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Conference paperGunawardana N, Matthews D, Rey-Garcia H, et al., 2017,
Adherence to BSACI guidance on drug allergy testing at a UK allergy centre
, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY, Pages: 1687-1687, ISSN: 0954-7894 -
Conference paperVlachantoni I, Ascough S, Grimaldi R, et al., 2017,
PHASE 1 TRIAL OF AN INTRANASAL RESPIRATORY SYNCYTIAL VIRUS (RSV) SUBUNIT CANDIDATE VACCINE: SAFETY RESULTS FROM THE MUC-SYNGEM STUDY
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A43-A44, ISSN: 0040-6376 -
Conference paperEifan A, Scadding G, Calderon M, et al., 2017,
Relationship between response to grass pollen nasal allergen challenge and seasonal symptoms and the effect of treatment compliance
, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY, Pages: 1686-1687, ISSN: 0954-7894 -
Conference paperAlzaher O, Macaluso C, Maritano J, et al., 2017,
THE IMPACT OF AZITHROMYCIN IN IDIOPATHIC PULMONARY FIBROSIS
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A36-A37, ISSN: 0040-6376 -
Journal articleGibson LM, Littlejohns TJ, Adamska L, et al., 2017,
Impact of detecting potentially serious incidental findings during multi-modal imaging [version 3; peer review: 2 approved, 1 approved with reservations]
, Wellcome Open Research, Vol: 2, ISSN: 2398-502XBackground: There are limited data on the impact of feedback of incidental findings (IFs) from research imaging. We evaluated the impact of UK Biobank's protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer 'flagging' with radiologist confirmation of potentially serious IFs) compared with systematic radiologist review of all images. Methods: Brain, cardiac and body magnetic resonance, and dual-energy x-ray absorptiometry scans from the first 1000 imaged UK Biobank participants were independently assessed for potentially serious IFs using both protocols. We surveyed participants with potentially serious IFs and their GPs up to six months after imaging to determine subsequent clinical assessments, final diagnoses, emotional, financial and work or activity impacts. Results: Compared to systematic radiologist review, radiographer flagging resulted in substantially fewer participants with potentially serious IFs (179/1000 [17.9%] versus 18/1000 [1.8%]) and a higher proportion with serious final diagnoses (21/179 [11.7%] versus 5/18 [27.8%]). Radiographer flagging missed 16/21 serious final diagnoses (i.e., false negatives), while systematic radiologist review generated large numbers of non-serious final diagnoses (158/179) (i.e., false positives). Almost all (90%) participants had further clinical assessment (including invasive procedures in similar numbers with serious and non-serious final diagnoses [11 and 12 respectively]), with additional impact on emotional wellbeing (16.9%), finances (8.9%), and work or activities (5.6%). Conclusions: Compared with systematic radiologist review, radiographer flagging missed some serious diagnoses, but avoided adverse impacts for many participants with non-serious diagnoses. While systematic radiologist review may benefit some participants, UK Biobank's responsibility to avoid both unnecessary harm to larger numbers of participants and burdening
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Journal articleFuruta R, Yasunaga J-I, Miura M, et al., 2017,
Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo.
