tbuckley/cabot-search huggingface dataset:
Murine Transporter Associated with Antigen Presentation (TAP) Preferences Influence Class I–restricted T Cell Responses
Authors: Amy J. Yellen-Shaw, Carol E. Laughlin, Robert M. Metrione, Laurence C. Eisenlohr
Journal: The Journal of Experimental Medicine (1997)

The transporter associated with antigen presentation (TAP) complex shuttles cytosolic peptides into the exocytic compartment for association with nascent major histocompatibility complex class I molecules. Biochemical studies of murine and human TAP have established that substrate length and COOH-terminal residue identity are strong determinants of transport efficiency. However, the existence of these specificities in the intact cell and their influences on T cell responses have not been demonstrated. We have devised a method for studying TAP- mediated transport in intact cells, using T cell activation as a readout. The approach makes use of a panel of recombinant vaccinia viruses expressing peptides containing the Kd-restricted nonamer influenza nucleoprotein residues 147–155. The COOH terminus of each construct was appended with a dipeptide composed of an internal threonine residue followed by a varying amino acid. Synthetic peptide versions of these 11-mers exhibit vastly different transport capabilities in streptolysin O–permeabilized cells, in accordance with the predicted influence of the COOH-terminal residues. Presentation of the endogenously expressed version of each construct requires TAP-mediated transport and cooexpression with a vac-encoded exocytic COOH-terminal dipeptidase, angiotensin converting enzyme, to allow liberation of the minimal epitope. Recognition by epitope-specific CTLs therefore signifies TAP-mediated transport of a complete 11-mer within the target cell. Under normal assay conditions no influences of the COOH-terminal residue were revealed. However, when T cell recognition was limited, either by blocking CD8 coreceptor interactions or by decreasing the amount of transport substrate synthesized, significant COOH-terminal effects were revealed. Under such conditions, those peptides that transported poorly in biochemical assays were less efficiently presented. Therefore, TAP specificity operates in the intact cell, appears to reflect previously defined rules with regard to the influence of the COOH-terminal residue, and can strongly influence T cell responses.
Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S
Authors: Felicity N. E. Gavins, Janice Russell, Elena L. Senchenkova, Lidiana De Almeida Paula, Amílcar S. Damazo, Charles T. Esmon, Daniel Kirchhofer, Robert P. Hebbel, D. Neil Granger
Journal: Blood (2011)
Screening for small for dates fetuses
Authors: J. Draper, S. Field, H A Thomas, M J Hare
Journal: BMJ (1985)

Finally, it is perhaps worth restating that the screening programme in Britain, though falling short of its potential effectiveness, has almost certainly not failed so completely as is sometimes assumed.There is no reasonable doubt that there has been a substantial increase in the incidence of carcinoma in situ and invasive cancer among younger women and this increase has probably been held in check as a result of screening.
Metabolic and Endocrine Physiology: An Introductory Text
Authors: T. Albert Farmer
Journal: JAMA (1968)

The attempt by a single author to prepare a 250-page volume reflecting balance of the rapidly developing knowledge in the area of metabolic and endocrine physiology is both a herculean and admirable task. As a physician involved with the teaching of endocrinology and metabolism to undergraduate medical students, I am in agreement with the author that "the study of Endocrinology can be viewed as one long exercise in correlation." However, it is in this area of correlation that this volume falls short of its goal. The statements that certain clinical conditions result because hormones are being metabolically inactivated at too slow a rate, that Simmonds' disease is a genetic or developmental defect in early childhood, that adrenal 21-hydroxylase defect is without disturbances in water and electrolyte metabolism, that metyrapone (Metopirone) is an experimental drug with clinical application not yet widespread, that desoxycorticosterone acetate causes hypertension without expansion of circulating blood
Indirect action of tumor necrosis factor-alpha in liver injury during the CD8+ T cell response to an adeno-associated virus vector in mice
Authors: Matthew Giannandrea, Robert H. Pierce, Ian Nicholas Crispe
Journal: Hepatology (2009)

