tbuckley/cabot-search huggingface dataset:
A1.54 Development of a novel bispecific therapeutic for rheumatoid arthritis
Authors: Mathieu Ferrari, Shimobi Onuoha, Daniele Sblattero, Costantino Pitzalis
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Despite the obvious success of current biological agents for treatment of rheumatoid arthritis (RA), achievement of broader efficacy and improved safety profile remains an unmet need in RA therapy. There is significant evidence demonstrating molecular heterogeneity within the vascular endothelium of different tissues, conferring organ tropism to migrating lymphocytes subsets by interaction with specific homing receptors. We have previously reported the isolation of a single-chain Fv (scFvA7) antibody with specificity for synovial arthritic microvasculature, following an in vivo phage display selection on SCID mice model of RA. The aim of the present study was to develop a tissue specific therapeutic for Rheumatoid Arthritis. <h3>Materials and Methods</h3> The scFvA7 was subcloned in fusion with the CH2-CH3 domain of human IgG (A7 scFv-Fc) and coupled with the anti-TNF antibody Adalimumab via a monocistronic RNA approach, to form a bispecifc antibody (BsAb) using the Knobs-into-Holes technology (A7/Adalimumab). The reactivity in frozen and paraffin embedded tissue sections was investigated using immunohistochemistry and immunofluorescence analysis. <i>In-vitro</i> functionality and biological activity was assessed in Biacore, TNF-ELISA and TNF cytotoxicity assay on L-929 cell line. <h3>Results</h3> The scFv-Fc fusion protein of Adalimumab showed analogous anti-TNF properties with the parent antibody, EC50 0.04nM (Adalimumab 0.025nM), confirming the validity of the scFv format. The BsAb A7/Adalimumab achieved a high degree of efficient heterodimerisation showing only 3% Adalimumab homodimers and was able to selectively bind TNFα <i>in vitro </i>with similar efficacy to the TNF blocker, EC50 0.06nM, with a KD of 31pM. Despite the monovalency for the anti-TNF activity, the BsAb showed a dose dependent rescue of TNF induced cytotoxicity in L-929 cell line with a 0.5nM IC50 (Adalimumab 0.17nM), demonstrating the biological functionality of the construct. In addition, the A7/Adalimumab antibody proved to efficiently and specifically target the stromal compartment of RA synovial microvasculature, maintaining unaltered the organ tropism of the original scFvA7. <h3>Conclusions</h3> Our results demonstrate the development of a bispecific antibody showing unaltered TNF blocking capacity and optimal synovial specificity, suggesting that the target molecule for A7 may have applications as a biomarker and immunotherapeutic target, potentially allowing reduction in the dosage and/or administration frequency, with the ultimate goal to reduce the systemic exposure and achieve a better therapeutic index and decreasing health care costs.
Myocardial contrast echocardiography is superior to Tc-99m single-photon emission computed tomography for the diagnosis of coronary artery disease in patients without prior acute myocardial infarction: A multicenter study
Authors: Roxy Senior, Wolfgang Lepper, Agnes Pasquet, George Chung, Rainer Hoffman, Jean-Louis J. Vanoverschelde, Manuel Cerqueria, Sanjiv Kaul
Journal: Journal of the American College of Cardiology (2003)
376 Antitumor effect of controlled expression of interleukin-12 in a murine model of liver metastases
Authors: I. Mauleoh, J. Crettaz, G. Gonzalez-Aseguinolaza, M. Zabala, M.G. Kramer, S. Kochanek, J. Prieto, R. Hernandez-Alcocebal
Journal: Journal of Hepatology (2006)
Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses?
Authors: Bodo Laube, Gábor Maksay, Rudolf Schemm, Heinrich Betz
Journal: Trends in Pharmacological Sciences (2002)

Transmitter-gated ion channels mediate rapid synaptic transmission in the CNS and constitute important targets for many neuroactive drugs. Inhibitory glycine receptors (GlyRs) are members of the nicotinic acetylcholine receptor superfamily and inhibit neuronal firing by opening Cl− channels following agonist binding. In this article, we discuss recent developments in GlyR pharmacology, delineate the receptor domains that are involved in binding of agonists and allosteric modulators, and present a molecular model of the extracellular architecture of the receptor. The recent discovery of compounds that act preferentially on specific GlyR isoforms and the differential expression of these isoforms in distinct regions of the developing and adult CNS show considerable promise towards the development of drugs that act in defined glycine-mediated pathways. In particular, compounds that can potentiate GlyR function should provide leads for novel muscle relaxants in addition to sedative and analgesic agents.
Infantile Overnutrition among Artificially Fed Infants in the Sheffield Region
Authors: L. S. Taitz
Journal: BMJ (1971)

