tbuckley/cabot-search huggingface dataset:
Effect of Nonspecific Binding to Plasma Proteins on the Antithrombin Activities of Unfractionated Heparin, Low-Molecular-Weight Heparin, and Dermatan Sulfate
Authors: Benilde Cosmi, James C. Fredenburgh, Janice Rischke, Jack Hirsh, Edward Young, Jeffrey I. Weitz
Journal: Circulation (1997)

Background Nonspecific binding to plasma proteins decreases the anti–factor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not that of low-molecular-weight heparin (LMWH). However, plasma proteins could influence the anti-thrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the anti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS binds to plasma proteins. Methods and Results There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plasma from each of 20 healthy volunteers. The addition of a chemically modified heparin with low affinity for antithrombin III to plasma containing UFH increased the anti-IIa activity in a concentration-dependent fashion by displacing UFH from plasma proteins. In contrast, addition of low-affinity heparin had no effect on the anti-IIa activity of LMWH. LMWH does not bind to plasma proteins because the bulk of the LMWH chains are &lt;6000 D, and only heparin fractions &gt;6000 D bind nonspecifically to plasma proteins. As further evidence that plasma proteins do not influence the anti-IIa activity of LMWH, the rate of thrombin inhibition in plasma in the presence of LMWH is virtually identical to that in buffer containing physiological amounts of the major antithrombins. In contrast, with UFH or DS, the rate of thrombin inhibition is twofold slower in plasma than in buffer. Conclusions Nonspecific binding of UFH to plasma proteins most likely contributes to the variable anti-IIa response to UFH in patients with thromboembolic disease. Although DS also binds to plasma proteins, the clinical significance of this finding is unclear. In contrast, because LMWH does not bind to plasma proteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.
Rifampicin and treatment of cholestatic pruritus
Authors: A F Hofmann
Journal: Gut (2002)

Prince et al described three patients with primary biliary cirrhosis who developed hepatotoxicity when given rifampicin to treat their cholestatic pruritus ( Gut 2002; 50 :436–9). They describe the use of rifampicin as “secondline” treatment of cholestatic pruritus. Firstline therapy is generally considered to be cholestyramine, a bile acid sequestrant. Use of this agent is frequently unsatisfactory because of gastrointestinal side effects, especially constipation. I am writing to summarise new evidence that retention of endogenous bile acids causes cholestatic pruritus, and to call attention to a recent abstract indicating that colesevalem, a new bile acid sequestrant, appears to be more potent than cholestyramine and does not induce constipation.

The view that bile acid retention causes pruritus is a very old one. Varco1 in 1947 noted that biliary drainage reduced pruritus in patients with extrahepatic biliary obstruction and that when bile was fed to patients, their pruritus returned. Huet and colleagues2 reported that biliary drainage improved cholestatic pruritus in patients with intrahepatic cholestasis. Administration of cholestyramine, an anion exchange resin with a strong affinity …
Exposure to Phthalates in Neonatal Intensive Care Unit Infants: Urinary Concentrations of Monoesters and Oxidative Metabolites
Authors: Jennifer Weuve, Brisa N. Sánchez, Antonia M. Calafat, Ted Schettler, Ronald A. Green, Howard Hu, Russ Hauser
Journal: Environmental Health Perspectives (2006)

We previously demonstrated that among 54 infants in neonatal intensive care units, exposure to polyvinyl chloride plastic medical devices containing the plasticizer di(2-ethylhexyl) phthalate (DEHP) is associated with urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP) , a DEHP metabolite. In this follow-up report, we studied the neonates' exposure to DEHP-containing devices in relation to urinary concentrations of two other DEHP metabolites, and to urinary concentrations of metabolites of dibutyl phthalate (DBP) and benzylbutyl phthalate (BzBP) , phthalates found in construction materials and personal care products.
Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain
Authors: Haiyan Fu, Joseph Muenzer, Richard J Samulski, George Breese, Jerillyn Sifford, Xinhua Zeng, Douglas M McCarty
Journal: Molecular Therapy (2003)

