35 research outputs found
(9R,9aS,12aR,13S)-9,13-Diphenyl-9,9a,12a,13-tetrahydro-9,13-methanotriphenyleno[2,3-c]furan-10,12,14-trione
X-ray crystallography was used to characterise the title compound for the first time, and the 1H NMR, 13C NMR and IR spectroscopic data from earlier reports were also updated.Publisher PDFPeer reviewe
The NCI Imaging Data Commons as a platform for reproducible research in computational pathology
Background and Objectives: Reproducibility is a major challenge in developing
machine learning (ML)-based solutions in computational pathology (CompPath).
The NCI Imaging Data Commons (IDC) provides >120 cancer image collections
according to the FAIR principles and is designed to be used with cloud ML
services. Here, we explore its potential to facilitate reproducibility in
CompPath research.
Methods: Using the IDC, we implemented two experiments in which a
representative ML-based method for classifying lung tumor tissue was trained
and/or evaluated on different datasets. To assess reproducibility, the
experiments were run multiple times with separate but identically configured
instances of common ML services.
Results: The AUC values of different runs of the same experiment were
generally consistent. However, we observed small variations in AUC values of up
to 0.045, indicating a practical limit to reproducibility.
Conclusions: We conclude that the IDC facilitates approaching the
reproducibility limit of CompPath research (i) by enabling researchers to reuse
exactly the same datasets and (ii) by integrating with cloud ML services so
that experiments can be run in identically configured computing environments.Comment: 13 pages, 5 figures; improved manuscript, new experiments with P100
GP
Highdicom: A Python library for standardized encoding of image annotations and machine learning model outputs in pathology and radiology
Machine learning is revolutionizing image-based diagnostics in pathology and
radiology. ML models have shown promising results in research settings, but
their lack of interoperability has been a major barrier for clinical
integration and evaluation. The DICOM a standard specifies Information Object
Definitions and Services for the representation and communication of digital
images and related information, including image-derived annotations and
analysis results. However, the complexity of the standard represents an
obstacle for its adoption in the ML community and creates a need for software
libraries and tools that simplify working with data sets in DICOM format. Here
we present the highdicom library, which provides a high-level application
programming interface for the Python programming language that abstracts
low-level details of the standard and enables encoding and decoding of
image-derived information in DICOM format in a few lines of Python code. The
highdicom library ties into the extensive Python ecosystem for image processing
and machine learning. Simultaneously, by simplifying creation and parsing of
DICOM-compliant files, highdicom achieves interoperability with the medical
imaging systems that hold the data used to train and run ML models, and
ultimately communicate and store model outputs for clinical use. We demonstrate
through experiments with slide microscopy and computed tomography imaging,
that, by bridging these two ecosystems, highdicom enables developers to train
and evaluate state-of-the-art ML models in pathology and radiology while
remaining compliant with the DICOM standard and interoperable with clinical
systems at all stages. To promote standardization of ML research and streamline
the ML model development and deployment process, we made the library available
free and open-source
Basic science232.âCertolizumab pegol prevents pro-inflammatory alterations in endothelial cell function
Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia Âź; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-ÎșB localization and IÎșB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-ÎșB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-ÎșB and degradation of IÎșB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-ÎșB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes
Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials
Background
Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response.
Methods
We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab.
Findings
In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, Îș-free light chain, ÎČ2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo.
Interpretation
Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases.
Funding
UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology
Qualitative Impact Assessment of Land Management Interventions on Ecosystem Services (âQEIAâ). Report-1: Executive Summary: QEIA Evidence Review & Integrated Assessment
The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten teams involving 45 experts drawn from the independent research community in a consistent series of Evidence Reviews covering the broad topics of:
âą Air quality
âą Greenhouse gas emissions
âą Soils
âą Water management
âą Biodiversity: croplands
âą Biodiversity: improved grassland
âą Biodiversity: semi-natural habitats
âą Biodiversity: integrated systems-based actions
âą Carbon sequestration
âą Cultural services (including recreation, geodiversity and regulatory services).
It should be noted that this piece of work is just one element of the wider underpinning work Defra has commissioned to support the development of the ELM schemes
Qualitative impact assessment of land management interventions on Ecosystem Services (âQEIAâ). Report-2: Integrated Assessment
The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten expert teams drawn from the independent research community in a consistent series of ten Evidence Reviews covering the broad topics of;
âą Air quality
âą Greenhouse gas emissions
âą Soils
âą Water management
âą Biodiversity: croplands
âą Biodiversity: improved grassland
âą Biodiversity: semi-natural habitats
âą Biodiversity: integrated systems-based actions
âą Carbon sequestration
âą Cultural services (including recreation, geodiversity and regulatory services)
These reviews were undertaken rapidly at Defraâs request by ten teams involving 45 experts who together captured more than 2,400 individual sources of evidence. This was followed by the Integrated Assessment (IA) reported here to provide a more accessible summary of these evidence reviews with a focus on capturing the actions with the greatest potential magnitude of change for the intended ES, and their potential co-benefits and trade-offs for the other ES
DICOM Structured Reporting and Cancer Clinical Trials Results
The use of biomarkers derived from radiological images as surrogate end-points in therapeutic cancer clinical trials is well established. DICOM is the ubiquitous standard for the interchange of images for both clinical use as well as research. It also has capabilities for the exchange of image-related information, including categorical and quantitative information derived from images. The use of DICOM Structured Reporting for the encoding and interchange of clinical trial results in a standard manner is reviewed