tbuckley/cabot-search huggingface dataset:
Active transport and inotropic state in guinea pig left atrium.
Authors: P Lechat, C R Malloy, T W Smith
Journal: Circulation Research (1983)

Although the positive inotropic effect of cardiac glycosides correlates well with inhibition of Na+ pump activity in many preparations, digitalis at low concentrations (10(-9) to 10(-8) M) may produce an apparent stimulation of monovalent cation transport in isolated intact myocardium or produce an inotropic effect that does not correlate with pump inhibition. Digitalis is known to modify tissue metabolism of endogenous neurotransmitters that may affect inotropic state, Na,K-ATPase activity, and K+ permeability. We examined the interactions of low concentrations of ouabain with adrenergic and cholinergic influences in isolated guinea pig left atria stimulated at 3.3 Hz in which inotropic state and monovalent cation transport (measured as 86Rb+ uptake) were assessed simultaneously. Ouabain (10(-9) M) stimulated Rb+ transport (+25%) without an inotropic response; the stimulatory effect on transport was abolished by propranolol or atropine pretreatment. In atria pretreated with atropine, 10(-8) M ouabain produced a small positive inotropic effect (+10%) without measurable associated Na+-K+ pump inhibition. This inotropic response was abolished in catecholamine-depleted atria. Ouabain (10(-7) M) always produced a positive inotropic response (about +25%) independent of catecholamine depletion, beta-adrenergic blockade, or muscarinic blockade, but Rb+ uptake inhibition was observed only in beta-adrenergically-blocked atria. In all preparations, ouabain concentrations greater than 10(-7) M caused an inotropic response associated with pump inhibition. At concentrations 3 X 10(-7) M and higher, mechanical toxicity was observed in all preparations except those pretreated with propranolol. Incubation with low concentrations of ouabain did not modify the inotropic response to isoproterenol. At concentrations of isoproterenol sufficient to stimulate Rb+ transport by 25%, there was a large (+80%) inotropic response. We conclude first, that, in guinea pig atria exposed to ouabain, the mechanism as well as the extent of inotropic response and of monovalent cation transport modification is concentration dependent, second, that at low concentrations (1-10 X 10(-9) M), in vitro inotropic and monovalent cation transport responses are in part mediated by an effect of ouabain on endogenous neurotransmitters; and third, that in this preparation at concentrations between 10(-9) and 10(-7) M ouabain, monovalent cation transport as measured by tissue 86Rb+ uptake does not correlate with inotropic response.
Apurinic/Apyrimidinic Endonuclease Activity Is Associated with Response to Radiation and Chemotherapy in Medulloblastoma and Primitive Neuroectodermal Tumors
Authors: Michael S. Bobola, Laura S. Finn, Richard G. Ellenbogen, J. Russell Geyer, Mitchel S. Berger, Justin M. Braga, Elizabeth H. Meade, Mary E. Gross, John R. Silber
Journal: Clinical Cancer Research (2005)

Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy.Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP).Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P < or = 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasic site repair.Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.
Contribution of IgE and immunoglobulin free light chain in the allergic reaction to cow's milk proteins
Authors: Bastiaan Schouten, Betty C.A.M. van Esch, Anders O.J. van Thuijl, Bart R.J. Blokhuis, Tom Groot Kormelink, Gerard A. Hofman, Guido E. Moro, Günther Boehm, Sertac Arslanoglu, Aline B. Sprikkelman, Linette E.M. Willemsen, Léon M.J. Knippels, Frank A. Redegeld, Johan Garssen
Journal: Journal of Allergy and Clinical Immunology (2010)
Suppression of class I human histocompatibility leukocyte antigen by c-myc is locus specific.
Authors: R Versteeg, K M Krüse-Wolters, A C Plomp, A van Leeuwen, N J Stam, H L Ploegh, D J Ruiter, P I Schrier
Journal: The Journal of Experimental Medicine (1989)

