tbuckley/cabot-search huggingface dataset:
Abstract P6-04-14: mRNA expressions of lamin B1 and lamin B receptor: Clinical correlations with human breast cancer
Authors: U Wazir, MH Ahmad, JM Bridger, A Harvey, WG Jiang, AK Sharma, K Mokbel
Journal: Cancer Research (2013)

Abstract BACKGROUND: Lamin B (LMNB) and lamin B receptor (LBR) are key components of the nuclear envelope, with roles in chromosomal stability, DNA repair, and cell differentiation. Lamins provide structural support to the nuclear envelope, while LBR is believed to anchor lamin B to the envelope. In addition, LBR also has a number of downstream mediators which affect cell cycle and cell differentiation. Classically, they have been implicated in a spectrum of largely congenital ailments including certain forms of muscle dystrophy and progeria. These conditions are collectively referred to as “laminopathies”. More recently, defects in the expression of lamins have been implicated in neoplasias of the colon, prostate, liver and ovaries. In this study, we have endeavoured to elucidate the relationships between the mRNA expressions of LMNB1 and LBR and the clinicopathological parameters of human breast cancer. METHODS: Breast cancer tissues (n = 115) and associated non-cancerous tissue (ANCT) (n = 30) underwent reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. RESULTS: LMNB1 mRNA expression was higher in ANCT as compared to cancerous tissue (ANCT vs. cancerous tissue: 0.12 vs. 0.00; p = &amp;lt;0.0001). This difference remained highly significant in all patient categories by tumour grade and clinical stage. In addition, the expression of LMNB1 declined with worsening clinical outcome. This association was statistically significant when comparing patient with disease-free survival with disease related mortalities (Disease-free vs. mortalities: 0.0011 vs. 0.000; p = 0.0177). LBR mRNA expression was found to be directly associated with tumour grade (grade 1 vs.3: 0.00 vs. 0.00; p = 0.0479) and the Nottingham Prognostic Index (NPI1 vs. 3: 0.00 vs. 0.00; p = 0.0551). CONCLUSIONS: To our knowledge, this is the first study to suggest such a role for LMNB1 and LBR in human breast cancer. The contrasting relationships of LMNB1 and LBR expressions with the clinicopathological parameters of human breast cancer may suggest that disruptions in the physiologically normal interactions between these molecules in the nuclear envelope may serve as pathway leading towards the pathogenesis of human breast cancer. Potentially this may be a significant pathway requiring further investigation to be better understood, in order to identify further potential areas for therapeutic intervention. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-14.
Human Neutrophil Heterogeneity Identified Using Flow Microfluorometry to Monitor Membrane Potential
Authors: Bruce Seligmann, Thomas M. Chused, John I. Gallin
Journal: Journal of Clinical Investigation (1981)

Previous studies of neutrophil nitroblue tetrazolium dye reduction in response to endotoxin and rosetting of IgG-coated erythryocytes have suggested functional heterogeneity of peripheral blood neutrophils. In the following study we utilized flow microfluorometry and the membrane potential-sensitive fluorescent dye 3-3′-dipentyloxacarbocyanine to assess the heterogeneity of neutrophils upon activation by a variety of stimuli. Unstimulated neutrophils from normal subjects exhibited a unimodal distribution of fluorescence, suggesting that all the cells possessed the same resting membrane potential. As neutrophils aged (>5 h), some cells lost fluorescence producing a bimodal distribution. In studies with fresh cells, the secretagogue phorbol myristate acetate (20 ng/ml) stimulated a uniform loss of fluorescence (apparent depolarization). The chemoattractant N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) (0.1 μM) caused the neutrophils to assume and maintain (for > 30 min) a bimodal fluorescence distribution in which 65±5% of the neutrophils first decreased and then increased fluorescence (apparent depolarization/partial repolarization), and 35±5% of the cells exhibited either an increase in fluorescence (apparent hyperpolarization) or no change. Treatment of neutrophils with cytochalasin B before stimulation caused the cells to respond homogeneously to f-Met-Leu-Phe. Additional studies using neutrophils from patients with chronic granulomatous disease, which exhibit abnormal membrane potential responses, indicated that this defect affected all such neutrophils uniformly. These observations demonstrate the need to investigate the physiological significance of the heterogeneity of neutrophil function and indicate that the f-Met-Leu-Phe-induced changes in membrane potential observed in bulk population cell studies are the summation of two different responses.
Abstract 5151: Transcriptional regulation of the pyruvate dehydrogenase kinase Pdk2 by tumor suppressors
Authors: Tanupriya Contractor, Chris Harris
Journal: Cancer Research (2012)

