tbuckley/cabot-search huggingface dataset:
IMMUNOLOGIC PRODUCTION OF ANTIANGIOTENSIN
Authors: Sharad D. Deodhar
Journal: The Journal of Experimental Medicine (1960)

Angiotensin II was coupled with bovine gamma-globulin (BGG) through the following series of reactions. See PDF for Structure By determinations of the aromatic amine and tyrosine contents of p-aminobenzoylangiotensin II, the number of p-aminobenzoyl residues introduced per molecule of angiotensin II was calculated. Absorption spectra (between 250 and 500 mmicro) of BGG complexes of p-aminobenzoylangiotensin II and six different para substituted aromatic amines were compared. Specific activities (dog units/millimicromole) of the different intermediate products were determined. Presence of a terminal, free amino group does not appear to be an absolute requirement for the biological activity of angiotensin II, since substitution of a p-aminobenzoyl radical in this group yields a product with 40 to 50 per cent of the activity of the parent compound. Angiotensin I, on the other hand, is completely inactivated under identical circumstances. Possible implication of this finding has been discussed.
H Bonding at the Helix-Bundle Crossing Controls Gating in Kir Potassium Channels
Authors: Markus Rapedius, Philip W. Fowler, Lijun Shang, Mark S.P. Sansom, Stephen J. Tucker, Thomas Baukrowitz
Journal: Neuron (2007)

Specific stimuli such as intracellular H+ and phosphoinositides (e.g., PIP2) gate inwardly rectifying potassium (Kir) channels by controlling the reversible transition between the closed and open states. This gating mechanism underlies many aspects of Kir channel physiology and pathophysiology; however, its structural basis is not well understood. Here, we demonstrate that H+ and PIP2 use a conserved gating mechanism defined by similar structural changes in the transmembrane (TM) helices and the selectivity filter. Our data support a model in which the gating motion of the TM helices is controlled by an intrasubunit hydrogen bond between TM1 and TM2 at the helix-bundle crossing, and we show that this defines a common gating motif in the Kir channel superfamily. Furthermore, we show that this proposed H-bonding interaction determines Kir channel pH sensitivity, pH and PIP2 gating kinetics, as well as a K+-dependent inactivation process at the selectivity filter and therefore many of the key regulatory mechanisms of Kir channel physiology.
Adipose Tissue α-Linolenic Acid and Nonfatal Acute Myocardial Infarction in Costa Rica
Authors: Ana Baylin, Edmond K. Kabagambe, Alberto Ascherio, Donna Spiegelman, Hannia Campos
Journal: Circulation (2003)

Alpha-linolenic acid may protect against cardiovascular disease. We examined the association between adipose tissue alpha-linolenic acid and nonfatal acute myocardial infarction (MI) in a population-based case-control study in Costa Rica.The 482 case patients with a first nonfatal acute MI and 482 population control subjects were matched by age, sex, and area of residence. Fatty acids were assessed by gas-liquid chromatography in adipose tissue samples collected from all subjects. ORs and 95% CIs were calculated from multivariate conditional logistic regression models. Subjects in the top quintiles of adipose tissue alpha-linolenic acid had a lower risk of MI than those in the lowest quintile: OR (95% CI), 1.00; 0.80 (0.52 to 1.24); 0.53 (0.34 to 0.82); 0.44 (0.28 to 0.67); and 0.37 (0.24 to 0.59); test for trend, P<0.0001. This association was strengthened after adjustment for established MI risk factors, including smoking, physical activity, income, and adipose tissue linoleic acid and trans fatty acids (OR for the top versus lowest quintile, 0.23; 95% CI, 0.10 to 0.50; test for trend, P<0.0001). Further adjustment for the intake of saturated fat, fiber, alcohol, and vitamin E did not change this association (OR for the top versus lowest quintile, 0.23; 95% CI, 0.10 to 0.55; test for trend, P<0.0001).The inverse association observed between alpha-linolenic acid and nonfatal acute MI suggests that consumption of vegetable oils rich in alpha-linolenic acid confers important protection against cardiovascular disease.
Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing
Authors: David C. Turner, Fariba Navid, Najat C. Daw, Shenghua Mao, Jianrong Wu, Victor M. Santana, Michael Neel, Bhaskar Rao, Jennifer Reikes Willert, David M. Loeb, K. Elaine Harstead, Stacy L. Throm, Burgess B. Freeman, Clinton F. Stewart
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results: Bevacizumab concentration–time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P &amp;lt; 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P &amp;lt; 0.05). Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res; 20(10); 2783–92. ©2014 AACR.
GC Factor 2 Represses Platelet-Derived Growth Factor A-Chain Gene Transcription and Is Itself Induced by Arterial Injury
Authors: Levon M. Khachigian, Fernando S. Santiago, Louise A. Rafty, Onza L.-W. Chan, Gabrielle J. Delbridge, Alex Bobik, Tucker Collins, Alfred C. Johnson
Journal: Circulation Research (1999)

