tbuckley/cabot-search huggingface dataset:
Increased myoepithelial cells of bronchial submucosal glands in fatal asthma
Authors: F H Y Green, D J Williams, A James, L J McPhee, I Mitchell, T Mauad
Journal: Thorax (2009)

<h3>Background:</h3> Fatal asthma is characterised by enlargement of bronchial mucous glands and tenacious plugs of mucus in the airway lumen. Myoepithelial cells, located within the mucous glands, contain contractile proteins which provide structural support to mucous cells and actively facilitate glandular secretion. <h3>Objectives:</h3> To determine if myoepithelial cells are increased in the bronchial submucosal glands of patients with fatal asthma. <h3>Methods:</h3> Autopsied lungs from 12 patients with fatal asthma (FA), 12 patients with asthma dying of non-respiratory causes (NFA) and 12 non-asthma control cases (NAC) were obtained through the Prairie Provinces Asthma Study. Transverse sections of segmental bronchi from three lobes were stained for mucus and smooth muscle actin and the area fractions of mucous plugs, mucous glands and myoepithelial cells determined by point counting. The fine structure of the myoepithelial cells was examined by electron microscopy. <h3>Results:</h3> FA was characterised by significant increases in mucous gland (p = 0.003), mucous plug (p = 0.004) and myoepithelial cell areas (p = 0.017) compared with NAC. When the ratio of myoepithelial cell area to total gland area was examined, there was a disproportionate and significant increase in FA compared with NAC (p = 0.014). Electron microscopy of FA cases revealed hypertrophy of the myoepithelial cells with increased intracellular myofilaments. The NFA group showed changes in these features that were intermediate between the FA and NAC groups but the differences were not significant. <h3>Conclusions:</h3> Bronchial mucous glands and mucous gland myoepithelial cell smooth muscle actin are increased in fatal asthma and may contribute to asphyxia due to mucous plugging.
Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier
Authors: Jessica A. Couch, Y. Joy Yu, Yin Zhang, Jacqueline M. Tarrant, Reina N. Fuji, William J. Meilandt, Hilda Solanoy, Raymond K. Tong, Kwame Hoyte, Wilman Luk, Yanmei Lu, Kapil Gadkar, Saileta Prabhu, Benjamin A. Ordonia, Quyen Nguyen, Yuwen Lin, Zhonghua Lin, Mercedesz Balazs, Kimberly Scearce-Levie, James A. Ernst, Mark S. Dennis, Ryan J. Watts
Journal: Science Translational Medicine (2013)

Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier.
Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study
Authors: Jeffrey C Kwong, Priya P Vasa, Michael A Campitelli, Steven Hawken, Kumanan Wilson, Laura C Rosella, Therese A Stukel, Natasha S Crowcroft, Allison J McGeer, Lorne Zinman, Shelley L Deeks
Journal: The Lancet Infectious Diseases (2013)
Abstract 2203: Characterization of raloxifene glucuronidation and the role of UGT genotypes on raloxifene metabolite profiles <i>in vivo</i>.
Authors: Dongxiao Sun, Nathan R. Jones, Manni Andrea, Philip Lazarus
Journal: Cancer Research (2013)

