tbuckley/cabot-search huggingface dataset:
Chronic hepatitis C viral infection subverts vaccine‐induced T‐cell immunity in humans
Authors: Christabel Kelly, Leo Swadling, Stefania Capone, Anthony Brown, Rachel Richardson, John Halliday, Annette von Delft, Ye Oo, David Mutimer, Ayako Kurioka, Felicity Hartnell, Jane Collier, Virginia Ammendola, Mariarosaria Del Sorbo, Fabiana Grazioli, Maria Luisa Esposito, Stefania Di Marco, Loredana Siani, Cinzia Traboni, Adrian V.S. Hill, Stefano Colloca, Alfredo Nicosia, Riccardo Cortese, Antonella Folgori, Paul Klenerman, Eleanor Barnes
Journal: Hepatology (2015)

Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high‐magnitude, durable CD4 + and CD8 + T‐cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce functional HCV‐specific immune responses and determine T‐cell cross‐reactivity to endogenous virus in patients with chronic HCV infection. HCV genotype 1‐infected patients were vaccinated using heterologous adenoviral vectors (ChAd3‐NSmut and Ad6‐NSmut) encoding HCV NS proteins in a dose escalation, prime‐boost regimen, with and without concomitant pegylated interferon‐α/ribavirin therapy. Analysis of immune responses ex vivo used human leukocyte antigen class I pentamers, intracellular cytokine staining, and fine mapping in interferon‐γ enzyme‐linked immunospot assays. Cross‐reactivity of T cells with population and endogenous viral variants was determined following viral sequence analysis. Compared to healthy volunteers, the magnitude of HCV‐specific T‐cell responses following vaccination was markedly reduced. CD8 + HCV‐specific T‐cell responses were detected in 15/24 patients at the highest dose, whereas CD4 + T‐cell responses were rarely detectable. Analysis of the host circulating viral sequence showed that T‐cell responses were rarely elicited when there was sequence homology between vaccine immunogen and endogenous virus. In contrast, T cells were induced in the context of genetic mismatch between vaccine immunogen and endogenous virus; however, these commonly failed to recognize circulating epitope variants and had a distinct partially functional phenotype. Vaccination was well tolerated but had no significant effect on HCV viral load. Conclusion: Vaccination with potent HCV adenoviral vectored vaccines fails to restore T‐cell immunity except where there is genetic mismatch between vaccine immunogen and endogenous virus; this highlights the major challenge of overcoming T‐cell exhaustion in the context of persistent antigen exposure with implications for cancer and other persistent infections. (H epatology 2016;63:1455‐1470)
High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma
Authors: X.-R. Yang, Y. Xu, B. Yu, J. Zhou, S.-J. Qiu, G.-M. Shi, B.-H. Zhang, W.-Z. Wu, Y.-H. Shi, B. Wu, G.-H. Yang, Y. Ji, J. Fan
Journal: Gut (2010)

<h3>Background/aims</h3> To investigate the prognostic values of putative hepatic stem/progenitor cell (HSC/HPC) biomarkers in patients with hepatocellular carcinoma (HCC). <h3>Methods</h3> Fourteen biomarkers related to HSCs/HPCs or tumour angiogenesis were assessed by qRT-PCR and then validated by tissue microarrays (TMAs) in three independent cohorts of patients with HCC undergoing curative resection (n=67, 314 and 73). <h3>Results</h3> Most of the biomarkers were found to be overexpressed in patients with recurrent HCC by quantitative reverse transcription–PCR (qRT–PCR). The HSC/HPC biomarkers cytokeratin 19, ATP-binding cassette subfamily G member 2 (ABCG2), CD133, Nestin and CD44, and the markers of angiogenesis microvessel density (MVD, determined by CD34 immunostaining), vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were confirmed as significant predictors for overall survival (OS) and/or relapse-free survival (RFS) in TMA analysis. As compared with the low HSC/HPC profile group, patients with a high HSC/HPC profile who had higher VEGF levels (p=0.012) and MVD (p=0.030) in tumours had significantly lower OS and RFS (p&lt;0.0001). Based on Cox regression, a simplified model including CD133, CD44, Nestin and MVD was constructed and confirmed as an independent predictor for OS (p&lt;0.0001) and RFS (p&lt;0.0001), regardless of α-fetoprotein level, tumour stage and recurrence time (p&lt;0.0001 for all). <h3>Conclusion</h3> High expression levels of HSC/HPC biomarkers are related to tumour angiogenesis and poor prognosis of HCC. The simplified model based on the HSC/HPC and tumour angiogenesis profile can be used to classify patients with HCC with a high risk of tumour recurrence after surgery.
A critical review of the role of the major histocompatibility complex in fertilization, preimplantation development and feto-maternal interactions
Authors: N Fernandez
Journal: Human Reproduction Update (1999)