Abstract Conversion of pyruvate into lactate despite the presence of oxygen is a hallmark of the Warburg effect, and distinguishes the metabolism of many tumors from the metabolism of many normal cell types. Pdk2, a pyruvate dehydrogenase kinase, facilitates conversion of pyruvate into lactate by inhibiting the pyruvate dehydrogenase complex, which would otherwise convert pyruvate into acetyl-CoA. Previously, Pdk2 activity was thought to be controlled exclusively in a post-translational fashion, through inhibition or activation by metabolites. But in this study we show that two important tumor suppressor pathways, p53 and retinoblastoma, prevent the Warburg effect, and do so through repression of pdk2 transcription. Importantly, a heterologous promoter that drives physiological expression of Pdk2, but disallows repression by p53 or Rb, prevents these tumor suppressors from blocking the Warburg effect. Another consequence of pdk2 repression is increased production of reactive oxygen species, which stimulates p53-dependent apoptosis. We further show that when unable to downregulate Pdk2 expression, p53 can no longer cause apoptosis. Thus two critical features of tumor suppression, apoptosis and pyruvate metabolism, are mediated by repression of pdk2 transcription. This study proves that proper transcriptional regulation of the pdk2 gene is critical for tumor suppression. 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 5151. doi:1538-7445.AM2012-5151
A Single Procalcitonin Level Does Not Predict Adverse Outcomes of Women with Pyelonephritis
Authors: Virginie Lemiale, Bertrand Renaud, Stéphane Moutereau, Alfred N'Gako, Mirna Salloum, Marie Jeanne Calmettes, Jérôme Hervé, Cyril Boraud, Aline Santin, Jean-Claude Grégo, François Braconnier, Eric Roupie
Journal: European Urology (2006)
Differences in Illness and Prognostic Signs in Two Groups of Young Men
Authors: William N. Christenson
Journal: JAMA (1961)

THERE are probably no biological interactions more complex than those which take place between men and the environment in which they live; yet, in spite of this, it has been customary to consider only quite circumscribed features of human activity—such as the pattern of eating, or the amount of physical activity associated with an occupation—as largely determining whether or not men will develop quite specific diseases, such as atherosclerosis or essential hypertension.  It has also been assumed that one can find populations which are essentially homogeneous with regard to all pertinent aspects of human activity except 1 or 2, and which, therefore, may be used to investigate the specific effects of these specific activities upon specific disease syndromes, without considering other and more complex human activities which might significantly influence the occurrence of many diseases, and which might significantly alter the interpretation of the findings. Having available an unusually
Subarachnoid Hemorrhage Following Ephedrine and MAO Inhibitor
Authors: Martin S. Hirsch
Journal: JAMA (1965)

