tbuckley/cabot-search huggingface dataset:
Differential Regulation of Vascular Tone and Remodeling via Stimulation of Type 2 and Type 6 Adenylyl Cyclases in the Ductus Arteriosus
Authors: Utako Yokoyama, Susumu Minamisawa, Ayako Katayama, Tong Tang, Sayaka Suzuki, Kousaku Iwatsubo, Shiho Iwasaki, Reiko Kurotani, Satoshi Okumura, Motohiko Sato, Shumpei Yokota, H. Kirk Hammond, Yoshihiro Ishikawa
Journal: Circulation Research (2010)

Prostaglandin (PG)E(2), which increases intracellular cAMP via activation of adenylyl cyclases (ACs), induces vasodilation and hyaluronan-mediated intimal thickening (IT) in the ductus arteriosus (DA) during late gestation. After birth, however, differential regulation of vasodilation and IT is preferable for treatment of patients with patent DA and DA-dependent congenital cardiac malformations.Our objectives were to examine whether AC isoforms play differential roles in DA vasodilation and IT.AC2 and AC6 were more highly expressed in rat DA than in the aorta during the perinatal period. AC6-targeted siRNA counteracted PGE(1)-induced hyaluronan production in rat DA smooth muscle cells. Overexpression of AC6 enhanced PGE(1)-induced hyaluronan production and induced IT in DA explants. Furthermore, IT of the DA was less marked in mice lacking AC6 than in wild-type and AC5-deficient mice. Stimulation of AC2 attenuated AC6-induced hyaluronan production via inhibition of the p38 mitogen-activated protein kinase pathway and AC6-induced IT of the DA. An AC2/6 activator, 6-[N-(2-isothiocyanatoethyl) aminocarbonyl] forskolin (FD1), did not induce hyaluronan-mediated IT in DA explants, although an AC5/6 activator, 6-[3-(dimethylamino)propionyl]-14,15-dihydroforskolin (FD6) did. Moreover, FD1 induced longer vasodilation of the DA than did PGE(1) without significant adverse effects in vivo.AC6 is responsible for hyaluronan-mediated IT of the DA and AC2 inhibited AC6-induced hyaluronan production. Stimulation of both AC2 and AC6 by FD1 induced longer vasodilation without hyaluronan-mediated IT in the DA in vivo. FD1 may be a novel alternative therapy to currently available PGE therapy for patients with DA-dependent congenital heart disease.
Haplotype Structure and Expression Divergence at the Drosophila Cellular Immune Gene eater
Authors: P. Juneja, B. P. Lazzaro
Journal: Molecular Biology and Evolution (2010)

The protein Eater plays an important role in microbial recognition and defensive phagocytosis in Drosophila melanogaster.We sequenced multiple alleles of the eater gene from an African and a North American population of D. melanogaster and found signatures of a partial selective sweep in North America that is localized around the second intron.This pattern is consistent with local adaptation to novel selective pressures during range expansion out of Africa.The North American sample is divided into two predominant haplotype groups, and the putatively selected haplotype is associated with a significantly higher gene expression level, suggesting that gene regulation is a possible target of selection.The eater alleles contain from 22 to 40 repeat units that are characterized by the presence of a cysteine-rich NIM motif.NIM repeats in the structural stalk of the protein exhibit concerted evolution as a function of physical location in the repeat array.Several NIM repeats within eater have previously been implicated in binding to microbial ligands, a function which in principle might subject them to special evolutionary pressures.However, we find no evidence of elevated positive selection on these pathogen-interacting units.Our study presents an instance where gene expression rather than protein structure is thought to drive the adaptive evolution of a pathogen recognition molecule in the immune system.
Toxicological properties of lead.
Authors: T Damstra
Journal: Environmental Health Perspectives (1977)