From conception to old age, the major histocompatibility complex (MHC) is at the centre of immune responses that aid survival, fitness and adaptation of mammalian species to the environment. Its main function is that of controlling adaptive immunity, particularly T-cell-mediated immunity towards pathogens. In several species, including humans, the MHC is also able to elicit T-cell-mediated immune responses to allogeneic MHC antigens (non-self MHC antigens expressed by another individual from the same species). Although this phenomenon was originally identified in mice by the somewhat unnatural means of tissue transplantation, it was soon realized that it may also play an important role in the natural state, since the mammalian fetus in the maternal uterus is semi-allogeneic, due to the presence of MHC genes inherited from the father. Thus, during normal pregnancy the maternal immune system undergoes changes that lead to tolerance of the fetus. The MHC can play a dual role in the reproduction process: firstly influencing mating choice in some species, affecting the mother-father MHC matching; and secondly influencing the development of the fertilized ovum during the preimplantation period. In this review we examine the role of the MHC at three distinct levels: (i) MHC expression in gametes and its role in fertilization; (ii) MHC expression in placental tissue; and (iii) MHC expression in embryonic tissue. We suggest that the MHC plays a pleiotropic role, both in fitness (survival and reproductive success) and in development, thereby ensuring the survival of the species in future generations.
Role of Specific Interactions Between Protein Kinase C and Triphenylethylenes in Inhibition of the Enzyme
Authors: C. A. O'Brian, N. E. Ward, B. W. Anderson
Journal: JNCI Journal of the National Cancer Institute (1988)

The tumor promoter receptor protein kinase C (PKC) has been implicated as a key enzyme in cellular growth regulation. It is, therefore, believed that specific PKC inhibitors may include effective antiproliferative agents. Previously, we have shown that the antiestrogen tamoxifen and related triphenylethylenes are potent inhibitors of PKC. Although the mechanism of inhibition of PKC by triphenylethylenes clearly involves non-specific interactions between the antiestrogens and the lipid cofactor of PKC, we recently demonstrated that PKC itself has specific triphenylethyl-ene-binding sites, suggesting that the inhibitory mechanism also involves specific drug-protein interactions. In this report, we characterize the direct interactions between PKC and triphenylethylenes and demonstrate their relevance to the inhibitory action of triphenylethylenes against PKC. We show (a) that the triphenylethylene-binding sites of PKC are located in the catalytic domain of the enzyme, (b) that MgATP (i.e., 10 mM MgCl2 plus 1 mM ATP) competes with the triphenylethylenes for binding sites on PKC, and (c) that triphenylethylenes are competitive inhibitors of the PKC with respect to MgATP. Taken together, these data provide strong evidence that triphenylethylenes can inhibit PKC by binding directly to the ATP-binding region of the active site of the enzyme. The specific interactions between triphenylethylenes and PKC characterized here may provide a rationale for developing more specific PKC inhibitors.
AT1b Receptor Predominantly Mediates Contractions in Major Mouse Blood Vessels
Authors: Yingbi Zhou, Yanfang Chen, Wessel P. Dirksen, Mariana Morris, Muthu Periasamy
Journal: Circulation Research (2003)

