tbuckley/cabot-search huggingface dataset:
High prevalence of <i>CCDC103</i> p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations
Authors: Amelia Shoemark, Eduardo Moya, Robert A Hirst, Mitali P Patel, Evelyn A Robson, Jane Hayward, Juliet Scully, Mahmoud R Fassad, William Lamb, Miriam Schmidts, Mellisa Dixon, Ramila S Patel-King, Andrew V Rogers, Andrew Rutman, Claire L Jackson, Patricia Goggin, Bruna Rubbo, Sarah Ollosson, Siobhán Carr, Woolf Walker, Beryl Adler, Michael R Loebinger, Robert Wilson, Andrew Bush, Hywel Williams, Christopher Boustred, Lucy Jenkins, Eamonn Sheridan, Eddie M K Chung, Christopher M Watson, Thomas Cullup, Jane S Lucas, Priti Kenia, Christopher O’Callaghan, Stephen M King, Claire Hogg, Hannah M Mitchison
Journal: Thorax (2017)

Rationale Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal. Objectives To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive. Methods Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay. Results Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed. Conclusions The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.
Source of Tumor Proteins. II. Nitrogen-Balance Studies of Tumor-Bearing Mice Fed a Low-Nitrogen Diet&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Florence R. White
Journal: JNCI Journal of the National Cancer Institute (1945)

Journal Article Source of Tumor Proteins. II. Nitrogen-Balance Studies of Tumor-Bearing Mice Fed a Low-Nitrogen Diet Get access Florence R. White Florence R. White associate biochemist National Cancer Institute, National Institute of Health, United States Public Health Service2 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 5, Issue 4, February 1945, Pages 265–268, https://doi.org/10.1093/jnci/5.4.265 Published: 01 February 1945
05.09 The role of the european consensus finding study group (ecfsg) in characterising new tentative reference standards for autoantibody measurement
Authors: Johan Rönnelid, Charlotte Dahle, Martin Blüthner, Eugen Feist, Carl Dolman, Susan J Thorpe, Pier Luigi Meroni, Dörte Hamann
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Since 1988, the European Consensus Finding Study Group on autoantibodies in rheumatic diseases (ECFSG), also known as the EULAR (European League Against Rheumatism) autoantibody study group, has been distributing sera with unspecified antibodies to European laboratories (presently n=43) for evaluation of different autoantibody measurement techniques in a clinical context. Use of international reference standards helps align test results by adopting internationally used measurement units, but there are no standards for many autoantibody specificities. Recently, the scope of ECFSG was expanded to include unbiased autoantibody characterisation of serum/plasma specimens with potential for serving as future autoantibody reference standards. <h3>Materials and methods</h3> Four samples were evaluated as tentative international reference standards for four different autoantibody specificities: double stranded/native DNA (dsDNA: 2013/14), IgG anti-beta2 glycoprotein 1 (b2GP1), proteinase 3 (PR3) and myeloperoxidase (MPO; 2015/16). The samples were evaluated 'blind' for multiple autoantibody specificities by participating laboratories. <h3>Results</h3> All or almost all participating laboratories detected the target specificities, and all samples showed restricted autoantibody specificities related to the target specificity. Anti-dsDNA was detected in the tentative anti-dsDNA standard by all laboratories using <i>Crithidia luciliae</i>, ELISA/EIA, FARR assay or ALBIA, together with a homogenous ANA pattern. Other specificities were restricted to histones, nucleosomes and anti-Ku. All laboratories but one detected IgG anti-b2GP1 and IgG anti-cardiolipin, mostly in high levels, in the tentative IgG anti-b2GP1 reference standard, whereas corresponding IgA and IgM antibodies were absent. All laboratories detected anti-MPO, mostly monospecific and in high levels together with P-ANCA pattern in the anti-MPO reagent. Anti-proteinase 3 and C-ANCA pattern, mostly in high levels/titers were detected by all laboratories in the tentative anti-PR3 reagent, <h3>Conclusions</h3> The expanded scope of ECFSG has enabled broad characterisation of new tentative autoantibody reference standards. The anti-dsDNA specimen has been processed by the National Institute for Biological Standards and Control (NIBSC) for consideration as the 2<sup>nd</sup> WHO anti-dsDNA reference standard. The other materials are basis for certified reference material for IgG anti-myeloperoxidase (ERM-DA476/IFCC), and the candidate reference materials for IgG anti-proteinase 3 (in certification) and for IgG anti-β2PG1 (in evaluation) from the Joint Research Centre of the EU Science Hub.
Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis
Authors: Changwan Ryu, Huanxing Sun, Mridu Gulati, Jose D. Herazo-Maya, Yonglin Chen, Awo Osafo-Addo, Caitlin Brandsdorfer, Julia Winkler, Christina Blaul, Jaden Faunce, Hongyi Pan, Tony Woolard, Argyrios Tzouvelekis, Danielle E. Antin-Ozerkis, Jonathan T. Puchalski, Martin Slade, Anjelica L. Gonzalez, Daniel F. Bogenhagen, Varvara Kirillov, Carol Feghali-Bostwick, Kevin Gibson, Kathleen Lindell, Raimund I. Herzog, Charles S. Dela Cruz, Wajahat Mehal, Naftali Kaminski, Erica L. Herzog, Glenda Trujillo
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.We aimed to define an association between mtDNA and fibroblast responses in IPF.We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.
NAD Deficiency, Congenital Malformations, and Niacin Supplementation
Authors: Hongjun Shi, Annabelle Enriquez, Melissa Rapadas, Ella M.M.A. Martin, Roni Wang, Julie Moreau, Chai K. Lim, Justin O. Szot, Eddie Ip, James N. Hughes, Kotaro Sugimoto, David T. Humphreys, Aideen M. McInerney-Leo, Paul J. Leo, Ghassan J. Maghzal, Jake Halliday, Janine Smith, Alison Colley, Paul R. Mark, Felicity Collins, David O. Sillence, David S. Winlaw, Joshua W.K. Ho, Gilles J. Guillemin, Matthew A. Brown, Kazu Kikuchi, Paul Q. Thomas, Roland Stocker, Eleni Giannoulatou, Gavin Chapman, Emma L. Duncan, Duncan B. Sparrow, Sally L. Dunwoodie
Journal: New England Journal of Medicine (2017)

Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients.We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system.Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects.Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).
RNA Docking and Local Translation Regulate Site-Specific Axon Remodeling In Vivo
Authors: Hovy Ho-Wai Wong, Julie Qiaojin Lin, Florian Ströhl, Cláudio Gouveia Roque, Jean-Michel Cioni, Roberta Cagnetta, Benita Turner-Bridger, Romain F. Laine, William A. Harris, Clemens F. Kaminski, Christine E. Holt
Journal: Neuron (2017)

Nascent proteins can be positioned rapidly at precise subcellular locations by local protein synthesis (LPS) to facilitate localized growth responses. Axon arbor architecture, a major determinant of synaptic connectivity, is shaped by localized growth responses, but it is unknown whether LPS influences these responses in vivo. Using high-resolution live imaging, we examined the spatiotemporal dynamics of RNA and LPS in retinal axons during arborization in vivo. Endogenous RNA tracking reveals that RNA granules dock at sites of branch emergence and invade stabilized branches. Live translation reporter analysis reveals that de novo β-actin hotspots colocalize with docked RNA granules at the bases and tips of new branches. Inhibition of axonal β-actin mRNA translation disrupts arbor dynamics primarily by reducing new branch emergence and leads to impoverished terminal arbors. The results demonstrate a requirement for LPS in building arbor complexity and suggest a key role for pre-synaptic LPS in assembling neural circuits.
Increasing Public Health Awareness of and Capacity for Arts-Based Therapy in Medicine
Authors: Waqas Ullah Khan, Hilary Moss
Journal: JAMA Neurology (2017)

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A COMPARISON OF CALCANEAL BONE DENSITY IN COLLEGIATE ATHLETES AND NON-ATHLETES
Authors: Jason Bennett
Journal: British Journal of Sports Medicine (2017)

