tbuckley/cabot-search huggingface dataset:
The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design
Authors: Annette von Delft, Isla S Humphreys, Anthony Brown, Katja Pfafferott, Michaela Lucas, Paul Klenerman, Georg M Lauer, Andrea L Cox, Silvana Gaudieri, Eleanor Barnes
Journal: Gut (2015)

<h3>Objective</h3> Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity. <h3>Design</h3> T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed. <h3>Results</h3> In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1. <h3>Conclusions</h3> HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.
Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF B signalling pathways
Authors: C. Potter, H. J. Cordell, A. Barton, A. K. Daly, K. L. Hyrich, D. A. Mann, A. W. Morgan, A. G. Wilson, J. D. Isaacs
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To determine whether genetic variation within genes integral to the Toll-like receptor (TLR) and NFκB signalling systems, two cardinal regulators of inflammatory and immune responses, contributes towards the observed variation in response to tumour necrosis factor (TNF) blocking agents in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 24 candidate genes were selected and genotyped in a large UK cohort of patients receiving anti-TNF therapy for RA. Multivariate regression analyses were performed to test association between individual genotypes, under an additive model, and treatment response at 6 months9 follow-up assessed using both the absolute change in 28-joint count Disease Activity Score (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Analyses were performed across subgroups comprising etanercept-, infliximab- and infliximab/adalimumab-treated patients as well as the combined anti-TNF-treated cohort. p Values &lt;0.05 were considered statistically significant. <h3>Results</h3> A total of 187 SNPs were successfully genotyped and analysed in 909 patients. Eight SNPs spanning six genes demonstrated nominal evidence of association with response (DAS28) across the anti-TNF-treated subgroups, six of which were restricted to etanercept-treated patients. Twelve SNPs spanning nine genes demonstrated nominal evidence of association with treatment response (DAS28 and/or EULAR) across the combined anti-TNF cohort. These included SNPs mapping to <i>MyD88</i> (rs7744) and <i>CHUK</i> (rs11591741), which were associated under each model applied (etanercept-treated and combined anti-TNF cohort analysis (DAS28 and EULAR)). <h3>Conclusions</h3> Several SNPs mapping to the TLR and NFκB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.
Improved exacerbation rates and asthma control in current and former smokers treated with salmeterol/fluticasone propionate: Results of the GOAL study
Authors: H.A. Boushey, S. Pedersen, E. Bateman, T. Clark, W. Busse, J. Bousquet, R. Pauwels
Journal: Journal of Allergy and Clinical Immunology (2005)
Microvascular reactivity of the myopathic Syrian hamster cremaster muscle
Authors: R. S CONWAY, S. M FACTOR, E. H SONNENBLICK, S. BAEZ
Journal: Cardiovascular Research (1987)

The myopathic Syrian hamster is a genetic model of congestive heart failure that exhibits focal myocytolytic necrosis in both heart and skeletal muscle. Previous investigations of microvascular morphology in heart and skeletal muscle have shown severe arteriolar constrictions without fixed anatomical vessel lesions. This study tested the hypothesis that these constrictions indicate a hyperreactivity of the myopathic microvasculature in vivo and that the reactivity corresponds to the developmental course of myocyte pathology. The microcirculation of the cremaster muscle was studied in eight myopathic and six control hamsters in the active stage of necrosis (39-81 days of age) and five myopathic and six control hamsters in the later stage of muscle healing (150-213 days of age). The internal diameter of second order arterioles was measured during topically applied noradrenaline. The myopathic arterioles of the younger group constricted at significantly lower concentrations of noradrenaline (p<0.01) and constricted to 35-50% of their resting internal diameter over a narrower range of noradrenaline (p<0.01). This indicated both a reduced threshold to noradrenaline and an enhanced response to the agonist. Active myocytolytic necrosis was found in the contralateral cremaster muscle of each myopathic hamster. The older myopathic and control hamsters showed no significant differences in arteriolar responsiveness to applied noradrenaline and no active necrosis. These results indicate a relation between a hyperreactive microvasculature and active necrosis and a normal reacting microvasculature and diminished necrosis in the two phases of the disease. Thus a general correspondence between vascular responsiveness and myocyte pathology exists in this model of heart failure and muscular dystrophy.
Pharmacogenomics: Challenges and Opportunities
Authors: Dan M. Roden
Journal: Annals of Internal Medicine (2006)

