tbuckley/cabot-search huggingface dataset:
A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs
Authors: L Klareskog, M Gaubitz, V Rodriguez-Valverde, M Malaise, M Dougados, J Wajdula
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. <b>Methods:</b> 549 patients entered this 5-year, open-label extension study and received etanercept 25 mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs before entry into the double-blind studies. Safety assessments were carried out at regular intervals. Primary efficacy end points were the numbers of painful and swollen joints; secondary variables included American College of Rheumatology (ACR) response rate, Disease Activity Score and acute-phase reactants. Efficacy was analysed using the last-observation-carried-forward approach. <b>Results:</b> Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%) completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis. A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the open-label trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively. Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site reactions. Rates of serious infections and malignancies remained unchanged over the course of the study; there were no reports of patients with central demyelinating disease or serious blood dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%, respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from 5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the 3-year time period. <b>Conclusion:</b> After 3 years of treatment, etanercept showed sustained efficacy and a favourable safety profile.
The burden of TB–HIV in the EU: how much do we know? A survey of surveillance practices and results
Authors: M.E. Kruijshaar, L. Pimpin, I. Abubakar, B. Rice, V. Delpech, L.N. Drumright, V. Hollo, E. Huitric, M. van de Laar, A. Amato-Gauci, D. Manissero, C. Ködmön
Journal: European Respiratory Journal (2011)

Information on the burden of tuberculosis (TB)–HIV co-infection is critical for the planning and evaluation of TB–HIV control and treatment strategies. This study assessed current practices in countries of the European Union (EU) and European Economic Area (EEA) for monitoring HIV co-infection in TB surveillance systems, countries’ current co-infection burden and associated clinical practice. An online survey was distributed to all national TB surveillance nominated European Centre for Disease Prevention and Control contact points in the EU/EEA. We received 25 responses from 30 countries (83% response rate). Patients’ HIV status was collected in 18 out of the 25 TB surveillance systems, usually via clinician reporting (16 out of 18 surveillance systems). Although most countries recommended routine testing of TB patients for HIV, the proportion actually tested varied from 5% to 90%. The burden of HIV co-infection was found to be elevated in countries with higher levels of HIV testing and higher prevalence of HIV. We suggest that TB–HIV co-infection be monitored in all EU/EEA countries to facilitate the planning and evaluation of TB–HIV control strategies. Strengthening collaboration between TB and HIV clinicians and surveillance departments, and consideration of patient confidentiality restraints would be advantageous. The level of HIV testing in TB patients is low despite national recommendations and testing should be further promoted and monitored.
Altered contractile function in heart failure
Authors: P de Tombe
Journal: Cardiovascular Research (1998)

The syndrome of congestive heart failure (CHF) is an entity of ever increasing clinical significance. CHF is characterized by a steady decrease in cardiac pump function which is eventually lethal. The mechanisms that underlie the decline in cardiac function are incompletely understood. End-stage CHF often involves the general loss of functional myocytes, a hyperplasia of the extracellular matrix, ventricular chamber remodeling, and decreased myocyte function. This review article focuses on the latter aspect of CHF, mechanisms of decreased myocyte function. Recent data from studies on human myocardial tissue obtained in the setting of cardiac transplantation or from studies that employed experimental animal models of CHF have suggested depressed myocyte function. The mechanisms that may be involved in the decline of myocyte contractile function include alterations in (i) calcium handling, (ii) myofilament function, and (iii) the cytoskeleton. At present, however, it is not known how or to what degree these alterations in cellular processes contribute to the decline of in vivo cardiac pump function in CHF. Accurate knowledge regarding the cellular processes that participate in the development of CHF is critical to the development of innovative strategies aimed to combat CHF.
Functional and binding characteristics of long-acting beta 2-agonists in lung and heart.
Authors: F J Roux, B Grandordy, J S Douglas
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Salmeterol and formoterol, two new long-acting beta 2-agonists were equipotent (values of negative log molar concentration eliciting half-maximal effect [pD2] 9.2 +/- 0.03 and 8.9 +/- 0.03, respectively) in relaxing maximally contracted guinea pig tracheal spirals (histamine, 100 microM). Both agonists were 10 times more potent than L-isoproterenol and fenoterol and 100 times more potent than albuterol. L-Isoproterenol and fenoterol induced > 90% relaxation (percentage of maximal aminophylline relaxation). Formoterol and albuterol were equally efficacious. Formoterol was more efficacious (86 +/- 5%) than salmeterol (62 +/- 3%) or soterenol (59 +/- 3%). In minimally contracted tissues (10 microM histamine), agonist potencies increased 10-fold and relaxation was complete. In [125I]iodocyanopindolol-labeled bronchial membranes, formoterol and salmeterol induced high-affinity states of the beta 2-receptor (pKh 9.6 +/- 0.4 and 10.4 +/- 0.7, respectively), the former inducing a higher percentage (57 +/- 6 versus 28 +/- 4, p < 0.05). Only low-affinity binding (pKI) was observed when guanine nucleotide was present. pD2 values were similar to pKh values and relative efficacies significantly correlated with percentage of pKI sites. Formoterol and salmeterol were highly selective for the beta 2 versus beta 1-subtype (pKI values were 8.2 +/- 0.09 and 6.25 +/- 0.06 and 8.3 +/- 0.04 and 5.7 +/- 0.04, respectively). Albuterol (5.83 +/- 0.06 and 4.71 +/- 0.16) and fenoterol (6.33 +/- 0.07 and 5.67 +/- 0.05) were less selective. These results can explain the potencies and efficacies of salmeterol and formoterol in humans.
Effect of a timed interval between inhalation of beta-agonist and corticosteroid aerosols on the control of chronic asthma.
Authors: M Muers, K Dawkins
Journal: Thorax (1983)

