tbuckley/cabot-search huggingface dataset:
Mechanisms by which E-Selectin Regulates Diapedesis of Colon Cancer Cells under Flow Conditions
Authors: Pierre-Luc Tremblay, Jacques Huot, François A. Auger
Journal: Cancer Research (2008)

Diapedesis, the passage of circulating tumor cells across the endothelium, is a critical determinant in most cases of metastasis. Using a laminar flow chamber and a tissue-engineered blood vessel, we found that E-selectin is required not only for the initial adhesion and rolling of circulating HT-29 colon cancer cells on the endothelium but also for their subsequent diapedesis. These processes require both the intracellular and extracellular domains of E-selectin. We also identified three distinct mechanisms by which circulating cancer cells interact with E-selectin to initiate their diapedesis: formation of a mosaic between cancer cells and endothelial cells, paracellular diapedesis at the junction of three endothelial cells, and transcellular diapedesis. We also obtained evidence indicating that E-selectin-dependent paracellular extravasation is independent of intercellular adhesion molecule and vascular cell adhesion molecule and that it requires the activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase downstream of E-selectin. This is supported by the observation that the adenoviral-mediated expression of the E-selectin mutant Y603F is associated with both an inhibition of ERK and paracellular extravasation. Our study is the first to clearly establish, under dynamic and shear stress conditions, how E-selectin regulates diapedesis of circulating cancer cells. These results provide new insights in understanding the metastatic process.
Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency.
Authors: P J Stanley, R Wilson, M A Greenstone, L MacWilliam, P J Cole
Journal: Thorax (1986)

Despite the in vitro ciliotoxicity of tobacco smoke and the abnormal mucociliary clearance found in smoking related chronic bronchitis, studies of mucociliary clearance in healthy smokers have produced variable results. The nasal mucociliary clearance of saccharin and the in vitro nasal ciliary beat frequency were studied in healthy smokers and non-smokers. One of 29 smokers had a nasal mucociliary clearance time of over 60 minutes; in the remaining 28 the mean (SD) clearance time was 20.8 (9.3) minutes, which was significantly longer (p less than 0.001) than the mean time of 11.1 (3.8) minutes in 27 lifelong non-smokers. There was no significant difference between the mean nasal ciliary beat frequency of 10 smokers and 10 non-smokers. There were no significant differences in mean ciliary beat frequency or mean nasal mucociliary clearance time after 10 healthy non-smoking volunteers had smoked two cigarettes each, exhaling the smoke through their nostrils. Unless there is a prompt reversal of any ciliotoxic effect of tobacco smoke when cilia are removed for in vitro examination, the defective clearance seen in chronic cigarette smokers seems unlikely to be due to slowed ciliary beat frequency. It may be due to reduction in number of cilia or to change in the viscoelastic properties of mucus. The failure to detect any acute effect of tobacco smoke is in keeping with this hypothesis.
Crotaline snake bite in the Ecuadorian Amazon: randomised double blind comparative trial of three South American polyspecific antivenoms
Authors: Roger Smalligan, Judy Cole, Narcissa Brito, Gavin D Laing, Bruce L Mertz, Steven Manock, Jeffrey Maudlin, Brad Quist, Gary Holland, Stephen Nelson, David G Lalloo, Gonzalo Rivadeneira, Maria Elena Barragan, Daniel Dolley, Michael Eddleston, David A Warrell, R David G Theakston
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To compare the efficacy and safety of three polyspecific antivenoms for bites by pit vipers. <b>Design</b> Randomised double blind comparative trial of three antivenoms. <b>Setting</b> Shell, Pastaza, southeastern Ecuador. <b>Participants</b> 210 patients with incoagulable blood were recruited from 221 consecutive patients admitted with snake bite between January 1997 and December 2001. <b>Intervention</b> One of three antivenoms manufactured in Brazil, Colombia, and Ecuador, chosen for their preclinical potency against Ecuadorian venoms. <b>Main outcome measures</b> Permanent restoration of blood coagulability after 6 and 24 hours. <b>Results</b> The snakes responsible for the bites were identified in 187 cases: 109 patients (58%) were bitten by <i>Bothrops atrox</i>, 68 (36%) by <i>B bilineatus</i>, and 10 (5%) by <i>B taeniatus, B brazili</i>, or <i>Lachesis muta</i>. Eighty seven patients (41%) received Colombian antivenom, 82 (39%) received Brazilian antivenom, but only 41 (20%) received Ecuadorian antivenom because the supply was exhausted. Two patients died, and 10 developed local necrosis. All antivenoms achieved the primary end point of permanently restoring blood coagulability by 6 or 24 hours after the start of treatment in &gt; 40% of patients. Colombian antivenom, however, was the most effective after initial doses of 20 ml (two vials), &lt; 70 ml, and any initial dose at both 6 and 24 hours. An initial dose of 20 ml of Colombian antivenom permanently restored blood coagulability in 64% (46/72) of patients after 6 hours (P = 0.054 compared with the other two antivenoms) and an initial dose of &lt; 70 ml was effective at 6 hours (65%, P = 0.045) and 24 hours (99%, P = 0.06). Early anaphylactoid reactions were common (53%, 73%, and 19%, respectively, for Brazilian, Colombian, and Ecuadorian antivenoms, P &lt; 0.0001) but only three reactions were severe and none was fatal. <b>Conclusions</b> All three antivenoms can be recommended for the treatment of snakebites in this region, though the reactogenicity of Brazilian and Colombian antivenoms is a cause for concern.
Bone disease in primary biliary cirrhosis: Does ursodeoxycholic acid make a difference?*1
Authors: K LINDOR
Journal: Hepatology (1995)