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.
Phrenic nerve stimulation in normal subjects and in patients with diaphragmatic weakness.
Authors: A Mier, C Brophy, J Moxham, M Green
Journal: Thorax (1987)

Phrenic nerve stimulation is often considered to be difficult and unreliable. The time taken for the phrenic nerves to be located and adequately stimulated was measured in 110 subjects, aged 21-89 years, 26 of whom had diaphragmatic weakness; and phrenic nerve conduction time was recorded in 76 of these individuals. Each phrenic nerve was stimulated transcutaneously in the neck with square wave impulses 0.1 ms in duration at 1 Hz and 80-160 volts while diaphragmatic muscle action potentials were recorded with surface electrodes. The time taken to locate either phrenic nerve ranged from two seconds to 22 minutes (median 10s). Both nerves were located in 83 of the 84 control subjects (99%) and in 21 of the 26 patients with diaphragmatic weakness (81%). Mean (SD) phrenic nerve conduction time in the control subjects was 6.94 (0.77) ms on the right and 6.61 (0.77) ms on the left. A weak relationship was found between conduction time and the subjects' age and height. Four out of 24 patients with diaphragmatic weakness had a prolonged phrenic nerve conduction time. Transcutaneous stimulation of the phrenic nerves was not a time consuming procedure, and it was well tolerated, reproducible, and successful in 95% of subjects.
Prognostic Significance of Defective Mismatch Repair and BRAF V600E in Patients with Colon Cancer
Authors: Amy J. French, Daniel J. Sargent, Lawrence J. Burgart, Nathan R. Foster, Brian F. Kabat, Richard Goldberg, Lois Shepherd, Harold E. Windschitl, Stephen N. Thibodeau
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for ∼15% to 20% of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome. Although the presence of dMMR seems to be a favorable prognostic marker, data suggest that these patients do not respond as well to adjuvant chemotherapy. Experimental Design: In this study, we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF (V600E) in a group of patients (n = 533) who participated in a randomized prospective clinical trial through the North Central Cancer Treatment Group. Results: Tumors with dMMR were found to be associated with higher tumor grade (P = 0.001), proximal location (P &amp;lt; 0.0001), and improved overall and disease-free survival (P = 0.05 and 0.04, respectively). Among all cases examined, evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival. Patients were then grouped into four categories for further analysis: dMMR/BRAF(−), dMMR/BRAF(+), pMMR/BRAF(−), and pMMR/BRAF(+). The dMMR/BRAF(−) group had a significantly improved overall survival (5-year overall survival of 100% versus 73%, P = 0.002) compared with all others. The remaining three groups had very similar survival outcomes. An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration. Results remained significant (P = 0.006) when the two groups were combined for analysis. Conclusions: Overall, these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients.
The Prion's Elusive Reason for Being
Authors: Adriano Aguzzi, Frank Baumann, Juliane Bremer
Journal: Annual Review of Neuroscience (2008)

The protein-only hypothesis posits that the infectious agent causing transmissible spongiform encephalopathies consists of protein and lacks any informational nucleic acids. This agent, termed prion by Stanley Prusiner, is thought to consist partly of PrP(Sc), a conformational isoform of a normal cellular protein termed PrP(C). Scientists and lay persons have been fascinated by the prion concept, and it has been subjected to passionate critique and intense experimental scrutiny. As a result, PrP(C) and its isoforms rank among the most intensively studied proteins encoded by the mammalian genome. Despite all this research, both the physiological function of PrP(C) and the molecular pathways leading to neurodegeneration in prion disease remain unknown. Here we review the salient traits of those diseases ascribed to improper behavior of the prion protein and highlight how the physiological functions of PrP(C) may help explain the toxic phenotypes observed in prion disease.
Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg–Strauss)
Authors: A J Mohammad, A Hot, F Arndt, F Moosig, M-J Guerry, N Amudala, R Smith, P Sivasothy, L Guillevin, P A Merkel, D R W Jayne
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg–Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. <h3>Methods</h3> Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. <h3>Results</h3> 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). <h3>Conclusions</h3> The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.
Psychopathology and the discontinuity of conscious experience
Authors: David R. Hemsley
Journal: Behavioral and Brain Sciences (1995)