A randomised double-blind crossover study was undertaken in 25 patients with variable airflow obstruction to assess the benefit of separating the inhalation of beta-agonist aerosols and corticosteroid aerosols by a timed interval of more than five minutes. Twenty-two patients (11 men and 11 women) completed 12 weeks of study; they inhaled 200 micrograms salbutamol followed either immediately or after a timed interval by 100 micrograms beclomethasone dipropionate two to four times daily. Morning and evening peak expiratory flow rates, symptom scores, additional beta-agonist inhaler usage, and subjective responses on a visual-analogue scale were recorded throughout. Results from the two last four-week periods, with and without the interval between drugs, were analysed. No differences were found. It is concluded that the theoretical benefit of delaying corticosteroid inhalation until optimum bronchodilatation has been achieved with a beta-agonist is not demonstrable in outpatient practice.
αB-Crystallin Modulates Protein Aggregation of Abnormal Desmin
Authors: Xuejun Wang, Raisa Klevitsky, Wei Huang, Joseph Glasford, Faqian Li, Jeffrey Robbins
Journal: Circulation Research (2003)

αB-crystallin (CryAB) is the most abundant small heat shock protein in the heart. Upregulation of CryAB in desmin-related myopathy and its downregulation in end-stage congestive heart failure have both been reported. We previously demonstrated via cardiac-specific transgenesis that modest increases in normal CryAB are not detrimental to the heart, whereas expression of the R120G mutation of CryAB caused a desminopathy. It is generally believed that CryAB plays an important role in protecting the intermediate filaments, but the underlying mechanism is unclear. We hypothesized that CryAB protects the desmin filaments via preventing abnormal desmin protein from aggregating adversely. To test this hypothesis in vivo, mice expressing a desmin mutation that causes a desmin-related cardiomyopathy (D7) were bred into the R120G-CryAB transgenic (TG) background to examine the accumulation and aberrant aggregation of desmin protein. Despite lower mRNA expression of D7-des than in the D7-des TG hearts, the double-TG myocardium exhibited significantly higher desmin protein levels and dramatically more aberrant desmin aggregates than the D7-des TG hearts. The double-TG mice displayed a significantly stronger cardiac hypertrophic response, with the mice dying of congestive heart failure before 7 weeks. To explore the ability of wild-type (WT) CryAB to protect against mutant desmin, a desmin mutant was expressed in both the conventional and WT-CryAB stably transfected HEK cells. Significantly less aberrant desmin aggregation was observed in the WT-CryAB–overexpressing cells than in the HEK cells. The results suggest that CryAB modulates abnormal desmin aggregation and can serve a cardioprotective role.
Overweight and Obese Humans Demonstrate Increased Vascular Endothelial NAD(P)H Oxidase-p47 <sup>phox</sup> Expression and Evidence of Endothelial Oxidative Stress
Authors: Annemarie E. Silver, Stacy D. Beske, Demetra D. Christou, Anthony J. Donato, Kerrie L. Moreau, Iratxe Eskurza, Phillip E. Gates, Douglas R. Seals
Journal: Circulation (2007)

