tbuckley/cabot-search huggingface dataset:
Cardiac Abnormalities in Diabetic Patients With Neuropathy
Authors: Brian F. Johnson, Richard W. Nesto, Michael A. Pfeifer, William R. Slater, Aaron I. Vinik, Deborah A. Chyun, Gordon Law, Frans J.Th. Wackers, Lawrence H. Young
Journal: Diabetes Care (2004)

OBJECTIVE—The goal of this study was to determine whether treatment with an aldose reductase inhibitor (ARI) has beneficial effects on asymptomatic cardiac abnormalities in diabetic patients with neuropathy. RESEARCH DESIGN AND METHODS—Diabetic subjects with neuropathy (n = 81) with either a low diastolic peak filling rate or impaired augmentation of left ventricular (LV) ejection fraction (LVEF) during maximal bicycle exercise were identified by gated radionuclide ventriculography. Coronary artery disease, left ventricular hypertrophy, and valvular heart disease were excluded by clinical evaluation, myocardial perfusion imaging, and echocardiography. Subjects were randomized to receive blinded treatment with either the placebo or the ARI zopolrestat 500 or 1,000 mg daily for 1 year. RESULTS—After 1 year of ARI treatment, there were increases in resting LVEF (P &amp;lt; 0.02), cardiac output (P &amp;lt; 0.03), LV stroke volume (P &amp;lt; 0.004), and exercise LVEF (P &amp;lt; 0.001). In placebo-treated subjects, there were decreases in exercise cardiac output (P &amp;lt; 0.03), stroke volume (P &amp;lt; 0.02), and end diastolic volume (P &amp;lt; 0.04). Exercise LVEF increased with ARI treatment independent of blood pressure, insulin use, or the presence of baseline abnormal heart rate variability. There was no change in resting diastolic filling rates in either group. CONCLUSIONS—Diabetic patients with neuropathy have LV abnormalities that can be stabilized and partially reversed by ARI treatment.
STAT5 Is Crucial to Maintain Leukemic Stem Cells in Acute Myelogenous Leukemias Induced by MOZ-TIF2
Authors: Winnie F. Tam, Patricia S. Hähnel, Andrea Schüler, Benjamin H. Lee, Rachel Okabe, Nan Zhu, Saskia V. Pante, Glen Raffel, Thomas Mercher, Gerlinde Wernig, Ernesto Bockamp, Daniel Sasca, Andreas Kreft, Gertraud W. Robinson, Lothar Hennighausen, D. Gary Gilliland, Thomas Kindler
Journal: Cancer Research (2012)

Abstract MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essential for MOZ-TIF2–induced leukemic transformation itself. Lack of STAT5 in fetal liver cells caused rapid differentiation and loss of replating capacity of MOZ-TIF2–transduced cells enriched for LSCs. Furthermore, mice serially transplanted with Stat5−/− MOZ-TIF2 leukemic cells develop AML with longer disease latency and finally incomplete penetrance when compared with mice transplanted with Stat5+/+ MOZ-TIF2 leukemic cells. These data suggest that STAT5AB is required for the self-renewal of LSCs and represents a combined signaling node of FLT3-ITD and MOZ-TIF2 driven leukemogenesis. Therefore, targeting aberrantly activated STAT5 or rewired downstream signaling pathways may be a promising therapeutic option. Cancer Res; 73(1); 373–84. ©2012 AACR.
A case of the Dubin-Johnson syndrome complicated by acute hepatitis
Authors: R. R. Varma, J. M. Grainger, P. J. Scheuer
Journal: Gut (1970)

A patient is described in whom the Dubin-Johnson syndrome was diagnosed after an attack of acute hepatitis at the age of 21. In the eight years following the hepatitis Dubin-Johnson pigment, initially scanty, developed to classical proportions. The defect in intracellular transport of bilirubin was thought to precede the attack of acute hepatitis.
N-Linked Glycosylation Is Critical for the Plasma Membrane Localization of Nephrin
Authors: Kunimasa Yan, Jamshid Khoshnoodi, Vesa Ruotsalainen, Karl Tryggvason
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The expression pattern, subcellular localization, and the role of glycosylation of the human nephrin was examined in transfected cells. Stable cell lines, constitutively expressing a full-length human nephrin cDNA construct, were generated from transfected immortalized mouse podocytes (IMP) and a human embryonic kidney cell line (HEK-293). Immunofluorescence confocal microscopy of transfected cells showed plasma membrane localization of the recombinant nephrin. Immunoblotting showed that the recombinant nephrin expressed in transfected cell lines migrated as a double band with a molecular weight of 185 kD. When cells were treated with the N -glycosylation inhibitor, tunicamycin, the molecular weight of nephrin was decreased to a single immunoband of 150 kD, indicating that the shift in the electrophoretic migration of nephrin is due to N -linked carbohydrate moieties. It was further shown that this glycosylation process is highly sensitive to inhibition by tunicamycin, which is a naturally occurring antibiotic, leading to retention of nonglycosylated nephrin molecules in the endoplasmic reticulum. It was concluded that N -glycosylation of nephrin is crucial for its proper folding and thereby plasma membrane localization; therefore, inhibition of this process might be an important factor in the onset of pathogenesis of some acquired glomerular diseases.
International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands
Authors: Arthur Christopoulos, Jean-Pierre Changeux, William A Catterall, Doriano Fabbro, Thomas P Burris, John A Cidlowski, Richard W Olsen, John A Peters, Richard R Neubig, Jean-Philippe Pin, Patrick M Sexton, Terry P Kenakin, Frederick J Ehlert, Michael Spedding, Christopher J Langmead
Journal: Pharmacological Reviews (2014)

Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein–coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties.
Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial
Authors: L. C. Chappell, V. Gurung, P. T. Seed, J. Chambers, C. Williamson, J. G. Thornton
Journal: BMJ (2012)

<b>Objectives</b> To evaluate current processes by which young children presenting with a febrile illness but suspected of having serious bacterial infection are diagnosed and treated, and to develop and test a multivariable model to distinguish serious bacterial infections from self limiting non-bacterial illnesses. <b>Design </b>Two year prospective cohort study. <b>Setting </b>The emergency department of The Children's Hospital at Westmead, Westmead, Australia. <b>Participants</b> Children aged less than 5 years presenting with a febrile illness between 1 July 2004 and 30 June 2006. <b>Intervention</b> A standardised clinical evaluation that included mandatory entry of 40 clinical features into the hospital's electronic record keeping system was performed by physicians. Serious bacterial infections were confirmed or excluded using standard radiological and microbiological tests and follow-up. <b>Main outcome measures </b>Diagnosis of one of three key types of serious bacterial infection (urinary tract infection, pneumonia, and bacteraemia), and the accuracy of both our clinical decision making model and clinician judgment in making these diagnoses.<b></b> <b>Results</b> We had follow-up data for 93% of the 15 781 instances of febrile illnesses recorded during the study period. The combined prevalence of any of the three infections of interest (urinary tract infection, pneumonia, or bacteraemia) was 7.2% (1120/15 781, 95% confidence interval (CI) 6.7% to 7.5%), with urinary tract infection the diagnosis in 543 (3.4%) cases of febrile illness (95% CI 3.2% to 3.7%), pneumonia in 533 (3.4%) cases (95% CI 3.1% to 3.7%), and bacteraemia in 64 (0.4%) cases (95% CI 0.3% to 0.5%). Almost all (&gt;94%) of the children with serious bacterial infections had the appropriate test (urine culture, chest radiograph, or blood culture). Antibiotics were prescribed acutely in 66% (359/543) of children with urinary tract infection, 69% (366/533) with pneumonia, and 81% (52/64) with bacteraemia. However, 20% (2686/13 557) of children without bacterial infection were also prescribed antibiotics. On the basis of the data from the clinical evaluations and the confirmed diagnosis, a diagnostic model was developed using multinomial logistic regression methods. Physicians' diagnoses of bacterial infection had low sensitivity (10-50%) and high specificity (90-100%), whereas the clinical diagnostic model provided a broad range of values for sensitivity and specificity. <b>Conclusions</b> Emergency department physicians tend to underestimate the likelihood of serious bacterial infection in young children with fever, leading to undertreatment with antibiotics. A clinical diagnostic model could improve decision making by increasing sensitivity for detecting serious bacterial infection, thereby improving early treatment.
SOME EFFECTS OF RESTRICTION OF CHEST CAGE EXPANSION ON PULMONARY FUNCTION IN MAN: AN EXPERIMENTAL STUDY*†
Authors: Colin G. Caro, John Butler, Arthur B. DuBois
Journal: Journal of Clinical Investigation (1960)

Certain alterations in pulmonary mechanics occur in man when an inspiration is taken from below the resting lung volume (1) and during shallow breathing (2). Some effects of a sustained reduction of the total lung capacity on respiration have been studied previously (3-5), yet the effects of chest strapping on pulmonary mechanics have received relatively little attention. In the preliminary experiments we tightly bound the chest in the expiratory position with either adhesive tape or a long strip of rubber. Subsequently we designed a special chest corset that permitted us to reduce the resting lung volume and inspiratory capacity at will. The entire pressure-volume curve of the lung was altered by these procedures, but was restored to normal when a deep inspiration was taken after release of the restricting apparatus. Simultaneously, the escape of gas from poorly ventilated regions of the lung was detected. The effect of these changes on other aspects of pulmonary and circulatory function was examined and our findings, together with a consideration of their physiological and clinical significance, form the basis of this report.
Type 1 Diabetes and Autism
Authors: Sloane J. Freeman, Wendy Roberts, Denis Daneman
Journal: Diabetes Care (2005)

