early version of the manuscript; S. Schauffler, V. Donets and R. Lueb for collecting and analysing AWAS samples; T. Robinson and O. Shieh for providing meteorology forecasts in the field; and the pilots and crews of the CAST BAe-146 and CONTRAST Gulfstream V aircrafts for their dedication and professionalism. CAST was funded by the Natural Environment Research Council; CONTRAST was funded by the National Science Foundation. Research at the Jet Propulsion Laboratory, California Institute of Technology, is performed under contract with the National Aeronautics and Space Administration (NASA). A number of the US-based investigators also benefitted from the support of NASA as well as the National Oceanic and Atmospheric Administration. The views, opinions, and findings contained in this report are those of the author(s) and should not be construed as an official National Oceanic and Atmospheric Administration or US Government position, policy or decision. We would like to acknowledge high-performance computing support from Yellowstone (ark:/85065/d7wd3xhc) provided by NCAR's Computational and Information Systems Laboratory. NCAR is sponsored by the National Science Foundation.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1026

A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development.Bill & Melinda Gates Foundation (51066

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC

Initial Assessment of the Performance of the First Wind Lidar in Space on Aeolus

Soon after its successful launch in August 2018, the spaceborne wind lidar ALADIN (Atmospheric LAser Doppler INstrument) on-board ESA's Earth Explorer satellite Aeolus has demonstrated to provide atmospheric wind profiles on a global scale. Being the first ever Doppler Wind Lidar (DWL) instrument in space, ALADIN contributes to the improvement in numerical weather prediction (NWP) by measuring one component of the horizontal wind vector. The performance of the ALADIN instrument was assessed by a team from ESA, DLR, industry, and NWP centers during the first months of operation. The current knowledge about the main contributors to the random and systematic errors from the instrument will be discussed. First validation results from an airborne campaign with two wind lidars on-board the DLR Falcon aircraft will be shown

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council

Gene expression markers of tendon fibroblasts in normal and diseased tissue compared to monolayer and three dimensional culture systems

<p>Abstract</p> <p>Background</p> <p>There is a paucity of data regarding molecular markers that identify the phenotype of the tendon cell. This study aims to quantify gene expression markers that distinguish between tendon fibroblasts and other mesenchymal cells which may be used to investigate tenogenesis.</p> <p>Methods</p> <p>Expression levels for 12 genes representative of musculoskeletal tissues, including the proposed tendon progenitor marker scleraxis, relative to validated reference genes, were evaluated in matched samples of equine tendon (harvested from the superficial digital flexor tendon), cartilage and bone using quantitative PCR (qPCR). Expression levels of genes associated with tendon phenotype were then evaluated in healthy, including developmental, and diseased equine tendon tissue and in tendon fibroblasts maintained in both monolayer culture and in three dimensional (3D) collagen gels.</p> <p>Results</p> <p>Significantly increased expression of scleraxis was found in tendon compared with bone (P = 0.002) but not compared to cartilage. High levels of COL1A2 and scleraxis and low levels of tenascin-C were found to be most representative of adult tensional tendon phenotype. While, relative expression of scleraxis in developing mid-gestational tendon or in acute or chronically diseased tendon did not differ significantly from normal adult tendon, tenascin-C message was significantly upregulated in acutely injured equine tendon (P = 0.001). Relative scleraxis gene expression levels in tendon cell monolayer and 3D cultures were significantly lower than in normal adult tendon (P = 0.002, P = 0.02 respectively).</p> <p>Conclusion</p> <p>The findings of this study indicate that high expression of both COL1A2 and scleraxis, and low expression of tenascin-C is representative of a tensional tendon phenotype. The <it>in vitro </it>culture methods used in these experiments however, may not recapitulate the phenotype of normal tensional tendon fibroblasts in tissues as evidenced by gene expression.</p