Abstract It is accepted that “primary awareness” may emerge from the integration of two classes of information. It is unclear, however, why this cannot take place within the comparator rather than in conjunction with feedback to the perceptual systems. The model has plausibility in relation to the continuity of conscious experience in the normal waking state and may be extended to encompass certain aspects of the “sense of self” which are frequently disrupted in psychotic patients.
Five Leading U.S. Commercial Brands of Moist Snuff in 1994: Assessment of Carcinogenic N-Nitrosamines
Authors: D. Hoffmann, M. V. Djordjevic, J. Fan, E. Zang, T. Glynn, G. N. Connolly
Journal: JNCI Journal of the National Cancer Institute (1995)

Moist snuff is the only tobacco product in the United States with increasing sales (an increase of 38.4% between 1981 and 1993) and with increased consumption, primarily by male adolescents aged 12–18 years old and young adults aged 19 years old or older. It is known from previous studies that levels of nicotine and the proportion of unprotonated (free) nicotine, as well as the pH, which affects nicotine delivery, vary considerably among the leading snuff brands. Whether concentrations of major carcinogens, such as the nicotine-derived tobacco-specific N -nitrosamines (TSNAs), like N′ -nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), also vary among these brands has not been determined previously. Our purpose was threefold: 1) to determine the concentrations of major carcinogenic nicotine-derived N -nitrosamines in each of the five most popular moist snuff brands; 2) to analyze the quantitative differences in the various snuff components (e.g., NNN) between two major brand categories: a category comprising the brands known to have high levels of unprotonated nicotine (Copenhagen, Skoal fine cut, and Kodiak) versus a category comprising the brands known to have low levels (Hawken and Skoal Bandits); and 3) to compare the differences in the concentrations of nicotine (previously determined), NNN, NNK, and total TSNAs between these two major brand categories. Three boxes of each of the five leading U.S. moist snuff brands were bought in July 1994 from retailers in six areas and transferred immediately to the analytical laboratory. After extraction, N -nitrosamino acids and TSNAs were determined on a gas chromatograph interfaced with a thermal energy analyzer (GC-TEA) and integrator. Each 5-g sample of ground, freeze-dried tobacco was extracted twice, and each extract was analyzed twice by GC-TEA. All P values reported are two sided. Copenhagen, Skoal fine cut, and Kodiak as a group had statistically significant higher levels of nicotine ( P = .0017), NNN ( P <.0001), NNK ( P = .0119), and total TSNAs ( P <.0001) than the Hawken and Skoal Bandits group. Concentrations (means ± SD) of nicotine, NNN, NNK, and total TSNAs comparing the two major brand categories are as follows: nicotine—11.6 ± 1.01 mg/g versus 6.96 ± 3.62 mg/g ( P = .0017), NNN—7.74 ± 1.70 μg/g versus 4.17 ± 1.35 μg/g ( P <.0001), NNK—1.23 ± 0.68 μg/g versus 0.61 ± 0.41 μg/g ( P = .0119), and total TSNAs—14.3 ± 3.82 μg/g versus 6.3 ± 2.56 μg/g ( P <.0001). The three leading U.S. snuff brands (Copenhagen, Skoal fine cut, and Kodiak; making up 92% of the U.S. market) showed not only high levels of pH, nicotine, and unprotonated (free) nicotine, but also high concentrations of the strongly carcinogenic TSNAs in comparison with the fourth and fifth best selling moist snuff brands, Hawken and Skoal Bandits (3% of the U.S. market). [J Natl Cancer Inst 1995;87:1862–9]
Interactions between tenocytes and monosodium urate monohydrate crystals: implications for tendon involvement in gout
Authors: Ashika Chhana, Karen E Callon, Michael Dray, Bregina Pool, Dorit Naot, Greg D Gamble, Brendan Coleman, Geraldine McCarthy, Fiona M McQueen, Jillian Cornish, Nicola Dalbeth
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Advanced imaging studies have demonstrated that urate deposition in periarticular structures, such as tendons, is common in gout. The aim of this study was to investigate the effects of monosodium urate monohydrate (MSU) crystals on tenocyte viability and function. <h3>Methods</h3> The histological appearance of tendons in joints affected by advanced gout was examined using light microscopy. In vitro, colorimetric assays and flow cytometry were used to assess cell viability in primary rat and primary human tenocytes cultured with MSU crystals. Real-time PCR was used to determine changes in the relative mRNA expression levels of tendon-related genes, and Sirius red staining was used to measure changes in collagen deposition in primary rat tenocytes. <h3>Results</h3> In joint samples from patients with gout, MSU crystals were identified within the tendon, adjacent to and invading into tendon, and at the enthesis. MSU crystals reduced tenocyte viability in a dose-dependent manner. MSU crystals decreased the mRNA expression of tendon collagens, matrix proteins and degradative enzymes and reduced collagen protein deposition by tenocytes. <h3>Conclusions</h3> These data indicate that MSU crystals directly interact with tenocytes to reduce cell viability and function. These interactions may contribute to tendon damage in people with advanced gout.
Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurised metered dose inhaler, as a dry powder, and as a nebulised solution.
Authors: B M Zainudin, M Biddiscombe, S E Tolfree, M Short, S G Spiro
Journal: Thorax (1990)