Abstract —Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for a wide variety of cell types. The genes encoding PDGF A chain (PDGF-A) and PDGF B chain (PDGF-B) reside on separate chromosomes and are independently regulated at the level of transcription. Regulatory events underlying inducible PDGF-A expression have been the focus of much investigation. However, mechanisms that inhibit transcription of this gene are not well understood. In this study, we report the capacity of a newly cloned DNA binding factor, GC factor 2 (GCF2), to repress expression driven by the human PDGF-A promoter. 5′ Deletion and transient cotransfection analysis in vascular endothelial cells revealed that GCF2 repression is mediated by a nucleotide region located in the proximal region of the PDGF-A promoter. Electrophoretic mobility shift assays demonstrate that GCF2 binds to this region in a specific and dose-dependent manner. Interestingly, the site bound by GCF2 overlaps those for specificity protein-1 (Sp1) and early growth response factor-1 (Egr-1), zinc finger transcription factors that direct basal and inducible expression of the PDGF-A gene. Gel shift experiments revealed that GCF2 competes with these factors for interaction with the PDGF-A promoter. Overexpression of GCF2 suppressed endogenous PDGF-A expression in vascular endothelial cells and smooth muscle cells. GCF2 was induced on mechanical injury of cells in culture as well as after balloon injury of the rat carotid artery wall. Time course studies revealed the sustained induction of GCF2 after injury while PDGF-A levels sharply returned to baseline. Smooth muscle cell proliferation was inhibited by GCF2, an effect reversed by the addition of exogenous PDGF-AA. These findings demonstrate negative regulation of PDGF-A expression by GCF2. This is the first report of the induction of an endogenous transcriptional repressor in the rat vessel wall.
The Wnt Antagonist Dickkopf-1 Mobilizes Vasculogenic Progenitor Cells via Activation of the Bone Marrow Endosteal Stem Cell Niche
Authors: Alexandra Aicher, Orit Kollet, Christopher Heeschen, Stefan Liebner, Carmen Urbich, Christian Ihling, Alessia Orlandi, Tsvee Lapidot, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2008)

Therapeutic mobilization of vasculogenic progenitor cells is a novel strategy to enhance neovascularization for tissue repair. Prototypical mobilizing agents such as granulocyte colony-stimulating factor mobilize vasculogenic progenitor cells from the bone marrow concomitantly with inflammatory cells. In the bone marrow, mobilization is regulated in the stem cell niche, in which endosteal cells such as osteoblasts and osteoclasts play a key role. Because Wnt signaling regulates endosteal cells, we examined whether the Wnt signaling antagonist Dickkopf (Dkk)-1 is involved in the mobilization of vasculogenic progenitor cells. Using TOP-GAL transgenic mice to determine activation of β-catenin, we demonstrate that Dkk-1 regulates endosteal cells in the bone marrow stem cell niche and subsequently mobilizes vasculogenic and hematopoietic progenitors cells without concomitant mobilization of inflammatory neutrophils. The mobilization of vasculogenic progenitors required the presence of functionally active osteoclasts, as demonstrated in PTPε-deficient mice with defective osteoclast function. Mechanistically, Dkk-1 induced the osteoclast differentiation factor RANKL, which subsequently stimulated the release of the major bone-resorbing protease cathepsin K. Eventually, the Dkk-1–induced mobilization of bone marrow–derived vasculogenic progenitors enhanced neovascularization in Matrigel plugs. Thus, these data show that Dkk-1 is a mobilizer of vasculogenic progenitors but not of inflammatory cells, which could be of great clinical importance to enhance regenerative cell therapy.
STING-Associated Vasculopathy with Onset in Infancy — A New Interferonopathy
Authors: Yanick J. Crow, Jean-Laurent Casanova
Journal: New England Journal of Medicine (2014)

