tbuckley/cabot-search huggingface dataset:
Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis
Authors: Michaela Granzow, Robert Schierwagen, Sabine Klein, Benita Kowallick, Sebastian Huss, Markus Linhart, Irela G. Reza Mazar, Jan Görtzen, Annabelle Vogt, Frank A. Schildberg, Maria A. Gonzalez-Carmona, Alexandra Wojtalla, Benjamin Krämer, Jacob Nattermann, Sören V. Siegmund, Nikos Werner, Dieter O. Fürst, Wim Laleman, Percy Knolle, Vijay H. Shah, Tilman Sauerbruch, Jonel Trebicka
Journal: Hepatology (2014)

Activation of the renin angiotensin system resulting in stimulation of angiotensin-II (AngII) type I receptor (AT1R) is an important factor in the development of liver fibrosis. Here, we investigated the role of Janus kinase 2 (JAK2) as a newly described intracellular effector of AT1R in mediating liver fibrosis. Fibrotic liver samples from rodents and humans were compared to respective controls. Transcription, protein expression, activation, and localization of JAK2 and downstream effectors were analyzed by real-time polymerase chain reaction, western blotting, immunohistochemistry, and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl4 intoxication, thioacetamide intoxication or continuous AngII infusion. JAK2 was inhibited by AG490. In vitro experiments were performed with primary rodent hepatic stellate cells (HSCs), Kupffer cells (KCs), and hepatocytes as well as primary human and human-derived LX2 cells. JAK2 expression and activity were increased in experimental rodent and human liver fibrosis, specifically in myofibroblastic HSCs. AT1R stimulation in wild-type animals led to activation of HSCs and fibrosis in vivo through phosphorylation of JAK2 and subsequent RhoA/Rho-kinase activation. These effects were prevented in AT1R(-/-) mice. Pharmacological inhibition of JAK2 attenuated liver fibrosis in rodent fibrosis models. In vitro, JAK2 and downstream effectors showed increased expression and activation in activated HSCs, when compared to quiescent HSCs, KCs, and hepatocytes isolated from rodents. In primary human and LX2 cells, AG490 blocked AngII-induced profibrotic gene expression. Overexpression of JAK2 led to increased profibrotic gene expression in LX2 cells, which was blocked by AG490.Our study substantiates the important cell-intrinsic role of JAK2 in HSCs for development of liver fibrosis. Inhibition of JAK2 might therefore offer a promising therapy for liver fibrosis.
Live, Attenuated Mumps-Virus Vaccine
Authors: Maurice R. Hilleman, Robert E. Weibel, Eugene B. Buynak, Joseph Stokes, James E. Whitman
Journal: New England Journal of Medicine (1967)

PREVIOUS reports1 2 3 4 described the development of the Jeryl Lynn B level live, attenuated mumps-virus vaccine, the findings in early clinical tests of the vaccine and the serologic and clinical responses to the vaccine in a controlled field study carried out in the Havertown–Springfield suburb of Philadelphia during the fall, winter and spring of 1965–66. The present report summarizes the data on the protective efficacy of the vaccine against natural mumps challenge in the Havertown–Springfield study.ResultsConduct of the StudyDetails of the study plan were previously described,3 and only the essential aspects are given here. Lot 137 of Jeryl . . .
831. Evaluation of Lentiviral Vectors for Gene Therapy of Wiskott-Aldrich Syndrome
Authors: Marguerite V. Evans-Galea, Matthew M. Wielgosz, Hideki Hanawa, Arthur W. Nienhuis
Journal: Molecular Therapy (2005)

