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  1. Article: Novel Therapeutic Targets in Axial Spondyloarthritis.

    Worth, Claudia / Bowness, Paul / Hussein Al-Mossawi, M

    Current treatment options in rheumatology

    2018  Volume 4, Issue 2, Page(s) 174–182

    Abstract: Purpose of review: Axial spondyloarthritis remains an area of significant unmet clinical need with only two immune pathways currently targeted by licenced therapies compared to other immune-mediated inflammatory joint disorders such as rheumatoid ... ...

    Abstract Purpose of review: Axial spondyloarthritis remains an area of significant unmet clinical need with only two immune pathways currently targeted by licenced therapies compared to other immune-mediated inflammatory joint disorders such as rheumatoid arthritis where a multitude of therapeutic options are available. This review will look at emerging therapeutic targets in axial spondyloarthritis beyond the neutralisation of IL-17A and TNF by monoclonal antibodies.
    Recent findings: Several promising targets are in various stages of pre-clinical and clinical development in axial spondyloarthritis. These include small molecule approaches to target transcription factors, epigenetic modification and intracellular modulation of cytokine signalling by kinase inhibition. GM-CSF has also emerged as a potential driver of inflammation.
    Summary: A number of novel and promising therapeutic options are in various stages of development in axial spondyloarthritis. The Janus kinase inhibitors have shown great promise in other immune-mediated inflammatory disorders and will be an exciting addition to the axial spondyloarthritis field as the first oral disease-modifying agents. GM-CSF blockade also shows great promise since antibodies for neutralising this cytokine are safe in patients and have shown efficacy in other immune-mediated inflammatory diseases.
    Language English
    Publishing date 2018-04-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ISSN 2198-6002
    ISSN 2198-6002
    DOI 10.1007/s40674-018-0095-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Treating to target in psoriatic arthritis

    Ines Rombach / William Tillett / Deepak Jadon / Laura Tucker / Marion Watson / Anne Francis / Yvonne Sinomati / Lucy Eldridge / Melina Dritsaki / Susan J. Dutton / Hussein Al-Mossawi / Nicola Gullick / Ben Thompson / Laura C. Coates

    Trials, Vol 22, Iss 1, Pp 1-

    assessing real-world outcomes and optimising therapeutic strategy for adults with psoriatic arthritis—study protocol for the MONITOR-PsA study, a trials within cohorts study design

    2021  Volume 14

    Abstract: Abstract Background The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of ‘step up’ therapy ( ... ...

    Abstract Abstract Background The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of ‘step up’ therapy (single disease modifying therapy (DMARD), combination DMARDs and then biologics) based on remission criteria. Based on this, a T2T approach is supported by European PsA treatment recommendations. However, it is not commonly implemented in routine care primarily due to feasibility and cost concerns. In the TICOPA trial, the same treatment regime was used for all participants regardless of their disease profile. Despite the recognition of PsA as a highly heterogeneous condition, no studies have tailored which drugs are used depending on disease severity. The cohort will establish real world outcomes for the T2T approach in PsA and also form the basis of a trials within cohorts (TWiCs) design to test alternative therapeutic approaches within embedded clinical trials providing an evidence base for treatment strategy in PsA. Methods The Multicentre Observational Initiative in Treat to target Outcomes in Psoriatic Arthritis (MONITOR-PsA) cohort will apply a T2T approach within routine care. It will recruit newly diagnosed adult patients with PsA starting systemic therapies. The cohort is observational allowing routine therapeutic care within NHS clinics but a T2T approach will be supported when monitoring treatment within the cohort. Eligible participants will be adults (≥18 years) with active PsA with ≥ 1 tender or swollen joints or enthesis who have not previously had treatment with DMARDs for articular disease. Discussion This study is the first TWiC designed to support a fully powered randomised drug trial. The results from the observational cohort will be compared with those observed in the TICOPA trial investigating the clinical effectiveness and health care costs of the pragmatic T2T approach. Nested trials will provide definitive RCT evidence establishing the optimal management of PsA within the T2T approach. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer-term outcomes. Trial registration ClinicalTrials.gov NCT03531073 . Retrospectively registered on 21 May 2018.
    Keywords Psoriatic arthritis ; Treat-to-target ; TWiCs ; Trials within cohorts ; Cohort multiple RCT or cmRCT ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Multi-omic single cell analysis resolves novel stromal cell populations in healthy and diseased human tendon

    Adrian R. Kendal / Thomas Layton / Hussein Al-Mossawi / Louise Appleton / Stephanie Dakin / Rick Brown / Constantinos Loizou / Mark Rogers / Robert Sharp / Andrew Carr

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: Abstract Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing ... ...

    Abstract Abstract Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing therapeutics to meet this challenge. Tendon cells are heterogenous and sparsely distributed in a dense collagen matrix; limiting previous methods to investigate cell characteristics ex vivo. We applied next generation CITE-sequencing; combining surface proteomics with in-depth, unbiased gene expression analysis of > 6400 single cells ex vivo from 11 chronically tendinopathic and 8 healthy human tendons. Immunohistochemistry validated the single cell findings. For the first time we show that human tendon harbours at least five distinct COL1A1/2 expressing tenocyte populations in addition to endothelial cells, T-cells, and monocytes. These consist of KRT7/SCX+ cells expressing microfibril associated genes, PTX3+ cells co-expressing high levels of pro-inflammatory markers, APOD+ fibro–adipogenic progenitors, TPPP3/PRG4+ chondrogenic cells, and ITGA7+ smooth muscle-mesenchymal cells. Surface proteomic analysis identified markers by which these sub-classes could be isolated and targeted in future. Chronic tendinopathy was associated with increased expression of pro-inflammatory markers PTX3, CXCL1, CXCL6, CXCL8, and PDPN by microfibril associated tenocytes. Diseased endothelium had increased expression of chemokine and alarmin genes including IL33.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

    Penkava, Frank / Velasco-Herrera, Martin Del Castillo / Young, Matthew D / Yager, Nicole / Nwosu, Lilian N / Pratt, Arthur G / Lara, Alicia Lledo / Guzzo, Charlotte / Maroof, Ash / Mamanova, Lira / Cole, Suzanne / Efremova, Mirjana / Simone, Davide / Filer, Andrew / Brown, Chrysothemis C / Croxford, Andrew L / Isaacs, John D / Teichmann, Sarah / Bowness, Paul /
    Behjati, Sam / Hussein Al-Mossawi, M

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 4767

    Abstract: Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass ... ...

