tbuckley/cabot-search huggingface dataset:
Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor
Authors: Tammie C. Yeh, Vivienne Marsh, Bryan A. Bernat, Josh Ballard, Heidi Colwell, Ron J. Evans, Janet Parry, Darin Smith, Barbara J. Brandhuber, Stefan Gross, Allison Marlow, Brian Hurley, Joe Lyssikatos, Patrice A. Lee, James D. Winkler, Kevin Koch, Eli Wallace
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models. Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models. Results: The IC50 of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor–induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate–induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday. Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.
Elevation Of Sputum Plasminogen Activator Inhibitor-1 Levels In The Subjects With Asthma
Authors: A. Habib, I. Kim, S. Lee, H. Boushey, T. Ward, J. Liu, R.P. Schleimer, P. Avila, S.H. Cho
Journal: Journal of Allergy and Clinical Immunology (2011)
Bacterial colonization as a potential source of nosocomial respiratory infections in two types of spirometer
Authors: F Burgos, A Torres, J Gonzalez, J Puig de la Bellacasa, R Rodriguez-Roisin, J Roca
Journal: European Respiratory Journal (1996)

The potential risk of spirometers in the transmission of respiratory infections has not been yet established. We performed a prospective cross-sectional study to determine the rate of colonization of a water-sealed spirometer and a pneumotachograph, and the potential risk of cross-transmission of microorganisms to patients using each of these devices. Fifty four patients (aged 51 +/- 18 (mean +/- SD) yrs) were included in the study. All of them had undergone forced spirometry with bronchodilator response by means of the water-sealed spirometer (n = 36) or the pneumotachograph (n = 18). None had a clinically apparent respiratory infection at the time of the study. Routine hygiene measures for respiratory equipment were performed before the study protocol. Samples for microbiological cultures of different parts both of the water-sealed spirometer (proximal and distal tubing, bell and water-bell) and pneumotachograph (proximal and distal tubing) were taken daily before and after the usual series of lung function tests during a 5 day period. Pharyngeal swab cultures were obtained before spirometry and 7 days later in each subject. Thirty six out of a total of 40 (90%) culture samples from the water-sealed spirometer showed microbial growth compared to 4 out of 30 (13%) samples obtained from the pneumotachograph (p &lt; 0.0001). Significant colonization of the water-sealed spirometer was apparent after the third day of the study. The microorganisms most frequently isolated were penicillium sp. (62%), Pseudomonas fluorescens (32%), and Burkholderia cepacea (48%). Distal tubing, water and water-bell were the parts of the water-sealed spirometer that showed higher colonization counts (&gt; or = 10(4) colony-forming units (cfu).mL-1). No transmission sequence of potentially pathogenic microorganisms from equipment to patients or vice versa could be demonstrated. In summary, the water-sealed spirometer frequently became colonized by microorganisms. The potential hazard of such equipment as reservoirs of microorganisms suggests a need for the implementation of new hygiene measures for their maintenance.
Folk psychology meets folk Darwinism
Authors: Jay Hegdé, Norman A. Johnson
Journal: Behavioral and Brain Sciences (2006)

The fact that beliefs in the supernatural are useful to people who hold them does not necessarily mean that these beliefs confer an evolutionary advantage to those who hold them. An evolutionary explanation for any biological phenomenon must meet rigorous criteria, but the facts in this case, even when taken at their face value, fall well short of these criteria.
Dendritic Cells Retrovirally Transduced with a Model Antigen Gene Are Therapeutically Effective against Established Pulmonary Metastases
Authors: Jennifer M. Specht, Gang Wang, My T. Do, John S. Lam, Richard E. Royal, Mark E. Reeves, Steven A. Rosenberg, Patrick Hwu
Journal: The Journal of Experimental Medicine (1997)

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.
Neurological complications of severe illness and prolonged mechanical ventilation.
Authors: C M Wiles
Journal: Thorax (1996)