The lung dose and deposition patterns of drug delivered by dry powder inhaler are not known. The effects of inhaling 400 micrograms salbutamol delivered by dry powder inhaler (two 200 micrograms salbutamol Rotacaps), by pressurised metered dose inhaler, and by Acorn nebuliser were studied in nine subjects with chronic stable asthma. Technetium-99m labelled Teflon particles were mixed with micronised salbutamol in the pressurised metered dose inhaler and in the capsules; technetium-99m labelled human serum albumin was mixed with the salbutamol solution for the nebuliser study. The pressurised metered dose inhaler deposited 11.2% (SEM 0.8%) of the dose within the lungs; this was significantly more than the dose deposited by the dry powder inhaler (9.1% (0.6%], but did not differ significantly from the dose delivered by the nebuliser (9.9% (0.7%]. Distribution within the peripheral third of the lung was significantly greater with the nebuliser than with the other two systems; FEV1 improved to a significantly greater extent after inhalation of 400 micrograms salbutamol from the pressurised metered dose inhaler (35.6% from baseline) than from the nebuliser (25.8%) or dry powder inhaler (25.2%). Thus after inhalation of similar doses of salbutamol a larger proportion of drug was deposited within the lungs when it was inhaled from a metered dose inhaler than from a dry powder system; the nebuliser achieved the greatest peripheral deposition. The bronchodilator response seems to depend on the amount of drug within the lungs rather than its pattern of distribution.
Level of radiographic damage and radiographic progression are determinants of physical function: a longitudinal analysis of the TEMPO trial
Authors: D van der Heijde, R Landewe, R van Vollenhoven, S Fatenejad, L Klareskog
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background:</h3> Many studies have examined the relationship between long-term radiographic damage and physical function. However, it is not known if short-term radiographic progression is also associated with physical function. <h3>Aim:</h3> To investigate the longitudinal relationship between physical function and both the level of radiographic damage and the radiographic progression rate in patients with early or advanced active rheumatoid arthritis. <h3>Methods:</h3> The database for the 2-year Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) was used for this study. Physical function was measured by the Health Assessment Questionnaire (HAQ) score at baseline, 6 months and 1 and 2 years. Radiographs of the hands and feet, taken at the same time points, were scored by the van der Heijde-modified Total Sharp Score (TSS). The HAQ score was modelled using generalised mixed linear modelling by TSS or progression in TSS (interval 0–1 year and 1–2 years) adjusted for age, sex, treatment and disease activity. <h3>Results:</h3> After adjustment for age, sex and disease activity, both TSS and the change in TSS (progression rate) were significant determinants of the HAQ score. When radiographic progression was divided into four categories (negative, zero, minor and greater progression), results showed that HAQ scores tended to be higher with a higher rate of progression. Patients with negative progression scores had lower HAQ scores than patients with positive progression scores. <h3>Conclusions:</h3> Patients with greater radiographic damage, and those with recent radiographic progression, have a higher degree of disability.
Deficient Cerebellar Long-Term Depression, Impaired Eyeblink Conditioning, and Normal Motor Coordination in GFAP Mutant Mice
Authors: Katsuei Shibuki, Hiroshi Gomi, Lu Chen, Shaowen Bao, Jeansok J Kim, Hidemitsu Wakatsuki, Toshiyuki Fujisaki, Kazushi Fujimoto, Akira Katoh, Toshio Ikeda, Chong Chen, Richard F Thompson, Shigeyoshi Itohara
Journal: Neuron (1996)