Retroviral vector-mediated activation of the LMO2 oncogene led to the onset of leukemia in two X-SCID patients who underwent gene therapy (Science 302: 415, 2003). This has necessitated the development of safer vectors for use in a therapeutic setting. Many pre-clinical studies have now incorporated the use of insulator elements that have boundary and/or enhancer blocking functions to isolate the transcriptional unit within the genome. The chicken beta-globin 5' DNase I hypersensitive site 4 (5'HS4) insulator possesses both of these properties and has been used to overcome positional variegation effects on transgene expression. Characterizing this aspect of insulator function is essential, but it is also of interest to know if there is any differential effect on the pattern of retroviral integration. We are developing lentiviral vectors for gene therapy of Wiskott-Aldrich syndrome (WAS) because of their greater efficiency at transducing repopulating stem cells (Blood 103:4062, 2004) compared to oncoretroviral vectors. WAS is a rare X-linked recessive disorder caused by mutations in the WASP gene which affect cells of the hematopoietic lineage. We have previously demonstrated correction of the T-cell proliferation defect, partial correction of the cytokine secretion defect and improvement in the impaired secondary response to influenza virus in Wasp- mice using MSCV onco-retroviral vectors (Blood 102:3108, 2003). Due to the modest selective advantage of gene-corrected lymphocytes and the variability in the level of gene expression, we are now exploring the use of lentiviral vectors. The efficiency of stem cell-targeted gene transfer achieved with lentiviral vectors and the consistency of gene expression are crucial factors that will determine the success of any therapeutic application for the treatment of WAS. Towards this goal, we are evaluating various vector designs in mice using GFP as a marker gene. To examine the effect of the 5'HS4 insulator within the context of our lentiviral backbone, we have generated advanced third generation vectors containing a modified MSCV promoter (Mp) driving GFP with or without the 5'HS4 insulator. Several single- and multiple-copy T-cell (Jurkat) clones have been isolated for each construct and their expression characterized by flow cytometry. Inclusion of the 5'HS4 insulator did not significantly affect the average mean fluorescence intensity (MFI = 370|[plusmn]|221 versus 329|[plusmn]|120[5'HS4+]), but did reduce the variability of expression amongst individual clones as indicated by a decrease in the co-efficient of variation from 57|[plusmn]|26 to 40|[plusmn]|3. To determine if this insulator has an effect on the position or frequency of insertion, the specific integration sites in clones containing the proviral genomes are being characterized by ligation-mediated (LM)-PCR.
Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome—Disease-Relevant or Benign?
Authors: Maria Chiara Marinozzi, Laura Vergoz, Tania Rybkine, Stephanie Ngo, Serena Bettoni, Anastas Pashov, Mathieu Cayla, Fanny Tabarin, Mathieu Jablonski, Christophe Hue, Richard J. Smith, Marina Noris, Lise Halbwachs-Mecarelli, Roberta Donadelli, Veronique Fremeaux-Bacchi, Lubka T. Roumenina
Journal: Journal of the American Society of Nephrology (2014)

Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association.
[441] MOLECULAR EPIDEMIOLOGY OF A HEPATITIS C VIRUS (HCV) OUTBREAK IN A HAEMODIALYSIS UNIT IN ITALY
Authors: E. Spada, I. Abbate, E. Sicurezza, A. Mariano, M. Cuccia, S. Rinnone, M.R. Capobianchi, A. Mele
Journal: Journal of Hepatology (2007)
Abstract 1548: Ultraviolet B-induced platelet-activating factor receptor agonists mediate augmentation of melanoma tumor growth via regulatory T cells: Implication of systemic immunosuppression
Authors: Ravi P. Sahu, Raymond L. Konger, Christopher E. Touloukian, Jeffrey B. Travers
Journal: Cancer Research (2012)