Background Limited evidence exists regarding calcaneal bone mineral density (cBMD) and lower extremity overuse bone injury (LEOBI). Objective Determine if there is an association between LEOBI (stress fractures and MTSS) and cBMD. Design Prospective cohort design. Setting NCAA Division I University. Patients (or Participants) 84 (64 females, 20 males) intercollegiate athletes and 103 (82 females, 21 males) non-athlete college students. Inclusion criteria: ≥18 years of age and no current lower extremity injury. Interventions (or Assessment of Risk Factors) In Phase I, athlete surveys regarding injury history and for females, menstrual history, and height and weight were measured. Athletes were followed for 9–10 months to identify the occurrence of LEOBI. In Phase II, non-athlete college students completed injury history, physical activity, and, for females, menstrual history surveys, and height and weight were measured. Main Outcome Measurements cBMD was assessed using ultrasound densitometry. At the end of the study, athletes received a second cBMD measurement. Results In Phase I, there was no difference in initial cBMD (p&gt;0.05) between athletes with and without LEOBI, but there was a trend towards decreased cBMD in athletes with LEOBI. At the end of the study, right cBMD (p=0.05) and left cBMD (p=0.07) were lower in athletes with LEOBI. In Phase II, non-athletes had significantly lower bilateral cBMD (p=.000) and speed of sound (SOS) (p=0.000) than athletes. Sub-analysis revealed highly significant differences in SOS (p=0.000) and cBMD (p=0.000) for females (non-athletes vs. athletes). Being a female non-athlete was a significant risk factor for a negative cBMD T-score for both the right (RR=2.2, 95% CI=1.4–3.3) and left (RR=1.7, 95% CI=1.1–2.6). Conclusions Athletes who did not experience LEOBI had significantly higher cBMD than non-athletes and athletes experiencing LEOBI. Future research should include larger sample sizes and adolescent subjects to identify influences on bone response to loading over time.
A phase I study to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of MEDI0562 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN).
Authors: Rom Samuel Leidner, Sandip Pravin Patel, Matthew G. Fury, Robert L. Ferris, Jennifer T. McDevitt, Mark C. Lanasa, Bonnie S. Glisson
Journal: Journal of Clinical Oncology (2015)

TPS6083 Background: Co-stimulatory signals delivered via binding to OX40 on T cells increase T-cell survival, proliferation, and effector function, and result in the generation of long-lived memory T cells. Experience to date with a human OX40 agonist murine antibody (MEDI6469) suggests targeting this pathway may provide antitumor activity with a manageable safety profile. In a Phase I study in advanced solid tumors, a single cycle of MEDI6469 had both an acceptable toxicity profile and regression of ≥ 1 metastatic lesion in 12 of 30 treated patients (pts)( Curti B, et al. Cancer Res 2013;73:7189–98). Humanized OX40 agonists are anticipated to have reduced immunogenicity relative to murine antibody, which may allow for repeat-dosing, potentially enhancing biologic and antitumor activity. MEDI0562 was developed through humanization of MEDI6469, and specifically binds to and activates signaling by human OX40. Methods: This is a Phase I, multicenter, open-label study (NCT02318394) in adults with R/M SCCHN. The primary endpoint is safety. Secondary endpoints include antitumor activity (objective response and disease control by immune-related RECIST, duration of response, progression-free survival, and overall survival), PK, immunogenicity, and pharmacodynamics. In the dose-escalation phase, sequential cohorts will receive 1 of 6 dose levels (3+3 design) of MEDI0562 IV for up to 48 weeks or until progressive disease (PD). Based on available data, any dose level not exceeding the maximum tolerated dose can be expanded. A dose-expansion phase may be initiated at the sponsor’s discretion in SCCHN pts to further examine MEDI0562 at the dose level and treatment schedule determined during dose escalation. Upon evidence of PD in follow up, pts in both dose escalation and expansion cohorts may have 1 round of MEDI0562 re-treatment according to their previous regimen. All pts will be followed for survival through to study end. Enrollment of ~50 pts ( ≤ 36 in dose escalation; ≤ 14 in dose expansion) is ongoing. Clinical trial information: NCT02318394.
Abstract 18815: Genetic Deletion of Telomerase Promotes Premature Cardiac Aging
Authors: Junghyun Kim, Fumihiro Sanada, Manila Candiracci, Fiorenza Valeriani, Anna Czarna, Antonio Cannata, Polina Goihberg, Toru Hosoda, Jan Kajstura, Marcello Rota, Piero Anversa, Annarosa Leri
Journal: Circulation (2013)