The past 20 years have seen remarkable progress in our understanding of pathogen recognition by hematopoietic and nonhematopoietic cells. Central to this process is the sensing of microbial components by germline-encoded receptors. In the case of viruses, viral RNA and DNA are chief among the biologic motifs recognized by these receptors.In 2006, it was shown that transfection of DNA into various cell types induced a toll-like receptor (TLR)–independent up-regulation of type 1 interferons.1,2 In this context, the stimulator of interferon genes (STING) protein, a transmembrane protein that is localized to the endoplasmic reticulum, was described in 2008 as . . .
Survival After Second Primary Neoplasms of the Brain or Spinal Cord in Survivors of Childhood Cancer: Results From the British Childhood Cancer Survivor Study
Authors: Aliki J. Taylor, Clare Frobisher, David W. Ellison, Raoul C. Reulen, David L. Winter, Roger E. Taylor, Charles A. Stiller, Emma R. Lancashire, Edward C.G. Tudor, Christina Baggott, Shaun May, Mike M. Hawkins
Journal: Journal of Clinical Oncology (2009)

Survival after brain or spinal cord neoplasms is poor and varies by diagnostic group, age, grade, treatment and pretreatment factors, and location and size of tumor. We carried out a study to investigate survival and factors affecting survival of all diagnostic types of second primary brain or spinal cord neoplasms.The British Childhood Cancer Survivor Study (BCCSS) is a long-term population-based follow-up study of 17,980 5-year survivors of childhood cancer. We used relative survival and multivariate Cox regression analysis to determine 5-year relative survival and factors affecting survival in second primary meningiomas and gliomas that developed in survivors included in the BCCSS.There were 247 second primary brain or spinal cord neoplasms, including 137 meningiomas and 73 gliomas in a young adult population. Five-year relative survival after meningiomas was similar for males (84.0%; 95% CI, 72.6% to 91.1%) and females (81.7%; 95% CI, 69.9% to 89.3%). For gliomas, 5-year relative survival was 19.5% (95% CI, 8.6% to 33.7%) for males and females. Multivariate analysis showed significant heterogeneity by decade of treatment (P = .04), grade (P = .03), and genetic risk (P = .03) for rate of mortality after a meningioma. For gliomas, survival was significantly affected by grade (P < .001).Our results indicate survival is poor after second primary glioma in this young adult population, although survival after second primary meningioma is good. Our study has clinical implications for the surveillance of childhood cancer survivors at risk of developing second primary brain tumors, in particular survivors of childhood acute lymphoblastic leukemia or childhood brain tumors.
EFFICACY OF LOW-DOSE HEPARIN IN PREVENTION OF EXTENSIVE DEEP-VEIN THROMBOSIS IN PATIENTS UNDERGOING TOTAL-HIP REPLACEMENT
Authors: S. Sagar, J.D. Stamatakis, A.F. Higgins, D. Nairn, F.H. Maffei, D.P. Thomas, V.V. Kakkar
Journal: The Lancet (1976)
Protein Tyrosine Phosphatase Shp2 (<i>Ptpn11</i>) Plays an Important Role in Maintenance of Chromosome Stability
Authors: Xia Liu, Hong Zheng, Cheng-Kui Qu
Journal: Cancer Research (2012)

