tbuckley/cabot-search huggingface dataset:
Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the Danish nationwide DANBIO registry
Authors: Bente Glintborg, Mikkel Østergaard, Niels Steen Krogh, Lene Dreyer, Hanne Lene Kristensen, Merete Lund Hetland
Journal: Annals of the Rheumatic Diseases (2010)

To use prospectively registered data from the Danish nationwide rheumatological database (DANBIO) to describe disease activity, clinical response, treatment duration and predictors of drug survival (ie, number of days individual patients maintained treatment) and clinical response among patients with ankylosing spondylitis (AS) receiving their first treatment series with a tumour necrosis factor α (TNFα) inhibitor.842 TNFα inhibitor naive patients with AS were identified in DANBIO. Clinical response, drug survival and predictors thereof were investigated. 'Clinical response' was defined as a 50% or 20 mm reduction in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) within 6 months compared with baseline. Achievement of a BASDAI <40 mm within 6 months was used as a second response parameter.603 patients (72%) were men, disease duration 5 (1-13) years (median (IQR), age 41 (32-50) years. 445 (53%) received infliximab, 247 (29%) adalimumab and 150 (18%) etanercept. Parameters at baseline/1-year follow-up were: C-reactive protein (CRP): 14 (7-27)/5 (2-10) mg/l, BASDAI 59 (44-72)/21 (8-39) mm, Bath Ankylosing Spondylitis Functional Index (BASFI) 50 (34-67)/24 (9-45) mm, Bath Ankylosing Spondylitis Metrology Index 40 (20-50)/20 (10-40) mm. Within 6 months, 407/644 patients (63%) achieved a clinical response. Median drug survival was 4.3 years. One- and 2-year survival rates were 74% and 63%, respectively. Baseline characteristics associated with longer drug survival were male gender, CRP >14 mg/l and low visual analogue scale fatigue (Cox regression analysis). Age, TNFα inhibitor and methotrexate use were insignificant. CRP >14 mg/l, lower BASFI and younger age at baseline was associated with clinical response and achievement of a BASDAI <40 mm (logistic regression analysis).TNFα inhibitors provide a rapid and sustained decrease of disease activity among patients with AS in clinical practice. Factors associated with continued treatment, clinical response and achievement of a BASDAI <40 mm were identified.
Mortality Differences Between Men and Women Following First Myocardial Infarction
Authors: J Marrugat, J Sala, R Masiá, M Pavesi, G Sanz, V Valle, L Molina, L Serés, R Elosua
Journal: JAMA (1998)