The pathological effects of lead on the renal, nervous, reproductive, endocrine, and immune systems have been reviewed. Emphasis is placed on reported subclinical effects due to chronic, low-level lead exposure. The crucial issue of whether subtle behavioral, intellectual, and developmental impairment occurs in young children, as a result of lead-induced CNS damage is discussed in detail. This issue remains unresolved. Further studies are needed in order to determine the long-term health effects of continuous, low-level lead exposure.
Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis
Authors: Jean-Louis Mas, Gilles Chatellier, Bernard Beyssen, Alain Branchereau, Thierry Moulin, Jean-Pierre Becquemin, Vincent Larrue, Michel Lièvre, Didier Leys, Jean-François Bonneville, Jacques Watelet, Jean-Pierre Pruvo, Jean-François Albucher, Alain Viguier, Philippe Piquet, Pierre Garnier, Fausto Viader, Emmanuel Touzé, Maurice Giroud, Hassan Hosseini, Jean-Christophe Pillet, Pascal Favrole, Jean-Philippe Neau, Xavier Ducrocq
Journal: New England Journal of Medicine (2006)

Carotid stenting is less invasive than endarterectomy, but it is unclear whether it is as safe in patients with symptomatic carotid-artery stenosis.We conducted a multicenter, randomized, noninferiority trial to compare stenting with endarterectomy in patients with a symptomatic carotid stenosis of at least 60%. The primary end point was the incidence of any stroke or death within 30 days after treatment.The trial was stopped prematurely after the inclusion of 527 patients for reasons of both safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval [CI], 2.0 to 7.2) and 9.6% after stenting (95% CI, 6.4 to 14.0); the relative risk of any stroke or death after stenting as compared with endarterectomy was 2.5 (95% CI, 1.2 to 5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5 to 4.2) and 3.4% after stenting (95% CI, 1.7 to 6.7); the relative risk was 2.2 (95% CI, 0.7 to 7.2). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P=0.02). There were more major local complications after stenting and more systemic complications (mainly pulmonary) after endarterectomy, but the differences were not significant. Cranial-nerve injury was more common after endarterectomy than after stenting.In this study of patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting. (ClinicalTrials.gov number, NCT00190398 [ClinicalTrials.gov].).
Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis
Authors: Yonghao Cao, Brittany A. Goods, Khadir Raddassi, Gerald T. Nepom, William W. Kwok, J. Christopher Love, David A. Hafler
Journal: Science Translational Medicine (2015)

CCR6 + myelin-reactive T cells from patients with multiple sclerosis secrete inflammatory cytokines compared to T cells from healthy subjects, showing a distinct pathogenic gene expression profile and sharing a transcriptome homology with encephalitogenic CD4 + T cells isolated from mice with experimental autoimmune encephalitis.
Early Growth Response-1 Worsens Ventilator-induced Lung Injury by Up-Regulating Prostanoid Synthesis
Authors: Nicola Ngiam, Vanya Peltekova, Doreen Engelberts, Gail Otulakowski, Martin Post, Brian P Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Ventilator-induced lung injury (VILI) is common and serious and may be mediated in part by prostanoids. We have demonstrated increased expression of the early growth response-1 (Egr1) gene by injurious ventilation, but whether—or how—such up-regulation contributes to injury is unknown.Objectives: We sought to define the role of Egr1 in the pathogenesis of VILI.Methods: An in vivo murine model of VILI was used, and Egr1+/+ (wild-type) and Egr1−/− mice were studied; the effects of prostaglandin E receptor subtype 1 (EP1) inhibition were assessed.Measurements and Main Results: Injurious ventilation caused lung injury in wild-type mice, but less so in Egr1−/− mice. The injury was associated with expression of EGR1 protein, which was localized to type II cells and macrophages and was concentrated in nuclear extracts. There was a concomitant increase in expression of phosphorylated p44/p42 mitogen-activated protein kinases. The prostaglandin E synthase (mPGES-1) gene has multiple EGR1 binding sites on its promoter, and induction of mPGES-1 mRNA (as well as the prostanoid product, PGE2) by injurious ventilation was highly dependent on the presence of the Egr1 gene. PGE2 mediates many lung effects via EP1 receptors, and EP1 blockade (with ONO-8713) lessened lung injury.Conclusions: This is the first demonstration of a mechanism whereby expression of a novel gene (Egr1) can contribute to VILI via a prostanoid-mediated pathway.
Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway
Authors: Simon D Bamforth, José Bragança, Cassandra R Farthing, Jürgen E Schneider, Carol Broadbent, Anna C Michell, Kieran Clarke, Stefan Neubauer, Dominic Norris, Nigel A Brown, Robert H Anderson, Shoumo Bhattacharya
Journal: Nature Genetics (2004)
Phosphorylation of Serine 188 Protects RhoA from Ubiquitin/Proteasome-Mediated Degradation in Vascular Smooth Muscle Cells
Authors: Malvyne Rolli-Derkinderen, Vincent Sauzeau, Laurent Boyer, Emmanuel Lemichez, Céline Baron, Daniel Henrion, Gervaise Loirand, Pierre Pacaud
Journal: Circulation Research (2005)