The blood-brain barrier is the main obstacle to efficient delivery of therapeutic reagents, including viral vectors, into the central nervous system (CNS) for treating global CNS diseases. In this study, the effects of mannitol infusions on global brain gene expression of a novel AAV vector were examined after intravenous (i.v.) or intracisternal injection. Initially, a self-complementary adeno-associated virus serotype 2 vector (scAAV) was compared to traditional single-stranded AAV2 vector for reporter gene expression in the brain of adult mice with or without pretreatment of an i.v. mannitol infusion. One to two months postinjection, analysis of vector-transduced green fluorescent protein (GFP) expression in the brain revealed that vector delivery to the CNS via i.v. injection required pretreatment with mannitol. This expression was observed only when scAAV vectors were used. Using these conditions, transgene expression was observed in various neurons and glial cells throughout the brain. The peripherally administered scAAV vectors also transduced the cells in multiple somatic tissues with efficient expression in liver (20-30% of hepatocytes), but was less efficient in other somatic tissues. Intracisternal injection of scAAV vector produced a broad and intense transgene expression in both neurons and glial cells in the CNS of injected mice ranging from the olfactory area to the brain stem and spinal cord. More than 50% of the Purkinje cells in the cerebellum expressed GFP. Intravenous infusion of mannitol before intracisternal injection of the scAAV vector enhanced the dispersion of the vector in the CNS. Further optimization of these steps combining peripheral and intracisternal scAAV gene delivery should facilitate the development of treatments for global CNS diseases, especially diseases involving both the somatic system and the CNS, such as lysosomal storage disorders.
Cesarean Section Delivery After Death of the Mother
Authors: Charles A. Behney
Journal: JAMA (1961)

POSTMORTEM cesarean section deliveries are infrequently reported in the literature. In 1956, Kelly and Winston<sup>1</sup>found only 111 cases reported in which the infant survived. To these they added 2 cases from the New York Metropolitan Hospital Center. De Kruif<sup>2</sup>provided 1 more; Weil and Graber,<sup>3</sup>an additional 2; Leonard and Stone,<sup>4</sup>2 more in 1958; Wacker,<sup>5</sup>1 in 1959; Hendrick,<sup>6</sup>1 in 1960, and Cloud,<sup>7</sup>4 in 1960. This makes a total of 124 cases in which the operation was followed by survival of the infant and his discharge from the hospital. Only in a few instances is the subsequent growth and development of these children mentioned. In these cases where the follow-up period ranged from 8 weeks to 18 months, it was said that the children grew and developed normally. In the Michigan Maternal Mortality Study, the fetal outcome is
Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell (CIK) cultures and anti-CD20 antibodies
Authors: Alice Pievani, Camilla Belussi, Christian Klein, Alessandro Rambaldi, Josée Golay, Martino Introna
Journal: Blood (2010)

Abstract We have investigated combining adoptive immunotherapy with cytokine-induced killer (CIK) cells and anti-CD20 monoclonal antibodies (mAb) GA101 or rituximab to optimize B-cell non-Hodgkin lymphoma (B-NHL) therapy. CIK cultures alone demonstrated significant cytotoxic activity against B-NHL cell lines or freshly isolated samples in either an autologous or allogeneic combination. This natural cytotoxicity (NC) was mainly due to the predominating CD3+CD56+ CIK population (40%–75%) present in the cultures. The addition of anti-CD20 mAb GA101 or rituximab further increased cytotoxicity by 35% and 15%, respectively. This enhancement was mainly due to antibody-dependent cytotoxicity (ADCC) mediated by the 1%–10% NK cells contaminating CIK cultures. The addition of human serum (HS) inhibited NK-cell activation induced by rituximab, but not activation induced by GA101.Overall lysis in presence of serum, even of a resistant B-NHL cell line, was significantly increased by 100 μg/mL of rituximab, but even more so by GA101, with respect to CIK cultures alone. This was due to the combined action of complement-mediated cytotoxicity (CDC), ADCC, and CIK-mediated NC. These data suggest that rituximab, and even more so GA101, could be used in vivo to enhance CIK therapeutic activity in B-NHL.
STUDIES ON RABBIT LYMPHOCYTES IN VITRO
Authors: Stewart Sell
Journal: The Journal of Experimental Medicine (1968)