Artificially-fed 6-week-old infants in the Sheffield region are heavier than would be predicted from their birth weights and show a greatly increased incidence of excessive weight gain. These findings are associated with caloric intakes that exceed the classic 50 calories/lb/day (110 calories/kg/day) with a universal tendency to early feeding with cereals and mixed infant foods.The possible harmful implications of the trend to infantile overnutrition are discussed.
NCX-4016 (NO-Aspirin) Inhibits Lipopolysaccharide-Induced Tissue Factor Expression In Vivo
Authors: Stefano Fiorucci, Andrea Mencarelli, Alessandra Meneguzzi, Alessandro Lechi, Antonio Morelli, Piero del Soldato, Pietro Minuz
Journal: Circulation (2002)

Background— NCX-4016 is an acetylsalicylic acid (ASA) derivative containing a nitric oxide–releasing moiety. Compared with ASA, NCX-4016 has a broader spectrum of antithrombotic and antiinflammatory activities. We hypothesized that NCX-4016 might inhibit in vivo lipopolysaccharide (LPS)-induced expression of tissue factor (TF). Methods and Results— Rats were administered 90 mg/kg NCX-4016 orally for 5 days. Placebo, 50 mg/kg ASA, and 80 mg/kg isosorbide-5-mononitrate (ISMN) were used in control groups. On day 5, rats were injected intraperitoneally with 100 μg/kg LPS and killed 6 hours later. The expression of TF in monocytes was measured by flow cytometry and Western blot analysis. Reverse transcriptase–polymerase chain reaction was performed to assess expression of TF and cyclooxygenase-2 (COX-2) genes. Plasma concentrations of interleukin-1β and tumor necrosis factor-α were measured. Urine samples were collected to evaluate the excretion of the thromboxane metabolite 11-dehydro-thromboxane (TX)B 2 . Gastric mucosa was inspected. LPS injection was followed by synthesis TF and COX-2 mRNAs in circulating monocytes, which were blunted by NCX-4016 but not by ASA or ISMN. Both NCX-4016 and ISMN reduced TF expression on surface of circulating monocyte. LPS increased the excretion 11-dehydro-TXB 2 , and this was prevented by NCX-4016 and ASA. Unlike ASA, NCX-4016 reduced plasma interleukin-1β and tumor necrosis factor-α. In addition, NCX-4016 almost completely prevented mucosal damage, whereas ASA increased the extension of gastric lesions in LPS-injected rats. Conclusions— NCX-4016 prevents monocyte TF expression; this is accompanied by inhibition of TX and cytokine biosynthesis. These additive effects of nitric oxide release and COX inhibition may help explain efficacy and tolerability of NCX-4016.
1046. Stable Correction of Hematopoietic Stem Cells with Non-Viral Gene Transfer
Authors: Meenakshi Noll, Ryan Bennett, Stephen Yant, Mark A. Kay, Markus Grompe
Journal: Molecular Therapy (2005)

The life span of patients with Fanconi Anemia (FA) is severely shortened by bone marrow failure and malignancies and currently, allogeneic bone-marrow transplantation is the only therapeutic option. Despite the successful modeling of FA viral vector gene therapy in the mouse, application of the same approach to humans is complicated by the requirement for prolonged ex vivo manipulation and the scarcity of HSCs in this disease. Here, we utilized the non-viral Sleeping Beauty (SB) transposon system to facilitate stable, gene transfer of the human FANCC cDNA without ex vivo culture. This was achieved either by electroporation of naked DNA into whole bone marrow or by direct injection into the femur cavity. Our studies demonstrate that a) hematopoietic stem cells from Fancc -/- mice can be transduced by plasmid DNA; b) stable integration of plasmid DNA into the genome of hematopoietic stem cells (HSC) is possible; c) animal model was phenotypically corrected; and d) long-term therapeutic benefit could be achieved using this method. Non-viral gene transfer may be a viable alternative for the treatment of hematopoietic diseases.
Exposure to Allergens and Endotoxin in Early Life and Recurrent Wheezing in Infants: a Cohort Study
Authors: V.E. Rullo, D. Solé, L. Arruda, V. Valente, C. Nakamura, A.S. Zampolo, L.R. Roberti, F.J. Nóbrega, C.K. Naspitz
Journal: Journal of Allergy and Clinical Immunology (2006)
A New Postoperative Predictor of Time to Urinary Continence after Laparoscopic Radical Prostatectomy: The Urine Loss Ratio
Authors: Mutlu Ates, Dogu Teber, Ali Serdar Gozen, Ahmet Tefekli, Marcel Hruza, Marto Sugiono, Sarper Erdogan, Jens Rassweiler
Journal: European Urology (2006)
TUBERCULOSIS OF THE LARYNX
Authors: W. G. Howarth
Journal: BMJ (1929)