Both activating and inactivating mutations in protein tyrosine phosphatase Ptpn11 (encoding Shp2) are associated with tumorigenesis. However, the underlying mechanisms remain unclear. Here, we show that Shp2 plays an important role in mitosis, dysregulation of which results in chromosome instability and cancer predisposition. Depletion of Shp2 compromised the mitotic checkpoint. Shp2-depleted cells exhibited a delay in mitotic entry and an earlier mitotic exit. Moreover, Shp2 deficiency caused defective kinetochore-microtubule attachment, chromosome misalignment, chromosomal congression defects, lagging chromosomes, and chromosome missegregation. Reintroduction of wild-type Shp2, but not a catalytically deficient mutant, restored the checkpoint function and chromosome alignment at metaphase in Shp2-deficient cells, establishing a requirement for the catalytic activity of Shp2 during mitosis. Further analyses revealed that Shp2 was required for the optimal activation of the mitotic kinases PLK1 and Aurora B and thereby the proper kinetochore localization and phosphorylation of BubR1, a core mitotic checkpoint protein that is also critical for chromosome alignment. Together, our findings show a previously unrecognized role for Shp2 in the maintenance of chromosome stability and suggest a new mechanism by which dysregulation of Shp2 signaling contributes to malignancy development.
A randomized controlled trial of a 12-month course of recombinant human interferon-α in chronic delta (type D) hepatitis: A multicenter Italian study
Authors: Floriano Rosina, Cristina Pintus, Carlton Meschievitz, Mario Rizzetto
Journal: Hepatology (1991)

To determine whether long-term therapy with recombinant interferon-alpha can improve the course of chronic delta hepatitis, 61 Italian patients with this disease were randomly assigned to receive either interferon-alpha-2b three times a week (5 MU/m2 for 4 mo and then 3 MU/m2 for another 8 mo) or no treatment. At the end of the 12-mo study, all patients were followed-up for 12 additional months. Normalization or decrease of more than 50% from baseline of serum ALT levels occurred in 42% of treated patients the fourth month of therapy, 26% the twelfth month and 3% the twenty-fourth month vs. 7%, 7% and 0%, respectively, in the control group. However, relapses occurred in 7 of 8 (87.5%) responders 1 to 10 mo (mean = 3.5 mo) after cessation of therapy. Liver biopsies were carried out at baseline and during the twelfth month of treatment. Histological improvement, mostly caused by decrease of portal inflammation, was observed in 57% of treated and 36% of untreated patients. Measures of antiviral activity (serum hepatitis delta virus RNA and intrahepatic hepatitis delta antigen) showed similar levels in treated and control patients. In treated patients the percentage of patients who were negative for HDV RNA never exceeded that of baseline. Although interferon-alpha in the dosage given in this study had no antiviral effect on patients with chronic hepatitis D, it reduced hepatic inflammation as measured by ALT levels. Whether a longer duration or reinstitution of interferon-alpha therapy would achieve long-term control of ALT levels and prevent chronic liver damage is not known.
Paediatrics in Barcelona: highlights from the 2010 ERS Annual Congress
Authors: E. Eber, K. C. Lodrup Carlsen, F. Ratjen, S. W. Turner, J. E. Dankert-Roelse, R. I. Ross-Russell, F. Midulla, P. Aurora, G. Hedlin
Journal: European Respiratory Journal (2011)

The aim of this update is to describe the paediatric highlights from the 2010 European Respiratory Society Annual Congress in Barcelona, Spain. Abstracts from the seven groups of the Paediatric Assembly (Respiratory physiology, Asthma and allergy, Cystic fibrosis, Respiratory infection and immunology, Neonatology and paediatric intensive care, Respiratory epidemiology and Bronchology) are presented in the context of the current literature.
Selective Modulation of Coupled Ryanodine Receptors During Microdomain Activation of Calcium/Calmodulin-Dependent Kinase II in the Dyadic Cleft
Authors: Eef Dries, Virginie Bito, Ilse Lenaerts, Gudrun Antoons, Karin R. Sipido, Niall Macquaide
Journal: Circulation Research (2013)

