tbuckley/cabot-search huggingface dataset:
Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation
Authors: Yue Cui, Katarzyna Franciszkiewicz, Yvonne K. Mburu, Stanislas Mondot, Lionel Le Bourhis, Virginie Premel, Emmanuel Martin, Alexandra Kachaner, Livine Duban, Molly A. Ingersoll, Sylvie Rabot, Jean Jaubert, Jean-Pierre De Villartay, Claire Soudais, Olivier Lantz
Journal: Journal of Clinical Investigation (2015)

Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%–10% in blood). Despite strong evolutionary conservation of the invariant TCR-α chain and restricting molecule MR1, this population is rare in laboratory mouse strains (≈0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-α locus and led to higher usage of the distal Vα segments, including Vα19. We generated a MAIThi congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44+) CD4–CD8lo/neg T cells with tissue-homing properties (CCR6+CCR7–). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18Rα, and IL-12Rβ and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptor γ (RORγt). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIThi congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.
Histamine‐induced bronchoconstriction in conscious guinea pigs measured by strain‐gauge transduction A new method
Authors: A. Engel, L. Lundberg, P. Faarup, P. Faurschou
Journal: Allergy (1992)

Engel A, Lundberg L, Faarup P, Faurschou P. Histamine‐induced bronchoconstriction in conscious guinea pigs measured by strain‐gauge transduction. A new method. A new objective method for measuring histaminedihydrochloride‐induced bronchoconstriction in conscious guinea pigs has been developed. The aim of the present work was to investigate whether identical results could be obtained when the clinical observation of conscious guinea pigs with symptoms of respiratory distress (bronchoconstriction) was compared to an objective measuring technique of this parameter. An evaluation of the repeatability of the method was made and the respiration frequence (fR) and histamincdihydrochloride challenge concentration were compared to see whether there was a correlation between the two. Consequently, an appartatus was built that allowed simultaneous recording of breathing pattern and clinical observation of the animal being challenged. The breathing pattern was recorded by a strain‐gauge transducer, connected to a measuring bridge, and the curves obtained on a jet ink x‐y writer were used for calculating changes in duration of expiratory phase (T e ) and fR. During the attacks of histaminedihydrochloride‐induced bronchoconstriction a significantly prolonged T e could be calculated from the respiration curves. A high degree of agreement was found between this objective measure and clinically observed respiratory distress. The repeatability of the method was comparable to that of corresponding methods used for histaminedihydrochloride challenge in man. No obvious correlation was found between changes in fR and histamincdihydrochloride challenge concentration.
The economy-wide impact of pandemic influenza on the UK: a computable general equilibrium modelling experiment
Authors: R. D Smith, M. R Keogh-Brown, T. Barnett, J. Tait
Journal: BMJ (2009)

<b>Objectives</b> To estimate the potential economic impact of pandemic influenza, associated behavioural responses, school closures, and vaccination on the United Kingdom. <b>Design</b> A computable general equilibrium model of the UK economy was specified for various combinations of mortality and morbidity from pandemic influenza, vaccine efficacy, school closures, and prophylactic absenteeism using published data. <b>Setting</b> The 2004 UK economy (the most up to date available with suitable economic data). <b>Main outcome measures</b> The economic impact of various scenarios with different pandemic severity, vaccination, school closure, and prophylactic absenteeism specified in terms of gross domestic product, output from different economic sectors, and equivalent variation. <b>Results</b> The costs related to illness alone ranged between 0.5% and 1.0% of gross domestic product (£8.4bn to £16.8bn) for low fatality scenarios, 3.3% and 4.3% (£55.5bn to £72.3bn) for high fatality scenarios, and larger still for an extreme pandemic. School closure increases the economic impact, particularly for mild pandemics. If widespread behavioural change takes place and there is large scale prophylactic absence from work, the economic impact would be notably increased with few health benefits. Vaccination with a pre-pandemic vaccine could save 0.13% to 2.3% of gross domestic product (£2.2bn to £38.6bn); a single dose of a matched vaccine could save 0.3% to 4.3% (£5.0bn to £72.3bn); and two doses of a matched vaccine could limit the overall economic impact to about 1% of gross domestic product for all disease scenarios. <b>Conclusion</b> Balancing school closure against “business as usual” and obtaining sufficient stocks of effective vaccine are more important factors in determining the economic impact of an influenza pandemic than is the disease itself. Prophylactic absence from work in response to fear of infection can add considerably to the economic impact.
Risk of Discharge to Postacute Care
Authors: Sanjay Mohanty, Yaoming Liu, Jennifer L. Paruch, Thomas E. Kmiecik, Mark E. Cohen, Clifford Y. Ko, Karl Y. Bilimoria
Journal: JAMA Surgery (2015)