The c-myc oncogene downregulates class I HLA expression in human melanoma. The major class I HLA antigens are encoded by three loci, A, B, and C, and we investigated whether these loci are suppressed equally by c-myc. In three melanoma cell lines with high c-myc expression, we analyzed mRNA, protein, and cell surface expression of the class I HLA antigens. Whereas the HLA-B locus expression was found to be strongly reduced, the HLA-A locus was expressed normally. Analysis of c-myc-transfected clones of two melanoma cell lines confirmed that c-myc preferentially suppresses the class I HLA-B locus. Immunohistochemical analysis of fresh melanoma lesions also showed that in the tumors the HLA-A loci are expressed normally, while on the majority of tumor cells no HLA-B antigen expression was found. This downregulation may have consequences for the recognition of malignant cells by tumor-infiltrating lymphocytes. Our results predict that HLA-B-restricted cytotoxic T cells will be unable to kill high c-myc-expressing melanoma cells.
The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter
Authors: Uzma A. Hasan, Claudia Zannetti, Peggy Parroche, Nadège Goutagny, Marine Malfroy, Guillaume Roblot, Christine Carreira, Ishraq Hussain, Martin Müller, Joyce Taylor-Papadimitriou, Didier Picard, Bakary S. Sylla, Giorgio Trinchieri, Ruslan Medzhitov, Massimo Tommasino
Journal: The Journal of Experimental Medicine (2013)

Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-κBp50–p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-κB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor.
Organizing pneumonia in textile printing workers: a clinical description
Authors: S Romero, L Hernandez, J Gil, I Aranda, C Martin, J Sanchez-Paya
Journal: European Respiratory Journal (1998)

In April 1992 an outbreak of severe respiratory illness occurred among aerographic textile workers in the area of Alcoi, Autonomous Community of Valencia, Spain. An epidemiological study linked this outbreak to the use of a reformulated aerosolized product, Acramin-FWN. We analyzed clinical, laboratory, and pathological data of the first 14 patients with confirmed organizing pneumonia (OP) secondary to this newly recognized occupational toxicant. The mean age of the patients was 30 yrs. The most common clinical findings were cough (86%), epistaxis (71%), dyspnoea (64%), oppressive chest pain (57%), and crackles (50%). A restrictive functional pattern was evident in 64%. Radiographic findings consisted predominantly of patchy infiltrates in 65% and a micronodular pattern in 35%. Treatment with corticosteroids did not prevent initial progression in 11 of the 14 patients and development of irreversible respiratory failure in five patients. At necropsy, besides features of OP, interstitial fibrosis and diffuse alveolar damage were evident. A low total lung capacity, the presence of crackles at admission, and increases in the alveolar-arterial oxygen difference were predictive of death. The organizing pneumonia caused by the inhalation of Acramin-FWN is characterized by a tendency to evolve into progressive interstitial fibrosis despite the use of corticosteroids. The illness is restricted to the respiratory system and once respiratory failure has developed the prognosis is poor.
Pancreatic Cancer hENT1 Expression and Survival From Gemcitabine in Patients From the ESPAC-3 Trial
Authors: William Greenhalf, Paula Ghaneh, John P. Neoptolemos, Daniel H. Palmer, Trevor F. Cox, Richard F. Lamb, Elizabeth Garner, Fiona Campbell, John R. Mackey, Eithne Costello, Malcolm J. Moore, Juan W. Valle, Alexander C. McDonald, Ross Carter, Niall C. Tebbutt, David Goldstein, Jennifer Shannon, Christos Dervenis, Bengt Glimelius, Mark Deakin, Richard M. Charnley, François Lacaine, Andrew G. Scarfe, Mark R. Middleton, Alan Anthoney, Christopher M. Halloran, Julia Mayerle, Attila Oláh, Richard Jackson, Charlotte L. Rawcliffe, Aldo Scarpa, Claudio Bassi, Markus W. Büchler
Journal: JNCI Journal of the National Cancer Institute (2013)

Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ 21 =0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ 21 = 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ 21 = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ 21 = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ 2 = 9.16; P = .003) but not 5-fluorouracil–treated (Wald χ 2 = 1.22; P = .27) patients. Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.
A pilot study of the eccentric decline squat in the management of painful chronic patellar tendinopathy
Authors: C R Purdam, P Jonsson, H Alfredson, R Lorentzon, J L Cook, K M Khan
Journal: British Journal of Sports Medicine (2004)