Objective.To test the hypothesis that prolonged motor recovery after long-term ventilation may be due to polyneuropathy and can be foreseen at an early stage by electromyography (EMG).Design.Cohort study with an entry period of 18 months.Polyneuropathy was identified by EMG studies in the intensive care unit (ICU).During a 1-year follow-up, amount of time was recorded to reach a rehabilitation end point.Setting.The general ICU of a community hospital.Patients.Fifty patients younger than 75 years who were receiving mechanical ventilation for more than 7 days.Main outcome measures.A rehabilitation end point was defined as return of normal muscle strength and ability to walk 50 m independently.Results.In 29 of 50 patients, an EMG diagnosis of polyneuropathy was made in the ICU.Patients with polyneuropathy had a higher mortality in the ICU (14 vs 4; P= 0.03), probably related to multiple organ failure (22 vs 11; P=0*08) or aminoglycoside treatment of suspected gram-negative sepsis (17 vs 4; P=0.05).Rehabilitation was more prolonged in 12 patients with polyneuropathy than in 12 without polyneuropathy (P=0.001).Of nine patients with delays beyond 4 weeks, eight had polyneuropathy, five of whom had persistent motor handicap after 1 year.In particular, axonal polyneuropathy with conduction slowing on EMG indicated a poor prognosis.Conclusions.Polyneuropathy in the critically ill is related to multiple organ failure and gram-negative sepsis, is associated with higher mortality, and causes important rehabilitation problems.EMG recordings in the ICU can identify patients at risk.(
Shoulder-hand syndrome and symmetrical arthralgia in patients with tubo-ovarian carcinoma.
Authors: A J Taggart, J M Iveson, V Wright
Journal: Annals of the Rheumatic Diseases (1984)

Two cases of bilateral shoulder-hand syndrome and symmetrical arthralgia are described in patients with tubo-ovarian carcinoma. Swelling and contracture of the hands continued to develop despite oral corticosteroid therapy, and one patient underwent surgery in an attempt to prevent the development of further deformity.
The influence of human immunodeficiency virus (HIV) on the course of chronic delta hepatitis: A prospective study
Authors: P. Farci, G. Orgiana, A. Coiana, M.E. Lai, G. Peddis, L. Orlando, M. Perra, G. Faa, P. Dessalvi, A. Balestrieri
Journal: Journal of Hepatology (1989)
Impact of Vascular Endothelial Growth Factor-A Expression, Thrombospondin-2 Expression, and Microvessel Density on the Treatment Effect of Bevacizumab in Metastatic Colorectal Cancer
Authors: Adrian M. Jubb, Herbert I. Hurwitz, Wei Bai, Eric B. Holmgren, Patti Tobin, A. Steven Guerrero, Fairooz Kabbinavar, Scott N. Holden, William F. Novotny, Gretchen D. Frantz, Kenneth J. Hillan, Hartmut Koeppen
Journal: Journal of Clinical Oncology (2005)

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab.In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizumab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. MVD was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses.In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22. VEGF or THBS-2 expression and MVD were not significant prognostic factors.These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD.
Metabolic profiling detects biomarkers of protein degradation in COPD patients
Authors: Baljit K. Ubhi, John H. Riley, Paul A. Shaw, David A. Lomas, Ruth Tal-Singer, William MacNee, Julian L. Griffin, Susan C. Connor
Journal: European Respiratory Journal (2011)

There is a paucity of biomarkers for chronic obstructive pulmonary disease (COPD). Metabolomics were applied to a defined COPD patient cohort from the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points). Results were correlated with accepted biomarkers for the disease. Baseline control serum (n=66) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II (n=70), III (n=64) and IV (n=44) COPD patients were analysed by proton nuclear magnetic resonance ( 1 H NMR). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to confirm amino acid changes detected by 1 H NMR. Data were correlated with body composition, emphysema and systemic inflammation. 1 H NMR identified decreased lipoproteins, N , N -dimethylglycine, and increased glutamine, phenylalanine, 3-methylhistidine and ketone bodies in COPD patients with decreased branched-chain amino acids (BCAAs) observed in GOLD stage IV patients. BCAAs, their degradation products, 3-methylhistidine, ketone bodies, and triglycerides were correlated negatively with cachexia and positively with systemic inflammation. Emphysema patients also displayed decreased serum creatine, glycine and N , N -dimethylglycine. LC-MS/MS confirmed 1 H NMR findings relating to BCAAs, glutamine and 3-methylhistidine in GOLD stage IV patients. NMR-based metabolomics characterised COPD patients based on systemic effects and lung function parameters. Increased protein turnover occurred in all COPD patients with increased protein degradation in individuals with emphysema and cachexia.
An analysis of risk factors for withdrawal from dialysis before death.
Authors: J E Leggat, W E Bloembergen, G Levine, T E Hulbert-Shearon, F K Port
Journal: Journal of the American Society of Nephrology (1997)

