tbuckley/cabot-search huggingface dataset:
Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study
Authors: Paul W. Jones, Dave Singh, Eric D. Bateman, Alvar Agusti, Rosa Lamarca, Gonzalo de Miquel, Rosa Segarra, Cynthia Caracta, Esther Garcia Gil
Journal: European Respiratory Journal (2012)

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV 1 ) at week 24. Other end-points included peak FEV 1 , health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI). Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV 1 (99 and 128 mL; both p&lt;0.0001) and peak FEV 1 (185 and 209 mL; both p&lt;0.0001). Peak FEV 1 improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p&lt;0.001 and p&lt;0.0001) and TDI focal score (0.6 and 1.0 units; p&lt;0.05 and p&lt;0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo. Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.
Computed Tomography — An Increasing Source of Radiation Exposure
Authors: David J. Brenner, Eric J. Hall
Journal: New England Journal of Medicine (2007)

The number of computed tomographic (CT) studies performed is increasing rapidly. Because CT scans involve much higher doses of radiation than plain films, we are seeing a marked increase in radiation exposure in the general population. Epidemiologic studies indicate that the radiation dose from even two or three CT scans results in a detectable increase in the risk of cancer, especially in children. This article summarizes the facts about this form of radiation exposure and the implications for public health.
A NEUTROPHIL-IMMOBILIZING FACTOR DERIVED FROM HUMAN LEUKOCYTES
Authors: Edward J. Goetzi, K. Frank Austen
Journal: The Journal of Experimental Medicine (1972)

A factor has been derived from human leukocytes which irreversibly inhibits the response of human neutrophils to diverse chemotactic stimuli without impairing their viability. It is released by both polymorphonuclear and mononuclear leukocytes during incubation in acidic medium, after endotoxin exposure and subsequent incubation in low potassium medium, and during phagocytosis of particles. It is extractable from both leukocyte types and therefore must be preformed. This chemotactic inhibitor is completely separable from contaminating chemotactic activity in the crude supernatants, has a mol wt of 5000, and is inactivated by digestion with trypsin or chymotrypsin. It has been termed a neutrophil-immobilizing factor because it inhibits neutrophils directly and independently of the chemotactic stimulus, and has relatively little effect on human monocyte chemotaxis.
PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis
Authors: Sven Francque, An Verrijken, Sandrine Caron, Janne Prawitt, Réjane Paumelle, Bruno Derudas, Philippe Lefebvre, Marja-Riitta Taskinen, Wim Van Hul, Ilse Mertens, Guy Hubens, Eric Van Marck, Peter Michielsen, Luc Van Gaal, Bart Staels
Journal: Journal of Hepatology (2015)
The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients
Authors: Nicole M. Warrington, Tao Sun, Jingqin Luo, Robert C. McKinstry, Patricia C. Parkin, Sara Ganzhorn, Debra Spoljaric, Anne C. Albers, Amanda Merkelson, Douglas R. Stewart, David A. Stevenson, David Viskochil, Todd E. Druley, Jason T. Forys, Karlyne M. Reilly, Michael J. Fisher, Uri Tabori, Jeffrey C. Allen, Joshua D. Schiffman, David H. Gutmann, Joshua B. Rubin
Journal: Cancer Research (2014)

Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.
Automatic implantable cardioverter/defibrillator discharges and acute myocardial injury.
Authors: B Avitall, S Port, R Gal, J McKinnie, P Tchou, M Jazayeri, P Troup, M Akhtar
Journal: Circulation (1990)