Ursodeoxycholic acid (UDCA) has been proposed as beneficial therapy for patients with primary biliary cirrhosis (PBC). The effects of UDCA on metabolic bone disease, a major source of morbidity in patients with PBC, are essentially unknown. Preliminary information suggests that UDCA may improve biochemical indices of bone disease, although information about the effects of UDCA on bone density is lacking. In this study, we describe the effects of UDCA on lumbar spine bone mineral densities over a 3-year period during which patients were enrolled in a randomized, double-blind, therapeutic trial of UDCA for the treatment of PBC. Lumbar spine dual-photon densitometry was measured at entry and annually. Eighty-eight patients, 50 in the UDCA group and 38 in the placebo group, had serial measurements available for up to 3 years. There was no statistical difference between the two treatment groups at entry with respect to histological stage, total bilirubin, age, use of calcium supplement, vitamin D levels, or estrogen. After 3 years of treatment, there was no significant difference in the lumbar spine bone densitometry measurements between the UDCA-treated and placebo groups. We conclude that, after 3 years of treatment, UDCA is not associated with statistically significant differences in the rate of bone loss from the lumbar spine in patients when compared with placebo despite beneficial effects of treatment on the underlying liver disease. Further efforts to define effective treatments for the bone disease need to be pursued.
Geriatric Syndromes in Elderly Patients Admitted to an Oncology–Acute Care for Elders Unit
Authors: Kellie L. Flood, Maria B. Carroll, Cyndi V. Le, Linda Ball, Debbie A. Esker, David B. Carr
Journal: Journal of Clinical Oncology (2006)

The goal of this study was to characterize an elderly population admitted to a novel Oncology-Acute Care for Elders (OACE) unit, determine the prevalence of functional dependencies and geriatric syndromes, and examine their suitability for an interdisciplinary model of care.We conducted a retrospective review of 119 patients age 65 years or older who had a primary oncologic or hematologic diagnosis and were admitted to the OACE Unit. Standard geriatric screens were administered to assess mood, functional, and cognitive status. Demographic and medical data were compiled by review of patients' medical records.The mean age of the patients was 74.1 years (standard deviation, 5.9 years). The sample was predominantly white, of equal sex, had limitations in instrumental and basic activities of daily living, and a mean length of stay of 6 days. Geriatric syndromes detected by the OACE interdisciplinary team included cognitive impairment (dementia and/or delirium), depression, weight loss, and use of high-risk medications. Adverse events such as falls, restraint use, and pressure sores were rare.In this descriptive study, many older cancer patients were found to have geriatric syndromes by the OACE team and these patients were considered appropriate for an interdisciplinary model of care. Additional studies are needed to compare the outcomes of hospitalized older oncology patients receiving an OACE intervention with those patients receiving usual care.
Putting the Brakes on Snake Venom Evolution: The Unique Molecular Evolutionary Patterns of Aipysurus eydouxii (Marbled Sea Snake) Phospholipase A2 Toxins
Authors: Min Li, Bryan G Fry, R Manjunatha Kini
Journal: Molecular Biology and Evolution (2005)