Rabbit antisera to immunoglobulin allotype Ab4 will stimulate a maximum of 77% (mean +/- SEM = 39.78 +/- 4.8) blast transformation of Ab4Ab4 homozygous lymphocytes in vitro and a maximum of 39% (mean +/- SEM = 19.77 +/- 1.6) blast transformation of heterozygous Ab4Ab5 lymphocytes. Similarly anti-Ab5 sera will induce a maximum of 82% (mean +/- SEM = 50.83 +/- 7.0) blast transformation of Ab5Ab5 homozygous lymphocytes in vitro and a, maximum of 42% (mean +/- SEM = 16.1 +/- 1.6) blast transformation of heterozygous Ab4Ab5 lymphocytes. Thus, the lymphocytes of an allotypically heterozygous rabbit appear to be selected to produce or express only one of the two genetically supplied allotypic determinants controlled by the "b" locus. A similar conclusion has been made in regard to allotypic expression by immunoglobulin-producing plasma cells. Previous data indicate that each lymphocyte carries or expresses more than one immunoglobulin group specificity (IgG, IgA, IgM) while each plasma cell carries only one. One possible interpretation of these data is that, while the production of immunoglobulin groups and allotypic specificities are under similar control in both the lymphocyte and the plasma cell, the lymphocyte produces immunoglobulin that remains in or attached to itself and the plasma cell produces immunoglobulins that are secreted rapidly.
Lower expression of PKAα impairs insulin secretion in islets isolated from low-density lipoprotein receptor (LDLR−/−) knockout mice
Authors: Maria Lúcia Bonfleur, Rosane Aparecida Ribeiro, Sandra Lucinei Balbo, Emerielle Cristine Vanzela, Everardo Magalhães Carneiro, Helena Coutinho Franco de Oliveira, Antonio Carlos Boschero
Journal: Metabolism (2011)
Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects.
Authors: E Melillo, K L Woolley, P J Manning, R M Watson, P M O'Byrne
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.
Low-Output, Low-Gradient Aortic Stenosis in Patients With Depressed Left Ventricular Systolic Function
Authors: Rick A. Nishimura, J. Aaron Grantham, Heidi M. Connolly, Hartzell V. Schaff, Stuart T. Higano, David R. Holmes
Journal: Circulation (2002)

Background— Although aortic valve replacement can be performed at an acceptable risk level in selected patients with left ventricular systolic dysfunction and low-output, low-gradient aortic stenosis, not all patients presenting with these hemodynamics will benefit from the operation. Some patients may have only mild aortic stenosis, despite a small calculated valve area. We report on the clinical utility of diagnostic dobutamine stimulation during cardiac catheterization in these diagnostically challenging patients. Methods and Results— Thirty-two patients with low-output, low-gradient aortic stenosis and an ejection fraction &lt;40% had dobutamine infusion in the catheterization laboratory. On the basis of the results of the dobutamine test, 21 patients underwent aortic valve replacement. All patients with a final aortic valve area ≤1.2 cm 2 at peak dobutamine infusion and a mean gradient of &gt;30 mm Hg were found to have severe calcific aortic stenosis at operation. In the 15 patients in whom contractile reserve was identified during dobutamine challenge (increase in stroke volume &gt;20%), 1 patient died perioperatively (7% mortality) and 12 patients were alive in New York Heart Association class I or II status at follow-up. Conclusions— In patients with left ventricular systolic dysfunction and aortic stenosis with a low output and a low mean gradient, dobutamine challenge may aid in selecting those who would benefit from an aortic valve operation.
Gamma-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro.
Authors: G K Hansson, L Jonasson, J Holm, M M Clowes, A W Clowes
Journal: Circulation Research (1988)