CD8+ T cells can cause hepatocellular injury by two distinct mechanisms. In addition to their direct cytotoxic effect, there is also collateral liver injury, which occurs when cells are killed in an antigen-independent manner. Whereas immune effector cytokines interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) have both been implicated in various forms of hepatitis, their respective roles in direct and/or collateral liver damage remains unclear. In order to investigate these elements of liver injury, we developed a new experimental model of CD8+ T-cell–mediated hepatitis based on an adeno-associated virus-based gene therapy vector. This vector is used to deliver antigen to hepatocytes, and CD8+ T cells specific for the vector-encoded transgene are adoptively transferred to produce liver immunopathology. In this experimental model, CD8+ T-cell IFNγ acts on Kupffer cells, inducing TNFα secretion and liver injury. Both IFNγ and TNFα are important in this injury process, but TNFα acts as an autocrine amplifier of Kupffer cell function, rather than as a direct effector of hepatocellular damage. Conclusions: TNFα indirectly promotes liver damage and is not a direct hepatotoxic agent. IFNγ also indirectly contributes to liver injury through Kupffer cell activation while, in parallel, directly promoting hepatitis through induction of hepatocyte major histocompatability complex class I. In principle, it may be possible to ameliorate this immunopathologic indirect mechanism by developing therapies that target Kupffer cells, without impairing CD8+ T-cell-mediated antiviral immunity. This would have great therapeutic potential in chronic viral hepatitis. (HEPATOLOGY 2009.)
<i>Helicobacter pylori</i>activation of PARP-1
Authors: Carlos W. Nossa, Steven R. Blanke
Journal: Gut Microbes (2010)

Chronic infection of the human stomach by Helicobacter pylori is an important risk factor for gastric cancer. H. pylori produces a cache of virulence factors that promote colonization and persistence, which, in turn, contributes to a robust inflammatory response at the host-pathogen interface. Recently, we reported that H. pylori activates the abundant nuclear regulator poly(ADP-ribose) polymerase (PARP)-1, resulting in the production of the catabolite poly(ADP-ribose) (PAR). PARP-1 is emerging as a key player in establishing homeostasis at the host-pathogen interface. In this article, we summarize the discovery of H. pylori-dependent PARP-1 activation, and discuss potential roles for PARP-1 in H. pylori-mediated gastric disease. In light of the remarkable successes that have reported for treating inflammatory disorders and cancers with PARP-1 inhibitors, we discuss the prospects of targeting PARP-1 for treatment of H. pylori-associated gastric disease.
594. Enhancement of Cellular and Nuclear Uptake of Macromolecules, Therapeutic Genes and Lipoplexes by Using NLS and PTD Containing Viral Peptides
Authors: Roosmarijn Vandenbroucke, Niek N. Sanders, Stefaan De Smedt, Joseph Demeester
Journal: Molecular Therapy (2005)

Gene therapy is a novel approach to treat genetic based diseases by bringing therapeutic genes inside target cells. Non-viral gene carriers are safe, but show low efficiency, since many barriers complicate the delivery of exogenous pDNA to the cell nucleus.
Surgical Outcome of Stage IIIA- cN2/pN2 Non–Small-Cell Lung Cancer Patients in Japanese Lung Cancer Registry Study in 2004
Authors: Ichiro Yoshino, Shigetoshi Yoshida, Etsuo Miyaoka, Hisao Asamura, Hiroaki Nomori, Yoshitaka Fujii, Yoichi Nakanishi, Kenji Eguchi, Masaki Mori, Noriyoshi Sawabata, Meinoshin Okumura, Kohei Yokoi
Journal: Journal of Thoracic Oncology (2012)
Cardiac recovery during 30 days of support with a left ventricular assist device. Preliminary results from the LVAD working group
Authors: Simon Maybaum, O.H. Frazier, Randall C. Starling, Leslie Miller, Srinivas Murali, Keith D. Aaronson, Kenneth Margulies, Susan McRee, Guillermo Torre
Journal: Journal of the American College of Cardiology (2003)
Cutaneous Localization of the Membrane Attack Complex in Discoid and Systemic Lupus Erythematosus
Authors: Gregory Biesecker, Linda Lavin, Michele Ziskind, David Koffler
Journal: New England Journal of Medicine (1982)

Biopsy specimens of skin lesions from three patients with discoid lupus erythematosus and six patients with systemic lupus erythematosus contained the membrane attack complex, which comprises C5b through C9, as well as immune complexes at the dermal-epidermal junction. The basilar epithelium in these areas was vacuolated and edematous, and the dermis contained an inflammatory infiltrate. In contrast, 19 of 29 specimens of normal-appearing skin from patients with discoid or systemic lupus erythematosus showed only immune complexes at the dermal-epidermal junction, without the membrane attack complex. The other 10 specimens, all from patients without cutaneous involvement, showed neither immune complexes nor membrane attack complexes. These data suggest that immune complexes within skin lesions selectively generate the assembly of the membrane attack complex, which mediates membrane injury. A synergistic interaction of immune complexes and cofactors may be required to activate complement in areas of skin that are predisposed to tissue injury.
Methylenedioxyphenyl insecticide synergists as potential human health hazards.
Authors: M R Franklin
Journal: Environmental Health Perspectives (1976)