Accelerated evolution of toxins is a unique feature of venoms, with the toxins evolving via the birth-and-death mode of molecular evolution. The venoms of sea snakes, however, are remarkably simple in comparison to those of land snakes, which contain highly complex venoms. Aipysurus eydouxii (Marbled sea snake) is a particularly unique sea snake, feeding exclusively upon fish eggs. Secondary to this ecological change, the fangs have been lost and the venom glands greatly atrophied. We recently showed that the only neurotoxin (a three-finger toxin) gene found in the sea snake A. eydouxii has a dinucleotide deletion, resulting in the loss of neurotoxic activity. During these studies, we isolated and identified a number of cDNA clones encoding isozymes of phospholipase A2 (PLA2) toxins from its venom gland. Sixteen unique PLA2 clones were sequenced from the cDNA library and TA cloning of reverse transcription-polymerase chain reaction products. Phylogenetic analysis of these clones revealed that less diversification of the PLA2 toxins has occurred in the A. eydouxii venom gland in comparison to equivalent terrestrial and other marine snakes. As there is no longer a positive selection pressure acting upon the venom, mutations have accumulated in the toxin-coding regions that would have otherwise had a deleterious effect upon the ability to use the venom for prey capture. Such mutations include substitutions of highly conserved residues; in one clone, the active site His48 is replaced by Arg, and in two other clones, highly conserved cysteine residues are replaced. These mutations significantly affect the functional and structural properties of these PLA2 enzymes, respectively. Thus, in A. eydouxii, the loss of the main neurotoxin is accompanied by a much slower rate of molecular evolution of the PLA2 toxins as a consequence of the snake's shift in ecological niche. This is the first case of decelerated evolution of toxins in snake venom.
N-Terminal Fragment of the Prohormone Brain-Type Natriuretic Peptide (NT-proBNP), Cardiovascular Events, and Mortality in Patients With Stable Coronary Heart Disease
Authors: Kirsten Bibbins-Domingo, Reena Gupta, Beeya Na, Alan H. B. Wu, Nelson B. Schiller, Mary A. Whooley
Journal: JAMA (2007)

Identification of individuals at high risk for cardiovascular events is important for the optimal use of primary and secondary prevention measures.To determine whether plasma levels of amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) predict cardiovascular events or death independent of other available prognostic tests.Prospective cohort study (2000-2002) of 987 individuals in California with stable coronary heart disease in the Heart and Soul Study, who were followed up for a mean of 3.7 (range, 0.1-5.3) years.The association of baseline NT-proBNP levels with death or cardiovascular events (myocardial infarction, stroke, or heart failure). Traditional clinical risk factors, echocardiographic measures, ischemia, other biomarkers, and New York Heart Association classification were adjusted for to determine whether NT-proBNP levels were independent of other prognostic factors. Receiver operating characteristic (ROC) curves were used to assess the incremental prognostic value of adding NT-proBNP level to these other measures.A total of 256 participants (26.2%) had a cardiovascular event or died. Each increasing quartile of NT-proBNP level (range of quartile 1, 8.06-73.95 pg/mL; quartile 2, 74-174.5 pg/mL; quartile 3, 175.1-459 pg/mL; quartile 4, > or =460 pg/mL) was associated with a greater risk of cardiovascular events or death, ranging from 23 of 247 (annual event rate, 2.6%) in the lowest quartile to 134 of 246 (annual event rate, 19.6%) in the highest quartile (unadjusted hazard ratio [HR] for quartile 4 vs quartile 1, 7.8; 95% confidence interval [CI], 5.0-12.1; P<.001). Each SD increase in log NT-proBNP level (1.3 pg/mL) was associated with a 2.3-fold increased rate of adverse cardiovascular outcomes (unadjusted HR, 2.3; 95% CI, 2.0-2.6; P<.001), and this association persisted after adjustment for all of the other prognostic measures (adjusted HR, 1.7; 95% CI, 1.3-2.2; P<.001). The addition of NT-proBNP level to standard clinical assessment and complete echocardiographic parameters significantly improved the area under the ROC curves for predicting subsequent adverse cardiovascular outcomes (0.80 for clinical risk factors and echocardiographic parameters plus log NT-proBNP vs 0.76 for clinical risk factors and echocardiographic parameters only; P = .006).Elevated levels of NT-proBNP predict cardiovascular morbidity and mortality, independent of other prognostic markers, and identify at-risk individuals even in the absence of systolic or diastolic dysfunction by echocardiography. Level of NT-proBNP may help guide risk stratification of high-risk individuals, such as those with coronary heart disease.
International consensus statement on idiopathic pulmonary fibrosis
Authors: U. Costabel, T.E. King
Journal: European Respiratory Journal (2001)