Context.—Mortality after acute myocardial infarction is worse in women than in men, even after adjustment for comorbidity and age dissimilarities between sexes.Objective.—To assess the influence of sex on survival after acute myocardial infarction.Design.—Inception cohort obtained in a prospective registry of patients with acute myocardial infarction from 1992 through 1994.Setting.—Four teaching hospitals in northeastern Spain.Patients.—All consecutive patients aged 80 years or younger with first acute myocardial infarction. A total of 331 women and 1129 men were included.Main Outcome Measure.—Survival at 28 days and mortality or readmission at 6 months.Results.—Women were older (mean, 68.6 vs 60.1 years), presented more often with diabetes (52.9% vs 23.3%), hypertension (63.9% vs 42.3%), or previous angina (44.6% vs 37.4%), and developed more severe myocardial infarctions than men (acute pulmonary edema or cardiogenic shock occurred in 24.8% of women and 10.5% of men) (all P<.02). Men were more likely than women to receive thrombolytic therapy (41.3% vs 23.9%; P<.001), but rates of percutaneous transluminal angioplasty and coronary artery bypass graft surgery at 28 days were similar among men and women. The 28-day mortality rate was significantly higher among women (18.5% for women, 8.3% for men; P<.001). Revascularization procedures at 6 months were performed in a similar proportion of women and men. However, women had higher 6-month mortality rates (25.8% in women, 10.8% in men; P<.001) and readmission rates (23.3% for women, 12.2% for men; P<.001). After adjustment, women had greater risk of death than men at 28 days (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.12-2.65) and at 6 months (OR, 1.73; 95% CI, 1.18-2.52).Conclusions.—In this study population, women experienced more lethal and severe first acute myocardial infarction than men, regardless of comorbidity, age, or previous angina.
Aerosolized Surfactant Improves Pulmonary Function in Endotoxin-induced Lung Injury
Authors: CHARLES LUTZ, DAVID CARNEY, CHRISTINE FINCK, ANTHONY PICONE, LOUIS A. GATTO, ANDREW PASKANIK, EDWARD LANGENBACK, GARY NIEMAN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Surfactant dysfunction is a primary pathophysiologic component in patients with adult respiratory distress syndrome (ARDS). In this study we tested the efficacy of aerosolized surfactant (Sf ) replacement in a severe lung injury model of endotoxin-induced ARDS. Twenty-one certified healthy pigs were anesthetized, surgically prepared for measurement of hemodynamic and lung function, then randomized into one of four groups: (1) control (n = 5), surgical instrumentation only; (2) lipopolysaccharide (LPS) (n = 6), infused with Escherichia coli LPS (100 μ g/kg) without positive end- expiratory pressure (PEEP) and ventilated with a nonhumidified gas mixture of 50% N2O and 50% O2; (3) LPS + PEEP (n = 4), infused with LPS, placed on PEEP (7.5 cm H2O), and ventilated with a humidified gas mixture; and (4) LPS + PEEP + Sf (n = 6), infused with LPS, placed on PEEP, and ventilated with aerosolized Sf (Infasurf, ONY, Inc.). All animals were studied for 6 h. Arterial Po 2 significantly decreased in both the LPS and LPS + PEEP groups (LPS + PEEP = 74 ± 19 mm Hg; LPS = 74 ± 19 mm Hg, p < 0.05) while venous admixture (Q˙ s/Q˙ t) increased in these groups (LPS + PEEP = 43.3 ± 3.9%; LPS = 47.7 ± 11%, p < 0.05) as compared with the control group. PEEP + Sf reduced the fall in Po 2 (142 ± 20 mm Hg) and rise in Q˙ s/Q˙ t (15.1 ± 3.6%) caused by LPS. Delayed induction of PEEP (2 h following LPS) did not significantly improve any parameter over the LPS group without PEEP in this ARDS model. LPS without PEEP (3.4 ± 0.2 cells/6,400 μ m2) caused a marked increase in the total number of sequestered leukocytes in the pulmonary parenchyma as compared with the control group (1.3 ± 0.1 cells/6,400 μ m2). LPS + PEEP + Sf (2.3 ± 0.2 cells/6,400 μ m2) significantly decreased while LPS + PEEP significantly increased (4.0 ± 0.2 cells/6,400 μ m2) the total number of sequestered leukocytes as compared with the LPS without PEEP group. In summary, aerosolized surfactant replacement decreased leukocyte sequestration and improved oxygenation in our porcine model of endotoxin-induced lung injury.
Metabolic Dysfunction Consistent With Premature Aging Results From Deletion of Pim Kinases
Authors: Shabana Din, Mathias H. Konstandin, Bevan Johnson, Jacqueline Emathinger, Mirko Völkers, Haruhiro Toko, Brett Collins, Lucy Ormachea, Kaitlen Samse, Dieter A. Kubli, Andrea De La Torre, Andrew S. Kraft, Asa B. Gustafsson, Daniel P. Kelly, Mark A. Sussman
Journal: Circulation Research (2014)