<h3>To the Editor:—</h3> Since 1957 the monoamine oxidase (MAO) inhibitors have been widely used in the treatment of depression, despite conflicting studies regarding their effectiveness. The adverse reactions associated with these drugs have been many and serious.<sup>1</sup>Particularly disquieting are the reports of hypertensive crises and intracranial bleeding when MAO inhibitors are used in conjunction with various sympathomimetic amines or their precursors. Among compounds reported to precipitate these complications in patients taking MAO inhibitors are tyramine (in beer, wine, cheese, yogurt),<sup>2</sup>amphetamine,<sup>3</sup>methamphetamine,<sup>4</sup>dihydroxyphenylalanine, ie, dopa (in broad beans),<sup>5</sup>and alphamethyl dopa.<sup>6</sup>The following is a report of a patient taking an MAO inhibitor who developed a subarachnoid hemorrhage immediately following the ingestion of one oral dose of ephedrine. A 49-year-old white woman was under treatment for a moderately severe depressive reaction with an MAO inhibitor, nialamide (Niamid), 100 to 150 mg daily since
Abstract 3220: Lichen derived polyphenols as potential anticancer drugs
Authors: Gajendra Shrestha, Michael Xiao, Richard Robison, Larry L. St. Clair, Kim O'Neill
Journal: Cancer Research (2014)

Abstract Polyphenols such as resveratrol, curcumin, (-)-epigallocatechin 3-gallate (EGCG) etc. have been shown to have anticancer properties. The anticancer activities of polyphenols include, but are not limited to, anti-oxidative effects, pro-apoptosis, DNA damage, anti-angiogenic effects, and immunostimulation. Lichens, symbiotic systems involving a fungus and an alga and/or cyanobacterium, are a rich source of polyphenols. Based on our previous research we have demonstrated that crude extracts of different lichen species affect cell proliferation, cell cycle dynamics, and cause apoptosis in Burkitt's lymphoma (Raji cells). This research examines the effects of a lichen-derived polyphenol compound, usnic acid, on human colon adenocarcinoma (HT-29) cells. We treated HT-29 cells with various concentrations (10, 30 and 50 µg/ml) of usnic acid for 24 hours. Although the viability was not affected by the treatment, there was a significant decrease in cell proliferation in dose-dependent manner. We also observed that after treatment, the morphology of treated cells was completely different from that of untreated control cells. Using transmission electron microscopy (TEM), we studied the morphological differences between control and treated HT-29 cells. The TEM micrographs clearly show that usnic acid damaged the mitochondria, reduced the amount of free ribosomes, and also distorted the shape of the nucleus. As the treatment of HT-29 with usnic acid reduced the rate of cell proliferation significantly, we investigated the effects of usnic acid on HT-29 cell cycle dynamics. Our results indicate that with the higher usnic acid concentrations (30 and 50 µg/ml) the cell cycle was stopped at the G0/G1 stage. These results further document the pattern of decreasing proliferation of HT-29 cells treated with usnic acid. With the distortion of the nucleus following exposure to usnic acid, we also investigated the effects of usnic acid on DNA the HT-29 cells. We performed a single cell gel electrophoresis (Comet Assay) to study the DNA damaging effects of various concentrations of usnic acid. Our results showed that there was a dose dependent increase in damage to the HT-29 cells' DNA resulting in 56.7% of the total DNA moving into the comet tail at 50 µg/ml concentration of usnic acid. These preliminary results suggest that lichen derived polyphenols could be a potential source of anticancer drug therapies. However, additional research is needed to further validate these findings. Citation Format: Gajendra Shrestha, Michael Xiao, Richard Robison, Larry L. St. Clair, Kim O'Neill. Lichen derived polyphenols as potential anticancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3220. doi:10.1158/1538-7445.AM2014-3220
Kupffer cell–derived 95-kd type IV collagenase/gelatinase B: Characterization and expression in cultured cells
Authors: Paul J. Winwood, Detlef Schuppan, John P. Iredale, Choudhury A. Kawser, Andrew J. P. Docherty, Michael J. P. Arthur
Journal: Hepatology (1995)

