tbuckley/cabot-search huggingface dataset:
Analysis of bronchoalveolar lavage fluid in patients with chronic hepatitis C before and after treatment with interferon alpha
Authors: S. Yamaguchi, K. Kubo, K. Fujimoto, T. Honda, M. Sekiguchi, T. Sodeyama
Journal: Thorax (1997)

BACKGROUND: Previous studies have shown that patients with idiopathic pulmonary fibrosis (IPF) were more likely to be seropositive for hepatitis C virus (HCV) than normal controls, and that patients with chronic hepatitis C treated with interferon alpha (IFN-alpha) sometimes developed pulmonary fibrosis. The possibility that HCV infection and/or treatment with IFN-alpha are involved in the pathogenesis of pulmonary fibrosis or alveolitis was investigated. METHODS: A prospective non-randomised study was performed in 13 healthy controls and in patients with chronic hepatitis C before (n = 13) and after (n = 10) treatment with IFN-alpha. Bronchoalveolar lavage (BAL) fluid cell counts, ratios and T cell subsets, and the concentrations of interleukin (IL)-1 beta, tumour necrosis factor(TNF)-alpha, and hepatocyte growth factor (HGF) were measured. RESULTS: Lymphocyte counts in the BAL fluid were significantly increased in both groups of patients (median (range) values: before treatment, 36.8 (1.5-226.0); after treatment, 16.2 (4.5-97.6)) compared with the normal controls (3.3 (0.5-32.3)). In the pretreatment group the activated T cell (HLA-Dr positive) count was also increased (51 (40-74)) compared with that in the normal controls (27 (4-52)), but after treatment it was decreased (40 (0-76)) compared with the pretreatment count. Administration of IFN-alpha did not affect these parameters. IL-1 beta, TNF-alpha, and HGF were not detected. CONCLUSIONS: These findings suggest that HCV infection is associated with increased counts of lymphocytes and neutrophils in BAL fluid and that treatment with IFN-alpha appears to alter lymphocyte surface markers.
Predicting hospital admissions in non-CF bronchiectasis using COPD specific severity tools
Authors: Lucy Poppelwell, Waleed Salih, Richard J. Stretton, Katherine Leighton, Elizabeth Furrie, Stuart Schembri, Sara Marshall, Tom C. Fardon, James D. Chalmers
Journal: European Respiratory Journal (2013)

Introduction  There are no accepted clinical severity criteria for bronchiectasis. There are, however, well-validated prognostic tools for COPD. This study tested the ability of 3 COPD specific prognostic tools to predict hospital admissions in patients with bronchiectasis.  Method  100 consecutive patients with bronchiectasis attending a specialist clinic were studied 2011-2012. Baseline data recorded were age, FEV1% predicted, MRC dyspnoea score, exacerbation history and body mass index. These were used to calculate 3 COPD prognostic tools: The GOLD 2011, ADO and BOD indices. The primary outcome was hospitalisation for a severe exacerbation during follow-up to February 2013. Scoring systems were assessed using the area under the receiver operator characteristic curve (AUC).  Results  The median age was 66 years (IQR 58-73). 27% of patients were hospitalised at least once during follow-up.  GOLD 2011 stage predicted hospitalisation risk AUC 0.71 (95% CI 0.65-0.77,p  The distribution of patients and hospitalisation risk according to GOLD stage is shown in figure 1.  Conclusion  In the absence of specific prognostic tools for bronchiectasis, COPD prognostic tools perform well in predicting hospital admissions in bronchiectasis.
An Ex(o)citing Machinery for Invasive Tumor Growth
Authors: An Hendrix, Wendy Westbroek, Marc Bracke, Olivier De Wever
Journal: Cancer Research (2010)