Abstract Ultraviolet B (UVB)-irradiation to human or mouse skin generates Platelet-activating factor (PAF) and novel oxidatively-modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma progression. As our studies demonstrated that B16F10 tumors do not express functional PAF-Rs, retroviral-mediated transduction of the PAF-R was used to create PAF-R-positive B16F10 melanoma tumor cells. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell, PAF-R-expression as UVB or the PAF-R agonist, carbamoyl- PAF (CPAF), both promote B16F10 tumor growth in wild-type mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in PAF-R deficient (Pafr -/-) mice. Systemic antioxidant treatment ameliorated UVB-mediated augmentation of tumor growth, indicating involvement of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice, or depletion of CD25-positive cells (suggestive of FoxP3 directed regulatory T cells) in FoxP3EGFP transgenic mice block UVB/CPAF-induced tumor growth, supporting a requirement for IL-10 and regulatory T cells (Tregs) in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression. These studies describe a previously unrecognized mechanism by which melanoma tumor cells can escape antitumor immunity. Inasmuch as other pro-oxidative stressors could potentially generate PAF-R agonists, this pathway could have clinical relevance in terms of devising better strategy for melanoma immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1548. doi:1538-7445.AM2012-1548
Abstract 2547: Caveolin-1 inhibits survivin and increases sensitivity to paclitaxel in breast cancer cells
Authors: Nadia Jafar, Ayesha N. Shajahan, Robert Clarke
Journal: Cancer Research (2010)

Abstract Breast cancer is the second leading cause of death due to cancer in women and approximately 194,280 new cases of breast cancer were diagnosed in 2009. The chemotherapeutic drugs known as taxanes disrupt the microtubule function and arrest cell cycle. Paclitaxel (Taxol) is a taxane that is commonly used to treat patients with breast cancer as well as other types of cancer. However, resistance to paclitaxel remains a hindrance to successful treatment. Previously, we have shown that signaling associated with caveolin-1 (CAV1), a structural protein, is an essential determinant of paclitaxel sensitivity in MCF-7 breast cancer cells. CAV1 is part of this family of proteins that has multiple functions in different cancers but it has been proposed to function as a tumor suppressor in breast cancer. Here we show that CAV1 may promote cell death in response to paclitaxel by inhibiting the function of a pro-survival protein called survivin. Survivin is encoded by the BIRC5 gene and is part of the inhibitors of apoptosis (IAP) family. This protein has numerous functions including inhibition of apoptosis and regulation of the cell cycle. Evidence shows that survivin inhibits cell apoptosis by preventing the activation of caspases, which are proteases associated with cell-mediated apoptosis. Up-regulation of survivin is associated with cancer and usually indicates a poor prognosis. We show that while over-expression of CAV1 down-regulates survivin, over-expression of survivin down-regulates CAV1 in MCF-7 cells. Moreover, MCF-7 cells that over-express survivin show decreased inhibition of cell proliferation in response to 10 nM paclitaxel compared to MCF-7 cells expressing the empty vector (EV, control). Thus, our work highlights the role of CAV1 expression in breast cancer cells as an essential determinant of paclitaxel sensitivity. Findings from this research can help researchers and clinicians to evaluate whether CAV1 expression in breast tumors can help predict its responsiveness to taxanes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2547.
Endocrine Withdrawal Syndromes
Authors: Ze’ev Hochberg, Karel Pacak, George P. Chrousos
Journal: Endocrine Reviews (2003)

