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  1. Article ; Online: A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity.

    Dowey, Rebecca / Iqbal, Ahmed / Heller, Simon R / Sabroe, Ian / Prince, Lynne R

    Frontiers in immunology

    2021  Volume 12, Page(s) 678771

    Abstract: Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. ... ...

    Abstract Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.
    MeSH term(s) COVID-19/immunology ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 2/immunology ; Humans ; Inflammation/immunology ; Neutrophils/immunology ; SARS-CoV-2
    Language English
    Publishing date 2021-06-03
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.678771
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Book ; Online: Geology Uprooted! Decolonising the Curriculum for Geologists

    Rogers, Steven L. / Dowey, Natasha / Lau, Lisa / Sheikh, Hinna / Williams, Rebecca

    eISSN: 2569-7110

    2021  

    Abstract: Geology is colonial. It has a colonial past, and a colonial present. The majority of the knowledge we accept as the modern discipline of geology was founded during the height of the early modern European Empires colonial expansion. Knowledge is not ... ...

    Abstract Geology is colonial. It has a colonial past, and a colonial present. The majority of the knowledge we accept as the modern discipline of geology was founded during the height of the early modern European Empires colonial expansion. Knowledge is not neutral and its creation and use can be damaging to individuals and peoples. The concept of knowledge being colonial or colonised has gathered attention recently, but this concept can be misunderstood or difficult to engage with by individuals who are not familiar or trained to work with the literature on the issue. This paper aims to demystify Decolonising the Curriculum, particularly with respect to geology. We explain what Decolonising the Curriculum is, and outline frameworks and terminology often found in decolonising literature. We discuss how geology is based on colonised knowledge and what effects this may have. We explore how we might decolonise the subject and most importantly, why it matters. Together, through collaborative networks, we need to decolonise geology to ensure our discipline is inclusive, accessible to all and relevant to the grand challenges facing our civilization.
    Subject code 950 ; 306
    Language English
    Publishing date 2021-10-04
    Publishing country de
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin.

    Dowey, Rebecca / Cole, Joby / Thompson, A A Roger / Hull, Rebecca C / Huang, Chenghao / Whatmore, Jacob / Iqbal, Ahmed / Bradley, Kirsty L / McKenzie, Joanne / Lawrie, Allan / Condliffe, Alison M / Kiss-Toth, Endre / Sabroe, Ian / Prince, Lynne R

    ERJ open research

    2022  Volume 8, Issue 2

    Abstract: Background: Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung ... ...

    Abstract Background: Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in coronavirus disease 2019 (COVID-19) and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients.
    Methods: Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3-4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays.
    Results: Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to lipopolysaccharide (LPS) compared to cells from healthy control subjects. A subset of patients was captured at follow-up clinics (3-4 months post-acute sampling), and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and phorbol myristate acetate (PMA)-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death.
    Conclusion: Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.
    Language English
    Publishing date 2022-04-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2827830-6
    ISSN 2312-0541
    ISSN 2312-0541
    DOI 10.1183/23120541.00596-2021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin

    Rebecca Dowey / Joby Cole / A.A. Roger Thompson / Rebecca C. Hull / Chenghao Huang / Jacob Whatmore / Ahmed Iqbal / Kirsty L. Bradley / Joanne McKenzie / Allan Lawrie / Alison M. Condliffe / Endre Kiss-Toth / Ian Sabroe / Lynne R. Prince

    ERJ Open Research, Vol 8, Iss

    2022  Volume 2

    Abstract: Background Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung ... ...

    Abstract Background Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in coronavirus disease 2019 (COVID-19) and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Methods Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3–4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays. Results Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to lipopolysaccharide (LPS) compared to cells from healthy control subjects. A subset of patients was captured at follow-up clinics (3–4 months post-acute sampling), and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and phorbol myristate acetate (PMA)-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Conclusion Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.
    Keywords Medicine ; R
    Subject code 610
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher European Respiratory Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin.

    Dowey, Rebecca / Cole, Joby / Thompson, A A Roger / Huang, Chenghao / Whatmore, Jacob / Iqbal, Ahmed / Bradley, Kirsty L / McKenzie, Joanne / Hull, Rebecca C / Lawrie, Allan / Condliffe, Alison M / Kiss-Toth, Endre / Sabroe, Ian / Prince, Lynne R

    medRxiv

    Abstract: Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, ... ...

    Abstract Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in COVID-19 and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to LPS compared to cells from healthy control subjects. A subset of patients were captured at follow-up clinics (3-4 month post-infection) and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and PMA-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.
    Keywords covid19
    Language English
    Publishing date 2021-08-26
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2021.08.24.21262336
    Database COVID19

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  6. Article ; Online: Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial.

    Keir, Holly R / Long, Merete B / Abo-Leyah, Hani / Giam, Yan Hui / Vadiveloo, Thenmalar / Pembridge, Thomas / Hull, Rebecca C / Delgado, Lilia / Band, Margaret / McLaren-Neil, Fiona / Adamson, Simon / Lahnsteiner, Eva / Gilmour, Amy / Hughes, Chloe / New, Benjamin Jm / Connell, David / Dowey, Rebecca / Turton, Helena / Richardson, Hollian /
    Cassidy, Diane / Cooper, Jamie / Suntharalingam, Jay / Diwakar, Lavanya / Russell, Peter / Underwood, Jonathan / Hicks, Alexander / Dosanjh, Davinder Ps / Sage, Beth / Dhasmana, Devesh / Spears, Mark / Thompson, Aa Roger / Brightling, Christopher / Smith, Andrew / Patel, Manish / George, Jacob / Condliffe, Alison M / Shoemark, Amelia / MacLennan, Graeme / Chalmers, James D

    The Lancet. Respiratory medicine

    2022  Volume 10, Issue 12, Page(s) 1119–1128

    Abstract: Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP- ...

    Abstract Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19.
    Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012.
    Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug.
    Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.
    Funding: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.
    MeSH term(s) Humans ; COVID-19 Drug Treatment ; Double-Blind Method ; Serine Proteases ; Treatment Outcome ; Cathepsin C/antagonists & inhibitors
    Chemical Substances Serine Proteases (EC 3.4.-) ; CTSC protein, human (EC 3.4.14.1) ; Cathepsin C (EC 3.4.14.1)
    Language English
    Publishing date 2022-09-05
    Publishing country England
    Document type Randomized Controlled Trial ; Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2686754-0
    ISSN 2213-2619 ; 2213-2600
    ISSN (online) 2213-2619
    ISSN 2213-2600
    DOI 10.1016/S2213-2600(22)00261-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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