Cancer cells communicate with the environment through delivery of surface proteins, release of soluble factors (growth factors and cytokines), and sophisticated nanovehicles (exosomes) for establishment of invasive tumor growth. This communication occurs in part through constitutive exocytosis, regulated exocytosis, or release of intraluminal vesicles, and is modulated by small Rab GTPases, the master regulators of vesicle traffic. We studied Rab GTPases implicated in regulated exocytosis and showed a unique role for Rab27B in invasive tumor growth. Emerging evidence indicates that various exocytic routes are implemented by cancer cells to relay crucial information for fostering growth, migration, and matrix degradation.
Wnt Coreceptor <i>Lrp5</i> Is a Driver of Idiopathic Pulmonary Fibrosis
Authors: Anna P. Lam, Jose D. Herazo-Maya, Joseph A. Sennello, Annette S. Flozak, Susan Russell, Gökhan M. Mutlu, G. R. Scott Budinger, Ramanuj DasGupta, John Varga, Naftali Kaminski, Cara J. Gottardi
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Wnt/β-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown.Objectives: To determine whether the Wnt coreceptor Lrp5 drives pulmonary fibrosis in mice and is predictive of disease severity in humans.Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-β. We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF).Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of β-catenin signaling by the small molecular inhibitor of β-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-β production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-β, Lrp5 null mice were not protected against lung fibrosis induced by TGF-β.Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-β signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.
A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise
Authors: Wataru Aoi, Yuji Naito, Tomohisa Takagi, Yuko Tanimura, Yoshikazu Takanami, Yukari Kawai, Kunihiro Sakuma, Liu Po Hang, Katsura Mizushima, Yasuko Hirai, Ryota Koyama, Sayori Wada, Akane Higashi, Satoshi Kokura, Hiroshi Ichikawa, Toshikazu Yoshikawa
Journal: Gut (2012)

Several epidemiological studies have shown that regular exercise can prevent the onset of colon cancer, although the underlying mechanism is unclear. Myokines are secreted skeletal muscle proteins responsible for some exercise-induced health benefits including metabolic improvement and anti-inflammatory effects in organs. The purpose of this study was to identify new myokines that contribute to the prevention of colon tumorigenesis.To identify novel secreted muscle-derived proteins, DNA microarrays were used to compare the transcriptome of muscle tissue in sedentary and exercised young and old mice. The level of circulating secreted protein acidic and rich in cysteine (SPARC) was measured in mice and humans that performed a single bout of exercise. The effect of SPARC on colon tumorigenesis was examined using SPARC-null mice. The secretion and function of SPARC was examined in culture experiments.A single bout of exercise increased the expression and secretion of SPARC in skeletal muscle in both mice and humans. In addition, in an azoxymethane-induced colon cancer mouse model, regular low-intensity exercise significantly reduced the formation of aberrant crypt foci in wild-type mice but not in SPARC-null mice. Furthermore, regular exercise enhanced apoptosis in colon mucosal cells and increased the cleaved forms of caspase-3 and caspase-8 in wild-type mice but not in SPARC-null mice. Culture experiments showed that SPARC secretion from myocytes was induced by cyclic stretch and inhibited proliferation with apoptotic effect of colon cancer cells.These findings suggest that exercise stimulates SPARC secretion from muscle tissues and that SPARC inhibits colon tumorigenesis by increasing apoptosis.
Allelic Heterogeneity in Hereditary Surfactant Protein B (SP-B) Deficiency
Authors: LAWRENCE M. NOGEE, SUSAN E. WERT, SHERRI A. PROFFIT, WILLIAM M. HULL, JEFFREY A. WHITSETT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Inability to produce surfactant protein B (SP-B) causes fatal neonatal respiratory disease. A frame-shift mutation (121ins2) is the predominant but not exclusive cause of disease. To determine the range of mechanisms responsible for SP-B deficiency, both alleles from 32 affected infants were characterized. Sixteen infants were homozygous for the 121ins2 mutation, 10 infants were heterozygous for the 121ins2 and another mutation, and six infants were homozygous for other mutations. Thirteen novel SP-B gene mutations were identified, which were not found in a control population. One novel mutation was found in two unrelated families. Surfactant protein expression was evaluated by immunohistochemistry and/or protein blotting. Absence of proSP-B and mature SP-B was associated with nonsense and frame-shift mutations. In contrast, proSP-B expresssion was associated with missense mutations, or mutations causing in-frame deletions or insertions, and low levels of mature SP-B expression were associated with four mutations. Extracellular staining for proSP-C and/or aberrantly processed SP-C was observed in lungs of all infants with SP-B gene mutations. Hereditary SP-B deficiency is caused by a variety of distinct mutations in the SP-B gene and may be associated with reduced, as well as absent, levels of mature SP-B, likely caused by impaired processing of proSP-B. Nogee LM, Wert SE, Proffit SA, Hull WM, Whitsett JA. Allelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency.
Cardiovascular Performance of Alaska Sled Dogs during Exercise
Authors: ROBERT L. VAN CITTERS, DEAN L. FRANKLIN
Journal: Circulation Research (1969)

