tbuckley/cabot-search huggingface dataset:
Systems Biology in Immunology: A Computational Modeling Perspective
Authors: Ronald N. Germain, Martin Meier-Schellersheim, Aleksandra Nita-Lazar, Iain D.C. Fraser
Journal: Annual Review of Immunology (2011)

Systems biology is an emerging discipline that combines high-content, multiplexed measurements with informatic and computational modeling methods to better understand biological function at various scales. Here we present a detailed review of the methods used to create computational models and to conduct simulations of immune function. We provide descriptions of the key data-gathering techniques employed to generate the quantitative and qualitative data required for such modeling and simulation and summarize the progress to date in applying these tools and techniques to questions of immunological interest, including infectious disease. We include comments on what insights modeling can provide that complement information obtained from the more familiar experimental discovery methods used by most investigators and the reasons why quantitative methods are needed to eventually produce a better understanding of immune system operation in health and disease.
Candidacidal activity of Crohn's disease neutrophils.
Authors: F T Curran, D J Youngs, R N Allan, M R Keighley
Journal: Gut (1991)

The ability of normal and Crohn9s disease neutrophils to kill Candida albicans has been studied using neutrophils isolated from peripheral blood and suspended in phosphate buffered saline at 5 x 10(6) cells per ml. C albicans was grown to a stationary phase in broth culture and suspended in phosphate buffered saline at 10(7) organisms/ml. Neutrophils and Candida were then incubated together at 37 degrees C in a shaking water bath in the presence of fresh serum. At 30 and 60 minutes samples were withdrawn, neutrophils lysed, and Candida survival assessed by colony counting. Results were compared with control suspensions of Candida incubated with serum alone. After 30 and 60 minutes in the presence of autologous serum normal neutrophils had killed significantly more Candida than Crohn9s disease neutrophils (mean (SD) 61.0 (16.7)% v 40.5 (16.2)% at 30 minutes, p less than 0.0001; 83.2 (7)% v 70.8) 16)% at 60 minutes, p less than 0.005). The results did not alter significantly when normal neutrophils were incubated with Candida in the presence of Crohn9s disease serum instead of normal serum. When Crohn9s disease neutrophils were incubated with Candida in the presence of normal serum instead of autologous serum there was some improvement in candidacidal ability at 30 minutes (48.9 (20.6)% v 40.5 (16.2)%, p less than 0.03) but not at 60 minutes. Phagocytosis, measured using a radiometric assay, was normal. Neutrophils from patients with Crohn9s disease have an impaired ability to kill this granuloma provoking organism. It is not due to serum inhibitors or defective phagocytosis.
Biomaterial-Associated Infection: Locating the Finish Line in the Race for the Surface
Authors: Henk J. Busscher, Henny C. van der Mei, Guruprakash Subbiahdoss, Paul C. Jutte, Jan J. A. M. van den Dungen, Sebastian A. J. Zaat, Marcus J. Schultz, David W. Grainger
Journal: Science Translational Medicine (2012)

Biomaterial-associated infections occur on both permanent implants and temporary devices for restoration or support of human functions. Despite increasing use of biomaterials in an aging society, comparatively few biomaterials have been designed that effectively reduce the incidence of biomaterial-associated infections. This review provides design guidelines for infection-reducing strategies based on the concept that the fate of biomaterial implants or devices is a competition between host tissue cell integration and bacterial colonization at their surfaces.
SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis
Authors: Mark L Everard, Daniel Hind, Kelechi Ugonna, Jennifer Freeman, Mike Bradburn, Cindy L Cooper, Elizabeth Cross, Chin Maguire, Hannah Cantrill, John Alexander, Paul S McNamara
Journal: Thorax (2014)