In the new millennium, idiopathic pulmonary fibrosis (IPF) is not what it was thought to be 20 years ago. In the past, the term was used for a heterogeneous group of interstitial lung disorders of unknown cause, after exclusion of possible exposures or associated conditions. Now IPF is more narrowly defined as a distinct clinical entity, with certain characteristic clinical, radiological and morphological features; specifically, the pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy 1. Historically, several histopathological subsets of the family of the idiopathic interstitial pneumonias were considered part of the spectrum of IPF (or cryptogenic fibrosing alveolitis (CFA), the preferred term in the British literature). The Liebow classification of 1969, divided the idiopathic interstitial pneumonias into several histological subsets: usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), bronchiolitis obliterans with interstitial pneumonia (BIP), lymphoid interstitial pneumonia (LIP), and giant cell interstitial pneumonia (GIP). LIP and GIP were dropped from this classification because many of the former cases were found to be lymphoproliferative disorders and many of the latter were cases of hard metal pneumoconiosis. Recently, Katzenstein and Myers 2 proposed that the entities acute interstitial pneumonia (AIP or diffuse alveolar damage of unknown aetiology) and nonspecific interstitial pneumonia (NSIP) be added to the spectrum of idiopathic interstitial pneumonia. Furthermore, the specific features of the UIP pattern have been more clearly defined, allowing for better separation of this lesion from the other patterns, particularly NSIP. The major reason for separating IPF/UIP, the most common idiopathic interstitial pneumonia, from the other entities, was the increasingly reported severe prognosis in the IPF/UIP subset compared to the other subgroups of the idiopathic interstitial pneumonias. Median survival for the more narrowly defined IPF patients is now only 2.8 yrs, compared to approximately 5 yrs in previous studies, which often included cases with …
Insertion of the v-Ha-ras oncogene induces differentiation of calcitonin-producing human small cell lung cancer.
Authors: M Mabry, T Nakagawa, S Baylin, O Pettengill, G Sorenson, B Nelkin
Journal: Journal of Clinical Investigation (1989)

Human small cell lung cancers (SCLC) and cell lines derived therefrom are phenotypically heterogeneous concerning neuroendocrine differentiation. Unlike most SCLC tumors and cell lines that express poorly differentiated neuroendocrine phenotypes, the SCLC cell line DMS 53 exhibits mature endocrine differentiation features, including unusually high expression of the gene for the peptide hormone, calcitonin (CT). We now report that introduction of the viral Harvey ras (v-rasH) oncogene into DMS 53 cells via retroviral infection, with resultant constitutive expression, results in increased features of neuroendocrine differentiation. 7-10 d after infection the cells demonstrated altered morphology, increased CT secretion, increased CT gene expression, markedly diminished cellular proliferation, and nearly abolished methylcellulose cloning efficiency. This response of DMS 53 cells to v-rasH is unlike the tumor progression effects we have previously observed in other SCLC lines. Significantly, the differentiation response that follows expression of the virally introduced v-rasH oncogene in DMS 53 cells is similar to that of neoplastic neuroendocrine cell lines derived from adrenal pheochromocytes and thyroid C cells. The effects of constitutive v-rasH expression in DMS 53 SCLC cells and other neuroendocrine cell lines suggest an important role for rasH or related genes in neuroendocrine differentiation.
Effect of amiodarone on the expression of myosin isoforms and cellular growth of cardiac muscle cells in culture.
Authors: A C Nag, M L Lee, D Shepard
Journal: Circulation Research (1990)