Withdrawal from dialysis has been a significant cause of mortality among dialysis patients, accounting for 6 to 22% of deaths. Since 1990, a new death notification form has allowed more detailed analyses of withdrawal from dialysis separate from causes of death. Using the U.S. Renal Data System data base, this study examined 116,829 deaths in adult patients from 1990 to 1995. Adjusted odds ratios were calculated for the risk of withdrawal using logistic regression. Adjustments included age at death, ethnicity, gender, cause of death, primary cause of end-stage renal disease, time on dialysis, and dialysis modality. In addition, odds ratios of withdrawal were calculated for deaths in patients who started dialysis after age 65. Death was preceded by withdrawal significantly more frequently in women than in men, more than twice as frequently in Caucasians than in African-Americans or Asians, and more frequently in older than in younger age groups. Patients who died of chronic diseases (e.g., dementia, malignancy) were much more likely to withdraw before death, whereas patients who died from more acute causes (e.g., coronary artery disease) were less likely to withdraw before death. It is concluded that patients who are Caucasian, female, older, or die of chronic or progressive diseases are more likely to withdraw from dialysis before death. The ethnic and gender differences in withdrawal do not appear to have a medical explanation from this analysis. Further research along sociologic lines is needed to better explain the differences in withdrawal from chronic dialysis.
Effects of lumbar sympathetic block on kidney function in cirrhotic patients with hepatorenal syndrome
Authors: J.A. Solis-Herruzo, A. Duran, V. Favela, G. Castellano, J.L. Madrid, M.T. Muñoz-Yagüe, J.D. Morillas, J. Estenoz
Journal: Journal of Hepatology (1987)
Effects of Chromium Supplementation on Serum High-Density Lipoprotein Cholesterol Levels in Men Taking Beta-Blockers
Authors: J R Roeback, K M Hla, L E Chambless, R H Fletcher
Journal: Annals of Internal Medicine (1991)

Objective: To determine the efficacy of glucose tolerance factor (GTF)-chromium for increasing serum levels of high-density lipoprotein (HDL) cholesterol in patients taking beta-blockers. Design: Randomized, double-blind, placebo-controlled trial. Setting: Mixed primary and referral-based outpatient clinic at a university-affiliated VA Medical Center. Patients: Referred sample of 72 men receiving beta-blockers, mainly for hypertension. Sixty-three patients (88%) completed the study. Interventions: Current medications, including beta-blockers, were continued. During the 8-week treatment phase, patients in the chromium group received a total daily dose of 600 µg of biologically active chromium divided into three equal doses; control patients received a placebo of identical appearance and taste. Measurements: Serum levels of total cholesterol and HDL cholesterol were measured. Main Results: Mean baseline levels of HDL and total cholesterol (± SD) were 0. 93 ± 0.28 mmol/L and 6.0 ± 1.0 mmol/L (36 ± 11.1 mg/dL and 232 ± 38.5 mg/dL), respectively. The difference between groups in adjusted mean change in HDL cholesterol levels, accounting for baseline HDL cholesterol levels, age, weight change, and baseline total cholesterol levels, was 0.15 mmol/L (5.8 mg/dL) (P = 0.01) with a 95% Cl showing that the treatment effect was > + 0.04 mmol/L (+ 1.4 mg/dL). Mean total cholesterol, triglycerides and body weight did not change significantly during treatment for either group. Compliance as measured by pill count was 85%, and few side effects were reported. Two months after the end of treatment, the between-group difference in adjusted mean change from baseline to end of post-treatment follow-up was - 0.003 mmol/L (- 0.1 mg/dL). Conclusion: Two months of chromium supplementation resulted in a clinically useful increase in HDL cholesterol levels in men taking beta-blockers.
17α-Hydroxylase/17,20-Lyase Deficiency: From Clinical Investigation to Molecular Definition*
Authors: TOSHIHIKO YANASE, EVAN R. SIMPSON, MICHAEL R. WATERMAN
Journal: Endocrine Reviews (1991)

THE term congenital adrenal hyperplasia (CAH) defines a group of syndromes resulting from inherited defects in any one of the five enzymes involved in the steps leading to cortisol biosynthesis from cholesterol. These include four distinct forms of cytochrome P450: P450scc, P450C21, P45011β, and P45017α, as well as 3β- hydroxysteroid dehydrogenase. Pathologically, CAH is characterized by hyperplastic growth of the adrenal stimulated by ACTH. A blockage in any one of the steps in normal steroid hormone synthesis leads to decreased synthesis of the steroid hormones and accumulation of intermediates, giving rise to the various clinical symptoms. The most common form of CAH, 21-hydroxylase deficiency, accounts for 90–95% of CAH (1). The high frequency of 21-hydroxylase deficiency is related to the structure of the P450C21 (CYP21) genes of which there are two, closely linked, a functional gene and a pseudo-gene (2, 3). Understanding of this unique gene structure and its location in the HLA locus has led to the definition of the molecular basis of a number of cases of 21-hydroxylase deficiency (4).
Hepatocyte-specific ABCA1 transfer increases HDL cholesterol but impairs HDL function and accelerates atherosclerosis
Authors: Yingmei Feng, Joke Lievens, Frank Jacobs, Menno Hoekstra, Eline Van Craeyveld, Stephanie C. Gordts, Jan Snoeys, Bart De Geest
Journal: Cardiovascular Research (2010)