cAMP and cyclic GMP-dependent kinases (PKA and PKG) phosphorylate the small G protein RhoA on Ser188. We have previously demonstrated that phosphorylation of Ser188 inhibits RhoA-dependent functions and positively regulates RhoA expression, and that the nitric oxide (NO)/cGMP-dependent protein kinase pathway plays an essential role, both in vitro and in vivo, in the regulation of RhoA protein expression and functions in vascular smooth muscle cells. Here we analyze the consequences of Ser188 phosphorylation on RhoA protein degradation. By expressing Ser188 phosphomimetic wild-type (WT-RhoA-S188E) and active RhoA proteins (Q63L-RhoA-S188E), we show that phosphorylation of Ser188 of RhoA protects RhoA, particularly its active form, from ubiquitin-mediated proteasomal degradation. Coimmunoprecipitation experiments indicate that the resistance of the phosphorylated active form of RhoA to proteasome-mediated degradation is because of its cytoplasmic sequestration through enhanced RhoGDI interaction. In rat aortic smooth muscle cells, stimulation of PKG and inhibition of proteasome by lactacystin, induce nonadditive increases in RhoA protein expression. In addition, stimulation of PKG leads to the accumulation of GTP-bound RhoA in the cytoplasm. In vivo stimulation of the NO/PKG signaling by treating rats with sildenafil increased RhoA level and RhoA phosphorylation, and enhanced its association to RhoGDI in the pulmonary artery, whereas opposite effects are induced by chronic inhibition of NO synthesis in N-ω -nitro- l -arginine-treated rats. Our results thus suggest that Ser188 phosphorylation-mediated protection against degradation is a physiological process regulating the level of endogenous RhoA and define a novel function for RhoGDI, as an inhibitor of Rho protein degradation.
Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells
Authors: Takaharu Ichimura, Edwin J.P.v. Asseldonk, Benjamin D. Humphreys, Lakshman Gunaratnam, Jeremy S. Duffield, Joseph V. Bonventre
Journal: Journal of Clinical Investigation (2008)

Following injury, the clearance of apoptotic and necrotic cells is necessary for mitigation and resolution of inflammation and tissue repair. In addition to macrophages, which are traditionally assigned to this task, neighboring epithelial cells in the affected tissue are postulated to contribute to this process. Kidney injury molecule-1 (KIM-1 or TIM-1) is an immunoglobulin superfamily cell-surface protein not expressed by cells of the myeloid lineage but highly upregulated on the surface of injured kidney epithelial cells. Here we demonstrate that injured kidney epithelial cells assumed attributes of endogenous phagocytes. Confocal images confirm internalization of apoptotic bodies within KIM-1-expressing epithelial cells after injury in rat kidney tubules in vivo. KIM-1 was directly responsible for phagocytosis in cultured primary rat tubule epithelial cells and also porcine and canine epithelial cell lines. KIM-1 was able to specifically recognize apoptotic cell surface-specific epitopes phosphatidylserine, and oxidized lipoproteins, expressed by apoptotic tubular epithelial cells. Thus, KIM-1 is the first nonmyeloid phosphatidylserine receptor identified to our knowledge that transforms epithelial cells into semiprofessional phagocytes.
CARD4/NOD1 is not involved in inflammatory bowel disease
Authors: H Zouali, S Lesage, F Merlin, J-P Cézard, J-F Colombel, J Belaiche, S Almer, C Tysk, C O'Morain, M Gassull, S Christensen, Y Finkel, R Modigliani, C Gower-Rousseau, J Macry, M Chamaillard, G Thomas, J-P Hugot
Journal: Gut (2002)