Rationale: In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs. Objective: Our aim was to test the hypothesis that coupled and noncoupled RyRs have distinct microdomain-dependent modulation. Methods and Results: We studied single myocytes from pig left ventricle. The T-tubule network was analyzed in 3-dimension (3D) to measure distance to membrane of release sites. The rising phase of the Ca 2+ transient was correlated with proximity to the membrane (confocal imaging, whole-cell voltage-clamp, K 5 fluo-4 as Ca 2+ indicator). Ca 2+ sparks after stimulation were thus identified as resulting from coupled or noncoupled RyRs. We used high-frequency stimulation as a known activator of Ca 2+ /calmodulin-dependent kinase II. Spark frequency increased significantly more in coupled than in noncoupled RyRs. This specific modulation of coupled RyRs was abolished by the Ca 2+ /calmodulin-dependent kinase II blockers autocamtide-2–related inhibitory peptide and KN-93, but not by KN-92. Colocalization of Ca 2+ /calmodulin-dependent kinase II and RyR was not detectably different for coupled and noncoupled sites, but the F-actin disruptor cytochalasin D prevented the specific modulation of coupled RyRs. NADPH oxidase 2 inhibition by diphenyleneiodonium or apocynin, or global reactive oxygen species scavenging, also prevented coupled RyR modulation. During stimulated Ca 2+ transients, frequency-dependent increase of the rate of Ca 2+ rise was seen in coupled RyR regions only and abolished by autocamtide-2–related inhibitory peptide. After myocardial infarction, selective modulation of coupled RyR was lost. Conclusions: Coupled RyRs have a distinct modulation by Ca 2+ /calmodulin-dependent kinase II and reactive oxygen species, dependent on an intact cytoskeleton and consistent with a local Ca 2+ /reactive oxygen species microdomain, and subject to modification with disease.
Virtual outreach: economic evaluation of joint teleconsultations for patients referred by their general practitioner for a specialist opinion
Authors: P B Jacklin
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objectives</b> To test the hypotheses that, compared with conventional outpatient consultations, joint teleconsultation (virtual outreach) would incur no increased costs to the NHS, reduce costs to patients, and reduce absences from work by patients and their carers. <b>Design</b> Cost consequences study alongside randomised controlled trial. <b>Setting</b> Two hospitals in London and Shrewsbury and 29 general practices in inner London and Wales. <b>Participants</b> 3170 patients identified; 2094 eligible for inclusion and willing to participate. 1051 randomised to virtual outreach and 1043 to standard outpatient appointments. <b>Main outcome measures</b> NHS costs, patient costs, health status (SF-12), time spent attending index consultation, patient satisfaction. <b>Results</b> Overall six months costs were greater for the virtual outreach consultations (£724 per patient) than for conventional outpatient appointments (£625): difference in means £99 ($162; €138) (95% confidence interval £10 to £187, P=0.03). If the analysis is restricted to resource items deemed "attributable" to the index consultation, six month costs were still greater for virtual outreach: difference in means £108 (£73 to £142, P &lt; 0.0001). In both analyses the index consultation accounted for the excess cost. Savings to patients in terms of costs and time occurred in both centres: difference in mean total patient cost £8 (£5 to £10, P &lt; 0.0001). Loss of productive time was less in the virtual outreach group: difference in mean cost £11 (£10 to £12, P &lt; 0.0001). <b>Conclusion</b> The main hypothesis that virtual outreach would be cost neutral is rejected, but the hypotheses that costs to patients and losses in productivity would be lower are supported.
Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors
Authors: Chandrashekhar R Gandhi, Noriko Murase, Vladimir M Subbotin, Tadahiro Uemura, Michael Nalesnik, Anthony J Demetris, John J Fung, Thomas E Starzl
Journal: Journal of Hepatology (2002)
Aldosterone responses to hyperkalemia in healthy elderly humans.
Authors: E Mulkerrin, F H Epstein, B A Clark
Journal: Journal of the American Society of Nephrology (1995)

Plasma aldosterone levels are reported to be lower in healthy elderly individuals compared with young individuals, a difference exaggerated by sodium depletion or upright posture. The aim of this study was to determine the aldosterone response to increases in serum potassium with advancing age. In the Clinical Research Center, six healthy young (20 to 35 yr of age) and six healthy elderly (65 to 85 yr of age) subjects underwent evaluation of their aldosterone responses to potassium infusion (0.5 mEq/kg over 45 min). Both young and elderly subjects had similar basal serum potassium levels (4.3 +/- 0.2 versus 4.4 +/- 0.1 mEq/L), similar sodium and potassium excretion amounts and similar increase in serum potassium levels during infusion (to 5.0 +/- 0.2 versus 5.1 +/- 0.1 mEq/L). However, elderly subjects had lower basal levels of plasma aldosterone and a blunted aldosterone response to potassium infusion (P < 0.05, analysis of variance). Advancing age is characterized by relative hypoaldosteronism in the basal state as well as in response to hyperkalemia. This may contribute to an increased susceptibility to hyperkalemia if other potassium regulatory systems fail.