The ATP-binding cassette transporter A1 (ABCA1) lipidates apolipoprotein (apo) A-I. The hypothesis that hepatocyte-specific ABCA1 overexpression results in high-density lipoprotein (HDL) dysfunction was evaluated by comparing the effects of murine ABCA1 (AdABCA1) and human apo A-I (AdA-I) transfer on lipoprotein profile, HDL function, and progression of atherosclerosis. Gene transfer in male and female C57BL/6 apo E−/− mice was performed at the age of 3 months with E1E3E4-deleted adenoviral vectors containing hepatocyte-specific expression cassettes. Atherosclerosis was quantified at baseline and 56 days later in AdABCA1, AdA-I, and control mice. HDL cholesterol after AdA-I transfer was 1.7-fold (P < 0.001) and 1.8-fold (P < 0.001) higher in male and female mice, respectively, and potently inhibited atherosclerosis progression compared with respective controls. Notwithstanding a 1.4-fold (P < 0.01) and a 1.7-fold (P < 0.01) increase of HDL cholesterol in male and female mice, respectively, after AdABCA1 transfer, the intima was 2.2-fold (P < 0.001) larger in male and 1.3-fold (P = NS) larger in female mice compared with respective controls. HDL isolated from control and AdA-I mice but not from AdABCA1 mice enhanced endothelial progenitor cell (EPC) migration in vitro and reduced endothelial cell death in vitro after serum and growth factor withdrawal. Scavenger receptor class B type I (SR-BI) protein level in the liver was significantly lower in AdABCA1 mice than in control and AdA-I mice. Hepatocyte-specific ABCA1 transfer decreases SR-BI protein level in the liver and abrogates beneficial effects of HDL on EPCs and endothelial cells. Decreased HDL function may underlie accelerated atherosclerosis in AdABCA1 apo E−/−mice.
Differential Contribution of Various Adhesion Molecules to Leukocyte Kinetics in Pulmonary Microvessels of Hyperoxia-exposed Rat Lungs
Authors: KAZUMI NISHIO, YUKIO SUZUKI, TAKUYA AOKI, KOICHI SUZUKI, ATSUSHI MIYATA, NAGATO SATO, KATSUHIKO NAOKI, HIROYASU KUDO, HARUKUNI TSUMURA, HIROSHI SERIZAWA, SHIGEAKI MOROOKA, YUZURU ISHIMURA, MAKOTO SUEMATSU, KAZUHIRO YAMAGUCHI
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

To elucidate the differential role of various adhesion molecules in distorting leukocyte behavior in the microvasculature of hyperoxia-exposed rat lungs, we investigated fluorescein-labeled leukocyte and erythrocyte kinetics in isolated lungs taken from the animals exposed to 90% O2 for 48 h under conditions in which endothelial intercellular adhesion molecule-1 (ICAM-1) and P-selectin were inhibited by appropriate monoclonal antibodies (1A29 for ICAM-1 and ARP2-4 for P-selectin), while leukocyte L-selectin was restrained with fucoidin. Measurements of blood cell kinetics were made by a confocal laser luminescence microscope coupled with a high-speed video camera. In addition, we histologically examined leukocyte accumulation within the alveolar septa and ICAM-1 as well as P-selectin expressions in the lung. We found that P-selectin expression was sparsely enhanced only in arterioles, whereas ICAM-1 was significantly induced in both venules and capillaries. Firm adhesion of leukocytes was not identified in arterioles and venules, whereas leukocyte rolling was evident in both the vessels. Arteriolar rolling was regulated via a P-selectin- and ICAM-1-independent but L-selectin-dependent mechanism, whereas venular rolling was mediated via a P-selectin-independent but ICAM-1- and L-selectin-dependent pathway. Leukocyte sequestration within capillaries was augmented by an ICAM-1-related mechanism. These findings may suggest that, in hyperoxia-exposed lungs, induction of adhesion molecules and their obstacles to leukocyte behavior are qualitatively different among arterioles, venules, and capillaries.