Individualized risk prediction tools have an important role as decision aids for use by patients and surgeons before surgery. Patient-centered outcomes should be incorporated into such tools to widen their appeal and improve their usability.To develop a patient-centered outcome for the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator, a web-based, individualized risk prediction tool.Retrospective cohort study using data from the ACS NSQIP, a national clinical data registry. A total of 973 211 patients from July 2010 to June 2012, encompassing 392 hospitals, were used in this analysis.Risk of discharge to a postacute care setting.The overall rate of discharge to postacute care was 8.8%. Significant predictors of discharge to postacute care included being 85 years or older (odds ratio [OR] = 9.17; 95% CI, 8.84-9.50), the presence of septic shock (OR = 2.43; 95% CI, 2.20-2.69) or ventilator dependence (OR = 2.81; 95% CI, 2.56-3.09) preoperatively, American Society of Anesthesiologists class of 4 or 5 (OR = 3.59; 95% CI, 3.46-3.71), and totally dependent functional status (OR = 2.27; 95% CI, 2.11-2.44). The final model predicted risk of discharge to postacute care with excellent accuracy (C statistic = 0.924) and calibration (Brier score = 0.05).Individualized risk of discharge to postacute care can be predicted with excellent accuracy. This outcome will be incorporated into the ACS NSQIP Surgical Risk Calculator.
Overexpression of Gs alpha protein in the hearts of transgenic mice.
Authors: C Gaudin, Y Ishikawa, D C Wight, V Mahdavi, B Nadal-Ginard, T E Wagner, D E Vatner, C J Homcy
Journal: Journal of Clinical Investigation (1995)

Alterations in beta-adrenergic receptor-Gs-adenylyl cyclase coupling underlie the reduced catecholamine responsiveness that is a hallmark of human and animal models of heart failure. To study the effect of altered expression of Gs alpha, we overexpressed the short isoform of Gs alpha in the hearts of transgenic mice, using a rat alpha-myosin heavy chain promoter. Gs alpha mRNA levels were increased selectively in the hearts of transgenic mice, with a level 38 times the control. Despite this marked increase in mRNA, Western blotting identified only a 2.8-fold increase in the content of the Gs alpha short isoform, whereas Gs activity was increased by 88%. The discrepancy between Gs alpha mRNA and Gs alpha protein levels suggests that the membrane content of Gs alpha is posttranscriptionally regulated. The steady-state adenylyl cyclase catalytic activity was not altered under either basal or stimulated conditions (GTP + isoproterenol, GTP gamma S, NaF, or forskolin). However, progress curve studies did show a significant decrease in the lag period necessary for GppNHp to stimulate adenylyl cyclase activity. Furthermore, the relative number of beta-adrenergic receptors binding agonist with high affinity was significantly increased. Our data demonstrate that a relatively small increase in the amount of the coupling protein Gs alpha can modify the rate of catalyst activation and the formation of agonist high affinity receptors.
Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship
Authors: S.L. Jones, P. Herbison, J.O. Cowan, E.M. Flannery, R.J. Hancox, C.R. McLachlan, D.R. Taylor
Journal: European Respiratory Journal (2002)