The senescent cardiac phenotype is accompanied by changes in mitochondrial function and biogenesis causing impairment in energy provision. The relationship between myocardial senescence and Pim kinases deserves attention because Pim-1 kinase is cardioprotective, in part, by preservation of mitochondrial integrity. Study of the pathological effects resulting from genetic deletion of all Pim kinase family members could provide important insight about cardiac mitochondrial biology and the aging phenotype.To demonstrate that myocardial senescence is promoted by loss of Pim leading to premature aging and aberrant mitochondrial function.Cardiac myocyte senescence was evident at 3 months in Pim triple knockout mice, where all 3 isoforms of Pim kinase family members are genetically deleted. Cellular hypertrophic remodeling and fetal gene program activation were followed by heart failure at 6 months in Pim triple knockout mice. Metabolic dysfunction is an underlying cause of cardiac senescence and instigates a decline in cardiac function. Altered mitochondrial morphology is evident consequential to Pim deletion together with decreased ATP levels and increased phosphorylated AMP-activated protein kinase, exposing an energy deficiency in Pim triple knockout mice. Expression of the genes encoding master regulators of mitochondrial biogenesis, PPARγ (peroxisome proliferator-activated receptor gamma) coactivator-1 α and β, was diminished in Pim triple knockout hearts, as were downstream targets included in mitochondrial energy transduction, including fatty acid oxidation. Reversal of the dysregulated metabolic phenotype was observed by overexpressing c-Myc (Myc proto-oncogene protein), a downstream target of Pim kinases.Pim kinases prevent premature cardiac aging and maintain a healthy pool of functional mitochondria leading to efficient cellular energetics.
Sensitization for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by the Chemopreventive Agent Resveratrol
Authors: Simone Fulda, Klaus-Michael Debatin
Journal: Cancer Research (2004)

Abstract Survivin is a member of the inhibitor of apoptosis proteins that is expressed at high levels in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Naturally occurring dietary compounds such as resveratrol have gained considerable attention as cancer chemopreventive agents. Here, we discovered a novel function of the chemopreventive agent resveratrol: resveratrol is a potent sensitizer of tumor cells for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through p53-independent induction of p21 and p21-mediated cell cycle arrest associated with survivin depletion. Concomitant analysis of cell cycle, survivin expression, and apoptosis revealed that resveratrol-induced G1 arrest was associated with down-regulation of survivin expression and sensitization for TRAIL-induced apoptosis. Accordingly, G1 arrest using the cell cycle inhibitor mimosine or induced by p21 overexpression reduced survivin expression and sensitized cells for TRAIL treatment. Likewise, resveratrol-mediated cell cycle arrest followed by survivin depletion and sensitization for TRAIL was impaired in p21- deficient cells. Also, down-regulation of survivin using survivin antisense oligonucleotides sensitized cells for TRAIL-induced apoptosis. Importantly, resveratrol sensitized various tumor cell lines, but not normal human fibroblasts, for apoptosis induced by death receptor ligation or anticancer drugs. Thus, this combined sensitizer (resveratrol)/inducer (e.g., TRAIL) strategy may be a novel approach to enhance the efficacy of TRAIL-based therapies in a variety of human cancers.
Transfection of airway epithelium by stable PEGylated poly-l-lysine DNA nanoparticles in vivo
Authors: Assem-Galal Ziady, Christopher R Gedeon, Timothy Miller, William Quan, Jennifer M Payne, Susannah L Hyatt, Tamara L Fink, Osman Muhammad, Sharon Oette, Tomasz Kowalczyk, Murali K Pasumarthy, Robert C Moen, Mark J Cooper, Pamela B Davis
Journal: Molecular Therapy (2003)

DNA can be compacted using polyethylene glycol-substituted poly-l-lysine into discrete unimolecular (with respect to DNA) nanoparticles with minor diameter <20 nm that are stable in normal saline for at least 23 months at 4°C. We compared the activity of firefly luciferase in lungs of C57BL/6 mice that received 100 μg compacted plasmid in 25 μl saline (shown to be the optimal dose) via intratracheal or intranasal instillation with levels in animals given 100 μg naked plasmid or in untreated mice. Mice dosed with compacted DNA nanoparticles had peak activity of luciferase in lung at 2 days postinstillation, which declined in log-linear fashion with a half-life of 1.4 days. Luciferase activity in animals dosed with naked DNA was 200-fold less. Addition of polyethylene glycol to the complex was necessary for efficient gene transfer and animals that received DNA compacted with unmodified poly-l-lysine did not exhibit luciferase activity above background. Immunohistochemical staining for bacterial β-galactosidase 2 days after administration of a compacted lacZ expression plasmid (n = 8) revealed expression predominantly in the dependent portions of the right lungs of mice, in alveolar and airway epithelial cells, though macrophages and sometimes endothelial cells also were transfected. No staining for β-galactosidase was observed in uninjected animals (n = 4) or those dosed with naked lacZ plasmid (n = 7). Tissue survey for transgene expression shows expression only in lung and trachea following intranasal administration. Stable compacted DNA nanoparticles transfer exogenous genes to airway epithelium and show promise for lung gene therapy.
Metabolism in patients with small cell lung carcinoma compared with patients with non-small cell lung carcinoma and healthy controls
Authors: A. J. Staal-van den Brekel, A. M. Schols, M. A. Dentener, G. P. ten Velde, W. A. Buurman, E. F. Wouters
Journal: Thorax (1997)