Tun burn= 749 -Whatever the explanlation, it mIIaV vet tll-II olit to be of ilmil)ortance fromii a pathogenic aiid a therapeutic standpoint tllat epileptic mianifestations are sometii.esconitr olled by N.\ature's owni mnethods.REFERENCES.
Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver
Authors: Heather A. Crosby, Stefan G. Hubscher, Ruth E. Joplin, Deirdre A. Kelly, Alastair J. Strain
Journal: Hepatology (1998)

The existence of progenitor (stem) cells in the human liver remains a matter of debate. In rodent models of hepatocarcinogenesis and injury, oval cells proliferate in the periportal regions of the portal tracts and are suggested to derive from a stem cell compartment, because they are capable of differentiating into hepatocytes or biliary epithelial cells. In this study, the rat oval cell marker, OV-6 has been used to investigate the hypothesis that there are stem cells present in fetal and pediatric human liver. The pattern of OV-6 expression was compared with the established adult biliary cell markers human epithelial antigen-125 (HEA-125) and cytokeratin-19 (CK-19). In normal pediatric liver (n = 7), bile ducts and ductules were immunostained with CK-19 and HEA-125, whereas OV-6 staining was consistently negative. In fetal tissue (n = 10), ductal plate cells, primitive bile ducts, and hepatoblasts were stained with CK-19 and HEA-125 although only some of the ductal plate cells and hepatoblasts were OV-6 positive. In biliary atresia (n = 6) and α1, anti-trypsin deficiency (α1,AT) (n = 4), CK-19 and HEA-125 immunostained ductular proliferative cells that tended to form finely anastomosing ductules, whereas OV-6 staining was found more on discrete cells confined to portal tract margins. Additionally, in diseased liver, OV-6 was strongly positive in hepatocyte lobules with greatest intensity in the periseptal regions. This widespread hepatocyte OV-6 positivity suggests that the antibody may identify cells of a less differentiated phenotype (transitional hepatocytes) that have replaced the mature cells. Therefore, it is proposed that in human liver, OV-6 is recognizing cells with a progenitor stem cell-like phenotype with the capacity to differentiate into OV-6 positive ductular cells or lobular hepatocytes.
<i>SPP1</i>rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis
Authors: Pierre-Antoine Juge, Hanna W van Steenbergen, Arnaud Constantin, Gabriel J Tobon, Thierry Schaeverbeke, Steven Gazal, Bernard Combe, Valérie Devauchelle-Pensec, Delphine Nigon, Annette H M van der Helm-van Mil, Philippe Dieude
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> We recently reported an association of the <i>SPP1</i> rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients. We hypothesised that <i>SPP1</i> may contribute to the severity of joint destruction in RA, specifically in the ACPA-negative population. <h3>Methods</h3> Patients with RA in the ESPOIR cohort underwent genotyping for <i>SPP1</i> rs9138 and rs11439060. Radiographs of the hands and feet were obtained at the first visit and at 1- and 2-year follow-up. Association analyses were performed by ACPA status. A replication study of the relevant subset of the Leiden Early Arthritis Clinic (EAC) cohort was performed. <h3>Results</h3> In the ESPOIR cohort (652 patients), rs9138 was significantly associated with radiological progression of joint destruction at 2 years, the association being restricted to 358 ACPA-negative patients (p=0.034). In the replication study with the Leiden EAC cohort (273 ACPA-negative patients), rs4754, which is in complete linkage disequilibrium with rs9138, was significantly associated with joint damage progression in ACPA-negative patients at 2- and 7-year follow-up (p=0.019 and p=0.005, respectively). Combined analysis of the two cohorts revealed a 0.95-fold rate of joint destruction per year per minor allele (p=0.022). <h3>Conclusions</h3> The <i>SPP1</i> rs9138 variant contributes to joint damage progression in ACPA-negative RA.
STANDARDIZATION AND PRESERVATION OF COMPLEMENT SERUM FOR WASSERMANN TEST
Authors: E. H. RUEDIGER
Journal: JAMA (1922)