The effect of amiodarone on the expression of myosin isoforms and the growth of neonatal rat cardiac muscle cells in culture was studied by native gel electrophoresis, assays of DNA and protein synthesis, and electron microscopy. Cardiac myocytes exposed to amiodarone in the absence of triiodothyronine (T3) showed predominant V1. When cardiac myocytes were exposed to amiodarone in the presence of T3, they expressed prevalent isomyosin V3, or both V3 and V1 equally. Supraphysiological concentration of T3 counteracted the effect of amiodarone on myocytes, showing the expression of predominant isomyosin V1. Amiodarone has inhibitory effects on DNA synthesis and differentiation of cardiac myocytes. Myocytes treated with amiodarone showed maximum labeling index with 11% labeled cells after day 1. Subsequently, the labeling indexes declined and on the third day ceased, as opposed to the control culture, which attained a peak in labeling index with 60% labeled myocytes on the third day. The labeling indexes declined, showing 11% labeled myocytes at the terminal time point. Myocytes treated with amiodarone lost most of the well-organized myofibrils and other organelles, and instead contained sparse, scattered segments of myofibrils, free myofilaments, many mitochondria with disrupted cristae, and autophagic vacuoles. The results demonstrated that amiodarone has a direct influence on the expression of isomyosin by cardiac myocytes. Furthermore, this drug has inhibitory and degrading effects on the growth and differentiation of cardiac myocytes.
Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1
Authors: Sonya M. Abraham, Toby Lawrence, Anna Kleiman, Paul Warden, Mino Medghalchi, Jan Tuckermann, Jeremy Saklatvala, Andrew R. Clark
Journal: The Journal of Experimental Medicine (2006)

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1−/− mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1α and 1β) was impaired in DUSP1−/− mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1−/− mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.
TANRIC: An Interactive Open Platform to Explore the Function of lncRNAs in Cancer
Authors: Jun Li, Leng Han, Paul Roebuck, Lixia Diao, Lingxiang Liu, Yuan Yuan, John N. Weinstein, Han Liang
Journal: Cancer Research (2015)

Abstract Long noncoding RNAs (lncRNA) have emerged as essential players in cancer biology. Using recent large-scale RNA-seq datasets, especially those from The Cancer Genome Atlas (TCGA), we have developed “The Atlas of Noncoding RNAs in Cancer” (TANRIC; http://bioinformatics.mdanderson.org/main/TANRIC:Overview), a user-friendly, open-access web resource for interactive exploration of lncRNAs in cancer. It characterizes the expression profiles of lncRNAs in large patient cohorts of 20 cancer types, including TCGA and independent datasets (&amp;gt;8,000 samples overall). TANRIC enables researchers to rapidly and intuitively analyze lncRNAs of interest (annotated lncRNAs or any user-defined ones) in the context of clinical and other molecular data, both within and across tumor types. Using TANRIC, we have identified a large number of lncRNAs with potential biomedical significance, many of which show strong correlations with established therapeutic targets and biomarkers across tumor types or with drug sensitivity across cell lines. TANRIC represents a valuable tool for investigating the function and clinical relevance of lncRNAs in cancer, greatly facilitating lncRNA-related biologic discoveries and clinical applications. Cancer Res; 75(18); 3728–37. ©2015 AACR.
KING EDWARD'S HOSPITAL FUND BILL
Authors: E. R. Fothergill
Journal: BMJ (1907)

Caldwell, and other members objected to the Bill on the grounds that the whole management of the Fund was given to one person, that the same power was given to future presidents as that to be confided in the Prince of Wales, and that the president was irremovable.The committee took no objection to the methods of selecting