In rodents, angiotensin (Ang) II type-1 (AT1) receptors exist as two pharmacologically identical subtypes: AT1a and AT1b. Recent studies have utilized mouse models with specific subtype receptor deletions to differentiate the functional difference between AT1 subtypes. However, little information is available on AT1 subtype expression in mouse vasculature. Therefore, in this study, AT1a −/− mice and wild-type littermates (AT1a +/+ ) were used to examine AT1 subtype expression and its functional relevance in mouse arterial vessels. Using RT-PCR and restriction enzyme digestion, we showed that AT1b accounts for most of the total AT1 mRNA in mouse abdominal aorta and femoral artery. In contrast, AT1a is the predominant subtype in kidney. To study the functional role of AT1 subtypes, we measured the in vitro contractility in vessels from AT1a −/− and AT1a +/+ mice. The Ang II concentration response curves in abdominal aorta and femoral artery were comparable between the two mouse strains. Furthermore, the Ang II response in AT1a −/− mouse vessels was completely antagonized by losartan, an AT1 antagonist. These results demonstrate that AT1b receptor is a major mediator for Ang II contractile response in mouse vessels, such as abdominal aorta and femoral artery.
Upper airway obstruction masquerading as exercise induced bronchospasm in an elite road cyclist
Authors: K E Fallon
Journal: British Journal of Sports Medicine (2004)

This case concerns an elite road cyclist who complained of occasional dyspnoea and inspiratory difficulty during intense exercise. Clinical examination was normal and the final diagnosis was vocal cord dysfunction, a paradoxical closure of the vocal cords during inspiration which is highly associated with inspiratory stridor at high rates of ventilation. Awareness by the sports physician of this not uncommon condition is important to avoid misdiagnosis.
Obstructive sleep apnoea in patients with type 2 diabetes
Authors: E. Kelly, G. Cullen, C. McGurk
Journal: Thorax (2007)

An increased body mass index (BMI) is a risk factor for type 2 diabetes mellitus and obstructive sleep apnoea (OSA). The question whether this is just a shared risk factor or whether there is a deeper relationship has been addressed by West et al 1 who used an initial screening Berlin questionnaire followed by overnight oximetry in selected respondents. …
Age- and height-based prediction bias in spirometry reference equations
Authors: Philip H. Quanjer, Graham L. Hall, Sanja Stanojevic, Tim J. Cole, Janet Stocks
Journal: European Respiratory Journal (2011)

Prediction bias in spirometry reference equations can arise from combining equations for different age groups, rounding age or height to integers or using self-reported height. To assess the bias arising from these sources, the fit of 13 prediction equations was tested against the Global Lungs Initiative (GLI) dataset using spirometric data from 55,136 healthy Caucasians (54% female). The effects on predicted values of using whole-year age versus decimal age, and of a 1% bias in height, were quantified. In children, the prediction bias relative to GLI ranged from -22% to +17%. Switching equations at 18 yrs of age led to biases of between -846 (-14%) and +1,309 (+38%) mL. Using age in whole years rather than decimal age introduced biases from -8% to +7%, whereas a 1% overestimation of height introduced bias that ranged from +1% to +40%. Bias was greatest in children and adolescents, and in short elderly subjects. Using a single spirometry equation applicable across all ages and populations reduces prediction bias. Measuring and recording age and height accurately are also essential if bias is to be minimised.
Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid.
Authors: M Fujimura, S Sakamoto, Y Kamio, T Matsuda
Journal: Thorax (1992)