This non-randomised pilot study investigated the effect of eccentric quadriceps training on 17 patients (22 tendons) with painful chronic patellar tendinopathy.Two different eccentric exercise regimens were used by subjects with a long duration of pain with activity (more than six months). (a) Nine consecutive patients (10 tendons; eight men, one woman; mean age 22 years) performed eccentric exercise with the ankle joint in a standard (foot flat) position. (b) Eight patients (12 tendons; five men, three women; mean age 28 years) performed eccentric training standing on a 25 degrees decline board, designed to increase load on the knee extensor mechanism. The eccentric training was performed twice daily, with three sets of 15 repetitions, for 12 weeks. Primary outcome measures were (a) 100 mm visual analogue scale (VAS), where the subject recorded the amount of pain during activity, and (b) return to previous activity. Follow up was at 12 weeks, with a further limited follow up at 15 months.Good clinical results were obtained in the group who trained on the decline board, with six patients (nine tendons) returning to sport and showing a significantly reduced amount of pain over the 12 week period. Mean VAS scores fell from 74.2 to 28.5 (p = 0.004). At 15 months, four patients (five tendons) reported satisfactory results (mean VAS 26.2). In the standard squat group the results were poor, with only one athlete returning to previous activity. Mean VAS scores in this group were 79.0 at baseline and 72.3 at 12 weeks (p = 0.144).In a small group of patients with patellar tendinopathy, eccentric squats on a decline board produced encouraging results in terms of pain reduction and return to function in the short term. Eccentric exercise using standard single leg squats in a similar sized group appeared to be a less effective form of rehabilitation in reducing pain and returning subjects to previous levels of activity.
Direct evidence that a class II molecule and a simple globular protein generate multiple determinants.
Authors: P M Allen, D J McKean, B N Beck, J Sheffield, L H Glimcher
Journal: The Journal of Experimental Medicine (1985)

We have examined the individual contributions of the I-A kappa alpha chain, the I-A kappa beta chain, and the foreign antigen hen egg-white lysozyme (HEL) in the formation of the determinant being recognized by the T cell receptor. As functional probes we have used (a) a panel of 10 HEL-specific T cell hybridomas, (b) a panel of antigen-presenting cells (APC) possessing mutations in either the I-A kappa alpha or I-A kappa beta chains, and (c) proteolytic fragment of HEL and related synthetic peptides. The ability of the I-A kappa beta and I-A kappa alpha mutant cell lines to present antigen to the 10 T cell hybridomas divided these T cells into six distinct groups. These HEL-specific T cells therefore appear to recognize several distinct domains on the I-A kappa molecule. The 10 T cell hybrids were then shown to recognize at least three distinct determinants on the HEL molecule, with 8 of the 10 hybrids recognizing one of two major determinants HEL(46-61) or HEL(34-45). Combining the response patterns to the panel of I-A kappa mutant APC lines with the antigen specificity revealed that the 10 T cell hybrids recognized at least eight unique determinants formed by the I-A kappa alpha chains, I-A kappa beta chains, and HEL peptides. This analysis provides direct evidence that a large number of different determinants or T cell receptor ligands can be generated from a single Ia molecule and a simple globular protein.
Tumor Ablation by Gene-Modified T Cells in the Absence of Autoimmunity
Authors: Leanne X.J. Wang, Jennifer A. Westwood, Maria Moeller, Connie P.M. Duong, Wei-Zen Wei, Jordane Malaterre, Joseph A. Trapani, Paul Neeson, Mark J. Smyth, Michael H. Kershaw, Phillip K. Darcy
Journal: Cancer Research (2010)

Adoptive immunotherapy involving genetic modification of T cells with antigen-specific, chimeric, single-chain receptors is a promising approach for the treatment of cancer. To determine whether gene-modified T cells could induce antitumor effects without associated autoimmune pathology, we assessed the ability of T cells expressing an anti-Her-2 chimeric receptor to eradicate tumor in Her-2 transgenic mice that express human Her-2 as a self-antigen in brain and mammary tissues. In adoptive transfer studies, we demonstrated significant improvement in the survival of mice bearing Her-2(+) 24JK tumor following administration of anti-Her-2 T cells compared with control T cells. The incorporation of a lymphoablative step prior to adoptive transfer of anti-Her-2 T cells and administration of IL-2 were both found to further enhance survival. The reduction in tumor growth was also correlated with localization of transferred T cells at the tumor site. Furthermore, an antigen-specific recall response could be induced in long-term surviving mice following rechallenge with Her-2(+) tumor. Importantly, antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. This study highlights the therapeutic potential of using gene-engineered T cells as a safe and effective treatment of cancer.
Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit
Authors: David Tooth, Klara Garsed, Gulzar Singh, Luca Marciani, Ching Lam, Imogen Fordham, Annie Fields, Rawinder Banwait, Melanie Lingaya, Robert Layfield, Maggie Hastings, Peter Whorwell, Robin Spiller
Journal: Gut (2013)