Exhaled nitric oxide (eNO) is an easily measured marker of airway inflammation. This study was undertaken to evaluate the usefulness of serial eNO in investigating the dose-response relationship for inhaled beclomethasone (BDP), and to compare eNO with other markers of airway inflammation. Following withdrawal of inhaled corticosteroid (ICS) therapy, 65 patients entered a double-blind, parallel-group, placebo-controlled trial of 50, 100, 200 or 500 µg·BDP·day<sup>−1</sup> for eight weeks. eNO and spirometry were performed weekly and a hypertonic saline challenge with sputum induction was performed at the beginning and end of treatment. The relationship between the dose of ICS and changes in eNO and forced expiratory volume in one second (FEV<sub>1</sub>) was linear at 1 week and at the end of treatment. A linear dose-response relationship was also seen for sputum eosinophils. Changes in eNO correlated significantly with changes in sputum eosinophils. Changes in the provocative dose of saline causing a 15% fall in FEV<sub>1</sub> saline did not differ across the treatment groups nor did they correlate with changes in other measurements. Exhaled nitric oxide may be used to assess the dose-response relationship for the anti-inflammatory effects of inhaled beclomethasone. The relationship found in this study was linear over the dose range 0–500 µg·day<sup>−1</sup> soon after commencing therapy and continued over time.
Long-term work disability in patients with psoriatic arthritis treated with anti-tumour necrosis factor: a population-based regional Swedish cohort study
Authors: Lars Erik Kristensen, Martin Englund, Martin Neovius, Johan Askling, Lennart T H Jacobsson, Ingemar F Petersson
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To study long-term work disability before and after tumour necrosis factor (TNF)-antagonist therapy in patients with psoriatic arthritis (PsA). <h3>Methods</h3> Using the population-based South Swedish Arthritis Treatment Group Register, we identified 191 patients with PsA (median age 43 years, range 18–58 years, 54% men), who between January 2003 and December 2007 started treatment with adalimumab, etanercept or infliximab. We linked data to the Swedish Social Insurance Agency and calculated the proportion of work disability in 30-day intervals from 12 months before the start of treatment until 3 years after. For each patient with PsA we randomly selected four matched reference subjects from the general population. <h3>Results</h3> At treatment initiation 67% of the patients with PsA were work disabled—that is, either on sick leave (41.5%) or receiving a disability pension (25.3%). Patients sustaining treatment were, on average, work disabled 12.5 days a month at treatment initiation declining to 10.6 days a month after 3 years of treatment. Patients for whom the first treatment course failed were work disabled 16.5 days at treatment start decreasing to 15.6 days after 3 years. The background population were 2.5 days and 3.0 days off work each month, respectively. Regression modelling identified prior work disability status, anti-TNF treatment failure, higher age, female gender and longer disease duration as significant predictors of working disability. <h3>Conclusions</h3> There was a decline in net work disability after initiation of anti-TNF treatment in patients with PsA. Patients withdrawing from treatment had a 50% increased risk of being work disabled. Prior work disability, higher age, female gender and longer disease duration were also associated with long-term work disability.
Generation of Urinary Albumin Fragments Does Not Require Proximal Tubular Uptake
Authors: Kathrin Weyer, Rikke Nielsen, Erik I. Christensen, Henrik Birn
Journal: Journal of the American Society of Nephrology (2012)