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD.The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test.Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence.Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.
Pathogenesis of Myeloproliferative Disorders
Authors: Jyoti Nangalia, Jacob Grinfeld, Anthony R. Green
Journal: Annual Review of Pathology Mechanisms of Disease (2016)

Myeloproliferative neoplasms (MPNs) are a set of chronic hematopoietic neoplasms with overlapping clinical and molecular features. Recent years have witnessed considerable advances in our understanding of their pathogenetic basis. Due to their protracted clinical course, the evolution to advanced hematological malignancies, and the accessibility of neoplastic tissue, the study of MPNs has provided a window into the earliest stages of tumorigenesis. With the discovery of mutations in CALR, the majority of MPN patients now bear an identifiable marker of clonal disease; however, the mechanism by which mutated CALR perturbs megakaryopoiesis is currently unresolved. We are beginning to understand better the role of JAK2(V617F) homozygosity, the function of comutations in epigenetic regulators and spliceosome components, and how these mutations cooperate with JAK2(V617F) to modulate MPN phenotype.
The distribution of lysozyme, alpha‐1‐antitrypsin, and alpha‐1‐antichymotrypsin in normal hematopoietic cells and in myeloid leukemias: An lmmunoperoxidase study on cytocentrifuge preparations, smears, and paraffin sections
Authors: Lena Krugliak, Paul R. Meyer, Clive R. Taylor
Journal: American Journal of Hematology (1986)

Abstract Blood and bone marrow samples from 20 individuals with reactive conditions and 26 cases of acute and chronic myeloid leukemias were tested for the presence of lysozyme, alpha‐1‐antitrypsin (α‐1‐AT), and alpha‐1‐antichymotrypsin (α‐1‐ACT). We compared the reactivity of samples in smears, cytocentrifuge preparations, and paraffin sections. Lysozyme, alpha‐1‐antitrypsin, and alpha‐1‐antichymotrypsin were found only in polymorphonuclear leukocytes and monocytes and their precursors. Lymphocytes, Erosetting cells, Con A‐activated lymphocytes, natural killer (NK) cells, red blood cells, erythroblasts, and megakaryocytes were consistently negative. Leukemic myeloblasts showed definite reactivity for both alpha‐1‐antitrypsin and α‐1‐ACT, but not for lysozyme. By contrast, lysozyme was present in poorly differentiated leukemic monoblasts, while alpha‐1‐antitrypsin and alpha‐1‐antichymotrypsin showed only weak reactivity. More mature myeloid and moncytic cells showed positive staining for all three antigens tested with differences in staining distribution and intensity. In four cases of chronic myeloid leukemia (CML), circulating mature polymorphonuclear leukocytes were deficient in both lysozymne and alpha‐1‐antitrypsin. The use of lysozyme, alpha‐1‐antitrypsin, and alpha‐1‐antichymotrypsin identifies normal and leukemic cells of the myeloid‐monocytic series at all stages of maturation and is applicable to a variety of sample preparations.
Isolation and characterization of murine cell surface components. I. Purification of milligram quantities of Thy-1.1
Authors: RK Zwerner, PA Barstad, RT Acton
Journal: The Journal of Experimental Medicine (1977)