Obesity may alter vascular endothelial cell protein expression (VECPE) of molecules that influence susceptibility to atherosclerosis.Quantitative immunofluorescence was performed on vascular endothelial cells collected from 108 men and women free of clinical disease who varied widely in adiposity (body mass index 18.4 to 36.7 kg/m2; total body fat 5.8 to 55.0 kg; waist circumference: 63.0 to 122.9 cm). All 3 expressions of adiposity were positively associated with VECPE of the oxidant enzyme subunit NAD(P)H oxidase-p47(phox) (part correlation coefficient [r(part)] 0.22 to 0.24, all P < 0.05) and the antioxidant enzyme catalase (r(part) = 0.71 to 0.75, all P < 0.001). Total body fat was positively associated with VECPE of nitrotyrosine (r(part) = 0.36, P = 0.003), a marker of protein oxidation, and, in men, with Ser1177-phosphorylated endothelial nitric oxide synthase (r(part) = 0.46, P = 0.02), an activated form of endothelial nitric oxide synthase. Overweight/obese subjects (body mass index > or = 25 kg/m2) had 35% to 130% higher VECPE of NAD(P)H oxidase-p47(phox), nitrotyrosine, catalase, and the cytosolic antioxidant CuZn superoxide dismutase (all P < 0.05), as well as a 56% greater VECPE of the potent local vasoconstrictor endothelin-1 (P = 0.05) than normal-weight subjects (body mass index < 25 kg/m2). Nuclear factor-kappaB protein expression was approximately 60% to 100% greater in the most obese adults than in the leanest adults (P < or = 0.01). These relations were independent of sex but were selectively reduced after accounting for the influence of plasma C-reactive protein, fasting glucose-insulin metabolism, or serum triglycerides.Compared with their normal-weight peers, overweight and obese adults demonstrate increased vascular endothelial expression of NAD(P)H oxidase-p47(phox) and evidence of endothelial oxidative stress, with selective compensatory upregulation of antioxidant enzymes and Ser1177-phosphorylated endothelial nitric oxide synthase. Endothelin-1 and nuclear factor-kappaB protein expression also appear to be elevated in obese compared with lean adults. These findings may provide novel insight into the molecular mechanisms linking obesity to increased risk of clinical atherosclerotic diseases in humans.
Five-year analysis from the ESPRIT 10-year postmarketing surveillance registry of adalimumab treatment for moderate to severe psoriasis
Authors: Alan Menter, Diamant Thaçi, Kim A. Papp, Jashin J. Wu, Mareike Bereswill, Henrique D. Teixeira, Simone Rubant, David A. Williams
Journal: Journal of the American Academy of Dermatology (2015)

ESPRIT is an ongoing, 10-year, observational registry, evaluating long-term safety and effectiveness of adalimumab treatment in routine clinical practice for patients with moderate to severe, chronic plaque psoriasis.Initial 5-year results are reported.Two populations were analyzed: the "all-treated" population received 1 or more adalimumab doses in registry, continuing adalimumab treatment from a current prescription or previous study participation, and included the "new-prescription" population initiating adalimumab 4 weeks or earlier preregistry entry.Data were collected from September 26, 2008, through November 30, 2013, for all-treated (n = 6059), which included new-prescription (n = 2580, 42.6%); median registry exposure was 765 and 677 days, respectively. In all-treated, rate (events per 100 patient-years of total adalimumab exposure [E/100PY]) of serious treatment-emergent adverse events (inside or outside of the registry) was 4.3 E/100PY, serious infection 1.0 E/100PY, malignancies 0.9 E/100PY (nonmelanoma skin cancers 0.6 E/100PY; melanomas <0.1 E/100PY). Standardized mortality ratio was 0.30 (95% confidence interval 0.19-0.44). Physician Global Assessment clear or minimal (effectiveness parameter) was achieved by 57.0% at 12 months and 64.7% at 60 months of treatment.Observational data are subject to outcome-reporting bias.No new safety signals were observed with adalimumab treatment during this initial 5-year registry review. Observed number of deaths was below expected. As-observed effectiveness remained stable through 60 months.
Efficacy and Tolerability Of Privigen® In Clinical Practice
Authors: Morna J. Dorsey, Viet Ho, Mohsen I. Mabudian, Pere Soler-Palacín, Nerea Domínguez-Pinilla, Robert W. Hellmers, Radha Gandhi Rishi, Rahul Rishi, Duane W. Wong, Mikhail Rojavin, Alphonse Hubsch, Melvin Berger
Journal: Journal of Allergy and Clinical Immunology (2014)

This retrospective chart review evaluated the efficacy and tolerability of Privigen® in patients with primary (PID) or secondary immunodeficiencies in clinical practice. Patients who had received Privigen® for ≥3 months in six clinical practices in Europe and the US were treated with individually determined regimens. Efficacy, serum IgG levels, and safety endpoints were assessed. Seventy-two patients (52.8% male, median age 30.5 years [range: 0.1‒90.0 years]) were included. Sixty patients (83.3%) had PID, 12 (16.7%) had immunodeficiency secondary to cancer. Three infants with severe combined immunodeficiency were analyzed separately due to continuous hospitalization and/or exceptionally high Privigen® doses (≥2700 mg/kg/month). In the remaining 69 patients, with a mean (±SD) Privigen® dose of 520±182 mg/kg/month, median trough serum IgG level was 954 mg/dL (range: 407–1581 mg/dL). Only 2 patients (2.9%) had documented IgG levels <500 mg/dL. Nine patients (13.0%) experienced 10 serious bacterial infections over a mean of 22.3±15.3 months of treatment (0.080 events/patient/year), the most common being pneumonia (n=7; 10.1%). The rates for any infections and hospitalization were 1.072 events/patient/year and 3.68 days/patient/year, respectively. However, two patients accounted for 303 hospital days. Thirteen patients (18.8%) experienced adverse events (AEs); 10 (14.5%) had AEs at least possibly related to study medication. The most common related AEs were headache after infusion (n=6; 8.7%), fever, and chills (n=2; 2.9% each), which are characteristic of IVIG. No related serious AEs were reported. Despite a more heterogeneous population, efficacy and tolerability of Privigen® in clinical practice were similar to those in clinical trials.
Steroid Receptor Family: Structure and Functions
Authors: MARY ANNE CARSON-JURICA, WILLIAM T. SCHRADER, BERT W. O'MALLEY
Journal: Endocrine Reviews (1990)