Abstract Raloxifene is a 2nd-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4’-glucuronide (ral-4’-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (ptrend=0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell line over-expressing UGT1A8 variants, the UGT1A8*2 variant was significantly (p=0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4’-Gluc exhibited 1/100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised ∼99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4’-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (ptrend=0.0025), ral-4’-Gluc (ptrend=0.001), and total raloxifene glucuronides (ptrend=0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] vs intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] vs fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene. Citation Format: Dongxiao Sun, Nathan R. Jones, Manni Andrea, Philip Lazarus. Characterization of raloxifene glucuronidation and the role of UGT genotypes on raloxifene metabolite profiles in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2203. doi:10.1158/1538-7445.AM2013-2203
Hydroxychloroquine treatment for primary Sjogren's syndrome: its effect on salivary and serum inflammatory markers
Authors: M. Tishler, I. Yaron, I. Shirazi, M. Yaron
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> To evaluate the effect of hydroxychloroquine treatment on interleukin 6 (IL6), hyaluronic acid (HA), and soluble interleukin 2 receptor (sIL2R) concentrations in the saliva and serum of patients with primary Sjögren's syndrome (SS). <h3>METHODS</h3> Fourteen SS patients treated with hydroxychloroquine 200 mg/day for 12 months were investigated in an open prospective study. Clinical parameters of efficacy and routine biochemical and haematological data to assess drug safety and tolerability were determined every three months. Salivary and serum IL6, sIL2R, and HA values were determined at study entry, 6 and 12 months, using ELISA and radiometric assays. <h3>RESULTS</h3> After hydroxychloroquine treatment, salivary IL6 concentrations decreased from 13.2 (1.2) to 7.3 (1.1) pg/ml (mean (SEM)) (p &lt; 0.0001). Similarly, salivary HA concentrations were also reduced from 577.8 (120) to 200 (34) ng/ml (mean (SEM) (p &lt; 0.003). Serum IL6 concentrations decreased from 5.4 (0.6) to 2.9 (0.2) pg/ml (mean (SEM) (p &lt; 0.001), while serum HA concentrations remained unchanged. No change has been detected in salivary or serum sIL2R concentrations after 12 months of treatment with hydroxychloroquine. Treatment also resulted in significant reduction in erythrocyte sedimentation rate, serum γ globulin, and C reactive protein values while only partial clinical improvement was noted in some patients. A more pronounced decrease of salivary IL6 and HA levels was found in the two patients in whom a reduction in the swelling of the parotid gland was noted. <h3>CONCLUSION</h3> In this open label study of hydroxychloroquine treatment for SS a significant reduction of some salivary inflammatory markers was seen at the end of 12 months. Although during the treatment period only a partial clinical effect could be noted, the findings suggest that a double blind controlled study of hydroxychloroquine in SS is indicated.
Donor Spontaneous Intracerebral Hemorrhage Is Associated With Systemic Activation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 and Subsequent Development of Coronary Vasculopathy in the Heart Transplant Recipient
Authors: Mohamad H. Yamani, Randall C. Starling, Daniel J. Cook, E. Murat Tuzcu, Ashraf Abdo, Philip Paul, Kimerly Powell, Norman B. Ratliff, Yang Yu, Patrick M. McCarthy, James B. Young
Journal: Circulation (2003)

Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy.We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69).This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.
Psychodermatology: An Overview
Authors: M Van Moffaert
Journal: Psychotherapy and Psychosomatics (1992)

As the skin is an organ that has a primary function in tactile receptivity and reacts directly upon emotional stimuli, dermatological practice involves a psychosomatic dimension. It is, however, the high visibility of dermatoses and their easy accessibility which make the skin a direct target for behavioural problems. Furthermore, self-destructive tendencies and hypochondriacal features often express themselves through dermatological symptoms: dermatits artefacta and skin hypochondriasis are among the specific psychocutaneous disorders discussed here. In view of the clinical interface between dermatology and psychiatry, general guidelines are formulated and specific aspects of psychotherapy, behavioural treatment and psychotropic drug treatment are discussed.
Colloidal Zirconyl Phosphate P 32 in the Treatment of Chronic Leukemia and Lymphomas
Authors: J. M. Hill, Ellen Loeb, R. J. Speer
Journal: JAMA (1964)

Colloidal zirconyl phosphate P 32, used as a preferred initial and long-term therapy, has given prolonged survival in 179 patients with chronic leukemia and lymphoma. A median survival time of 93.6 months from apparent onset of disease was obtained in 97 patients with chronic lymphocytic leukemia. For chronic myelogenous leukemia, lymphosarcoma, and Hodgkins disease, corresponding survival figures were 49.8 months, 59 months, and 25.7 months, respectively. The digital computer was used to calculate survival times. Radiocolloid zirconyl phosphate is recommended for therapeutic effectiveness related to the concentration of irradiation at the sites of leukemic and lymphomatous infiltrations.
Endoplasmic Reticulum Stress in Disease Pathogenesis
Authors: Jonathan H. Lin, Peter Walter, T.S. Benedict Yen
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which, collectively, represent a large fraction of the total protein output of a mammalian cell. Therefore, the protein flux through the ER must be carefully monitored for abnormalities, including the buildup of misfolded proteins. Mammalian cells have evolved an intricate set of signaling pathways from the ER to the cytosol and nucleus, to allow the cell to respond to the presence of misfolded proteins within the ER. These pathways, known collectively as the unfolded protein response, are important for normal cellular homeostasis and organismal development and may also play key roles in the pathogenesis of many diseases. This review provides background information on the unfolded protein response and discusses a selection of diseases whose pathogenesis involves ER stress.
Natural Immunization Against Malaria: Causal Prophylaxis with Antibiotics
Authors: Johannes Friesen, Olivier Silvie, Elyzana Dewi Putrianti, Julius C. R. Hafalla, Kai Matuschewski, Steffen Borrmann
Journal: Science Translational Medicine (2010)

