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Journal articleBercusson A, de Boer L, Armstrong-James D, 2016,
Endosomal sensing of fungi: current understanding and emerging concepts
, Medical Mycology, ISSN: 1460-2709Endosomal sensing represents a key strategy by which mammalian cells detect parasitization by invading pathogens. This is critical for the control of fungal pathogens, which are for the most part phagocytosed by effector cells of the innate immune system. Despite rapid overall progress in our understanding of endosomal responses in recent times, relatively little is known about how the endosomal sensing system detects fungi and the ensuing immunological consequences. Considering that many fungal pathogens must overcome and evade endosomal killing in order to survive in the host, understanding this key area of the early innate response is crucial for our understanding of fungal infection. In this review we present a summary of our current knowledge of endosomal sensing within the context of fungal pathogens, with a focus on the myeloid compartment.
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Journal articleEsmail H, Lai RP, Lesosky M, et al., 2016,
Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography
, Nature Medicine, Vol: 22, Pages: 1090-1093, ISSN: 1546-170XTuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.
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Journal articleRamaswami R, Pria AD, Parker K, et al., 2016,
Outcomes of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory HIV-associated lymphoma
, Bone Marrow Transplantation, Vol: 51, Pages: 1609-1611, ISSN: 1476-5365 -
Conference paperNolan CM, Maddocks M, Canavan JL, et al., 2016,
The reliability and validity of the 4 metre gait speed (4MGS) in idiopathic pulmonary fibrosis (IPF)
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936 -
Conference paperSpiteri M, Chang W, Chaudhuri N, et al., 2016,
First Insights from the BTS Idiopathic Pulmonary Fibrosis (IPF) registry
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936- Author Web Link
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- Citations: 1
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Conference paperSinha A, Patel AS, Siegert R, et al., 2016,
The King's brief interstitial lung disease (K-BILD) questionnaire; an updated minimal important difference
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936- Cite
- Citations: 3
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Conference paperMaher T, Flaherty KR, Inoue Y, et al., 2016,
No effect of baseline diffusing capacity of lung for carbon monoxide on benefit of nintedanib
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936- Cite
- Citations: 4
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Journal articleGruber R, Panayiotou R, Nye E, et al., 2016,
YAP1 and TAZ control pancreatic cancer initiation in Mice by Direct Up-regulation of JAK-STAT3 signaling
, Gastroenterology, Vol: 151, Pages: 526-539, ISSN: 0016-5085Background & AimsPancreatitis is the most important risk factor for pancreatic ductal adenocarcinoma (PDAC). Pancreatitis predisposes to PDAC because it induces a process of acinar cell reprogramming known as acinar-to-ductal metaplasia (ADM)—a precursor of pancreatic intraepithelial neoplasia lesions that can progress to PDAC. Mutations in KRAS are found at the earliest stages of pancreatic tumorigenesis, and it appears to be a gatekeeper to cancer progression. We investigated how mutations in KRAS cooperate with pancreatitis to promote pancreatic cancer progression in mice.MethodsWe generated mice carrying conditional alleles of Yap1 and Taz and disrupted Yap1 and Taz using a Cre-lox recombination strategy in adult mouse pancreatic acinar cells (Yap1fl/fl;Tazfl/fl;Ela1-CreERT2). We crossed these mice with LSL-KrasG12D mice, which express a constitutively active form of KRAS after Cre recombination. Pancreatic tumor initiation and progression were analyzed after chemically induced pancreatitis. We analyzed pancreatic tissues from patients with pancreatitis or PDAC by immunohistochemistry.ResultsOncogenic activation of KRAS in normal, untransformed acinar cells in the pancreatic tissues of mice resulted in increased levels of pancreatitis-induced ADM. Expression of the constitutive active form of KRAS in this system led to activation of the transcriptional regulators YAP1 and TAZ; their function was required for pancreatitis-induced ADM in mice. The JAK–STAT3 pathway was a downstream effector of KRAS signaling via YAP1 and TAZ. YAP1 and TAZ directly mediated transcriptional activation of several genes in the JAK–STAT3 signaling pathway; this could be a mechanism by which acinar cells that express activated KRAS become susceptible to inflammation.ConclusionsWe identified a mechanism by which oncogenic KRAS facilitates ADM and thereby generates the cells that initiate neoplastic progression. This process involves activation of YAP1 and TAZ in aci
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Journal articleWatt FE, Paterson E, Freidin A, et al., 2016,
Acute molecular changes in synovial fluid following human knee injury: association with early clinical outcomes
, Arthritis & Rheumatology, Vol: 68, Pages: 2129-2140, ISSN: 2326-5205ObjectiveTo investigate whether molecules found to be up-regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient-reported outcomes in the 3 months after injury.MethodsSeven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (<8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme-linked immunosorbent assay.ResultsSix of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin-6 (IL-6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), activin A, and tumor necrosis factor–stimulated gene 6 (TSG-6). There was low-to-moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL-6, TIMP-1, or TSG-6 had lower KOOS4). These 3 molecules, MMP-3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors. Of these, IL-6 alone significantly accounted for the molecular contribution to baseline KOOS4 and change in KOOS4 over 3 months.ConclusionOur findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient-reported outcomes over this early period, with SF IL-6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease ris
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Conference paperCook J, Bush A, Saglani S, et al., 2016,
Higher doses of inhaled steroid are associated with bacterial bronchitis in children with severe therapy resistant asthma (STRA)
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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