BACKGROUND: Weight loss is a frequently occurring problem in patients with lung cancer due to an increased resting energy expenditure (REE) and a decreased energy intake. The aim of the present study was to compare the metabolic and inflammatory characteristics of patients with small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). The metabolic parameters of the lung cancer population were compared with those of a healthy control group. METHODS: REE was measured in 66 patients with lung cancer, subdivided according to their histology, and in 33 healthy controls matched for sex, age, and fat free mass (FFM). Inflammatory mediators were measured in the plasma of the patients with lung cancer. RESULTS: An increased REE adjusted for FFM was found in the patients with lung cancer. Those with small cell lung carcinoma (SCLC) had an increased REE adjusted for FFM (mean 1925 kcal/day) compared with those with non-small cell lung carcinoma (NSCLC) (mean 1789 kcal/day, 95% CI for difference 36 to 236). FFM accounted for 69% and 48% of the inter-individual variation in REE in controls and those with NSCLC, respectively, while FFM accounted for only 25% of the variation in REE in patients with SCLC in whom the fat mass (FM) also contributed significantly (28%) to the variation in REE. Increased concentrations of soluble TNF-receptor 75 (sTNF-R75) and cortisol were found in patients with SCLC compared with those with NSCLC. Lipopolyasccharide binding protein (LBP) and sTNF-R55 were related to plasma levels of cortisol. CONCLUSION: An enhanced REE adjusted for FFM occurred in patients with SCLC compared with those with NSCLC.
In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients.
Authors: M S Hershfield, N M Kredich, D R Ownby, H Ownby, R Buckley
Journal: Journal of Clinical Investigation (1979)

The cytotoxic nucleoside 2'-deoxyadenosine is excreted in excessive amounts by individuals with genetic deficiency of adenosine deaminase, and may be in part responsible for the severe combined immune dysfunction from which they suffer. Earlier studies from this laboratory showed that 2'-deoxyadenosine causes the irreversible inactivation of the enzyme S-adenosylhomocysteine hydrolase by an active site-directed, "suicide-like" process. In this communication we have demonstrated similar inactivation of S-adenosylhomocysteine hydrolase in hemolysate and in intact erythrocytes, as well as a striking deficiency of S-adenosylhomocysteine hydrolase activity in the erythrocytes of three adenosine deaminase-deficient patients. In vivo suicide-like inactivation of S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine may contribute to the cytotoxicity of 2'-deoxyadenosine and to the immune dysfunction in adenosine deaminase deficiency.
High BCL6 expression predicts better prognosis, independent of BCL6 translocation status, translocation partner, or BCL6-deregulating mutations, in gastric lymphoma
Authors: Yun-Wen Chen, Xiao-Tong Hu, Anthony C. Liang, Wing-Yan Au, Chi-Chiu So, Michelle L. Wong, Lijun Shen, Qian Tao, Kent-Man Chu, Yok-Lam Kwong, Raymond H. Liang, Gopesh Srivastava
Journal: Blood (2006)
The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (<i>TRADD</i>)
Authors: Jennifer J Pointon, David Harvey, Tugce Karaderi, Louise H Appleton, Claire Farrar, Millicent A Stone, Roger D Sturrock, John D Reveille, Michael H Weisman, Michael M Ward, Matthew A Brown, B Paul Wordsworth
Journal: Annals of the Rheumatic Diseases (2009)

Objective To replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. Methods Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. Results The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. Conclusions The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain ( TRADD ), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.
Influence of gender on survival in patients with stage I malignant melanoma
Authors: K A Vossaert, M K Silverman, A W Kopf, R S Bart, D S Rigel, R J Friedman, M Levenstein
Journal: Journal of the American Academy of Dermatology (1992)