Urinary albumin excretion is an important diagnostic and prognostic marker of renal function. Both animal and human urine contain large amounts of albumin fragments, but whether these fragments originate from renal tubular degradation of filtered albumin is unknown. Here, we used mice with kidneys lacking megalin and cubilin, the coreceptors that mediate proximal tubular endocytosis of albumin, to determine whether proximal tubular degradation of albumin forms the detectable urinary albumin fragments. After intravenous administration of 125I-labeled mouse albumin to knockout and control mice, we examined kidney uptake of albumin and urinary excretion of both intact albumin and its fragments using size exclusion chromatography. In control mice, all labeled albumin eluted as albumin fragments in the urine. In megalin/cubilin-deficient mice, we observed decreased uptake and degradation of albumin and increased urinary excretion of intact albumin; we did not, however, detect a decrease in the excretion of albumin fragments. These results show that the generation of urinary albumin fragments occurs independently of renal tubular uptake and degradation of albumin, suggesting that the pathophysiological implications of changes in urinary albumin fragments require reevaluation.
Reasons for heterogeneous change in LCI in children with cystic fibrosis after antibiotic treatment
Authors: Sophie Yammine, Anja Bigler, Carmen Casaulta, Florian Singer, Philipp Latzin
Journal: Thorax (2013)

With great interest we read the paper of Horsley et al .1 In their prospective observational study they showed significant improvement in indices of ventilation capacity (spirometry) and ventilation heterogeneity (multiple-breath washout (MBW)) after a course of intravenous antibiotics in subjects with cystic fibrosis (CF). There was considerable heterogeneity of lung clearance index (LCI) response as observed previously.2 Here we aim to disentangle underlying physiological mechanisms of this heterogeneous response.

We assessed changes of lung function parameters before and after 23 courses of intravenous antibiotics in 19 children with CF aged 5–18 years. Children performed arterial blood oxygen measurement, nitrogen MBW,3 , …
New Directions in Toxicity Testing
Authors: Daniel Krewski, Margit Westphal, Mustafa Al-Zoughool, Maxine C. Croteau, Melvin E. Andersen
Journal: Annual Review of Public Health (2011)

In 2007, the U.S. National Research Council (NRC) published a groundbreaking report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The purpose of this report was to develop a long-range strategic plan to update and advance the way environmental agents are tested for toxicity. The vision focused on the identification of critical perturbations of toxicity pathways that lead to adverse human health outcomes using modern scientific tools and technologies. This review describes how emerging scientific methods will move the NRC vision forward and improve the manner in which the potential health risks associated with exposure to environmental agents are assessed. The new paradigm for toxicity testing is compatible with the widely used four-stage risk assessment framework originally proposed by the NRC in 1983 in the so-called Red Book. The Nrf2 antioxidant pathway provides a detailed example of how relevant pathway perturbations will be identified within the context of the new NRC vision for the future of toxicity testing. The implications of the NRC vision for toxicity testing for regulatory risk assessment are also discussed.
Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays
Authors: Madhumita Chatterjee, Saroj Mohapatra, Alexei Ionan, Gagandeep Bawa, Rouba Ali-Fehmi, Xiaoju Wang, James Nowak, Bin Ye, Fatimah A. Nahhas, Karen Lu, Steven S. Witkin, David Fishman, Adnan Munkarah, Robert Morris, Nancy K. Levin, Natalie N. Shirley, Gerard Tromp, Judith Abrams, Sorin Draghici, Michael A. Tainsky
Journal: Cancer Research (2006)

