tbuckley/cabot-search huggingface dataset:
Genetic influence on inflammatory response in rats exposed to nanosized titanium dioxide particles
Authors: Åsa Gustafsson, Sofia Jonasson, Johnny Lorentzen, Anders Bucht
Journal: European Respiratory Journal (2013)

The emerging nanotechnologies have resulted in large productions of engineered nanomaterials (NM). Despite the increased production, health effects following inhalation of NM have not been fully assessed. This study aimed to investigate and monitor health effects following inhalation of TiO2 nanoparticles (NP) in healthy rats and in rats with ongoing airway inflammation (asthmatic rats). We compared the responsiveness between two rat strains with differences in genetic susceptibility to develop inflammatory diseases; the Dark Agouty (DA) rat that is susceptible to develop chronic autoimmune diseases while the Brown Norwegian (BN) rat that is prone to develop allergic airway inflammation. Health effects of TiO2 inhalation were studied in healthy rats and in rats with allergic airway inflammation induced by an experimental allergen (ovalbumin). We assessed respiratory function, inflammatory response in airways, activation of the immune system and effects on general health condition. Repeated exposure to TiO2 NPs in healthy individuals resulted in an airway inflammation dominated by neutrophils in both strains. In DA rats there was also an increased hyperreactivity in airways and elevated levels of cytokines/chemokines in BAL. These changes were not seen in the BN strain. Both strains responded to challenge with the respiratory allergen by airway eosinophilia and bronchial hyperreactivity, but no significant strain differences was observed when rats with ongoing allergic airway inflammation were exposed to TiO2 NPs. Our data implies that susceptibility to develop adverse effects in airways following NP exposure is influenced by genetic determinants.
Immunodrugs: Therapeutic VLP-Based Vaccines for Chronic Diseases
Authors: Gary T. Jennings, Martin F. Bachmann
Journal: The Annual Review of Pharmacology and Toxicology (2008)

Worldwide, the prevalence of noncommunicable chronic diseases is increasing. The use of vaccines to induce autoantibodies that neutralize disease-related proteins offers a means to effectively and affordably treat such diseases. Twenty vaccines designed to induce therapeutic autoantibodies were clinically tested in the past 12 years. Immunodrugs are therapeutic vaccines comprising virus-like particles (VLPs) covalently conjugated with self-antigens that induce neutralizing autoantibody responses. Four such VLP-based vaccines have been clinically tested and one has achieved proof of principle: a reduction of blood pressure in hypertensive patients. To facilitate preliminary clinical testing, novel nonclinical study programs have been developed. Safety study designs have considered the underlying B and T cell immunology and have examined potential toxicities of vaccine components and primary and secondary pharmacodynamic action of the vaccines.
4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses
Authors: Walter W. Shuford, Kerry Klussman, Douglas D. Tritchler, Deryk T. Loo, Jan Chalupny, Anthony W. Siadak, T. Joseph Brown, John Emswiler, Hong Raecho, Christian P. Larsen, Thomas C. Pearson, Jeffrey A. Ledbetter, Alejandro Aruffo, Robert S. Mittler
Journal: The Journal of Experimental Medicine (1997)

The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-gamma production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.
Plasma and Cerebrospinal Fluid Pharmacokinetics of Clofarabine in Nonhuman Primates
Authors: Stacey L. Berg, Peter L. Bonate, Jed G. Nuchtern, Robert Dauser, Leticia McGuffey, Bruce Bernacky, Susan M. Blaney
Journal: Clinical Cancer Research (2005)

Abstract Introduction: Clofarabine (2-chloro-2′fluoro-2′-deoxy-9-β-d-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model. Methods: A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four animals. Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy. Results: The median clofarabine clearance was 17 mL/min/kg (range, 15-20), the median plasma area under the concentration-time curve was 452 μmol/L minutes (range, 380-487), and the median terminal half-life was 105 minutes (range, 78-138). Concentrations of clofarabine in CSF could not be modeled reliably because the terminal rate constant was not well defined. The median CSF penetration was 5% (range, 3-26%). Conclusion: Clofarabine penetrates into the CSF only modestly, but the concentrations obtained may approach those that are cytotoxic in vitro. Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies.
Reduction of renal mass is lethal in mice lacking vimentin. Role of endothelin-nitric oxide imbalance.
Authors: F Terzi, D Henrion, E Colucci-Guyon, P Federici, C Babinet, B I Levy, P Briand, G Friedlander
Journal: Journal of Clinical Investigation (1997)