<h3>Aim</h3> Acute bronchiolitis is the commonest cause for hospitalisation in infancy. Supportive care remains the cornerstone of current management and no other therapy has been shown to influence the course of the disease. It has been suggested that adding nebulised hypertonic saline to usual care may shorten the duration of hospitalisation. To determine whether hypertonic saline does have beneficial effects we undertook an open, multi-centre parallel-group, pragmatic RCT in ten UK hospitals. <h3>Methods</h3> Infants admitted to hospital with a clinical diagnosis of acute bronchiolitis and requiring oxygen therapy were randomised to receive usual care alone or nebulised 3% hypertonic saline (HS) administered 6-hourly. Randomisation was within 4 h of admission. The primary outcome was time to being assessed as 'fit' for discharge with secondary outcomes including time to discharge, incidence of adverse events together with follow up to 28 days assessing patient centred health related outcomes. <h3>Results</h3> A total of 317 infants were recruited to the study. 158 infants were randomised to HS (141 analysed) and 159 to standard care (149 analysed). There was no difference between the two arms in time to being declared fit for discharge (hazard ratio: 0−95, 95% CI: 0.75−1.20) nor to actual discharge (hazard ratio: 0.97, 95% CI: 0.76−1.23). There was no difference in adverse events. One infant in the HS group developed bradycardia with desaturation. <h3>Conclusion</h3> This study does not support the use of nebulised HS in the treatment of acute bronchiolitis over usual care with minimal handlings. <h3>ClinicalTrials.gov registration number</h3> NCT01469845.
Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody.
Authors: K H Grabstein, T J Waldschmidt, F D Finkelman, B W Hess, A R Alpert, N E Boiani, A E Namen, P J Morrissey
Journal: The Journal of Experimental Medicine (1993)

The effects of interleukin 7 (IL-7) on the growth and differentiation of murine B cell progenitors has been well characterized using in vitro culture methods. We have investigated the role of IL-7 in vivo using a monoclonal antibody that neutralizes IL-7. We find that treatment of mice with this antibody completely inhibits the development of B cell progenitors from the pro-B cell stage forward. We also provide evidence that all peripheral B cells, including those of the B-1 and conventional lineages, are derived from IL-7-dependent precursors. The results are consistent with the rapid turnover of B cell progenitors in the marrow, but a slow turnover of mature B cells in the periphery. In addition to effects on B cell development, anti-IL-7 treatment substantially reduced thymus cellularity, affecting all major thymic subpopulations.
Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-κB
Authors: Svetlana Frank, Marvin A Peters, Corinna Wehmeyer, Simon Strietholt, Christina Koers-Wunrau, Jessica Bertrand, Marianne Heitzmann, Anja Hillmann, Joanna Sherwood, Christine Seyfert, Steffen Gay, Thomas Pap
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> Based on previous data that have linked the small ubiquitin-like modifier-1 (SUMO-1) to the pathogenesis of rheumatoid arthritis (RA), we have investigated the expression of the highly homologous SUMO family members SUMO-2/3 in human RA and in the human tumour necrosis factor α transgenic (hTNFtg) mouse model of RA and studied their role in regulating disease specific matrixmetalloproteinases (MMPs). <h3>Methods</h3> Synovial tissue was obtained from RA and osteoarthritis (OA) patients and used for histological analyses as well as for the isolation of synovial fibroblasts (SFs). The expression of SUMO-2/3 in RA and OA patients as well as in hTNFtg and wild type mice was studied by PCR, western blot and immunostaining. SUMO-2/3 was knocked down using small interfering RNA in SFs, and TNF-α induced MMP production was determined by ELISA. Activation of nuclear factor-κB (NF-κB) was determined by a luciferase activity assay and a transcription factor assay in the presence of the NF-κB inhibitor BAY 11-7082. <h3>Results</h3> Expression of SUMO-2 and to a lesser extent of SUMO-3 was higher in RA tissues and RASFs compared with OA controls. Similarly, there was increased expression of SUMO-2 in the synovium and in SFs of hTNFtg mice compared with wild type animals. In vitro, the expression of SUMO-2 but not of SUMO-3 was induced by TNF-α. The knockdown of SUMO-2/3 significantly increased the TNF-α and interleukin (IL)-1β induced expression of MMP-3 and MMP-13, accompanied by increased NF-κB activity. Induction of MMP-3 and MMP-13 was inhibited by blockade of the NF-κB pathway. TNF-α and IL-1β mediated MMP-1 expression was not regulated by SUMO-2/3. <h3>Conclusions</h3> Collectively, we show that despite their high homology, SUMO-2/3 are differentially regulated by TNF-α and selectively control TNF-α mediated MMP expression via the NF-κB pathway. Therefore, we hypothesise that SUMO-2 contributes to the specific activation of RASF.
Development of a Human Monoclonal Antibody for Potential Therapy of CD27-Expressing Lymphoma and Leukemia
Authors: Laura A. Vitale, Li-Zhen He, Lawrence J. Thomas, Jennifer Widger, Jeffrey Weidlick, Andrea Crocker, Thomas O'Neill, James Storey, Martin J. Glennie, Deanna M. Grote, Stephen M. Ansell, Henry Marsh, Tibor Keler
Journal: Clinical Cancer Research (2012)