<h3>Objectives</h3> Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing and transit time. <h3>Design</h3> Faecal samples were obtained from 30 healthy volunteers (HV) and 79 patients with IBS-D participating in a trial of ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Samples were also obtained from 24 HV before and after colonic cleansing with the osmotic laxative MoviPrep. FSPs were purified from faecal extracts using benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem mass spectrometry. Functional protease activity in faecal extracts was measured using a colorimetric assay based on the proteolysis of azo-casein. <h3>Results</h3> Protein analysis identified the most abundant FSPs as being of human origin and probably derived from pancreatic juice. Functional assays showed increased faecal protease (FP) and amylase in patients with IBS-D compared with HV. Those with higher amylase had significantly higher FP and greater anxiety. FP activity correlated negatively with whole gut transit in patients with IBS-D (Spearman r=−0.32, p=0.005) and HV (r=−0.55, p=0.014). Colon cleansing caused a significant rise in FP activity in HV from a baseline of median (IQR) 253 (140–426) to 1031 (435–2296), levels similar to those seen in patients with IBS-D. FSP activity correlated positively with days/week with urgency. <h3>Conclusions</h3> The most abundant FSPs are of human origin. Rapid transit through the colon and/or decreased (possibly bacterial) proteolytic degradation increases their faecal concentration and could contribute to visceral hypersensitivity in patients with IBS-D. <h3>ClinicalTrials.gov</h3> NCT00745004.
Adverse events associated with dietary supplements: an observational study
Authors: Mary E Palmer, Christine Haller, Patrick E McKinney, Wendy Klein-Schwartz, Anne Tschirgi, Susan C Smolinske, Alan Woolf, Bruce M Sprague, Richard Ko, Gary Everson, Lewis S Nelson, Teresa Dodd-Butera, W Dana Bartlett, Brian R Landzberg
Journal: The Lancet (2003)
Standardization of IVGTT to Predict IDDM
Authors: Polly J Bingley, Peter Colman, George S Eisenbarth, Richard A Jackson, David K McCulloch, William J Riley, Edwin A Gale
Journal: Diabetes Care (1992)

OBJECTIVE To review current practice in centers that use the IVGTT for prediction of IDDM. To establish consensus protocol for performance of the test. RESEARCH DESIGN AND METHODS Postal questionnaires were delivered to 12 centers. RESULTS Eleven centers used a glucose dose of 0.5 g/kg and 1 used 0.3 g/kg; the dosage in adults was limited to a maximum of 25–50 g in some centers but others applied no upper limit. The glucose concentration of the infusate varied between 20 and 66%. Eight centers injected glucose manually, two used a syringe pump, and two used gravity infusion. The period of infusion ranged from 30 ± 10 s to 4 ± 2 min, and time zero was taken as the start (1 center), middle (1 center), or end (10 centers) of the infusion. The potential range in timing of the + 1-min sample varied between 1 and 7 min from the start of the infusion. Quality-assurance standards for the insulin assays used were not always appropriate for the fasting and low stimulated range of insulin levels. CONCLUSIONS The first-phase insulin response to the IVGTT is widely measured as an index of risk of progression to IDDM. We established that methodology varies widely. Because of this, a new standard protocol for use in prediction of IDDM was agreed by an ICARUS working group and is described herein.
The future for lung disease in children
Authors: W. Lenney
Journal: Thorax (2007)

of active disease, and treatment regimens really will be shorter and less potentially toxic.I'm less optimistic about stigma.Twenty years ago, HIV/AIDS could reasonably be regarded as ''the new leprosy'' in terms of the public reaction to those with the condition.TB has now moved into that role and, unlike HIV/AIDS, it has too few articulate, high profile and powerful sufferers to alter public perceptions.If we are to do better in the next 25 years than we have done in the last 25, there must be social and political changes, not just scientific ones. 17