Abstract A noninvasive screening test would significantly facilitate early detection of epithelial ovarian cancer. This study used a combination of high-throughput selection and array-based serologic detection of many antigens indicative of the presence of cancer, thereby using the immune system as a biosensor. This high-throughput selection involved biopanning of an ovarian cancer phage display library using serum immunoglobulins from an ovarian cancer patient as bait. Protein macroarrays containing 480 of these selected antigen clones revealed 65 clones that interacted with immunoglobulins in sera from 32 ovarian cancer patients but not with sera from 25 healthy women or 14 patients having other benign or malignant gynecologic diseases. Sequence analysis data of these 65 clones revealed 62 different antigens. Among the markers, we identified some known antigens, including RCAS1, signal recognition protein-19, AHNAK-related sequence, nuclear autoantogenic sperm protein, Nijmegen breakage syndrome 1 (Nibrin), ribosomal protein L4, Homo sapiens KIAA0419 gene product, eukaryotic initiation factor 5A, and casein kinase II, as well as many previously uncharacterized antigenic gene products. Using these 65 antigens on protein microarrays, we trained neural networks on two-color fluorescent detection of serum IgG binding and found an average sensitivity and specificity of 55% and 98%, respectively. In addition, the top 6 of the most specific clones resulted in an average sensitivity and specificity of 32% and 94%, respectively. This global approach to antigenic profiling, epitomics, has applications to cancer and autoimmune diseases for diagnostic and therapeutic studies. Further work with larger panels of antigens should provide a comprehensive set of markers with sufficient sensitivity and specificity suitable for clinical testing in high-risk populations. (Cancer Res 2006; 66(2): 1181-90)
Tobacco company fights order to turn over mystery memorandum
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

British American Tobacco is continuing its two year fight against producing a document that is thought to describe the company's efforts to destroy incriminating records while pretending to preserve them. The so called Foyle memorandum was written in 1990 by Andrew Foyle, a partner in a British law firm representing the tobacco company.

“The document was quoted in part in court in Australia but has never been made public,” said Richard Daynard, a law professor and chairman of the Tobacco Products Liability Project at Northeastern University in Boston.

Although British American Tobacco has less than 1% of …
MHCII glycosylation modulates <i>Bacteroides fragilis</i> carbohydrate antigen presentation
Authors: Sean O. Ryan, Jason A. Bonomo, Fan Zhao, Brian A. Cobb
Journal: The Journal of Experimental Medicine (2011)

N-linked glycans are thought to protect class II major histocompatibility complex (MHC) molecules (MHCII) from proteolytic cleavage and assist in arranging proteins within the immune synapse, but were not thought to directly participate in antigen presentation. Here, we report that antigen-presenting cells (APCs) lacking native complex N-glycans showed reduced MHCII binding and presentation of the T cell activating glycoantigen (GlyAg) polysaccharide A from Bacteroides fragilis but not conventional peptides. APCs lacking native N-glycans also failed to mediate GlyAg-driven T cell activation but activated T cells normally with protein antigen. Mice treated with the mannosidase inhibitor kifunensine to prevent the formation of complex N-glycans were unable to expand GlyAg-specific T cells in vivo upon immunization, yet adoptive transfer of normally glycosylated APCs into these animals overcame this defect. Our findings reveal that MHCII N-glycosylation directly impacts binding and presentation of at least one class of T cell–dependent antigen.
Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment
Authors: Jürg P.F. Nüesch, Jeannine Lacroix, Antonio Marchini, Jean Rommelaere
Journal: Clinical Cancer Research (2012)

Abstract Rodent parvoviruses (PV) are recognized for their intrinsic oncotropism and oncolytic activity, which contribute to their natural oncosuppressive effects. Although PV uptake occurs in most host cells, some of the subsequent steps leading to expression and amplification of the viral genome and production of progeny particles are upregulated in malignantly transformed cells. By usurping cellular processes such as DNA replication, DNA damage response, and gene expression, and/or by interfering with cellular signaling cascades involved in cytoskeleton dynamics, vesicular integrity, cell survival, and death, PVs can induce cytostasis and cytotoxicity. Although productive PV infections normally culminate in cytolysis, virus spread to neighboring cells and secondary rounds of infection, even abortive infection or the sole expression of the PV nonstructural protein NS1, is sufficient to cause significant tumor cell death, either directly or indirectly (through activation of host immune responses). This review highlights the molecular pathways involved in tumor cell targeting by PVs and in PV-induced cell death. It concludes with a discussion of the relevance of these pathways to the application of PVs in cancer therapy, linking basic knowledge of PV–host cell interactions to preclinical assessment of PV oncosuppression. Clin Cancer Res; 18(13); 3516–23. ©2012 AACR.