The TNF receptor superfamily member CD27 is best known for its important role in T-cell immunity but is also recognized as a cell-surface marker on a number of B- and T-cell malignancies. In this article, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27.The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro. Severe combined immunodeficient (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct antitumor effects. A pilot study of 1F5 was conducted in non-human primates to assess toxicity.1F5 binds with high affinity and specificity to human and macaque CD27 and competes with ligand binding. 1F5 activates T cells only in combination with T-cell receptor stimulation and does not induce proliferation of primary CD27-expressing tumor cells. 1F5 significantly enhanced the survival of SCID mice bearing Raji or Daudi tumors, which may be mediated through direct effector mechanisms such as antibody-dependent cellular cytotoxicity. Importantly, administration of up to 10 mg/kg of 1F5 to cynomolgus monkeys was well tolerated without evidence of significant toxicity or depletion of circulating lymphocytes.Collectively, the data suggest that the human mAb 1F5, which has recently entered clinical development under the name CDX-1127, may provide direct antitumor activity against CD27-expressing lymphoma or leukemia, independent of its potential to enhance immunity through its agonistic properties.
Serum cytidine deaminase as a laboratory test for acute inflammation in rheumatoid arthritis.
Authors: I M Chalmers, G T Thomson, P Desjardins
Journal: Annals of the Rheumatic Diseases (1988)

Atlantoaxial subluxation and spinal cord compression in psoriatic arthropathy SIR, We read with interest the report by Pease and Pozo on atlantoaxial subluxation and spinal cord compression in psoriatic arthropathy.'It appears, however, that even in
Epistaxis after sildenafil
Authors: S. R J Bott, I. Shergill, M. Arya
Journal: Journal of the Royal Society of Medicine (2002)

Ms Hicklin and colleagues (August 2002 JRSM1) describe two cases of epistaxis after use of sildenafil to enhance penile erection. Such a complication is not unexpected, for two reasons. First, the enzyme inhibited by the drug, cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5), is present at several sites other than the corpus cavernosum, and known effects of the consequent vascular smooth muscle relaxation include headache in 16%, facial flushing in 10%, and hypotension and dizziness in 2% of patients2. Second, in-vitro research suggests that sildenafil can inhibit PDE5-induced platelet aggregation3. Cerebrovascular haemorrhage is a recognized, albeit rare, side-effect and bleeding from oesophageal varices4 and from haemorrhoids5 has been described after use of sildenafil.

In case 2 of Hicklin et al. the patient had been prescribed amlodipine. This drug is metabolized by the same enzyme (cytochrome p450) and could therefore affect the pharmacokinetics of sildenafil, rendering haemorrhage more likely.
Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice
Authors: Edward Kerschen, Irene Hernandez, Mark Zogg, Shuang Jia, Martin J. Hessner, Jose A. Fernandez, John H. Griffin, Claudia S. Huettner, Francis J. Castellino, Hartmut Weiler
Journal: Journal of Clinical Investigation (2010)

Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset of CD8+ conventional dendritic cells. Adoptive transfer of splenic CD11chiPDCA-1- dendritic cells from wild-type mice into animals with hematopoietic EPCR deficiency restored the therapeutic efficacy of aPC, whereas transfer of EPCR-deficient CD11chi dendritic cells or wild-type CD11chi dendritic cells depleted of EPCR+ cells did not. In addition, 5A-aPC inhibited the inflammatory response of conventional dendritic cells independent of EPCR and suppressed IFN-gamma production by natural killer-like dendritic cells. These data reveal an essential role for EPCR and PAR1 on hematopoietic cells, identify EPCR-expressing dendritic immune cells as a critical target of aPC therapy, and document EPCR-independent antiinflammatory effects of aPC on innate immune cells.
Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen
Authors: Christophe Lurquin, Bernard Lethé, Etienne De Plaen, Véronique Corbière, Ivan Théate, Nicolas van Baren, Pierre G. Coulie, Thierry Boon
Journal: The Journal of Experimental Medicine (2005)