Release of 92-kd type IV collagenase/gelatinase, also known as gelatinase B, by inflammatory and tumor cells is increasingly recognized and is believed to facilitate cellular migration across basement membranes. It has been implicated in the pathogenesis of many diseases, but little is known of its cellular origin(s) and function in liver. In this study we have demonstrated synthesis and release of gelatinase B by human and rat Kupffer cells in primary culture. Northern analysis of RNA extracted from Kupffer cells stimulated with phorbol ester demonstrated a 2.8 kb transcript for gelatinase B. Immunoblotting and zymography of serum-free Kupffer cell-conditioned media demonstrated extracellular release of immunoreactive enzyme and gelatinase activity, Mr 92,000 (95,000 from rat cells). The organomercurial 4-aminophenyl mercuric acetate (APMA) activated the enzyme in vitro, indicating secretion primarily as a proenzyme. Stimulation of Kupffer cells by phorbol ester markedly induced gelatinase B release, which was inhibited by cycloheximide. In contrast, cycloheximide had no effect on constitutive secretion in culture, suggesting that there is some intracellular storage. Kupffer cell-derived gelatinase B was also partially purified and characterized. After separation by gelatin sepharose and gel filtration chromatogrpahy, gelatin-degrading activities of 95, 88, 75, and 65 kd were detected, the three lower-molecular-weight species probably representing activated forms. Enzyme activity was inhibited by ethyl-enediaminetetra-acetic acid (EDTA), but not by serine- and thiol-protease inhibitors, and was restored by zinc. Activity was also inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1) and alpha-2 macroglobulin. The partially purified enzyme rapidly degraded denatured collagens (gelatin) as well as native types III, IV, and V collagens, but had no activity against casein, types I and VI collagens.
Impact of Quality-of-Care Factors on Pediatric Intensive Care Unit Mortality
Authors: Murray M. Pollack
Journal: JAMA (1994)

<h3>Objective.</h3> —To determine the importance of the following care factors previously associated with hospital quality on survival from pediatric intensive care: size of the intensive care unit (ICU), medical school teaching status of the hospital housing the ICU, specialist status (pediatric intensivist), and unit coordination. <h3>Design.</h3> —After a national survey, consecutive case series were collected at 16 sites randomly selected to represent unique combinations of quality-of-care factors. <h3>Setting.</h3> —Pediatric ICUs. <h3>Patients.</h3> —Consecutive admissions to each site. <h3>Main Outcome Measure.</h3> —Patient mortality adjusted for physiologic status, diagnosis, and other mortality risk factors. <h3>Results.</h3> —There were 5415 pediatric ICU admissions and 248 ICU deaths. The ICUs differed significantly with respect to descriptive variables, including mortality (range, 2.2% to 16.4%). Analysis of risk-adjusted mortality indicated that the hospital teaching status and the presence of a pediatric intensivist were significantly associated with a patient's chance of survival. The probability of patient survival after hospitalization in an ICU located in a teaching hospital was decreased (relative odds of dying, 1.79; 95% confidence interval [Cl], 1.23 to 2.61;<i>P</i>=.002). In contrast, the probability of patient survival after hospitalization in an ICU with a pediatric intensivist was improved (relative odds of dying, 0.65; 95% Cl, 0.44 to 0.95;<i>P</i>=.027). Post hoc analysis indicated that the higher severity-adjusted mortality in teaching hospitals may be explained by the presence of residents caring for ICU patients. <h3>Conclusion.</h3> —Characteristics indicative of the best overall hospital quality may not be associated, or may be negatively associated, with quality of care in specialized care areas, including the pediatric ICU. (<i>JAMA</i>. 1994;272:941-946)
When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?
Authors: M Dougados
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. <b>Methods:</b> Patients with active RA ((DAS28) &gt;3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. <b>Results:</b> 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. <b>Conclusion:</b> Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.
Inspiratory muscle strength and endurance during hyperinflation and histamine induced bronchoconstriction.
Authors: R B Gorman, D K McKenzie, S C Gandevia, B L Plassman
Journal: Thorax (1992)