The Thy-l.1 molecule was isolated from the BW5147 murine lymphoblastoid cell line. The initial step in purification was the preparation of a crude plasma membrane fraction followed by acetone precipitation. The acetone pellet was solubilized using deoxycholate (DOC) and Thy-1.1 was purified by use of a Lens culinaris lectin affinity column and an AcA-34 gel filtration column. The purified glycoprotein with Thy-1.1 activity had a mol wt of approximately 25,000 daltons. The isolation of this molecule was effected by detecting Thy-I activity utilizing rabbit anti- mouse brain serum tested on rat thymocytes. Congenic anti-Thy-l.1 serum was ineffective in detecting Thy-l.1 after DOC solubilization. An antiserum prepared in rabbits to the purified Thy-1.1 was found to be cytotoxic to mouse and rat thymocytes. The cytotoxic activity of this antisera could be completely absorbed with AKR/Jax brain and thymus but was not absorbed by liver. In addition, AKR/Jax thymocytes totally absorbed all cytotoxic activity of the rabbit anti-purified Thy-1 serum for BW5147 cells suggesting that the cell line shares identical specificities with normal thymocytes. The purified Thy-1.1 molecule was able to totally absorb the cytotoxic activity of mouse congenic anti-Thy-1. These studies serve as a model for the isolation of other murine lymphoid cell surface components in quantities for detailed structural and functional analysis.
ECHO-PLANAR MAGNETIC RESONANCE IMAGING IN ABNORMAL PREGNANCIES
Authors: M.K. Stehling, P. Mansfield, R.J. Ordidge, R. Coxon, B. Chapman, A. Blamire, P. Gibbs, I.R. Johnson, E.M. Symonds, B.S. Worthington, R.E. Coupland
Journal: The Lancet (1989)
Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients
Authors: Sandrine Ostermann, Chantal Csajka, Thierry Buclin, Serge Leyvraz, Ferdy Lejeune, Laurent A. Decosterd, Roger Stupp
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 h−1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma→CSF), 7.2 × 10−4h−1 and the backwards rate, 0.76 h−1. Body surface area significantly influenced both clearance and VD, and clearance was sex dependent. The AUCCSF corresponded to 20% of the AUCplasma. A trend toward an increased Kplasma→CSF of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUCCSF/AUCplasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.
Economic evaluation of docetaxel–gemcitabine versus vinorelbine–cisplatin combination as front-line treatment of patients with advanced/metastatic non-small-cell lung cancer in Greece: a cost-minimization analysis
Authors: N. Maniadakis, V. Fragoulakis, A.G. Pallis, E. Simou, V. Georgoulias
Journal: Annals of Oncology (2009)
Ego defense mechanisms in COPD: Impact on health-related quality of life and dyspnoea severity
Authors: Saulo C. Albuquerque, Eduardo R. Carvalho, Rebeka S. Lopes, Igor S. Marques, Daniele S. Macêdo, Eanes D. Pereira, Thomas N. Hyphantis, André F. Carvalho
Journal: European Respiratory Journal (2011)

Purpose: To assess chronic obstructive pulmonary disorder (COPD) patients' defensive profile compared to healthy participants and to test whether specific ego defense mechanisms are associated with health-related quality of life (Hrolf) and self-reported dyspnoea severity.

Methods: In a cross-sectional study, we assessed in 80 patients with COPD and 80 age and gender-matched healthy participants, psychological distress (Hospital Anxiety and Depression Scale) and defense mechanisms/styles (Defense Style Questionnaire). Patients had their HRQOL evaluated with the St. George's Respiratory Questionnaire and underwent a comprehensive clinical evaluation with determination of functional parameters and dyspnoea severity.

Results: COPD patients presented higher scores in undoing, acting out, autistic fantasy, denial and splitting defenses compared to healthy-controls. Overall, patients showed a more immature (p=0.001) and/or neurotic (p=0.006) defensive profile. Higher scores of denial (p=0.044), somatization (p=0.009) and undoing (p=0.032) defenses were associated with poorer HRQoL, independently of the anticipated significant associations of clinical and psychological distress variables with impaired HRQoL. Somatization was strongly independently associated with more severe self-reported dyspnoea.

Conclusions: COPD patients exhibit a relatively immature and neurotic defensive profile. Pneumologists and consultation-liaison psychiatrists should consider the patients' underlying personality structure, especially somatization tendencies, since it is independently associated with HRQoL and dyspnoea severity.