Hypersecretion of endogenous hormones or chronic administration of high doses of the same hormones induces varying degrees of tolerance and dependence. Elimination of hormone hypersecretion or discontinuation of hormone therapy may result in a mixed picture of two syndromes: a typical hormone deficiency syndrome and a generic withdrawal syndrome. Thus, hormones with completely different physiological effects may produce similar withdrawal syndromes, with symptoms and signs reminiscent of those observed with drugs of abuse, suggesting shared mechanisms. This review postulates a unified endocrine withdrawal syndrome, with changes in the hypothalamic-pituitary-adrenal axis and the central opioid peptide, in which noradrenergic and dopaminergic systems of the brain act as common links in its pathogenesis. Long-term adaptations to hormones may involve relatively persistent changes in molecular switches, including common intracellular signaling systems, from membrane receptors to transcription factors. The goals of therapy are to ease withdrawal symptoms and to expedite weaning of the patient from the hormonal excess state. Clinicians should resort to the fundamentals of tapering hormones down over time, even in the case of abrupt removal of a hormone-producing tumor. In addition, the prevention of stress and concurrent administration of antidepressants may ameliorate symptoms and signs of an endocrine withdrawal syndrome.
Central apnea index decreases after prolonged treatment with acetazolamide.
Authors: W A DeBacker, J Verbraecken, M Willemen, W Wittesaele, W DeCock, P Van deHeyning
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Only a limited number of studies dealing with the epidemiology and therapy of central sleep apnea syndrome (CA) are available. The treatment strategies are poorly defined and not well evaluated. The aim of our present study was to treat selected CA patients with low dose acetazolamide (ACET) for a longer time period than has been done before. Previous studies were performed with high dose ACET provoking severe metabolic acidosis, not for more than 1 wk or only in obstructive apnea patients. Referred patients with suspicion of sleep-related breathing disorders (SRBD) were included in the study if, after a first selection night, their central apnea index (CAI) was > 5 or their apnea-hypopnea index (AHI) > 10 and their obstructive apnea index (OAI) < 5. Of 327 screened patients, 14 (4.3%) fulfilled these criteria. Patients were then treated with ACET (250 mg, 1 h before sleep): Polysomnography was repeated once after one single dose (N2) and twice after 1-mo chronic treatment without (N3) and with (N4) additional ACET administration. After each study night, arterial blood gases and chemical drive were measured. CAI (25.5 +/- 6.8 at N1) already decreased during N2 (13.8 +/- 5.2) and further during N3 (6.6 +/- 2.9) and N4 (6.8 +/- 2.8) p < 0.01). OAI remained unchanged. Total sleep time (TST) and sleep efficiency index (SEI) did not change significantly. The number of arousals decreased from 62 +/- 11 at N1 to 40 +/- 5 at N3 (p = 0.019).(ABSTRACT TRUNCATED AT 250 WORDS)
EXPERIMENTAL TYPHUS INFECTION IN THE EASTERN COTTON RAT (SIGMODON HISPIDUS HISPIDUS)
Authors: Charles R. Anderson
Journal: The Journal of Experimental Medicine (1944)

1. The course of typhus infection in cotton rats has been described, and a relationship between the dose administered and the time of death has been demonstrated. 2. Rather incomplete pathological studies indicated that typhus in the cotton rat is an acute infection primarily involving mesothelial tissue, and tissues of mesothelial origin. Depending somewhat upon the route of infection, rickettsiae were most easily demonstrated in smears from liver, brain, and pericardial and peritoneal exudates. By subinoculation into the yolk sacs of fertile eggs, rickettsiae were readily isolated from these sources and, with rather less facility, from blood. 3. Although relatively large numbers of rickettsiae were found necessary to produce lethal infections, the susceptibility of the cotton rat as measured by the development of an immunizing infection proved to be very high. The supporting data suggest that cotton rats might be suitable for the isolation of new strains. 4. Contrary to the earlier report (1), age was not found to influence markedly the susceptibility of the cotton rat to lethal infection with any of the strains studied. 5. Comparative studies indicated that cotton rats were just as susceptible to murine infection as white mice and more susceptible to Breinl infection than the latter animal. The susceptibility of cotton rats and of guinea pigs to Breinl infection was found to be about the same. Comparative studies in these animals were not made with other strains. 6. No toxic activity of rickettsial suspensions could be demonstrated for cotton rats, although suspensions of infected cotton rat livers were shown to be toxic for mice. 7. A method has been described by which three strains of Rickettsia prowazeki were carried in serial intracardial passage as fatal infections for cotton rats. No evidence was obtained that prolongation of such passage increased the virulence of the strains for the rats. 8. Cotton rats surviving typhus infection were shown to be solidly immune to reinfection with homologous virus and to possess nearly complete immunity to rickettsiae of heterologous immunologic character. Sera from recovered rats, furthermore, were shown to possess neutralizing, complement-fixing, and antitoxic antibodies but no agglutinins for proteus OX19. 9. The technique of a serum neutralization test in cotton rats has been described in which the test antigen consists of suspensions of infected cotton rat livers. By this technique neutralizing antibody was demonstrated in human, rabbit, guinea pig, and cotton rat sera. Although some degree of cross-neutralization could be shown, serum titers against homologous antigen were uniformly greater than against comparable doses of antigen of heterologous immune nature.
AUTOLOGOUS BONE MARROW CELLS TRANSPLANTATION IN PATIENTS WITH ADVANCED CRITICAL LIMB ISCHEMIA: NO DIFFERENCE IN INTRA-ARTERIAL AND INTRAMUSCULAR APPLICATION
Authors: Juraj Madaric, Andrej Klepanec, Martin Mistrik, Cestmir Altaner, Martina Valachovicova, Roman Necpal, Roman Slysko, Terezia Urlandova, Tibor Balazs, Ivan Vulev
Journal: Journal of the American College of Cardiology (2011)
Anaphylaxis and Stinging Insect Hypersensitivity
Authors: Martin D. Valentine
Journal: JAMA (1992)