The prevalence of diabetes in children and youth <18 years of age is ∼1 in 400–500 (1). The prevalence of diabetes for those aged <19 years from 1995–2000 in Ontario was 1.87 per 1,000 (2). Type 1 diabetes is recognized as a T-cell–mediated autoimmune process with a strong genetic contribution (3,4).

In 2003, the prevalence of autism spectrum disorder was reported in one study as 3.4 per 1,000 children (5) and in another as 6.7 per 1,000 children (4 per 1,000 children with autism) aged 3–10 years (6) in the U.S. Like type 1 diabetes, both immune-mediated and genetic factors have been implicated in the development of autism (7,8). Based on recent clinical experiences and on the putative autoimmune etiology of these two conditions, we hypothesized that there would be an increased prevalence of autism spectrum disorder in a population of children with type 1 diabetes.

To investigate this hypothesis, a retrospective chart review of nearly …
Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-<i>Hcs4</i> Rat
Authors: Maria R. De Miglio, Patrizia Virdis, Diego F. Calvisi, Maddalena Frau, Maria R. Muroni, Maria M. Simile, Lucia Daino, Giovanni M. Careddu, Eraldo Sanna-Passino, Rosa M. Pascale, Francesco Feo
Journal: Cancer Research (2006)

Abstract Hepatocellular carcinoma (HCC) is prevalent in human and rodent males. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant Brown Norway (BN) rats. B alleles at Hcs4 locus, on RNO16, control neoplastic nodule volume. We constructed the F344.BN-Hcs4 recombinant congenic strain (RCS) by introgressing a 4.41-cM portion of Hcs4 from BN strain in an isogenic F344 background. Preneoplastic and neoplastic lesions were induced by the “resistant hepatocyte” protocol. Eight weeks after initiation, lesion volume and positivity for proliferating cell nuclear antigen (PCNA) were much higher in lesions of F344 than BN rats of both sexes. These variables were lower in females than in males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but in females corresponded to those of BN females. Carcinomatous nodules and HCC developed at 32 and 60 weeks, respectively, in male F344 and congenics and, rarely, in F344 females. BN and congenic females developed only eosinophilic/clear cells nodules. Gonadectomy of congenic males, followed by β-estradiol administration, caused a decrease in Ar expression, an increase in Er-α expression, and development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to Ar increase and development of preneoplastic lesions as in F344 males. This indicates a role of homozygous B alleles at Hcs4 in the determination of phenotypic patterns of female RCS and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibited/unaffected by testosterone, conferring resistance to females in which the B alleles provide higher resistance. (Cancer Res 2006; 66(21): 10384-90)
Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction
Authors: Gunnar H. Gislason, Søren Jacobsen, Jeppe N. Rasmussen, Søren Rasmussen, Pernille Buch, Jens Friberg, Tina Ken Schramm, Steen Z. Abildstrom, Lars Køber, Mette Madsen, Christian Torp-Pedersen
Journal: Circulation (2006)

Background— The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. We analyzed the risk of rehospitalization for acute myocardial infarction (MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with prior MI. Methods and Results— All patients with first-time MI between 1995 and 2002 as well as all prescription claims for NSAIDs after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was studied with the use of multivariable proportional hazards models and case-crossover analysis. A total of 58 432 patients were discharged alive and included in the study; 9773 experienced rehospitalization for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. Conclusions— Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI and should therefore be used with particular caution in these patients.
Increased Risk of Malignant Mullerian Tumor of the Uterus Among Women With Breast Cancer Treated by Tamoxifen
Authors: C. Bouchardy, H.M. Verkooijen, G. Fioretta, A.P. Sappino, G. Vlastos
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.174 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12409344 Increased Risk of Malignant Mullerian Tumor of the Uterus Among Women With Breast Cancer Treated by Tamoxifen C. BouchardyxC. BouchardySearch for articles by this author , H.M. VerkooijenxH.M. VerkooijenSearch for articles by this author , G. FiorettaxG. FiorettaSearch for articles by this author , A.P. SappinoxA.P. SappinoSearch for articles by this author , G. VlastosxG. VlastosSearch for articles by this author Show More Geneva Cancer Registry, Institute for Social and Preventive Medicine, University of GenevaGeneva University Hospitals, Geneva, Switzerland https://doi.org/10.1200/JCO.2002.99.174 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Cancer Stem Cells: Models and Concepts
Authors: Piero Dalerba, Robert W. Cho, Michael F. Clarke
Journal: Annual Review of Medicine (2006)