Telomere length shortens with age and predicts the onset of cellular senescence and organ aging with progressive deterioration of function. It remains, however, to be documented whether loss of telomeric DNA in cardiac stem cells (CSCs) and myocytes is causally involved in the manifestations of the aging cardiomyopathy. To test this possibility, the third generation of mice carrying a deletion of the RNA component of telomerase (Terc -/- mice) was studied early in life at 3-12 months of age. Wild type (WT) senescent mice at 30 months of age were included in the analysis to establish whether accelerated aging in Terc -/- mice recapitulates physiological aging. Initial studies indicated that Terc -/- mice, at 4 months of age, displayed attenuated left ventricular (LV) function with respect to age-matched WT by echocardiography and hemodynamics. In contrast, severe alterations in cardiac performance were apparent at 12 months. Telomere length in Terc -/- mouse CSCs and myocytes was ~50-70% shorter than in age-matched WT cells at 4-6 months of age but was comparable to that found in 30 month-old WT cells. CSC number was 60% lower in Terc -/- than age-matched WT mice, and the fraction of BrdU-positive CSCs decreased 1.4-fold. The absence of Terc led to a 50% reduction in myocyte turnover, which was coupled with myocyte loss. BrdU and Ki67 labeling were decreased, respectively, 65% and 60% in Terc -/- myocytes. Old CSCs formed a senescent progeny composed of myocytes, which carried markedly shortened telomeres, were more prone to apoptosis, and showed a severe depression in cell shortening and re-lengthening. By mRNA screening performed in Terc -/- myocytes at 12 months, multiple apoptosis-related genes, including protein kinase A (PKA), PI3KR1, Caspase 1, and BAG3 were found to be modified. Moreover, the renewal of endothelial cells was 75% lower in Terc -/- mice mimicking the rarefaction in capillary typically seen in the old myocardium. Our findings document that loss of telomerase is a critical determinant of cardiac aging with reduced cardiomyogenesis and vasculogenesis. Understanding basic mechanisms of telomere biology in CSCs and cardiomyocytes holds the potential to advance the clinical paradigm of the senescent myopathy.
06.07 Disease-inducible interleukin-10 gene therapy suppresses innate cytokine response in the 3d micromass model of the synovial membrane
Authors: Mathijs Ga Broeren, Miranda B Bennink, Onno J Arntz, Wim B van den Berg, Fons Aj van de Loo
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> No disease-modifying drugs are available for osteoarthritis (OA). Although the aetiology is still unknown, inflammation is indicated to be involved in the disease pathogenesis in many patients. Gene therapy can enable transduced joint cells to express an anti-inflammatory biological drug with long-lasting bioavailability. In addition, off-target effects can be further reduced by regulating the expression using a disease-responsive promoter that is only active during disease flares. Clinical studies in chronic diseases with anti-inflammatory recombinant Interleukin-10 (IL-10) are impeded by its short half-life. Disease-inducible gene therapy might therefore be the ideal system to provide IL-10 in an OA joint in a regulated fashion. The objective of this study was to test the feasibility of this approach in a human <i>in-vitro</i> model of the synovial membrane. <h3>Methods</h3> Cell suspensions of digested joint biopsies were mixed with Matrigel to form micromasses, in which the cells migrate to the surface. The micromasses were transduced with a lentiviral vector containing the IL-10 gene under control of the inflammation-sensitive <i>CXCL10</i> promoter (CXCL10p-IL10) or the constitutive active <i>PGK</i> promoter (PGK-IL10). Subsequently, micromasses were stimulated with inflammatory triggers Tumour Necrosis Factor-alpha (TNFα) and lipopolysaccharide (LPS). Gene expression effects were determined by qPCR and the production of cytokines by the synovial micromasses was measured by multiplex ELISA. <h3>Results</h3> In 1 week cultured micromasses, migrated cells formed a lining containing both synovial fibroblasts and macrophages similar to that seen in the synovium. This lining could be efficiently targeted by lentiviruses. After stimulation with LPS and TNFα, the production of CXCL10-controlled IL-10 expression increased by 9.7-fold and 7.2-fold respectively. The IL-10 production after transduction with PGK-IL10 was not influenced by proinflammatory stimulation. The induced levels of IL-10 were high enough to significantly reduce the production of IL-1β and IL-6 by the micromasses. The anti-inflammatory effect of CXCL10-controlled IL-10 might be mediated by SOCS3. Recombinant IL-10 increased SOCS3 expression by 3.0-fold 2 hour after stimulation. <h3>Conclusions</h3> This study on primary human synovial micromasses suggest that the CXCL10p-IL-10 gene therapeutic approach to suppress the innate cytokine response in the osteoarthritic joint might be a feasible approach for local treatment of OA.