Radiotelemetry was used to study regional blood flow distribution in Alaska sled dogs during cross-country runs. Doppler ultrasonic flowmeter transducers were chronically implanted on the coronary, renal, and mesenteric arteries, terminal abdominal aorta, and ascending aorta or pulmonary artery, and a miniature blood pressure gauge was installed in the aorta or carotid artery. Flow and pressure data telemetered from dogs running on the trail were received and recorded remotely. The heart rate, 40 to 60/min in sleeping dogs, increased to 80 to 100/min when the dogs were ambulatory and to 100 to 150/min when the dogs were excited before a race. Heart rate accelerated to 300/min at the start of exercise and commonly remained at that level throughout prolonged runs. Aortic blood pressure averaged 130/90 mm Hg at rest, but the systolic pressure often exceeded 300 mm Hg when the dogs were running. A transient drop in mean pressure occurred at the onset of running, but mean pressure during sustained exercise was practically identical to that at rest. Flow in the terminal aorta increased 9 to 12 times and coronary flow 5 to 6 times, but mesenteric and renal flows were unchanged during violent, prolonged exercise. These findings contrast with diminished visceral flows recorded in exercising humans and suggest that compensatory redistribution of flow is not a significant reserve mechanism in these animals during exercise.
Failure of ipratropium bromide to modify the diurnal variation of asthma in asthmatic children.
Authors: P D Sly, L I Landau, A Olinsky
Journal: Thorax (1987)

Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind, randomised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity. Subjects measured peak expiratory flow rate approximately eight hourly, before and after inhaled salbutamol, for four week periods. Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol. Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20% fall in FEV1 (geometric mean PD20 = 0.78 v 0.49 mg/ml, p less than 0.05), despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge. It did not, however, diminish the diurnal variation in airway calibre (mean amplitude = 12.7 v 10.1) or in bronchodilator responsiveness (mean amplitude = 62.4 v 63.5). There was no improvement in the clinical state of subjects while they were taking ipratropium bromide.
Grandparental transfers and kin selection
Authors: Raymond Hames
Journal: Behavioral and Brain Sciences (2010)

Abstract In the analysis of intergenerational transfer, several improvements can be made. First, following kin selection theory, grandparents have kin other than grandchildren in which to invest and therefore any investigation into grandparents should take this perspective. Secondly, how transfers actually enhance the survivorship of younger relatives such as grandchildren must be better measured, especially in the ethnographic literature. Finally, the problem of indirect investments or targeting must be considered.
Targeting Protein-Protein Interaction by Small Molecules
Authors: Lingyan Jin, Weiru Wang, Guowei Fang
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Protein-protein interactions (PPIs) are critical regulatory events in physiology and pathology, and they represent an important target space for pharmacological intervention. However, targeting PPIs with small molecules is challenging owing to the large surface area involved in protein-protein binding and the lack of obvious small-molecule-binding pockets at many protein-protein interfaces. Nonetheless, successful examples of small-molecule modulators of PPIs have been growing in recent years. This article reviews some of the recent advances in the discovery of small-molecule regulators of PPIs that involve key oncogenic proteins. Our discussion focuses on the three key modes of action for these small-molecule modulators: orthosteric inhibition, allosteric regulation, and interfacial binding/stabilization. Understanding the opportunities and challenges of these diverse mechanisms will help guide future efforts in developing small-molecule modulators against PPIs.
Meta-analysis: Should It be More Than the Sum of Its Parts?
Authors: P. Herbolsheimer, S. M. Swain
Journal: JNCI Journal of the National Cancer Institute (2010)