Melanoma patients have high frequencies of T cells directed against antigens of their tumor. The frequency of these antitumor T cells in the blood is usually well above that of the anti-vaccine T cells observed after vaccination with tumor antigens. In a patient vaccinated with a MAGE-3 antigen presented by HLA-A1, we measured the frequencies of anti-vaccine and antitumor T cells in several metastases to evaluate their respective potential contribution to tumor rejection. The frequency of anti–MAGE-3.A1 T cells was 1.5 × 10−5 of CD8 T cells in an invaded lymph node, sixfold higher than in the blood. An antitumor cytotoxic T lymphocyte (CTL) recognizing a MAGE-C2 antigen showed a much higher enrichment with a frequency of ∼10%, 1,000 times higher than its blood frequency. Several other antitumor T clonotypes had frequencies &amp;gt;1%. Similar findings were made on a regressing cutaneous metastasis. Thus, antitumor T cells were ∼10,000 times more frequent than anti-vaccine T cells inside metastases, representing the majority of T cells present there. This suggests that the anti-vaccine CTLs are not the effectors that kill the bulk of the tumor cells, but that their interaction with the tumor generates conditions enabling the stimulation of large numbers of antitumor CTLs that proceed to destroy the tumor cells. Naive T cells appear to be stimulated in the course of this process as new antitumor clonotypes arise after vaccination.
2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer
Authors: W.E.E. Eberhardt, D. De Ruysscher, W. Weder, C. Le Péchoux, P. De Leyn, H. Hoffmann, V. Westeel, R. Stahel, E. Felip, S. Peters, Rolf Stahel, Enriqueta Felip, Solange Peters, Keith Kerr, Benjamin Besse, Johan Vansteenkiste, Wilfried Eberhardt, Martin Edelman, Tony Mok, Ken O'Byrne, Silvia Novello, Lukas Bubendorf, Antonio Marchetti, Paul Baas, Martin Reck, Konstantinos Syrigos, Luis Paz-Ares, Egbert F. Smit, Peter Meldgaard, Alex Adjei, Marianne Nicolson, Lucio Crinó, Paul Van Schil, Suresh Senan, Corinne Faivre-Finn, Gaetano Rocco, Giulia Veronesi, Jean-Yves Douillard, Eric Lim, Christophe Dooms, Walter Weder, Dirk De Ruysscher, Cecile Le Pechoux, Paul De Leyn, Virginie Westeel
Journal: Annals of Oncology (2015)
High Court rules against Birmingham University in investigation of leading diabetologist
Authors: Clare Dyer
Journal: BMJ (2015)

A diabetologist who faces a disciplinary investigation over his conduct of five clinical trials has won the right to be accompanied to an investigatory meeting by an adviser from his medical defence organisation.

The High Court in London has ruled that Birmingham University’s refusal to let a representative of the Medical Protection Society accompany Martin Stevens to the meeting breached an implied term of the employment contract: that the employer will do nothing without good reason to undermine the mutual trust and confidence between employer and employee.

Stevens, who was appointed to the chair of medicine (diabetes and metabolism) at Birmingham University in 2004, took the case to the High Court after the university insisted that he …
Predictors of symptomatic response to glucosamine in knee osteoarthritis: an exploratory study: Table 1
Authors: Alexander N Bennett, Kay M Crossley, Peter D Brukner, Rana S Hinman
Journal: British Journal of Sports Medicine (2007)

