Recent Submissions

  • PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD.

    Keasey, Matt P; Razskazovskiy, V; Jia, C; Peterknecht, E D; Bradshaw, P C; Hagg, T; Peterknecht, Elizabeth; Sandwell and West Birmingham NHS Trust; Medical and Dental; Sandwell and West Birmingham NHS Trust; East Tennessee State University (BioMed Central, 2021-12-18)
    Background: Protein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described. Methods: Mitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen-glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury. Results: We show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen-glucose deprivation, while STAT3 inhibition reduced the protective effect. Conclusions: We have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation.
  • Safety of haem arginate in overdose: report of an uneventful fourfold accidental overdose.

    Patel, Nandesh C; Wroe, Nicholas; McNally, Daniel; Stein, Penny; Bradberry, Sally M; Elamin, Muhammad E M O; Patel, Nandesh C; Bradberry, Sally M; Sandwell and West Birmingham NHS Trust; Allied Health Professional; et al. (Taylor and Francis Group, 2021-09-20)
    Safety of haem arginate in overdose: report of an uneventful fourfold accidental overdose
  • Treatment of chronic or relapsing COVID-19 in immunodeficiency.

    Brown, Li-An K; Moran, Ed; Goodman, Anna; Baxendale, Helen; Bermingham, William; Buckland, Matthew; AbdulKhaliq, Iman; Jarvis, Hannah; Hunter, Michael; Karanam, Surendra; et al. (Mosby, 2021-11-12)
    Background: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. Objective: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. Methods: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting ≥21 days) or relapsing (≥2 episodes) of COVID-19. Results: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of ≤20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. Conclusions: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise.
  • A UK multicentre audit of the management of patients with primary hypercholesterolaemia or mixed dyslipidaemia with bempedoic acid against published lipid-lowering treatment targets

    Ramachandran, Sudarshan; Maarouf, Amro; Mitchell, Karen; Avades, Tony; Smith, Peter; Boulton, Lee; Kelly, Jennifer; Vekaria, Nitasha; Hughes, Elizabeth; Hughes, Elizabeth; et al. (Bioexcel Publishing, 2024-08-08)
    Background: Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, was introduced to UK practice via a pre-reimbursement access scheme for adults with primary hypercholesterolaemia or mixed dyslipidaemia who are at high risk of cardiovascular disease, in whom statins are either not tolerated or contraindicated, who have not achieved target cholesterol, despite being on ezetimibe therapy, and do not qualify for PCSK9 inhibitor treatment. This retrospective multicentre audit aimed to evaluate the achievement of lipid-lowering targets with bempedoic acid in UK patients based on recommendations in the Joint British Societies (JBS) guidelines for the prevention of cardiovascular disease. Methods: Pseudo-anonymized medical record data for 221 adults treated with bempedoic acid as part of the UK scheme were entered into a bespoke data collection tool at four UK hospitals. Patient demographics, clinical characteristics, treatment pathways and lipid assessment results (against JBS lipid-lowering targets) were collected against pre-specified criteria. Results: Overall, 54% (99/184) of patients achieved the JBS2 audit standard (total cholesterol (TC) <5 mmol/L and low-density lipoprotein cholesterol (LDL-C) <3 mmol/L or ≥25% reduction in TC and ≥30% reduction in LDL-C) at 12 weeks post-initiation. At week 12, the mean absolute change in LDL-C was -1.0 mmol/L; the mean percentage reduction from baseline was 22.0%. Additionally, 52% (96/185) of patients had an LDL-C of <3 mmol/L and 10% (18/185) an LDL-C of <1.8 mmol/L at 12 weeks (as per JBS3). Conclusion: This audit highlights the role of bempedoic acid as part of combination therapy for a population with previously limited treatment options.