, PLoS Pathogens, Vol: 13, ISSN: 1553-7366Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+CCR4+ effector/memory T cells in vivo. However, it remains unknown whether HTLV-1 preferentially infects these T cells or this virus converts infected precursor cells to specialized T cells. Expression of viral genes in vivo is critical to study viral replication and proliferation of infected cells. Therefore, we first analyzed viral gene expression in non-human primates naturally infected with simian T-cell leukemia virus type 1 (STLV-1), whose virological attributes closely resemble those of HTLV-1. Although the tax transcript was detected only in certain tissues, Tax expression was much higher in the bone marrow, indicating the possibility of de novo infection. Furthermore, Tax expression of non-T cells was suspected in bone marrow. These data suggest that HTLV-1 infects hematopoietic cells in the bone marrow. To explore the possibility that HTLV-1 infects hematopoietic stem cells (HSCs), we analyzed integration sites of HTLV-1 provirus in various lineages of hematopoietic cells in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a HTLV-1 carrier using the high-throughput sequencing method. Identical integration sites were detected in neutrophils, monocytes, B cells, CD8+ T cells and CD4+ T cells, indicating that HTLV-1 infects HSCs in vivo. We also detected Tax protein in myeloperoxidase positive neutrophils. Furthermore, dendritic cells differentiated from HTLV-1 infected monocytes caused de novo infection to T cells, indicating that infected monocytes are implicated in viral spreading in vivo. Certain integration sites were re-detected in neutrophils from HAM/TSP patients at different time points, indicating that infected HSCs persist and differentiate in vivo. This study demonstrates that HTLV-1 infects HSCs, and infected stem cells differentiate into diverse cell lineages. These data indicate that infection of HSCs can contribute to the persistence and spread
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Journal articleMontgomery KS, Davidson RWM, Cao B, et al., 2017,
Effective macrophage delivery using RAFT copolymer derived nanoparticles
, Polymer Chemistry, Vol: 9, Pages: 131-137, ISSN: 1759-9954Reversible addition fragmentation chain transfer (RAFT) polymerisation provides a highly controlled means to assemble copolymers of different architectures for a variety of applications, including drug delivery. Polymers consisting of a butyl methacrylate-co-methacrylic acid p(BMA-co-MAA) hydrophobic block and a poly(ethylene glycol) methyl ether methacrylate p(PEGMA-475) hydrophilic block were synthesised via RAFT polymerisation and self-assembled into micelles. A range of micelle particles of different sizes were obtained by varying the composition of the block copolymers. The micelles were crosslinked to form nanoparticles and fluorescently labelled to study cellular internalisation. The prepared nanoparticles were extensively taken up by primary murine macrophages and a promising candidate was identified. To demonstrate effective delivery of a cell impenetrable cargo a fluorescent dye, 4′,6-diamidino-2-phenylindole (DAPI), was encapsulated inside the nanoparticles and successfully delivered to macrophages. The nanoparticles’ stability at increased temperatures and at low concentrations, the tunability of their synthesis and their extensive internalisation by macrophages and performance makes them highly promising delivery vehicles for a range of therapeutics and imaging agents.
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Journal articleTanigaki K, Sacharidou A, Peng J, et al., 2017,
Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance.
, Journal of Clinical Investigation, Vol: 128, Pages: 309-322, ISSN: 0021-9738Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we have shown that activation of the IgG receptor FcγRIIB in endothelium by hyposialylated IgG plays an important role in obesity-induced insulin resistance. Despite becoming obese on a high-fat diet (HFD), mice lacking FcγRIIB globally or selectively in endothelium were protected from insulin resistance as a result of the preservation of insulin delivery to skeletal muscle and resulting maintenance of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as the pathogenetic ligand for endothelial FcγRIIB in obesity-induced insulin resistance. Moreover, IgG transferred from patients with T2DM but not from metabolically healthy subjects caused insulin resistance in IgG-deficient mice via FcγRIIB, indicating that similar processes may be operative in T2DM in humans. Mechanistically, the activation of FcγRIIB by IgG from obese mice impaired endothelial cell insulin transcytosis in culture and in vivo. These effects were attributed to hyposialylation of the Fc glycan, and IgG from T2DM patients was also hyposialylated. In HFD-fed mice, supplementation with the sialic acid precursor N-acetyl-D-mannosamine restored IgG sialylation and preserved insulin sensitivity without affecting weight gain. Thus, IgG sialylation and endothelial FcγRIIB may represent promising therapeutic targets to sever the link between obesity and T2DM.
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Journal articleOwen DRJ, Fan J, Campioli E, et al., 2017,
TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
, Biochemical Journal, Vol: 474, Pages: 3985-3999, ISSN: 1470-8728The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
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Journal articleTeo SM, Tang HHF, Mok D, et al., 2017,
Dynamics of the upper airway microbiome in the pathogenesis of asthma-associated persistent wheeze in preschool children
, BiorxivRepeated cycles of infection-associated lower airway inflammation drives the pathogenesis of persistent wheezing disease in children. Tracking these events across a birth cohort during their first five years, we demonstrate that >80% of infectious events indeed involve viral pathogens, but are accompanied by a shift in the nasopharyngeal microbiome (NPM) towards dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change in NPM frequently precedes the appearance of viral pathogens and acute symptoms. In non-sensitized children these events are associated only with "transient wheeze" that resolves after age three. In contrast, in children developing early allergic sensitization, they are associated with ensuing development of persistent wheeze, which is the hallmark of the asthma phenotype. This suggests underlying pathogenic interactions between allergic sensitization and anti-bacterial mechanisms.
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