IT HAS been known for several years that steroid hormones function through the action of specific receptor proteins. In target tissues, receptors are activated by hormonal ligands and thereafter modulate the expression of a network of specific target genes (1–5). Receptors for the steroids, glucocorticoid, androgen, estrogen, progesterone, and mineralocorticoid, and the sterol, 1,25-dihydroxyvitamin D3, have been identified and characterized by biochemical and molecular biological methods (6–10). Other nonsteroid, seemingly unrelated molecules such as T4 and retinoic acid have been found to have receptors that are structurally related to steroid receptor hormones (11–13) and appear to act through similar mechanisms as the steroid receptors. The mechanism by which receptors function from the time of the initial appearance of hormone, to resultant effects at the gene level, to the cessation of the hormone effect, must be complex. Although there may be a general pathway of receptor function, selective differences must exist in the pathway of action of different receptor molecules which produce the effects unique to their particular hormones. In this review, we will summarize recent information on the functional pathway whereby steroid hormones mediate their effects on cellular function and development. We will stress certain aspects of progesterone receptor action, notably PR synthesis, but will attempt to present a balanced view of the salient features of all receptors in the superfamily. The similarities and differences in the various receptors will be summarized, and for issues that remain unresolved, opposing theories will be presented.
Stem Cell–Related “Self-Renewal” Signature and High Epidermal Growth Factor Receptor Expression Associated With Resistance to Concomitant Chemoradiotherapy in Glioblastoma
Authors: Anastasia Murat, Eugenia Migliavacca, Thierry Gorlia, Wanyu L. Lambiv, Tal Shay, Marie-France Hamou, Nicolas de Tribolet, Luca Regli, Wolfgang Wick, Mathilde C.M. Kouwenhoven, Johannes A. Hainfellner, Frank L. Heppner, Pierre-Yves Dietrich, Yitzhak Zimmer, J. Gregory Cairncross, Robert-Charles Janzer, Eytan Domany, Mauro Delorenzi, Roger Stupp, Monika E. Hegi
Journal: Journal of Clinical Oncology (2008)

Purpose Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide. Patients and Methods Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. Results An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a “self-renewal” signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response. Conclusion This study provides first clinical evidence for the implication of a “glioma stem cell” or “self-renewal” phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.
Progression of osteoarthritis as a state of inertia
Authors: David Felson, Jingbo Niu, Burton Sack, Piran Aliabadi, Charles McCullough, Michael C Nevitt
Journal: Annals of the Rheumatic Diseases (2012)

Objectives To test whether knees which recently developed disease were at higher risk for subsequent x-ray progression than knees which had been stable, suggesting that recent change produces further change and recent stability yields subsequent stability (a pattern of inertia). Methods We used central readings of the annual posteroanterior x-rays obtained in the Osteoarthritis Initiative (OAI) focusing on change in Kellgren and Lawrence (KL) grade and change in semiquantitative joint space. We examined whether knees that had developed incident disease (KL grade 2) were at higher risk of subsequent progression than knees that were already grade 2 and had had stable disease. We combined data from multiple examinations. Using generalised estimating equations to adjust for the correlation between knees, we carried out logistic regression evaluating the risk for disease progression testing incident versus stable disease adjusting for age, sex, body mass index, physical activity, quadriceps strength and mechanical alignment. Results 1562 OAI subjects with grade 2 disease had a mean age of 61.8 years, mean BMI of 29.4, and 61.7% were women. Of knees with stable disease, 4.1% showed progression within the next 12 months in KL grade versus 13.7% in those with incident disease (adjusted OR 4.0; 95% CI 2.4 to 6.7). For progression of joint space loss, we found a similar relation with incident versus stable disease (adjusted OR 5.3; 95% CI 3.6 to 7.9). Conclusions Knee osteoarthritis radiographic progression follows a pattern of inertia. Factors that trigger the transition from stable disease to progression should be sought.