Laboratory workers who are familiar with the Wassermann test know that the serums from different guinea-pigs differ greatly in complement activity, and that under ordinary conditions complement rapidly deteriorates but can be preserved for varying lengths of time under suitable conditions. About two years ago I<sup>1</sup>showed that a number of complement serums from guinea-pigs gave results with the same human serum varying from 2 + to 10 +. Even greater differences have been observed since; serums from some guinea-pigs have given negative results while serums from other guinea-pigs gave 10 + with the same human serum. Such irregularities can be eliminated by selection of complement serum, probably by selective breeding of guinea-pigs, by selective feeding of guinea-pigs and by preservation of the good complement serums. <h3>SELECTION OF SERUM AND GUINEA-PIGS</h3> The preserved positive control serum, composed of a mixture of twenty syphilitic human serums, I diluted to such an extent that
Recent Advances in Coloproctology.
Authors: A LEATHER
Journal: Gut (2001)

Recent Advances in Coloproctology. Edited by J Beynon, ND Carr (Pp182; illustrated; £80/$149). Germany: Springer-Verlag, 1999. ISBN1-85233-169-0.

This book addresses 10 topics in which there has been significant development over the past decade. The subjects discussed are diverse, ranging from the combined surgical treatment for advanced pelvic malignancy to incontinence surgery, and from imaging of the anal canal and rectum to the management of anal fissure.

All topics have dual authorship with the exception of the useful chapter on legal matters by PF Schofield. These authors are all UK based apart from MR Salum …
Khushru Mancherji Mehta
Authors: J. Mehta
Journal: BMJ (2014)

Khushru Mancherji Mehta was one of nine children, born in Bharuch, India, to a middle class Parsi family and fought to pursue a career in medicine against his father’s wishes that he become an accountant. After qualifying he travelled to Edinburgh to complete his FRCS and thence several registrarships in the UK. In 1952 he accepted a posting with the Colonial Service to …
The Genesis of Contemporary American Anesthesiology
Authors: Jane Matjasko
Journal: JAMA (1983)

This volume documents the development of anesthesiology as a specialty in the United States by focusing on the men, ideas, and events responsible. It consists of biographical sketches of memorable individuals written by their contemporaries based on recall and correspondence. It has an easily readable style and presentation and can be leisurely completed in four hours or less. The pioneers or "visionaries" such as Ralph Waters realized that the founding and development of a specialty depended, "first upon men, second upon publications and third upon organizations through which men meet for mutual development by exchange of ideas." The book is structured to highlight the men—the visionaries like McMechan, McKesson, Guedel, Lundy, and Waters; "activators" Rovenstine, Tovell, Beecher, Cullen, Adriani, Dripps, Papper, and Volpitto; and the organizations and publications forming the "matrix" of modern anesthesiology (the American Society of Anesthesiologists, the American Board of Anesthesiology, and the journal<i>Anesthesiology</i>). The essays
Transformation of BALB/c-3T3 cells: V. Transformation responses of 168 chemicals compared with mutagenicity in Salmonella and carcinogenicity in rodent bioassays.
Authors: E J Matthews, J W Spalding, R W Tennant
Journal: Environmental Health Perspectives (1993)