JNCI | Editorials 1817 In this issue of the Journal, Bonilla et al. (1) present the results of what the authors call a systematic review and meta-analysis of dosedense chemotherapy in nonmetastatic breast cancer. The rationale for dosing chemotherapy at shorter intervals (“dose-dense” chemotherapy) is based on Gompertzian kinetics, as described by Norton et al. (2). This mathematical model predicts that tumor doubling time decreases with increasing tumor size. Conversely, tumor cells grow faster as the tumor burden decreases with the initiation of chemotherapy (2). Dose-dense chemotherapy is predicted to attack rapidly dividing tumor cells more effectively compared with the conventional dosing schedule. The safety and feasibility of dosedense chemotherapy dosing were first demonstrated in a pilot phase II study that used an anthracycline-based chemotherapy agent with growth factor support (3). The results were validated in a large phase III trial, the cancer and leukemia group B (CALGB) trial 9741, which showed better clinical outcomes in the dose-dense arm when using an anthracycline and taxane-based chemotherapy regimen (4). Since this landmark trial, the dose-dense regimen has been widely adopted in clinical practice. It is important to distinguish the concept of dose density from dose intensity. Dose intensity is defined by the amount of treatment delivered per unit of time (5). For example, 60 mg/m2 of doxorubicin given every 3 weeks results in a dose intensity of 20 mg/m2/wk. Multiple other studies comparing frequent dosing with conventional dosing schedule have been published in an attempt to validate the results published by Citron et al. (4) for CALGB 9741. Some of these studies are included in the article by Bonilla et al. (1) and are discussed. Meta-analysis is a statistical combination of results from two or more separate studies on a specific subject (6). The purpose of the meta-analysis is to estimate the effect size by means of the weighted average. The advantages of meta-analysis include higher statistical power than a small individual study; a meta-analysis also allows for generalizations to the studied population. However, meta-analysis has several potential weaknesses. Even a statistically Meta-analysis: Should It be More Than the Sum of Its Parts?
Abstract 1034: Induction of miR183 and miR21 is associated with down regulation of cellular signaling in nitrogen mustard mediated inhibition of tumor cell proliferation.
Authors: Hong Duck Kim, Michael P. Shakarjian, Anna M. Vetrano, Jeffrey D. Laskin, Diane E. Heck
Journal: Cancer Research (2013)

Abstract Nitrogen mustard (HN2) is a chemotherapeutic agent used to treat skin cancers and lymphomas including squamous cell carcinomas (SCC) and cutaneous T cell lymphoma. Although HN2 non-selectively alkylates DNA, many tumors exhibit resistance to HN2 therapy. To evaluate additional mechanisms potentially underlying the activity of HN2 we tested the effects of HN2 on Pam 212 murine squamous cell carcinoma cells. We found that mustard treatment reduced cell viability, and that this result was associated with an increase in PKCδ phosphorylation. Furthermore, cytotoxicity was antagonized by the PKCδ selective inhibitor, rottlerin, implicating this PKC isoform in HN2 action. The p38MAPK inhibitor, SB203580, acted in a similar manner to rottlerin, increasing viability 30% in HN2-treated Pam 212 cells. In contrast, PI3kinase inhibitor, wortmannin, enhanced HN2-mediated cytotoxicity, suggesting a protective role for this signaling pathway. Recent reports indicate that the activity of the p38MAPK and PKCδ signaling cascades, pathways involved in regulating glucose uptake and metabolism, growth, motility, and other essential functions for cell survival, is hallmarked by increases in levels of miRNAs 21 and 183. Therefore we next evaluated the effects of HN2 on microRNA (miR) levels using microRNA PCR arrays. In these experiments we found that HN2 treatment enhanced levels of miR21 and miR183 in Pam 212 keratinocytes, effects that were time and dose-dependent dependent. In additional studies we found that transfection of PAM cells with miR21 and miR183 resulted in enhanced sensitivity to inhibitors of PI3 kinase and p38MAPK regulated mTOR activity. Using techniques in real time PCR we observed that HN2-mediated increases in miRNA 21 and 183 levels were inhibited by the mTOR inhibitors 3-MA, rapamycin and LY294002 in PAM cells. Taken together these data indicate that signaling pathways play significant roles in HN2-mediated inhibition of tumor cell proliferation. We speculate that PKCδ, PI3 kinase, p38MAPK and mTOR pathways are important in the anti-cancer activities of HN2 and may be modified in tumors resistant to this agent. Citation Format: Hong Duck Kim, Michael P. Shakarjian, Anna M. Vetrano, Jeffrey D. Laskin, Diane E. Heck. Induction of miR183 and miR21 is associated with down regulation of cellular signaling in nitrogen mustard mediated inhibition of tumor cell proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1034. doi:10.1158/1538-7445.AM2013-1034
Selecting between intelligent options
Authors: Roi Cohen Kadosh, Vincent Walsh, Avishai Henik
Journal: Behavioral and Brain Sciences (2007)

Abstract In this commentary we make two rejoinders to Jung &amp; Haier (J&amp;H). First, we highlight the response selection component in tasks as a confounding variable that may explain the parieto-frontal involvement in studies of human intelligence. Second, we suggest that efficient response selection may be an integral part of the definition of intelligence.
Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis
Authors: Roy Fleischmann, Joel Kremer, John Cush, Hendrik Schulze-Koops, Carol A. Connell, John D. Bradley, David Gruben, Gene V. Wallenstein, Samuel H. Zwillich, Keith S. Kanik
Journal: New England Journal of Medicine (2012)

Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis.In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity).At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).