Women with stage I malignant melanoma (MM) have a survival advantage over men as judged by univariate analysis. However, on multivariate analysis, gender was found to be an independent predictor of survival in only 8 of 14 published studies.This study attempts to explain the disparate findings for gender as a prognostic factor in different multivariate analyses.Univariate and multivariate analyses were performed on 832 patients with stage I MM in the New York University Melanoma Cooperative Group (NYU-MCG) data base. The results were compared with those of 14 similar studies.In the NYU-MCG data base, gender, age of the patient, and number of mitoses per square millimeter were not independent factors on multivariate analysis, whereas thickness, anatomic site, and presence of ulceration were. The statistically significant difference in survival by gender on univariate analysis, in the NYU-MCG data base, could be explained by the differences in thickness and anatomic site of the MMs in the sexes. Comparison of these results with the reviewed reports from the literature consistently shows thickness and ulceration to be independent prognosticators of survival. Likewise, most authors agree that age is not an independent predictor. However, there is no consensus with respect to gender and site, each of which was found to be an independent predictor of survival in only about half the studies reviewed.The disparate findings for gender in different multivariate analyses are explained by a gender-related difference in anatomic distribution of MM. Gender and site appear to have a similar influence in multivariate analysis and thus either one or the other is a dominant factor in different multivariate analyses.
Effect of Glucagon-Like Peptide 1 on Non–Insulin-Mediated Glucose Uptake in the Elderly Patient With Diabetes
Authors: Graydon S. Meneilly, Christopher H.S. McIntosh, Raymond A. Pederson, Joel F. Habener, Ronald Gingerich, Josephine M. Egan, Diane T. Finegood, Dariush Elahi
Journal: Diabetes Care (2001)

An important cause of elevated glucose levels in elderly patients with diabetes is an alteration in non–insulin-mediated glucose uptake (NIMGU). Glucagon-like peptide 1 (GLP-1) is an intestinal insulinotropic hormone. It has been proposed that this hormone also lowers glucose levels by enhancing NIMGU. This study was conducted to determine whether GLP-1 augments NIMGU in elderly patients with diabetes, a group in which NIMGU is known to be impaired. Studies were conducted on 10 elderly patients with type 2 diabetes (aged 75 ± 2 years, BMI 27 ± 1 kg/m2) who underwent paired 240-min glucose clamp studies. In each study, octreotide was infused to suppress endogenous insulin release, and tritiated glucose methodology was used to measure glucose production and disposal rates. For the first 180 min, no glucose was infused. From 180 to 240 min, glucose was increased to 11 mmol/l using the glucose clamp protocol. In the GLP-1 study, GLP-1 was infused from 30 to 240 min. In a subsequent control study, insulin was infused using the glucose clamp protocol from 30 to 240 min to match the insulin levels that occurred during the GLP-1 infusion study. During hyperglycemia, GLP-1 enhanced glucose disposal (control study: 2.52 ± 0.19 mg · kg–1 · min–1; GLP-1 study: 2.90 ± 0.17 mg · kg–1 · min–1; P &amp;lt; 0.0001). Hepatic glucose output was not different between studies. We conclude that GLP-1 may partially reverse the defect in NIMGU that occurs in elderly patients with diabetes.
International Differences in Drug Prices
Authors: Judith L. Wagner, Elizabeth McCarthy
Journal: Annual Review of Public Health (2004)

This paper addresses how and why drug prices differ across countries. Studies of international variation in drug prices reach varied conclusions owing to methodological and data disparities. Price differences do exist across countries, with the United States footing the highest bill, but the differences are not nearly as large as they appear at first glance. The higher prices in the United States are concentrated among a subset of brand-name drugs and among those without insurance covering drugs. Some U.S. health plans obtain price concessions from manufacturers similar to those obtained by national governments. Price concessions occur whenever purchasers are willing to let price be a consideration in decisions about access and utilization. In low-income countries the vast majority are unwilling to pay for effective drugs simply because they are unable to pay. Low-income nations need more price discrimination--and vastly lower prices--if they are ever to afford the world's most effective medicines.