Multiple defibrillations by the automatic implantable cardioverter/defibrillator (AICD) have been reported to result in localized epicardial damage. No data exist, however, regarding whether this damage can be detected in the clinical setting or whether it interferes with the detection of true myocardial infarction. Forty-nine patients who received defibrillations by patch electrodes were studied prospectively. We attempted to document the presence of myocardial injury with the following three commonly used modalities for the detection of myocardial infarction: serial electrocardiographic changes, serial creatine phosphokinase (CPK) and CPK-MB release, and technetium 99m pyrophosphate scanning. Fifteen patients received defibrillations by AICD patches at the time of AICD generator replacement. Nine patients received defibrillations at the time of new AICD lead placement. The average total energy delivered was 85 +/- 29 J. None of these patients had detectable myocardial injury. Ten patients had defibrillations by the AICD patches at the time of bypass operation. One patient in this group developed acute myocardial infarction in the inferior wall after posterior descending coronary bypass operation, as detected by electrocardiogram, 99mTc pyrophosphate scanning, and CPK-MB analysis. Fifteen patients were evaluated for spontaneous AICD discharges. Thirteen had a maximum of five consecutive shocks, and cumulative energy delivered was not greater than 330 J. None of these patients had detectable injury. Two patients had CPK-MB release of 15.3% and 7.5%, respectively. One of these patients had a positive 99mTc pyrophosphate scan. These two patients received 12 and 17 rapid and consecutive AICD discharges, respectively, with cumulative delivered energy of 360 and 510 J, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Castration-Dependent Pharmacokinetics of Docetaxel in Patients With Prostate Cancer
Authors: Ryan M. Franke, Michael A. Carducci, Michelle A. Rudek, Sharyn D. Baker, Alex Sparreboom
Journal: Journal of Clinical Oncology (2010)

Purpose To assess whether the low incidence of severe neutropenia in castrated men with prostate cancer treated with docetaxel is the result of changes in systemic clearance. Patients and Methods A total of 10 noncastrated and 20 castrated men with prostate cancer were studied to achieve 80% power (α = .05) to detect at least a 25% change in the clearance of docetaxel. The erythromycin breath test was evaluated to determine hepatic activity of cytochrome P450 3A4 (CYP3A4), the main docetaxel-metabolizing enzyme. Additional studies were performed in rats and transfected cells overexpressing human or rodent transporters. Results Docetaxel clearance was increased by approximately 100% in castrated men and was associated with a two-fold reduction in area under the curve (P = .0001), although hepatic activity of CYP3A4 was unchanged (P = .26). In rats, castration was associated with higher uptake of docetaxel in the liver and a concurrent increase in the expression of rOat2 (Slc22a7), an organic anion transporter that regulates, in part, the transfer of docetaxel from the circulation into hepatocytes. Conclusion It is recommended that castration- and/or hormone-related changes in the clearance of oncology drugs should be considered as a possible risk factor for treatment failure.
Abstract 3651: Foxp3 expression correlates with survival in urothelial carcinoma of the bladder
Authors: Hanwei Zhang, Xiaoyan Wang, David Seligson, Allan Pantuck, Arnold I. Chin
Journal: Cancer Research (2012)