Modulation of vascular tone by chemical and mechanical stimuli is a crucial adaptive phenomenon which involves cytoskeleton elements. Disruption, by homologous recombination, of the gene encoding vimentin, a class III intermediate filament protein mainly expressed in vascular cells, was reported to result in apparently normal phenotype under physiological conditions. In this study, we evaluated whether the lack of vimentin affects vascular adaptation to pathological situations, such as reduction of renal mass, a pathological condition which usually results in immediate and sustained vasodilation of the renal vascular bed. Ablation of 3/4 of renal mass was constantly lethal within 72 h in mice lacking vimentin (Vim-/-), whereas no lethality was observed in wild-type littermates. Death in Vim-/- mice resulted from end-stage renal failure. Kidneys from Vim-/- mice synthesized more endothelin, but less nitric oxide (NO), than kidneys from normal animals. In vitro, renal resistance arteries from Vim-/- mice were selectively more sensitive to endothelin, less responsive to NO-dependent vasodilators, and exhibited an impaired flow (shear stress)- induced vasodilation, which is NO dependent, as compared with those from normal littermates. Finally, in vivo administration of bosentan, an endothelin receptor antagonist, totally prevented lethality in Vim-/- mice. These results suggest that vimentin plays a key role in the modulation of vascular tone, possibly via the tuning of endothelin-nitric oxide balance.
Prospective comparative study of spiral computer tomography and magnetic resonance imaging for detection of hepatocellular carcinoma
Authors: J Stoker, M G Romijn, R A de Man, J T Brouwer, G J Weverling, J M van Muiswinkel, P E Zondervan, J S Lameris, J N M Ijzermans
Journal: Gut (2002)

<b>Background:</b> Hepatocellular carcinoma (HCC) is often detected at a relatively late stage when tumour size prohibits curative surgery. Screening to detect HCC at an early stage is performed for patients at risk. <b>Aim:</b> The aim of this study was to compare prospectively the diagnostic accuracy and classification for management of the two state of the art secondline imaging techniques: triphasic spiral computer tomography (CT) and super paramagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI). <b>Patients:</b> Sixty one patients were evaluated between January 1996 and January 1998. Patients underwent CT and MRI within a mean interval of 6.75 days. <b>Methods:</b> CT and MRI were evaluated blindly for the presence and number of lesions, characterisation of these lesions, and classification for management. For comparison of the data on characterisation, the CT and MRI findings were compared with histopathological studies of the surgical specimens and/or follow up imaging. Data of patients not lost to follow up were available to January 2001. <b>Results:</b> SPIO enhanced MRI detected more lesions and overall smaller lesions than triphasic spiral CT (number of lesions 189 <i>v</i> 124; median diameter 1.0 <i>v</i> 1.8 cm; Spearman rank9s correlation coefficient 0.63, p&lt;0.001). There was no significant difference in accuracy between CT and MRI for lesion characterisation. The agreement in classification for management was very good (weighted kappa 0.91, 95% CI 0.83–0.99). <b>Conclusion:</b> SPIO enhanced MRI detects more and smaller lesions, but both techniques are comparable in terms of classification for management. SPIO enhanced MRI may be preferred as there is no exposure to ionising radiation.
Editorial: Additional support for the problem-oriented system
Authors: J. W. Hurst
Journal: JAMA (1974)

The article "The Problem-Oriented Medical Record: Experiences in a Community Military Hospital" by Juan Aranda strongly supports the use of the problem-oriented system. (See the section of the article identified as "Results" and "Comment" rather than the abstract). Even more support might have been forthcoming if the following had been considered. There is a vast difference between the mere use of a problem-oriented record and the utilization of the entire problem-oriented system. The problem-oriented record is the vehicle one uses to accomplish an objective. Dr. Weed<sup>1</sup>has never claimed that the record would guarantee anything. He<i>has</i>said that a carefully executed problem-oriented record will allow one to<i>assess</i>the quality of patient care, education, and other factors.<sup>1,2,3,4</sup> How does one<i>assess</i>the quality of patient care, education, and other factors? The problem-oriented record is the first step of the four-step system that includes ( 1) the establishment of
<i>In vivo</i> Evaluation of Mucoadhesive Nanoparticulate Docetaxel for Intravesical Treatment of Non–Muscle-Invasive Bladder Cancer
Authors: Clement Mugabe, Yoshiyuki Matsui, Alan I. So, Martin E. Gleave, Jennifer H. E. Baker, Andrew I. Minchinton, Irina Manisali, Richard Liggins, Donald E. Brooks, Helen M. Burt
Journal: Clinical Cancer Research (2011)