A significant fraction of the arterial smooth muscle cells in atherosclerotic plaques and injury-induced intimal thickenings express class II major histocompatibility complex (Ia) antigens. This might be the consequence of gamma-interferon secretion by T lymphocytes also present in these lesions. We have therefore analyzed the effects of gamma-interferon on cultured rat aortic smooth muscle cells. Recombinant gamma-interferon inhibited smooth muscle proliferation in vitro in a dose-response relation; inhibition was detectable down to a concentration of 1 unit/ml. In similar concentrations, gamma-interferon also induced Ia expression by the cells. This suggested that Ia antigens might be selectively expressed by nonproliferating smooth muscle cells. In vivo, there was a strong negative correlation between Ia expression and 3H-thymidine labeling of smooth muscle cells in intimal thickenings induced by balloon catheter injury. In rats receiving continuous infusions of 3H-thymidine for two weeks after injury, Ia-positive 3H-positive cells had undergone fewer rounds of replication than Ia-negative ones. This indicates that Ia-expression both in vivo and in vitro is associated with a reduced proliferative capacity. These results suggest that gamma-interferon, a secretory product of activated T lymphocytes, acts as a natural regulator of smooth muscle cell growth and Ia expression in injury-induced intimal thickenings and atherosclerotic plaques.
Effects of glycosylated hemoglobin on vascular responses in vitro
Authors: Christine L Oltman, David D Gutterman, Eric C. Scott, Jennifer M Bocker, Kevin C Dellsperger
Journal: Cardiovascular Research (1997)

Vascular responses to endothelium-dependent vasodilators are greatly impaired in vivo, while isolated blood vessels from animals with diabetes mellitus demonstrate less consistent degrees of impairment. Glycation of proteins, such as hemoglobin, has been implicated in the vascular abnormalities associated with diabetes. Objective: The purpose of this study was to test the hypothesis that glycosylated hemoglobin is capable of reducing endothelium-dependent vasodilator responses, possibly explaining impaired dilation observed in vivo. Methods: To test this hypothesis, the effect of glycosylated hemoglobin (GH) on vascular responses was studied in several vascular beds, including ventricular microvessels and coronary, mesenteric, femoral, and renal arteries. Coronary arterioles were isolated and mounted between two glass pipettes in a pressurized (30 cmH2O) organ chamber. Isolated artery segments were studied using a standard isometric ring technique. Results: In ventricular microvessels, 10 nM nGH (non-GH) and GH both attenuated the relaxation to Ach. A lower concentration, 1 nM nGH or GH, did not alter dilation to Ach. In coronary, femoral, mesenteric and renal artery segments, endothelium-dependent responses were not altered by the presence of 10 or 100 nM nGH or GH. Conclusion: In coronary microvessels, and coronary, femoral, mesenteric and renal arteries, GH is not responsible for the impaired endothelial function associated with diabetes mellitus.
Abstract 5181: Dynamic cellular adhesivity of breast cancer cells conferred by CD44 varies with mesenchymal or epithelial phenotype
Authors: Luis F. Delgadillo, Venktesh S. Shirure, Tiantian Liu, Douglas J. Goetz, Fabian Benencia, Monica M. Burdick
Journal: Cancer Research (2012)