Abstract Introduction and Objective The transcription factor Forkhead box p3 (Foxp3), originally described during the development of CD4+CD25+ T regulatory cells, has recently been implicated in divergent roles in human prostate, breast, pancreatic cancer, and melanoma. Here, we investigate the inducibility of Foxp3 in bladder cancer models and assess the prognostic role of Foxp3 in patients with bladder cancer. Methods Foxp3 expression in the human bladder cancer cell line SW780 was examined in in vitro cultures by flow cytometry and in in vivo subcutaneous implanted tumor models in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice by immunohistochemistry. Proliferation and invasion of SW780 cells in the absence of Foxp3 was performed by transfection of siRNA in vitro. Correlation of Foxp3 expression to urothelial carcinoma grade, stage, recurrence-free survival, and overall survival was examined in a human tumor microarray from a cohort of 280 patients by Cox proportional hazards regression and Kaplan-Meier analysis. Results Foxp3 expression correlates to higher cellular proliferation in vitro and in vivo. Knockdown of Foxp3 in SW780 cells resulted in decreased proliferation as well as invasion in vitro. Foxp3 expression increases with higher T stage, but not grade, as expression in adjacent normal bladder, Tis, Ta-1, T2-4, and lymph node metastasis was 1.2%, 3.8%, 15.2%, 26.5%, and 23.4% respectively, suggesting higher expression in muscle invasive and lymph node metastatic disease, but not carcinoma in situ. Using a cutoff of 10%, Foxp3 expression negatively correlates with survival following radical cystectomy with a median survival of 9.3 vs 2.8 years and a 10-year survival probability of 47% vs 27%. Conclusions This work implicates Foxp3 as novel transcription factor driving proliferation and tumor invasion in urothelial carcinoma. Expression of Foxp3 correlates with T stage and is a novel predictor of overall survival following radical cystectomy. Future studies will need to understand the mechanistic regulation of Foxp3 expression, as well examine Foxp3-mediated gene expression in urothelial carcinoma. Foxp3 expression may improve selection of patients to therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3651. doi:1538-7445.AM2012-3651
In Silico Predicted Robustness of Viroids RNA Secondary Structures. I. The Effect of Single Mutations
Authors: R. Sanjuan
Journal: Molecular Biology and Evolution (2006)

Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. Despite this genomic simplicity, they are able of inducing devastating symptoms in susceptible plants. Most of the 29 described viroid species fold into a rodlike or quasi-rodlike structure, whereas a few of them fold as branched structures. The shape of these RNA structures is perhaps one of the most characteristic properties of viroids and sometimes is considered their only phenotype. Here we use RNA thermodynamic secondary structure prediction algorithms to compare the mutational robustness of all viroid species. After characterizing the statistical properties of the distribution of mutational effects on structure stability and the wideness of neutral neighborhood for each viroid species, we show an evolutionary trend toward increased structural robustness during viroid radiation, giving support to the adaptive value of robustness. Differences in robustness among the 2 viroid families can be explained by the larger fragility of branched structures compared with the rodlike ones. We also show that genomic redundancy can contribute to the robustness of these simple RNA genomes.
High Serum Uric Acid as a Novel Risk Factor for Type 2 Diabetes
Authors: Abbas Dehghan, Mandy van Hoek, Eric J.G. Sijbrands, Albert Hofman, Jacqueline C.M. Witteman
Journal: Diabetes Care (2008)

To investigate the association between serum uric acid level and risk of type 2 diabetes.The population for analysis consisted of 4,536 subjects free from diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes.The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96-1.76) for the second, 1.63 (1.21-2.19) for the third, and 2.83 (2.13-3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78-1.49), 1.12 (0.81-1.53), and 1.68 (1.22-2.30), respectively.The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.
Studies of gene transcription and translation in regenerating rat liver
Authors: Brian E. Huber, Carole A. Heilman, Peter J. Wirth, Mark J. Miller, Snorri S. Thorgeirsson
Journal: Hepatology (1986)