THE TERM<i>anaphylaxis</i>was coined by the biologists Portier and Richet<sup>1</sup>at the beginning of the 20th century. While guests aboard the yacht of the Prince of Monaco on a Mediterranean cruise, they injected dogs with the toxin of sea anemones in hopes of promoting tolerance to the venom's toxic effects on reinjection. To the contrary, the dogs had more severe reactions on repeat injection. The phenomenon was dubbed<i>anaphylaxis</i>("ana" + "phylaxis" = antiprotection) to denote a state without protection. In the modern era, von Pirquet and Schick,<sup>2</sup>when writing about serum sickness, observed that individuals who developed serum sickness after the administration of heterologous serum antitoxin produced in rabbits or horses, eg, diphtheria antitoxin, were prone to severe, acute reactions when reexposed to a smaller dose of the same serum that caused the original episode of serum sickness. Anaphylaxis is now the term applied to the clinical manifestations
New trends in assessing the outcomes of mental health interventions
Authors: Graham Thornicroft, Mike Slade
Journal: World Psychiatry (2014)

Assessing the outcomes of interventions in mental health care is both important and challenging. The aim of this paper is to advance the field of outcomes research by proposing a taxonomy of the decisions that clinicians and researchers need to consider when evaluating outcomes. Our taxonomy has eight components, framed as decisions: Whose outcome will be considered? Which scientific stage is being investigated? What outcome domain(s) matter? What level of assessment will be used? Will clinical and/or recovery outcomes be assessed? Whose perspective will be considered? Will deficits and/or strengths be the focus? Will invariant or individualized measures be preferred? We propose a future focus on understanding what matters most to people using mental health services, and on the use of measures rated by service users as the primary approach to evaluating outcome.
In-training assessment for specialist registrars: views of trainees and trainers in the Mersey Deanery
Authors: J. Bache, J. Brown, D. Graham
Journal: Journal of the Royal Society of Medicine (2002)

Annual review of specialist registrars and production of a record of in-training assessment (RITA) is a mandatory component of training that has attracted criticism. Mersey Deanery has established a system of review that includes wider evaluation of the trainee's needs and of training requirements. We conducted a survey to ascertain whether this broadened review process was thought beneficial. In one year 1093 questionnaires were distributed to trainees and trainers. 605 (81%) of 744 trainees and 309 (89%) of 349 trainers responded. At least 89% of both groups said that the procedure had been effective in reviewing the previous year and the most recent post and in identifying training requirements. More than 90% rated the overall process positively. Trainees particularly appreciated the advice on future training, on careers and on research.