Although monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. An additional explanation, however, envisages human tumors not as mere monoclonal expansions of transformed cells, but rather as complex tridimensional tissues where cancer cells become functionally heterogeneous as a result of differentiation. According to this second scenario, tumors act as caricatures of their corresponding normal tissues and are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. We review the biological basis and the therapeutic implications of the stem cell model of cancer.
P23 Target And Biomarker Discovery For Hedgehog Pathway Activity In Idiopathic Pulmonary Fibrosis In Support Of A Phase 2 Randomised, Double-blind, Placebo-controlled Study To Assess Efficacy And Safety Of Vismodegib In Ipf (island)
Authors: G. Jia, S. Chandriani, A. Abbas, D. DePianto, E. N'Diaye, M. Yaylaoglu, H. Collard, P. Wolters, J. Egen, A. Scalori, A. Ackrill, J. Hou, J. Kaminski, T. Maher, J. Arron
Journal: Thorax (2014)

<h3>Objectives</h3> Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of signalling pathways involved in embryonic development, including the Hedgehog (Hh) pathway. Hh can promote multiple profibrotic processes including myofibroblast differentiation, expression of extracellular matrix genes, migration, and survival. Vismodegib is a small-molecule inhibitor of the Hedgehog (Hh) signalling pathway approved for the treatment of basal cell carcinoma. We sought to evaluate the activity of Hh signalling in IPF lung tissue and identify blood biomarkers of Hh pathway activity in IPF patients. <h3>Methods</h3> Gene expression in biopsies from IPF and control unused donor lungs, and in fibroblasts stimulated with Shh <i>in vitro</i>. CXCL14 protein was measured in plasma from IPF patients and from solid tumour patients treated with vismodegib in a phase 1b clinical trial (NCT00968981). <h3>Results</h3> We observed significantly increased expression levels of Hh pathway genes including SMO, PTCH2, GLI1, and GLI2 in IPF vs control lungs. To identify candidate systemic biomarkers of Hh pathway activity, we compared transcriptional data from IPF lung biopsies and fibroblasts stimulated <i>in vitro</i> with Shh. The gene most significantly upregulated in both datasets was CXCL14, which encodes a soluble secreted chemokine whose expression is inhibited <i>in vitro</i> by the addition of vismodegib. Circulating CXCL14 protein levels were significantly higher in plasma from IPF patients than controls. In solid tumour patients, circulating CXCL14 levels were significantly reduced upon treatment with vismodegib. <h3>Conclusions</h3> We observed strong evidence for Hedgehog pathway activity in IPF lungs. CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of vismodegib in IPF. The ISLAND trial is a phase 2 randomised, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of vismodegib in IPF patients. ISLAND will enrol 129 patients with IPF, randomised 2:1 to vismodegib or placebo for 60 weeks. The primary efficacy objective is to evaluate the effect of vismodegib on mean change in forced vital capacity (FVC). Secondary outcome measures include IPF and/or Hh-associated biomarkers, progression-free survival, and change in quantitative lung fibrosis on HRCT. Enrollment is expected to start in October 2014.
Immunization Against Transplantable Leukemia Impaired in Copper-Deficient Mice&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: O A Lukasewycz, J R Prohaska
Journal: JNCI Journal of the National Cancer Institute (1982)

Inbred C58 mice, kept on a copper-deficient (-Cu) diet from birth, were tested for their ability to be immunized to, and subsequently challenged with, line Ib syngeneic transplantable malignant lymphocytes (Ib cells). -Cu mice had significantly lowered hematocrits and serum ceruloplasmin (EC 1.16.3.1) values in contrast to those of the copper-supplemented (+Cu) controls. All male +Cu mice (17/17) survived the immunization regimen (consisting of approximately 10(3) viable and 10(7) inactivated Ib cells) and the challenge dose (10(6) viable Ib cells). Male -Cu mice had a survival rate of only 15% (4/27) after the immunization process and an overall survival rate of 11% (3/27). Female +Cu mice had survival rates of 86% (19/22) after immunization and of 74% (14/19) after the challenge dose, compared to 54% (15/28) and 47% (7/15) survival rates, respectively, for the female -Cu mice. Overall, the +Cu mice had a 79% (31/39) survival of both immunization and challenge compared to an 18% (10/55) survival for the -Cu mice. These results indicate that the initiation and maintenance of cell-mediated immunity to leukemia cells are severely impaired in -Cu animals.