The effects of methylenedioxyphenyl insecticide synergists on human health arise, not from their intrinsic toxicity which is relatively low, but from their dual effect on the oxidative detoxication or intoxication processes of the body. They are able to inhibit these reactions by two mechanisms. They are substrates for mixed function oxidation and, thus, compete with other xenobiotics for available enzyme, and an intermediate in their metabolism is able to bind with cytochrome P-450 to form an inactive complex which absorbs maximally at 455 nm. In addition, they are able to activate xenobiotic metabolism by induction (the increased synthesis and retention) of microsomal oxidative enzymes. Evidence for these effects is presented, including spectroscopic and enzyme kinetic data. Correlations with existing in vivo observations are outlined. The inhibition and induction of cytochrome P-450, the central enzyme in the metabolism of xenobiotics, thus provides the focus for consideration of methylenedioxyphenyl synergists as potential hazards.
Cyclosporin A (CyA) reduces sCD30 serum levels in atopic dermatitis: a possible new immune intervention
Authors: V Bottari, A Frezzolini, M Ruffelli, P Puddu, O De Pità, L Fontana
Journal: Allergy (1999)

Atopic dermatitis (AD) is a chronic inflammatory skin disease frequently associated with asthma, rhinitis, and food allergy. Lymphocytes producing Th2‐type cytokines (such as interleukin [IL]‐3, IL‐4, and IL‐5) have been thought to have a key role in the pathogenesis of the disease. We have recently demonstrated that elevated serum levels of the soluble form of CD30 (sCD30), an activation marker of Th2‐cell clones, correlates with disease activity in pediatric patients suffering from AD. Clinical trials have demonstrated that cyclosporin A (CyA) treatment resulted in significant improvement of clinical symptoms in patients affected with AD. In this study, we evaluated the role of CyA in modulating sCD30 release in a group of adult patients affected by severe AD treated with CyA at the dosage of 3.5 mg/kg body weight for 12 weeks. Our results demonstrated, in parallel with an improvement of clinical symptoms, a significant reduction of serum levels of both IL‐4 and sCD30, thus suggesting that CyA can prevent the activation of Th2 cells observed in AD.
Portable flanking sequences modulate CTL epitope processing
Authors: Sylvie Le Gall, Pamela Stamegna, Bruce D. Walker
Journal: Journal of Clinical Investigation (2007)

Peptide presentation is critical for immune recognition of pathogen-infected cells by CD8+ T lymphocytes. Although a limited number of immunodominant peptide epitopes are consistently observed in diseases such as HIV-1 infection, the relationship between immunodominance and antigen processing in humans is largely unknown. Here, we have demonstrated that endogenous processing and presentation of a human immunodominant HIV-1 epitope is more efficient than that of a subdominant epitope. Furthermore, we have shown that the regions flanking the immunodominant epitope constitute a portable motif that increases the production and antigenicity of otherwise subdominant epitopes. We used a novel in vitro degradation assay involving cytosolic extracts as well as endogenous intracellular processing assays to examine 2 well-characterized HIV-1 Gag overlapping epitopes presented by the same HLA class I allele, one of which is consistently immunodominant and the other subdominant in infected persons. The kinetics and products of degradation of HIV-1 Gag favored the production of peptides encompassing the immunodominant epitope and destruction of the subdominant one. Notably, cytosolic digestion experiments revealed flanking residues proximal to the immunodominant epitope that increased the production and antigenicity of otherwise subdominant epitopes. Furthermore, specific point mutations in these portable flanking sequences modulated the production and antigenicity of epitopes. Such portable epitope processing determinants provide what we believe is a novel approach to optimizing CTL responses elicited by vaccine vectors.
Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction
Authors: Shinji Negoro, Hidemasa Oh, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Kenneth Walsh, Tadamitsu Kishimoto, Keiko Yamauchi-Takihara
Journal: Circulation (2001)

We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown.We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation.Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.
Associations between Arsenic in Drinking Water and Pterygium in Southwestern Taiwan
Authors: Wei Lin, Shu-Li Wang, Horng-Jiun Wu, Kuang-Hsi Chang, Peter Yeh, Chien-Jen Chen, How-Ran Guo
Journal: Environmental Health Perspectives (2008)