Abstract CD44 is a highly pleiotropic molecule whose many structural variants and glycan modifications determine function, particularly with respect to cell adhesion. In this study, we investigated the E-selectin ligand function of CD44 and its relationship with the mesenchymal versus epithelial cell phenotypes of breast cancer cells. Real time RT-PCR analysis for epithelial and mesenchymal cell markers showed that MDA-MB-231 and Hs-578T breast cancer cells are mesenchymal-like cells, but BT-20 and MDA-MB-468 breast cancer cells are epithelial-like cells. Flow cytometry revealed that all cell lines expressed CD44. Further exploration of the expression of specific CD44 isoforms at the mRNA level (by real time RT-PCR) and at the protein level (by flow cytometry) showed that mesenchymal-like breast cancer cells predominantly expressed CD44s but nearly undetectable levels of CD44v isoforms. On the other hand, epithelial-like cells expressed CD44s as well as CD44v isoforms. These results indicate that there are divergent CD44 isoform expression patterns in mesenchymal-like versus epithelial-like breast cancer cell lines. Further distinctions were observed in CD44 function in cells of the two phenotypes. Western blot analysis demonstrated that CD44 expressed by BT-20 cells were positive for E-selectin ligand activity, whereas CD44 of MDA-MB-231 cells failed to exhibit such functionality. Moreover, CD44v isoforms expressed by BT-20 cells, but not CD44s by MDA-MB-231 cells, mediated E-selectin adhesion under physiological flow conditions. Despite the positive ligand activity, none of the CD44v isoforms expressed by BT20 cells possessed HECA-452 reactivity by Western blot analysis. This finding indicates the absence of conventional sialofucosylated carbohydrates and the presence of potentially novel E-selectin reactive glycans. Collectively, these results show that CD44 expressed by epithelial-like cells, but not mesenchymal-like cells, are functional E-selectin ligands. Our investigation therefore implies an association of breast cancer cell adhesivity with the epithelial phenotype. Thus, future studies mechanistically linking the E-selectin ligand activity of CD44 isoforms with epithelial-to-mesenchymal transition may provide targets for novel breast cancer diagnostics, prognostics, and therapeutics. 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 5181. doi:1538-7445.AM2012-5181
Abstract 1823: AZ20, a novel potent and selective inhibitor of ATR kinase with in vivo antitumour activity
Authors: Xavier Jacq, Lisa Smith, Elaine Brown, Adina Hughes, Rajesh Odedra, Dan Heathcote, Jen Barnes, Steve Powell, Sharon Maguire, Victoria Pearson, Joana Boros, Peter Caie, Pia A. Thommes, Willem Nissink, Kevin Foote, Philip J. Jewsbury, Sylvie M. Guichard
Journal: Cancer Research (2012)

Abstract The DNA damage response (DDR) comprises a range of mechanisms that ensure the integrity of the genome. As part of the DDR and in response to specific DNA damage, the master kinases ATM, ATR and DNA-PK are activated in a coordinated fashion inducing cell cycle arrest and repair of the damage before resuming DNA replication. Alternatively they may induce apoptosis if the DNA damage is incompatible with cell viability. Due to their genetic instability, tumour cells may be more reliant on the DNA damage response and so inhibiting specific DDR components may lead to antitumour activity while minimizing toxicity in normal tissue. ATR (Ataxia telangectasia and Rad 3 mutated) is recruited at specific sites of DNA damage, namely ssDNA (single stranded DNA) coated with RPA (Replication Protein A). ATR activates downstream substrates that regulate replication fork progression, cell cycle checkpoint, and DNA repair proteins. Here we report the discovery of AZ20, a novel potent and selective inhibitor of ATR kinase identified by screening a subset of the AZ compound collection against the target enzyme. In vitro, AZ20 decreases pChk1 Ser345, pChk1 Ser317 and pChk1 Ser296 levels in a concentration-dependent manner. Prolonged exposure with AZ20 increases γH2AX pan-nuclear staining, indicative of replication stress. This is associated with S-phase arrest and increase in phospho-histone H3. AZ20 induces growth inhibition and cell death in vitro and its profile of activity is distinct from other cytotoxic agents such as platinum derivatives, permetrexed or docetaxel. The cytotoxic effect of AZ20 can be increased in combination with the selective ATM inhibitor KU-60019. AZ20 induces significant tumour growth inhibition in vivo at well tolerated doses. This is associated with a persistent elevation of γH2AX pan-nuclear staining in xenograft tissue, but a transient increase in mouse bone marrow at therapeutic doses, suggesting a favourable therapeutic index. 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 1823. doi:1538-7445.AM2012-1823