Specific transcriptional and translational products associated with regenerating liver were analyzed by differential hybridization to a cDNA library and by two-dimensional electrophoresis of hepatic proteins, respectively. Comparisons of approximately 800 soluble and 800 particulate liver proteins from normal and 70% partially hepatectomized Fischer rats resulted in the identification of only three apparently unique polypeptides in 70% partially hepatectomized livers, although many quantitative changes were observed. A subset of these quantitative changes were also observed after sham operation. A cDNA library was generated from polyadenylated RNA isolated 18 hr post-70% partial hepatectomy. Comparative analysis of 6,000 transformants with single-stranded cDNA probes prepared from 18 hr post-70% partial hepatectomy and sham-operated animals identified three clones whose sequences were preferentially expressed 4- to 6-fold 18 hr post-70% partial hepatectomy. Southern blot analysis of one clone, REG-A, showed no homology to albumin, alpha-fetoprotein, three different forms of cytochrome P-450, ornithine decarboxylase, globin, or to a putative tumor promotion associated gene called PRO-2. A single, REG-A specific 2.5 kb band was identified by Northern blot analysis of liver samples. REG-A expression was increased 2-fold 18 hr postsham operation; 4-fold 18 hr post-70% partial hepatectomy and following chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin or phenobarbital treatment. REG-A expression returned to control levels 1 week after 70% partial hepatectomy. Furthermore, expression of REG-A was reduced in chemically induced preneoplastic nodules and in primary and transplantable hepatomas. Hybrid selection studies indicated that the REG-A sequence selected a mRNA(s) species, that in an in vitro translation assay, produced two major polypeptides of 21,000 and 25,000 molecular weight with a pI of 6.9. Thus, these data support the hypothesis that liver regeneration is characterized by quantitative changes in genes normally expressed at low levels in the Go hepatocyte and is not the result of major qualitative changes in gene expression.
<i>BCL-2/IgH</i> Polymerase Chain Reaction Status at the End of Induction Treatment Is Not Predictive for Progression-Free Survival in Relapsed/Resistant Follicular Lymphoma: Results of a Prospective Randomized EORTC 20981 Phase III Intergroup Study
Authors: Marinus H.J. van Oers, Evelyn Tönnissen, Martine Van Glabbeke, Livia Giurgea, Joop H. Jansen, Richard Klasa, Robert E. Marcus, Max Wolf, Eva Kimby, Andrej Vranovsky, Harald Holte, Anton Hagenbeek, Bert A. van der Reijden
Journal: Journal of Clinical Oncology (2010)

The prognostic value of residual BCL2/immunoglobulin heavy chain (BCL2/IgH) -positive cells in peripheral blood (PB) or bone marrow (BM) after induction treatment in follicular lymphoma (FL) is still controversial. In a prospective randomized phase III intergroup trial of 465 patients with relapsed/resistant follicular lymphoma (FL), we showed that addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone induction results in increased overall and complete response rates, and that rituximab maintenance strongly improves median progression-free survival (PFS) as well as overall survival. Here, we studied whether BCL2/IgH major break point levels in PB/BM correlated with response rates/quality for the induction phase and PFS for the maintenance phase.Samples were obtained before and after induction therapy and at the end of the 2 years maintenance/observation period. BCL2/IgH major break point-positive cells were quantified by genomic quantitative polymerase chain reaction in 792 samples from 238 patients.Pretreatment BCL2/IgH levels had no significant prognostic value for overall response or complete remission rates after induction treatment, but pretreatment positive BM results had an adverse prognostic value for PFS from first randomization (P = .023). Importantly, BCL2/IgH levels at the end of induction treatment had no prognostic value for PFS from second randomization. The highly significant improved PFS by rituximab maintenance was observed in both BCL2/IgH PB/BM-positive and -negative groups.Postinduction BCL2/IgH major break point status in BM/PB is not useful for decisions on subsequent therapy for patients with relapsed/resistant FL.
Fine particulate air pollution, resuspended road dust and respiratory health among symptomatic children
Authors: P. Tiitanen, K.l Timonen, J J. Ruskanen, A Mirme, J Pekkanen
Journal: European Respiratory Journal (1999)