This study investigated whether the inspiratory muscles are susceptible to fatigue during acute airway narrowing because of increased airway resistance and hyperinflation.Asthmatic subjects performed up to four series (on separate days) of 18 maximal static inspiratory efforts of 10 seconds' duration with 10 second rest intervals (50% duty cycle; total duration six minutes): at functional residual capacity (FRC) (control); after histamine induced bronchoconstriction, which decreased forced expiratory volume in one second (FEV1) to a mean of 55% (SD 11%) of the initial value; at a voluntarily increased lung volume (initial volume held at 140% control); and after inhalation of histamine at a voluntarily increased lung volume.For the group of subjects the mean (SD) maximal inspiratory pressure (MIP) in the control experiments was 114 (22) cmH2O and the initial volume was 3.5 (1.2) 1. After histamine inhalation the initial lung volume for contractions increased to 118% (5%) of the control volume. In the high lung volume experiments initial volumes were 140% (12%) of the control (volume without histamine) and 140% (15%) (with histamine). The relation between MIP and initial absolute lung volume was determined for each subject before fatigue developed. When the inspiratory pressures for each contraction in the endurance test were normalised to the pressure expected for that lung volume, no significant differences were found between the four experimental conditions for MIP, or between pressures sustained over the 18 contractions.Histamine induced bronchoconstriction and hyperinflation had no detectable effect on inspiratory muscle strength or endurance in these asthmatic subjects.
Statins for Aortic Stenosis
Authors: Raphael Rosenhek
Journal: New England Journal of Medicine (2005)

Calcific aortic stenosis is affecting an increasing number of patients in developed countries. It is a progressive disease that leads to a need for aortic-valve replacement when stenosis becomes severe and symptoms develop.14 The growing number of valve-replacement procedures is a burden on health care systems.The active inflammatory component of calcific aortic-valve disease has been recognized, and similarities with atherosclerotic disease have been identified. Both calcific aortic-valve disease and atherosclerosis are characterized by lipid infiltration, inflammation, neoangiogenesis, and calcification,5,6 and the two diseases often coexist. Patients with any degree of aortic-valve disease (e.g., aortic sclerosis, mild-to-moderate stenosis, . . .
Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.
Authors: J D Fulmer, W C Roberts, E R von Gal, R G Crystal
Journal: Journal of Clinical Investigation (1979)

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of lung parenchyma characterized by a chronic inflammatory cellular infiltration and varying degrees of interstitial fibrosis. Current data indicate that the severity of fibrosis and the degree of cellularity determine, in part, the prognosis of IPF and the response to therapy. Whereas lung biopsy gives the best assessement of fibrosis and cellularity, physiologic studies are used to stage and monitor the disease process. To determine which physiologic studies correlate best with severity of fibrosis and degree of cellularity, these parameters were graded in lung biopsies of 23 patients with IPF and compared with a variety of physiologic studies. Although vital capacity, total lung capacity, and diffusing capacity are commonly used as objective monitors of the disease process, none of these parameters correlated with either the severity of fibrosis or the degree of cellularity in biopsy specimens. In contrast, almost all parameters of lung distensibility correlated with the morphologic assessment of degree of fibrosis; compliance had the best correlation. Parameters of distensibility, however, correlated poorly with the degree of cellularity. In comparison, gas exchange during exercise correlated with both morphologic parameters; the exercise-induced changes in arterial oxygen pressure per liter of oxygen consumed had a high correlation with the degree of fibrosis (r = 0.89; P less than 0.001) and correlated to a lesser extent with the degree of cellularity (r = 0.56; P = 0.009). In contrast, neither the resting arterial oxygen tension nor the arterial oxygen tension at maximal exercise correlated with the morphologic assessment of degree of fibrosis or the degree of cellularity. These morphologic-physiologic comparisons suggest that (a) lung volumes and diffusing capacity are poor monitors of both the degree of fibrosis and the degree of cellularity; (b) the fibrotic process contributes, at least in part, to parameters of lung distensibility, and both fibrosis and cellularity contribute to gas exchange alterations during exercise; and (c) parameters of lung distensibility and exercise-induced gas exchange alterations may be useful in staging the severity of disease in IPF.