The present work describes the development and in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy.Mucoadhesive formulations based on hyperbranched polyglycerols (HPG), hydrophobically derivatized with C(8)/C(10) alkyl chains in the core and modified with methoxy-polyethylene glycol (MePEG) and amine groups in the shell (HPG-C(8/10)-MePEG-NH(2)) were synthesized and DTX was loaded into these by a solvent evaporation method. Both low-grade (RT4, MGHU3) and high-grade (UMUC3) human urothelial carcinoma cell lines were treated with various concentrations of DTX formulations in vitro. KU7 cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumors were given a single intravesical instillation with PBS, Taxotere (DTX from Sanofi-aventis), and DTX-loaded HPG-C(8/10)-MePEG and/or HPG-C(8/10)-MePEG-NH(2). Drug uptake was conducted using LC/MS-MS (liquid chromatography/tandem mass spectrometry) and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed.In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX-loaded HPG-C(8/10)-MePEG-NH(2) (mucoadhesive DTX) was the most effective formulation to inhibit tumor growth in an orthotopic model of bladder cancer. Furthermore, mucoadhesive DTX significantly increased drug uptake in mouse bladder tissues. In addition, rhodamine labeled HPG-C(8/10)-MePEG-NH(2) showed enhanced uptake of these nanoparticles in bladder tumor tissues.Our data show promising in vivo antitumor efficacy and provide preclinical proof of principle for the intravesical application of mucoadhesive nanoparticulate DTX formulation in the treatment of bladder cancer.
HFEand alcoholic liver disease
Authors: D K GEORGE, L W POWELL
Journal: Gut (1999)

Editor,—We read with interest the recent paper by Grove et al ( Gut 1998; 43 :262–6) which concludes that the two haemochromatosis mutations (C282Y and H63D) influence neither the liver iron content nor risk of fibrosis in alcoholic liver disease. Two factors in this study may have led to an underestimation of the contribution of the haemochromatosis gene ( HFE ) to hepatic iron loading.

Most of the patients in the study had established cirrhosis. Cirrhosis, particularly alcoholic cirrhosis, may itself be a potent cause of hepatic iron loading once it has developed.1 This rapid iron loading may result in hepatic iron concentrations usually associated with the homozygous haemochromatosis state and might obscure the effect of any iron loading that might occur due to the heterozygous genotype. Also, in haemochromatosis, excess alcohol consumption, although not affecting the hepatic iron concentration, seems to cause iron to redistribute from hepatocytes to reticuloendothelial cells.2 The same may be true of hepatic iron stores in heterozygous haemochromatosis when excess alcohol is consumed, thus causing an underestimation of the hepatic iron stores if only hepatocellular …
CXCL12 expression by invasive trophoblasts induces the specific migration of CD16– human natural killer cells
Authors: Jacob Hanna, Ori Wald, Debra Goldman-Wohl, Diana Prus, Gal Markel, Roi Gazit, Gil Katz, Ronit Haimov-Kochman, Nobutaka Fujii, Simcha Yagel, Amnon Peled, Ofer Mandelboim
Journal: Blood (2003)
The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice
Authors: W AARTSEN, M SCHUIJT, A DANSER, M DAEMEN, J SMITS
Journal: Cardiovascular Research (2002)