Malaria-infected mice treated with antibiotics remain healthy and are protected against subsequent malaria infection.
Cognitive systems optimize energy rather than information
Authors: Arthur B. Markman, A. Ross Otto
Journal: Behavioral and Brain Sciences (2011)

Abstract Cognitive models focus on information and the computational manipulation of information. Rational models optimize the function that relates the input of a process to the output. In contrast, efficient algorithms minimize the computational cost of processing in terms of time. Minimizing time is a better criterion for normative models, because it reflects the energy costs of a physical system.
Localized Immunotherapy via Liposome-Anchored Anti-CD137 + IL-2 Prevents Lethal Toxicity and Elicits Local and Systemic Antitumor Immunity
Authors: Brandon Kwong, S. Annie Gai, Jamal Elkhader, K. Dane Wittrup, Darrell J. Irvine
Journal: Cancer Research (2013)

Immunostimulatory agonists such as anti-CD137 and interleukin (IL)-2 have elicited potent antitumor immune responses in preclinical studies, but their clinical use is limited by inflammatory toxicities that result upon systemic administration. We hypothesized that by rigorously restricting the biodistribution of immunotherapeutic agents to a locally accessible lesion and draining lymph node(s), effective local and systemic antitumor immunity could be achieved in the absence of systemic toxicity. We anchored anti-CD137 and an engineered IL-2Fc fusion protein to the surfaces of PEGylated liposomes, whose physical size permitted dissemination in the tumor parenchyma and tumor-draining lymph nodes but blocked entry into the systemic circulation following intratumoral injection. In the B16F10 melanoma model, intratumoral liposome-coupled anti-CD137 + IL-2Fc therapy cured a majority of established primary tumors while avoiding the lethal inflammatory toxicities caused by equivalent intratumoral doses of soluble immunotherapy. Immunoliposome therapy induced protective antitumor memory and elicited systemic antitumor immunity that significantly inhibited the growth of simultaneously established distal tumors. Tumor inhibition was CD8(+) T-cell-dependent and was associated with increased CD8(+) T-cell infiltration in both treated and distal tumors, enhanced activation of tumor antigen-specific T cells in draining lymph nodes, and a reduction in regulatory T cells in treated tumors. These data suggest that local nanoparticle-anchored delivery of immuno-agonists represents a promising strategy to improve the therapeutic window and clinical applicability of highly potent but otherwise intolerable regimens of cancer immunotherapy. Cancer Res; 73(5); 1547-58. ©2012 AACR.
Plasma cross linked fibrin degradation products in pulmonary embolism.
Authors: B J Rowbotham, J Egerton-Vernon, A N Whitaker, M J Elms, I H Bunce
Journal: Thorax (1990)

Plasma concentrations of cross linked fibrin degradation products, a marker of intravascular thrombosis and fibrinolysis, were measured in 495 patients with suspected pulmonary embolism referred for ventilation-perfusion lung scanning to determine whether concentrations are increased in pulmonary embolism and their potential use in diagnosis. Lung scans were described as normal (n = 66) or as showing a low (n = 292), indeterminate (n = 58), or high probability (n = 79) of pulmonary embolism. There was a difference between the mean levels of cross linked fibrin degradation products in each scan category: normal scans, 142 ng/ml; low probability scans, 295 ng/ml; indeterminate probability scans, 510 ng/ml; high probability scans, 952 ng/ml (p less than 0.001). Of the patients with high probability scans, 96% had raised concentrations. Explanations for discrepant low results include incorrect scan diagnosis, delay in blood sampling, and anticoagulation. Of the patients with a low or indeterminate probability of pulmonary embolism, 43% had increased concentrations of cross linked fibrin degradation products that could be attributed in most cases to another illness. Owing to the wide range of values in each lung scan diagnostic category, raised concentrations of these fibrin degradation products cannot be used without reference to the patient9s clinical state as a discriminatory test for pulmonary embolism. Further evaluation of the significance of normal concentrations in excluding a diagnosis of pulmonary embolism appears to be warranted.
EFFECT OF MULTIPLICITY OF INFECTION ON NEWCASTLE DISEASE VIRUS-H<scp>E</scp>L<scp>A</scp> CELL INTERACTION
Authors: E. Frederick Wheelock, Igor Tamm
Journal: The Journal of Experimental Medicine (1961)