The short-term association of particulate air pollution with peak expiratory flow rate (PEF) and respiratory symptoms was examined. Forty-nine children with chronic respiratory symptoms aged 8-13 yrs were followed daily for six weeks in spring, 1995, in Kuopio, Finland. Daily concentrations of particulate material with a 50% cut-off aerodynamic diameter &lt; or = 10 microm and &lt; or = 2.5 microm (PM10 and PM2.5, respectively), black carbon, and the number concentrations of particles from 0.01-10 microm diameter were measured. During the study period, PM10 were mainly resuspended soil and street dust, and the concentration was estimated using aluminum content of PM10 samples. No consistent effect of particles was found as the associations varied by lag. Of the lags examined, only 1-day lagged PM2.5 was statistically significantly associated with morning PEF (beta=-1.06, SE=0.52 (per interquartile increase in pollutant)). Evening PEF was significantly associated with the 1-day lagged number of particles in the size range 0.1-1.0 microm (beta=-1.56, SE=0.72). One-day lagged PM10, PM2.5-10, PM2.5 and resuspended PM10, and 4-day average of PM2.5 were significantly associated with increased risk of cough. Given the short duration of the study, separating the effects of different types of particles was difficult. The present study demonstrates the highly variable size and number distribution and chemical composition of particles in Finland, and underlines the importance of measuring the size and chemical composition of particles to determine which types of particles are associated with health effects.
A story of success: continuous quality improvement in cystic fibrosis care in the USA
Authors: B. S. Quon, C. H. Goss
Journal: Thorax (2011)

Continuous quality improvement (CQI) in healthcare can be described as a reiterative approach to improving processes to reduce unexpected variation in health outcomes. CQI represents one model to achieve quality improvement (QI) and has long been recognized as a key to success in the manufacturing industry with companies like Toyota leading the way.Healthcare, and specifically pulmonary, critical care and sleep medicine represent ideal settings for the application of CQI.This opinion piece will describe QI and CQI initiatives in the US Cystic fibrosis (CF) population.QI in CF care in the United States has been ongoing since inception of the US CF Foundation (CFF) in 1955. This effort has included work to improve the quality of clinical care provided at CF centers and work to improve clinical outcomes in CF. More recently, QI methods have been applied to the conduct of clinical research.The CF community has become a leader in the area of QI and has pointed out the opportunities for others to follow in the area of lung diseases.
Heart Failure and Asymptomatic Left Ventricular Systolic Dysfunction in Lymphoma Survivors Treated With Autologous Stem-Cell Transplantation: A National Cross-Sectional Study
Authors: Klaus Murbraech, Knut B. Smeland, Harald Holte, Jon Håvard Loge, May Brit Lund, Torgeir Wethal, Espen Holte, Assami Rösner, Håvard Dalen, Stein Kvaløy, Ragnhild S. Falk, Svend Aakhus, Cecilie E. Kiserud
Journal: Journal of Clinical Oncology (2015)

We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD), including symptomatic (ie, heart failure [HF]) and asymptomatic LVSD in adult lymphoma survivors (LSs) after autologous hematopoietic stem-cell transplantation (auto-HCT) and to identify risk factors for LVSD in this population.All LSs treated with auto-HCT as adults in Norway from 1987 to 2008 were eligible for this national cross-sectional study. Asymptomatic LVSD was defined as left ventricular ejection fraction less than 50% by echocardiography, and HF was defined according to current recommendations. The results in LSs were compared with those found in an age- and sex-matched (1:1) control group.We examined 274 LSs (69% of all eligible survivors); 62% were men, the mean (± standard deviation) age was 56 ± 12 years, and mean follow-up time from lymphoma diagnosis was 13 ± 6 years. The mean cumulative doxorubicin dose was 316 ± 111 mg/m(2), and 35% of LSs had received additional radiation therapy involving the heart. We found LVSD in 15.7% of the LSs, of whom 5.1% were asymptomatic. HF patients were symptomatically mildly affected, with 8.8% of all LSs classified as New York Heart Association class II, whereas more severe HF was rare (1.8%). Compared with controls, LSs had a substantially increased LVSD risk (odds ratio, 6.6; 95% CI, 2.5 to 17.6; P < .001). A doxorubicin dose ≥ 300 mg/m(2) and cardiac radiation therapy dose greater than 30 Gy were independent risk factors for LVSD.LVSD was frequent and HF more prevalent than previously reported in LSs after auto-HCT. Our results may help to identify LSs at increased LVSD risk and can serve as a basis for targeted surveillance strategies.