To evaluate whether patient characteristics and/or radiographic disease patterns predict symptomatic response to treatment with glucosamine in osteoarthritis (OA) of the knee.Exploratory prospective correlational study.Institutional.39 participants with chronic knee pain from the local community.Glucosamine sulphate (1.5 g/day) for 12 weeks.Pain and physical function were assessed with visual analogue scales (VASs) and participant-perceived global change scores (GCSs). Regression modelling evaluated the relationship between treatment outcome and age, body mass index (BMI), pain and function self-efficacy and presence/absence of osteophytes in the medial and lateral tibiofemoral joint (TFJ) and patellofemoral joint (PFJ) compartments.13 (33%) participants were men. The mean (SD) age and BMI were 53.6 (13.1) years and 27.9 (4.6) kg/m(2), respectively. 13 (33%), 19 (49%) and 24 (62%) participants had medial TFJ, lateral TFJ and PFJ osteophytes, respectively. Glucosamine significantly improved pain (mean change on VAS = -1.4, 95% CI -0.6 to -2.2; p = 0.002) and activity restriction (-1.9, 95% CI -1.0 to -2.8; p<0.001). At 12 weeks, 30 (77%) and 27 (69%) participants reported improvement in pain and physical function, respectively. Regression modelling showed that no evaluated variables predicted change in pain on VAS. Decreased function self-efficacy, presence of PFJ osteophytes and absence of medial TFJ osteophytes predicted functional improvement on VAS. BMI, pain self-efficacy and function self-efficacy predicted improvement in pain by GCS.Although glucosamine significantly improved symptoms, most of the variance in outcome at 12 weeks was unexplained by the predictors evaluated. However, glucosamine may be more effective at improving symptoms in patients with knee OA who have a lower BMI, PFJ osteophytes and lower functional self-efficacy.
Glucocorticoids and neonatal brain injury: the hedgehog connection
Authors: Alberto Gulino, Enrico De Smaele, Elisabetta Ferretti
Journal: Journal of Clinical Investigation (2009)

Glucocorticoids (GCs) play a critical role in neural development; however, their prenatal or neonatal therapeutic use can have detrimental effects on the developing brain. In this issue of the JCI, Heine and Rowitch report that the molecular mechanisms underlying these detrimental effects involve the sonic hedgehog (Shh) signaling pathway, a crucial regulator of brain development and neural stem/progenitor cells (see the related study beginning on page 267). They show that GCs suppress Shh-induced proliferation of cerebellar progenitor cells in postnatal mice and that, conversely, Shh signaling is protective against GC-induced neonatal cerebellar injury by inducing the enzyme 11betaHSD2, which inactivates the GCs corticosterone and prednisolone, but not dexamethasone. The data provide a rationale for the therapeutic use of 11betaHSD2-sensitive GCs, but not dexamethasone, or for the exploitation of the neuroprotective effect of Shh agonists to prevent GC-induced pre- or neonatal brain injury.
Predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men.
Authors: J R Stradling, J H Crosby
Journal: Thorax (1991)

One thousand and one men, aged 35-65 years, were identified from the age-sex register of one group general practice. Over four years 900 men were visited at home and asked questions about symptoms potentially related to sleep apnoea and snoring. Height, weight, neck circumference, resting arterial oxygen saturation (SaO2), and spirometric values were also determined. All night oximetry was then performed at home and the tracing analysed for the number of dips in SaO2 of more than 4%. Subjects with more than five dips of 4% SaO2 or more per hour were invited for sleep laboratory polysomnography. Seventeen per cent of the men admitted to snoring "often." Multiple linear regression techniques identified and ranked neck circumference (r2 = 7.2%), cigarette consumption (r2 = 3.4%), and nasal stuffiness (r2 = 2%) as the only significant independent predictors of snoring. Together these account for at least a sixfold variation in the likelihood of being an "often" snorer. Forty six subjects (5%) had greater than 4% SaO2 dip rates of over five an hour and 31 of these had full sleep studies. Three subjects had clinically obvious and severe symptomatic obstructive sleep apnoea, giving a prevalence of three per 1001 men (0.3%; 95% confidence interval 0.07-0.9%). Eighteen men had obstructive sleep apnoea only when supine and in 10 the cause of the SaO2 dipping on the original home tracing was not elucidated. The greater than 4% SaO2 dip rates correlated with the history of snoring. Multiple linear regression techniques identified and ranked neck circumference (r2 = 7.9%), alcohol consumption (r2 = 3.7%), age (r2 = 1%) and obesity (r2 = 1%) as the only significant independent predictors of the rate of overnight hypoxic dipping. This study shows that snoring in this randomly selected population correlates best with neck size, smoking, and nasal stuffiness. Obstructive sleep apnoea, defined by nocturnal hypoxaemia, correlates best with neck size and alcohol, and less so with age and general obesity.