Pterygium is a fibrovascular growth of the bulbar conjunctiva and underlying subconjunctival tissue that may cause blindness. The mechanism of pterygium formation is not yet fully understood, but pterygium has some tumorlike features.The objective of this study was to evaluate the association between arsenic exposure through drinking water and the occurrence of pterygium in southwestern Taiwan.We recruited participants > 40 years of age from three villages in the arseniasis-endemic area in southwestern Taiwan (exposure villages) and four neighboring nonendemic villages (comparison villages). Each participant received an eye examination and a questionnaire interview. Photographs taken of both eyes were later graded by an ophthalmologist to determine pterygium status.We included 223 participants from the exposure villages and 160 from the comparison villages. The prevalence of pterygium was higher in the exposure villages across all age groups in both sexes and increased with cumulative arsenic exposure. We found a significant association between cumulative arsenic exposure and the prevalence of pterygium. After adjusting for age, sex, working under sunlight, and working in sandy environments, we found that cumulative arsenic exposure of 0.1-15.0 mg/L-year and > or = 15.1 mg/L-year were associated with increased risks of developing pterygium. The adjusted odds ratios were 2.04 [95% confidence interval (CI), 1.04-3.99] and 2.88 (95% CI, 1.42-5.83), respectively.Chronic exposure to arsenic in drinking water was related to the occurrence of pterygium, and the association was still observed after adjusting for exposures to sunlight and sandy environments.
Quantitative Evaluation of Epstein-Barr-Virus-Infected Mononuclear Peripheral Blood Leukocytes in Infectious Mononucleosis
Authors: Giovanni Rocchi, Annapaola de Felici, Giuseppe Ragona, Andreas Heinz
Journal: New England Journal of Medicine (1977)

We devised a quantitative assay for Epstein-Barr-virus-infected mononuclear leukocytes (virocytes) to determine their prevalence in the blood of patients with acute-phase and convalescent-phase infectious mononucleosis and in healthy Epstein-Barr-virus-seropositive controls. Mononuclear peripheral blood leukocyte suspensions were tested for virus-determined cytoproliferative activity by cocultivation with human cord-cell indicator cultures. The highest levels of virocytes among circulating mononuclear leukocytes were found in the early acute phase of infectious mononucleosis (up to 0.05 per cent). Virocytemia decreased to levels comparable with those of healthy controls (less than 0.00001 per cent) by the third month after onset of infectious mononucleosis. These findings provide a quantitative profile of the course of the infection at cellular level and support existing evidence of the efficiency of immune control mechanisms in limiting Epstein-Barr-virus infection during the course of infectious mononucleosis.
Screening for Thalassemia Trait by Electronic Measurement of Mean Corpuscular Volume
Authors: Howard A. Pearson, Richard T. O'Brien, Sue McIntosh
Journal: New England Journal of Medicine (1973)

THALASSEMIAS are a group of hereditary blood conditions with clinical and genetic implications that occur frequently in Mediterranean ethnic groups. There have been few attempts to screen high-prevalence populations for thalassemia trait in the United States, and a major deterrent has been the lack of a reliable, inexpensive screening method. The studies described below indicate that electronic determination of red-cell mean corpuscular volume is a valid screening test for thalassemia trait.A comprehensive pilot screening program for thalassemia trait was offered to members of two Greek Orthodox churches, and to families of persons known to have thalassemia; 300 subjects were . . .
Survival of Kidney Transplantation Patients in the United States After Cardiac Valve Replacement
Authors: Alok Sharma, David T. Gilbertson, Charles A. Herzog
Journal: Circulation (2010)

Background— Few published studies address the survival of kidney transplantation patients after valve surgery, and none address relative outcomes related to tissue versus nontissue prosthesis. This study aimed to assess survival of US kidney transplantation patients after cardiac valve replacement and to compare associations of valve selection. Methods and Results— Of 1 698 706 patients in the US Renal Data System database, we identified 1335 kidney transplantation patients hospitalized in 1991 to 2004 for cardiac valve replacement. Survival was estimated by the Kaplan-Meier method; independent predictors of death were examined in a comorbidity-adjusted (by Charlson and propensity score) Cox model. Of the cohort, 17% were 0 to 44 years of age, 50% were 45 to 64 years of age, 28% were 65 to 74 years of age, and 5% were ≥75 years of age; 78% were white; 63% were men; and 20% had kidney failure caused by diabetes mellitus. Of 369 patients (28%) who received tissue valves, 75% had aortic valve replacement, 20% had mitral valve replacement, and 5% had both. Use of tissue valves increased from 13% in 1991 to 1995 to 38% in 2000 to 2004. Age, diabetes mellitus, and combined aortic and mitral valve replacement were the strongest predictors of all-cause mortality. In-hospital mortality was 14.0% overall, 11.4% for tissue-valve patients, and 15.0% for nontissue-valve patients ( P =0.09). Two-year survival estimates were 61.5% for tissue-valve and 59.5% for nontissue-valve patients ( P =0.30). The adjusted hazard ratio of death for tissue- versus nontissue-valve patients was 0.83 (95% confidence interval, 0.70 to 0.99). Conclusions— Renal transplantation patients requiring valve replacement have high mortality rates (≈20%/y). These data suggest minimally reduced mortality risk for patients receiving tissue versus nontissue valves.
Lipid-Lowering Therapy and Risk of Coronary Events
Authors: L. Mascitelli
Journal: JAMA (2003)

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