This report describes the activities of 168 chemicals tested in a standard transformation assay using A-31-1-13 BALB/c-3T3 cells. The data set includes 84 carcinogens, 77 noncarcinogens, and 7 research chemicals. Carcinogens included 49 mutagens and 35 nonmutagens; noncarcinogens included 24 mutagens and 53 nonmutagens. The transformation assay did not use an exogenous activation system, thus, all chemical responses depended on the inherent target cell metabolic capacity where metabolic activation was required. The upper dose limit was 100 milli-osmolar because the assay could not discriminate active and inactive chemicals tested above this concentration. Certain physicochemical properties resulted in technical problems that affected chemical biological activity. For example, chemicals that reacted with plastic were usually nonmutagenic carcinogens. Similarly, chemicals that were insoluble in medium, or bound metals, were usually nonmutagenic and nontransforming. Multifactorial data analyses revealed that the transformation assay discriminated between nonmutagenic carcinogens and noncarcinogens; it detected 64% of the carcinogens and only 26% of the noncarcinogens. In contrast, the transformation assay detected most mutagenic chemicals, including 94% of the mutagenic carcinogens and 70% of the mutagenic noncarcinogens. Thus, transformation or Salmonella typuimurium mutagenicity assays could not discriminate mutagenic carcinogens from mutagenic noncarcinogens. Data analyses also revealed that mutagenic chemicals were more cytotoxic than nonmutagenic chemicals; 88% of the mutagens had an LD50 < 5 mM, whereas half of the nonmutagens had an LD50 > 5 mM. Binary data analyses of the same data set revealed that the transformation assay and rodent bioassay had a concordance of 71%, a sensitivity for carcinogens of 80.0%, and a specificity for detecting noncarcinogens of 60%. In contrast, Salmonella mutagenicity assays and rodent bioassays had a concordance of 63%, a sensitivity of 58%, and a specificity of 69%. The transformation assay complemented the Salmonella mutagenesis assay in the identification of nonmutagenic carcinogens; thus, the two assays had a combined 83% sensitivity for all carcinogens and a 75% specificity for nonmutagenic noncarcinogens.
A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis
Authors: Robert M. Knobler, Lars E. French, Youn Kim, Emil Bisaccia, Winfried Graninger, Hesam Nahavandi, Frank J. Strobl, Edward Keystone, Marilyn Mehlmauer, Alain H. Rook, Irwin Braverman
Journal: Journal of the American Academy of Dermatology (2006)
Subtle Acquired Renal Injury as a Mechanism of Salt-Sensitive Hypertension
Authors: Richard J. Johnson, Jaime Herrera-Acosta, George F. Schreiner, Bernardo Rodríguez-Iturbe
Journal: New England Journal of Medicine (2002)

Salt sensitivity is present in about half of people with essential hypertension; decreasing salt intake ameliorates the hypertension. This review provides an explanation of how initially subtle renal injury promotes a tendency toward hypertension. The kidneys, initially normal in many persons with early primary hypertension, sustain subclinical injury over time, resulting in arteriolosclerosis and tubulointerstitial disease that lead to established hypertension.
Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells
Authors: Axel M. Gressner, Birgit Lahme, Arnfried Brenzel
Journal: Hepatology (1995)

The activation of proliferation of rat liver hepatic stellate cells (HSC) in cooperation with hepatocytes (PC) was studied using a coculture system and cell-conditioned media, respectively. The proliferation of HSC was followed by incorporation of [3H] thymidine and BrdU into DNA and by DNA content per culture. Strong stimulation of HSC proliferation was noticed under reduced fetal calf serum (FCS) conditions (0.2%) during a 48-hour coculture with PC, rat hepatoma, human hepatoma, and transforming growth factor (TGF)-alpha-transgenic mouse PC, respectively. The extent of stimulation was frequently higher than that observed by the addition of 10% FCS. Transformed HSC (myofibroblasts) could also be stimulated by cocultured PC, but the magnitude of activation was lower than that of (untransformed) HSC. Using radioreceptor assays, we could demonstrate significant concentrations of insulinlike growth factor (IGF)-1 (300 ng/10(6) cells x 48 hours) and quite lower concentrations of bFGF and TGF-alpha in the hepatocyte-conditioned media (PCcM), whereas IGF-2 was not detectable. With anti-IGF-1 neutralizing antibody, the stimulatory activity of PCcM could be reduced by approximately 50%. PCcM, which mimics the effects of cocultures and supports strongly the action of exogenous IGF-1 on HSC proliferation, leaving that of other cytokines (TGF-alpha, IL-1 alpha, bFGF, aFGF, TNF-alpha), added either separately or in various combinations, uninfluenced. The latter cytokines were without significant effects on HSC proliferation. The mitogenic activity of cytokine combinations containing IGF-1 could be enhanced severalfold by limiting amounts of PCcM. Maximum stimulation of cell proliferation of 40-fold above control cultures was reached by IGF-1 in combination with TGF-alpha and bFGF in presence of diluted PCcM, which is approximately 6-fold higher than in the absence of PCcM. [125I] IGF-1 added to PCcM was bound by more than 90% to carrier proteins. The results confirm in cocultures strong mitogenic activation of HSC by PC. It is suggested that IGF-1 and respective IGF-binding proteins are of great importance in the mitogenic signal transfer between hepatocytes and hepatic stellate cells.