The effects of a hundred-fold difference in virus/cell multiplicity on the interaction of Newcastle disease virus (NDV) with HeLa cells were studied, and various phases of the virus reproductive cycle were related to cellular consequences of infection. At both multiplicities used all cells were infected. The following events occurred 1 to 2 hours earlier in cells which were inoculated with the higher multiplicity: (a) first appearance of newly made virus antigen, and the amount present at any time during the period of rapid increase; (b) onset and time course of production of infective virus; (c) development by infected cells of hemadsorbing ability; (d) onset and time course of inhibition of mitosis; and (e) onset and time course of marked cell damage. Double infection of HeLa cells with NDV and NWS was demonstrated by the fluorescent antibody technique, and was used to show that the establishment of interference against NWS was also dependent upon the multiplicity of NDV. In cells inoculated at each multiplicity, newly made virus antigen appeared at the same time as the first infective virus particles. Infective virus rapidly reached a peak, and then declined. Viral antigen continued to increase for several hours after the decline in infective virus had begun. Thus, only a small fraction of the virus antigen produced was incorporated into new infective particles. The maximal yield of such particles was only 6 to 11 per HeLa cell. Over 95 per cent of new virus was cell-associated, but could be neutralized by treatment with antiserum before disruption of cells. Mitosis occurred in cells which had produced and released infective NDV. Progressive inhibition of mitotic activity in infected cells was correlated with continued production of viral antigen. Marked cytopathic changes developed after mitotic activity had decreased to low levels. The mechanism by which NDV inhibits mitosis in HeLa cells is discussed.
Preferential Interaction of a Novel Tumor Surface Protein (p38.5) with Naive Natural Killer Cells
Authors: Ballabh Das, Mary O. Mondragon, Shi-Zhen Tao, Allen J. Norin
Journal: The Journal of Experimental Medicine (1997)

A receptor–ligand interaction exclusive to natural killer (NK) cell–mediated recognition and triggering of tumor cell destruction has not yet been identified. In contrast, molecules that are involved in cellular adhesion and regulation of NK cytolysis have been well studied. In this report, a novel tumor surface protein is identified that exhibits characteristics of a recognition structure for naive NK cells. A tagged ligand–cell adsorption technique revealed a 38.5-kD plasma membrane protein (p38.5) from a prototypical NK-susceptible cell line (K562) that preferentially bound to NK cells (CD3−CD5−CD16+) relative to T lymphocytes (CD3+CD5+ CD16−). The molecule was purified to apparent homogeneity for further characterization. An amino acid sequence of an 11-mer internal peptide of p38.5 did not exhibit homology to known proteins. Affinity-purified antibody generated against this peptide (anti-p38.5) reacted with a single protein of 38.5 kD on Western blots of whole cell extracts of K562. Flow cytometry and immunoprecipitation studies of surface-labeled tumor cells demonstrated expression of p38.5 on NK-susceptible tumor cell lines (K562, MOLT-4, Jurkat), whereas p38.5 was not detected on NK-resistant tumor cell lines (A549, Raji, MDA-MB-231). Significantly, p38.5 loss variants derived from wild-type Jurkat and Molt-4 cell lines exhibited decreased susceptibility to NK cell–mediated lysis demonstrating a strong association between cell surface expression of p38.5 and cytotoxicity. Purified p38.5 retained preferential binding to NK cells and inhibited NK activity in a dose-dependent manner, thereby providing direct evidence of a role in the lytic process. Binding studies identified a 70-kD membrane protein from NK cells as a possible receptor for the p38.5 tumor ligand. Consistent with cellular adsorption studies, the 70-kD, p38.5 binding protein was not detected on T lymphocytes. Based on studies demonstrating selective binding of p38.5 to NK cells, lack of expression on NK-resistant tumor cell lines and ability of the purified molecule to block cytolysis, we conclude that p38.5 may serve as a recognition/triggering ligand for naive human NK cells.