    Abstract Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.
    MeSH term(s) Arthritis, Psoriatic/blood ; Arthritis, Psoriatic/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Clonal Selection, Antigen-Mediated ; Gene Expression Profiling ; Humans ; Immunologic Memory ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Receptors, Chemokine/metabolism ; Receptors, Lymphocyte Homing/genetics ; Receptors, Lymphocyte Homing/metabolism ; Single-Cell Analysis ; Synovial Fluid/immunology ; Synovial Membrane/immunology
    Chemical Substances Receptors, Antigen, T-Cell, alpha-beta ; Receptors, Chemokine ; Receptors, Lymphocyte Homing
    Language English
    Publishing date 2020-09-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-18513-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Towards stratified treatment of JIA

    Stephanie J.W. Shoop-Worrall / Saskia Lawson-Tovey / Lucy R. Wedderburn / Kimme L. Hyrich / Nophar Geifman / Aline Kimonyo / Alyssia McNeece / Andrew Dick / Andrew Morris / Annie Yarwood / Athimalaipet Ramanan / Bethany R. Jebson / Chris Wallace / Daniela Dastros-Pitei / Damian Tarasek / Elizabeth Ralph / Emil Carlsson / Emily Robinson / Emma Sumner /
    Fatema Merali / Fatjon Dekaj / Helen Neale / Hussein Al-Mossawi / Jacqui Roberts / Jenna F. Gritzfeld / Joanna Fairlie / John Bowes / John Ioannou / Melissa Kartawinata / Melissa Tordoff / Michael Barnes / Michael W. Beresford / Michael Stadler / Paul Martin / Rami Kallala / Sandra Ng / Samantha Smith / Sarah Clarke / Soumya Raychaudhuri / Stephen Eyre / Sumanta Mukherjee / Teresa Duerr / Thierry Sornasse / Vasiliki Alexiou / Victoria J. Burton / Wei-Yu Lin / Wendy Thomson / Zoe Wanstall

    EBioMedicine, Vol 100, Iss , Pp 104946- (2024)

    machine learning identifies subtypes in response to methotrexate from four UK cohortsResearch in context

    2024  

    Abstract: Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To ... ...

    Abstract Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Methods: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year.Clusters of MTX ‘response’ were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. Findings: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65–0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Interpretation: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis ...
    Keywords Juvenile idiopathic arthritis ; Machine learning ; Treatment outcome ; Epidemiology ; Methotrexate ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 310
    Language English
    Publishing date 2024-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele

    Hussein Al-Mossawi / Nicole Yager / Chelsea A. Taylor / Evelyn Lau / Sara Danielli / Jelle de Wit / James Gilchrist / Isar Nassiri / Elise A. Mahe / Wanseon Lee / Laila Rizvi / Seiko Makino / Jane Cheeseman / Matt Neville / Julian C. Knight / Paul Bowness / Benjamin P. Fairfax

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of ... ...

    Abstract Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of monocytes in IL-7-related autoimmunity.
    Keywords Science ; Q
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele

    Hussein Al-Mossawi / Nicole Yager / Chelsea A. Taylor / Evelyn Lau / Sara Danielli / Jelle de Wit / James Gilchrist / Isar Nassiri / Elise A. Mahe / Wanseon Lee / Laila Rizvi / Seiko Makino / Jane Cheeseman / Matt Neville / Julian C. Knight / Paul Bowness / Benjamin P. Fairfax

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of ... ...

    Abstract Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of monocytes in IL-7-related autoimmunity.
    Keywords Science ; Q
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

    Frank Penkava / Martin Del Castillo Velasco-Herrera / Matthew D. Young / Nicole Yager / Lilian N. Nwosu / Arthur G. Pratt / Alicia Lledo Lara / Charlotte Guzzo / Ash Maroof / Lira Mamanova / Suzanne Cole / Mirjana Efremova / Davide Simone / Andrew Filer / Chrysothemis C. Brown / Andrew L. Croxford / John D. Isaacs / Sarah Teichmann / Paul Bowness /
    Sam Behjati / M. Hussein Al-Mossawi

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 11

    Abstract: Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, ... ...

    Abstract Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, but not peripheral blood, CD8 T cells from PsA patients to provide a molecular immune landscape for PsA.
    Keywords Science ; Q
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

    Frank Penkava / Martin Del Castillo Velasco-Herrera / Matthew D. Young / Nicole Yager / Lilian N. Nwosu / Arthur G. Pratt / Alicia Lledo Lara / Charlotte Guzzo / Ash Maroof / Lira Mamanova / Suzanne Cole / Mirjana Efremova / Davide Simone / Andrew Filer / Chrysothemis C. Brown / Andrew L. Croxford / John D. Isaacs / Sarah Teichmann / Paul Bowness /
    Sam Behjati / M. Hussein Al-Mossawi

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 11

    Abstract: Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, ... ...

    Abstract Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, but not peripheral blood, CD8 T cells from PsA patients to provide a molecular immune landscape for PsA.
    Keywords Science ; Q
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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