BACKGROUND: The direct effect of bronchoconstriction on cough receptor sensitivity is unknown, and the antitussive effect of beta 2 adrenergic agonists in man has been controversial. This study was designed to throw light on these questions. METHODS: The threshold of the cough response to inhaled capsaicin, a stimulant acting on C fibre endings, and tartaric acid, a chemostimulant, was measured before and 10 minutes after inhalation of methacholine, which caused a nearly 20% fall in forced expiratory volume in one second (FEV1), in 14 normal subjects (study 1), and also before and 30 minutes after inhalation of procaterol (30 micrograms), placebo, and saline in eight normal subjects (study 2). Progressively increasing concentrations of capsaicin and tartaric acid solutions were inhaled for 15 seconds by mouth tidal breathing at one minute intervals and cough threshold was defined as the lowest concentration of capsaicin and tartaric acid that elicited five or more coughs. RESULTS: In study 1 the geometric mean values of the cough threshold of response to capsaicin and tartaric acid before methacholine callenge, 2.98 (GSE 1.30) micrograms/ml and 46.6 (1.22) mg/ml, were not significantly different from those of the response to methacholine inhalation, 3.45 (1.33) micrograms/ml and 32.9 (1.37) mg/ml. In study 2 the geometric mean value of the cough threshold of response to capsaicin before inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml) was not different from that after inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml), which had significant bronchodilator effects. The cough threshold was not altered by placebo or saline. CONCLUSIONS: These findings suggest that muscarinic receptor stimulation, bronchoconstriction, beta 2 receptor stimulation, or bronchodilation might have no direct effect on the sensitivity of the cough receptors in normal subjects.
Decreased Sensitivity of Distal Nephron and Collecting Duct to Parathyroid Hormone in Pseudohypoparathyroidism Type I
Authors: MASAKO GOTO, KAZUTOSHI MIZUNASHI, NORIKO KIMURA, YOHTARO FURUKAWA
Journal: Journal of the American Society of Nephrology (2001)

Parathyroid hormone (PTH) transiently increases urinary excretion of the lysosomal enzyme, N-acetyl-beta-D-glucosaminidase, which is distributed mainly in proximal tubules. The response is reduced in pseudohypoparathyroidism (PHP) type I, which is characterized by target-organ resistance to PTH. Evidenced by normal calcium resorption, distal tubule sensitivity to PTH has been believed to be normal in this disorder. This hypothesis was tested through a search for another marker of distal nephron sensitivity to PTH. In the human kidney, cathepsin D was expressed predominantly in distal segments of the nephron, cortical and medullary thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules and in cortical collecting ducts and medullary collecting ducts. PTH infusion transiently increased cathepsin D excretion in normal subjects. The cathepsin D response to PTH was reduced in the patients with PHP type I. The decrease in cathepsin D response in PHP type I indicates a resistance to PTH in the distal nephron (cortical thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules) and cortical collecting ducts. These observations suggest that the preservation of renal tubular sensitivity to PTH in this disorder may be confined to PTH-dependent calcium resorption in distal tubules.
Ovarian Cancer G Protein Coupled Receptor 1, a New Metastasis Suppressor Gene in Prostate Cancer
Authors: L. S. Singh, M. Berk, R. Oates, Z. Zhao, H. Tan, Y. Jiang, A. Zhou, K. Kirmani, R. Steinmetz, D. Lindner, Y. Xu
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundMetastasis is a process by which tumors spread from primary organs to other sites in the body and is the major cause of death for cancer patients. The ovarian cancer G protein–coupled receptor 1 (OGR1) gene has been shown to be expressed at lower levels in metastatic compared with primary prostate cancer tissues.
Effectiveness of St John's Wort in Major Depression
Authors: Richard C. Shelton, Martin B. Keller, Alan Gelenberg, David L. Dunner, Robert Hirschfeld, Michael E. Thase, James Russell, R. Bruce Lydiard, Paul Crits-Christoph, Robert Gallop, Linda Todd, David Hellerstein, Paul Goodnick, Gabor Keitner, Stephen M. Stahl, Uriel Halbreich
Journal: JAMA (2001)

ContextExtracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation.ObjectiveTo compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression.Design and SettingRandomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States.ParticipantsTwo hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20.InterventionParticipants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks.Main Outcome MeasuresThe primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression–Severity and –Improvement scales (CGI-S and CGI-I).ResultsThe random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P&lt;.001, P = .16, and P = .58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P = .02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively).ConclusionIn this study, St John's wort was not effective for treatment of major depression.
Farming in childhood, diet in adulthood and asthma history
Authors: R. Varraso, M. P. Oryszczyn, N. Mathieu, N. Le Moual, M. C. Boutron-Ruault, F. Clavel-Chapelon, I. Romieu, F. Kauffmann
Journal: European Respiratory Journal (2011)

The decrease in the number of children living on traditional farms in France during early childhood and changes in diet could both play a role in the increase in asthma prevalence over the last decades. This study aimed to assess 1) the association of farming lifestyle in childhood and asthma, and 2) whether diet in adulthood modifies the association between farming lifestyle in childhood and adult-onset asthma. In the French Etude Epidemiologique des Femmes de la Mutuelle Générale de l9Education Nationale (E3N) study (54,018 females; age 43–68 yrs), three indicators of farming lifestyle were defined: one using individual data (having farmer parents) and two using ecological data (born in a rural area and exposure to cattle). All farming lifestyle indicators were related to childhood- (&lt;16 yrs) and adult-onset asthma (OR (95% CI) values for farmer parents were 0.54 (0.42–0.70) and 0.72 (0.62–0.84), respectively), and to diet in adulthood, in particular to high fruit and low wine intakes. The association between farmer parents and adult-onset asthma was not modified by diet in adulthood. Results extend previous observations in younger cohorts on the protective role of contact with livestock and farming lifestyle on asthma, in particular during childhood.
Meta-Analysis of the Association Between the 7-Repeat Allele of the Dopamine D<sub>4</sub> Receptor Gene and Attention Deficit Hyperactivity Disorder
Authors: Stephen V. Faraone, Alysa E. Doyle, Eric Mick, Joseph Biederman
Journal: American Journal of Psychiatry (2001)

Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D(4) receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain.Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias.For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias.Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.
Randomised controlled trial of a short course of traditional acupuncture compared with usual care for persistent non-specific low back pain
Authors: K J Thomas, H MacPherson, L Thorpe, J Brazier, M Fitter, M J Campbell, M Roman, S J Walters, J Nicholl
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To determine whether a short course of traditional acupuncture improves longer term outcomes for patients with persistent non-specific low back pain in primary care. <b>Design</b> Pragmatic, open, randomised controlled trial. <b>Setting</b> Three private acupuncture clinics and 18 general practices in York, England. <b>Participants</b> 241 adults aged 18-65 with non-specific low back pain of 4-52 weeks9 duration. <b>Interventions</b> 10 individualised acupuncture treatments from one of six qualified acupuncturists (160 patients) or usual care only (81 patients). <b>Main outcome measures</b> The primary outcome was SF-36 bodily pain, measured at 12 and 24 months. Other outcomes included reported use of analgesics, scores on the Oswestry pain disability index, safety, and patient satisfaction. <b>Results</b> 39 general practitioners referred 289 patients of whom 241 were randomised. At 12 months average SF-36 pain scores increased by 33.2 to 64.0 in the acupuncture group and by 27.9 to 58.3 in the control group. Adjusting for baseline score and for any clustering by acupuncturist, the estimated intervention effect was 5.6 points (95% confidence interval −0.2 to 11.4) at 12 months (n = 213) and 8.0 points (2.8 to 13.2) at 24 months (n = 182). The magnitude of the difference between the groups was about 10%-15% of the final pain score in the control group. Functional disability was not improved. No serious or life threatening events were reported. <b>Conclusions</b> Weak evidence was found of an effect of acupuncture on persistent non-specific low back pain at 12 months, but stronger evidence of a small benefit at 24 months. Referral to a qualified traditional acupuncturist for a short course of treatment seems safe and acceptable to patients with low back pain. <b>Trial registration</b>ISRCTN80764175[controlled-trials.com].