Angiotensin II, generated from angiotensin I by angiotensin converting enzyme (ACE), induces multiple effects including vasoconstriction, positive cardiac inotropy, hypertrophy of cardiomyocytes and proliferation of fibroblasts. ACE exists both in a tissue-bound (t-ACE) and a soluble form. The functional importance of locally produced angiotensin II is still unclear. In the present study, mice lacking tissue-bound angiotensin converting enzyme (t-ACE -/-) were used to investigate the importance of t-ACE during cardiac remodeling after myocardial infarction.Mice were subjected to coronary artery occlusion or sham surgery. At 14 days after MI, stroke volume (SV) was determined with an electromagnetic flow probe around the ascending aorta. Mean arterial pressure (MAP) was measured through a cannula in the abdominal aorta. Both parameters were determined at rest and after a volume loading of 2.5 ml warm (37 degrees C) Ringer's solution in 60 s. Hearts were dissected and formalin-fixed to measure infarct size, cardiac dimensions and collagen concentration. Tissue levels of angiotensin I and II were determined in hearts and kidneys.At rest, under pentobarbital anaesthesia, t-ACE -/- mice (n=12) exhibited a significantly lower MAP (26+/-3 vs. 45+/-3 mmHg) than t-ACE +/+ (n=11). SV was similar in both strains. Maximal SV was significantly reduced after MI. Furthermore, infarcted t-ACE -/- (n=6) exhibited a significantly lower maximal SV compared to infarcted t-ACE +/+ mice (n=5; 20.4+/-1.5 vs. 29.6+/-2.3 microl). Structural cardiac parameters as well as cardiac and renal angiotensin II levels in t-ACE -/- and t-ACE +/+ were comparable.These results suggest that the structural adaptations of the heart that follow MI are independent of t-ACE. However, the presence of t-ACE is necessary for maintenance of cardiac function.
Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared Renal Transplant Recipients
Authors: Irmgard Neumann, Michael Haidinger, Heidemarie Ja[Combining Diaeresis]ger, Hans Gru[Combining Diaeresis]tzmacher, Andrea Griesmacher, Mathias M. Mu[Combining Diaeresis]ller, Peter M. Bayer, Franz Thomas Meisl
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Mycophenolate mofetil (MMF), being effectively used as immunosuppressant in transplant medicine, has recently attracted interest as therapeutic agent for autoimmune diseases (AID). For these patients, no pharmacokinetic (PK) data are available. This study is an investigation of single-dose concentration-time profiles of 1 g off MMF in 16 patients with AID, including 10 patients with ANCA-associated vasculitis and 6 patients with systemic lupus erythematosus, and compares them with profiles of 16 renal transplant recipients (RTX). Mycophenolic acid (MPA) blood levels were measured by both HPLC and EMIT, and MPA-glucuronide was determined by HPLC. In AID, mean MPA concentrations at 12 h were significantly higher compared with RTX (4.1 ± 3.27 versus 1.8 ± 1.15 mg/L; P = 0.018), whereas peak concentrations were lower (P = 0.017). However, mean MPA-AUC at 12 h as well as at 24 h were comparable between both groups. In contrast to RTX, there was an association in AID between MPA trough levels at 12 h and at 24 h with AUC0-12 (P < 0.05 and P < 0.01). MPA trough concentrations at 24 h provided an estimation of AUC0-24 h in both patient groups (P < 0.001 and P < 0.01; AID and RTX, respectively). Compared with RTX, MPA-PK seems to be less affected in AID by renal function. Inter-individual variability of PK parameters was high in both groups. These data indicate that there are differences of MPA-PK between RTX and AID. The use of therapeutic drug monitoring in patients with AID appears to be clinically practicable and may be valuable to optimize individual immunosuppressive therapy. E-mail: i[email protected] or [email protected]
Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis
Authors: Vadim Pedchenko, Olga Bondar, Agnes B. Fogo, Roberto Vanacore, Paul Voziyan, A. Richard Kitching, Jörgen Wieslander, Clifford Kashtan, Dorin-Bogdan Borza, Eric G. Neilson, Curtis B. Wilson, Billy G. Hudson
Journal: New England Journal of Medicine (2010)

In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by alloantibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis.We used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture's disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture's disease and 2 patients with Alport's post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the alpha345NC1 hexamer.In patients with Goodpasture's disease, both autoantibodies to the alpha3NC1 monomer and antibodies to the alpha5NC1 monomer (and fewer to the alpha4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha3NC1 and alpha5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, alloantibodies bound to the E(A) region of the alpha5NC1 subunit in the intact hexamer, and binding decreased on dissociation.The development of Goodpasture's disease may be considered an autoimmune "conformeropathy" that involves perturbation of the quaternary structure of the alpha345NC1 hexamer, inducing a pathogenic conformational change in the alpha3NC1 and alpha5NC1 subunits, which in turn elicits an autoimmune response. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)