tbuckley/cabot-search huggingface dataset:
Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis
Authors: Niklas Beyersdorf, Stefanie Gaupp, Karen Balbach, Jens Schmidt, Klaus V. Toyka, Chia-Huey Lin, Thomas Hanke, Thomas Hünig, Thomas Kerkau, Ralf Gold
Journal: The Journal of Experimental Medicine (2005)

CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.
A Double-blind Study on the Effect of Inhaled Corticosteroids on Plasma Protein Exudation in Asthma
Authors: ROB E. T. NOCKER, FRANK R. WELLER, THEO A. OUT, MARIËLLE J. de RIEMER, HENK M. JANSEN, JARING S. van der ZEE
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Plasma protein exudation into the airways is an important pathophysiological event in asthma. The effect of 12 wk of treatment with inhaled fluticasone propionate (FP; 250 μ g twice a day) or salbutamol (Sb; 400 μ g twice a day) on plasma protein leakage was compared in a double-blind, randomized parallel-group study of 30 patients with asthma. Primary outcomes were plasma protein leakage and size selectivity of the blood–airway lumen barrier, cell differentials in BAL fluid, and bronchial responsiveness to histamine (PC20histamine). Two independent procedures to account for the effect of variable dilution of BAL on the levels of albumin (Alb) and α2-macroglobulin (A2M) in BAL fluid consisted of correction based on urea levels and on the application of the relative coefficient of excretion [RCE = ([A2M] in BAL fluid/[A2M] in serum)/([Alb] in BAL fluid/[Alb] in serum)]. In the FP group a significant decrease was found in the A2M level and the RCE, and in the percentage of eosinophils in BAL fluid. The PC20histamine increased significantly (mean increase, 2.4 doubling doses), whereas PC20histamine decreased in the Sb group. Differences between groups were significant except for the decrease in eosinophils. We conclude that 12 wk of FP (250 μ g twice a day) decreased the permeability of the blood–airway lumen barrier, in particular for high molecular weight proteins.
Evidence in hyponatremia related to inappropriate secretion of ADH that V1 receptor stimulation contributes to the increase in renal uric acid clearance.
Authors: G Decaux, B Namias, B Gulbis, A Soupart
Journal: Journal of the American Society of Nephrology (1996)

In hyponatremia related to syndrome of inappropriate antidiuretic hormone (SIADH), hypouricemia is explained primarily by the high uric acid clearance rate that results from the decrease in tubular uric acid reabsorption. This modification of tubular handling of uric acid is considered to be induced by the increase in the "effective vascular volume". This study was designed to determine if V1-receptor stimulation participates in the development of a high uric acid clearance rate as in SIADH, in which the antidiuretic hormone acts on V1 and V2 receptors. Therefore, the urate clearance rate was measured in seven volunteers with 1-desamino-8-D-arginine vasopressin (dDAVP)-induced hyponatremia, with dDVAP stimulating exclusively the V2 receptors (Group I), and in six patients with SIADH (Group II) during both normo- and hyponatremia. As expected, in both groups, the serum uric acid concentration decreased during hyponatremia, but did so to a larger extent in the patients with SIADH (-53% versus -29%, P < 0.02). Despite similar levels of hyponatremia (126 +/- 5 mmol/L and 125 +/- 5.5 mmol/L), of hypoproteinemia (64 +/- 5 g/L and 63 +/- 5 g/L) and of salt excretion (FENa, 0.66 +/- 0.28% and 0.73 +/- 0.25%), the urate clearance (8.3 +/- 3.3 mL/min) and the fractional excretion of filtered uric acid (5.7 +/- 2%) in Group I were not significantly different during hyponatremia than during normonatremia (6.4 +/- 1.5 mL/min and 5.4 +/- 0.9%). On the other hand, in Group II, both parameters were increased (17.8 +/- 2.9 mL/min and 19.6 +/- 5.3%; P < 0.001) and both values were higher than in the dDAVP-induced hyponatremia (P < 0.01). Additionally, the administration of a potent V1-receptor agonist (triglycyl-lysine-vasopressin) in a patient with central diabetes insipidus with preexisting dDAVP-induced hyponatremia produced a rapid increase of urate clearance. Because dDAVP acts only on the V2 receptors, these data suggest that the higher urate clearance observed during hyponatremia related to SIADH is not only the consequence of an increased "effective vascular volume," but that V1-receptor stimulation also contributes to it, by a mechanism that remains to be determined.
IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival
Authors: S. Leu, S. von Felten, S. Frank, E. Vassella, I. Vajtai, E. Taylor, M. Schulz, G. Hutter, J. Hench, P. Schucht, J.-L. Boulay, L. Mariani
Journal: Neuro-Oncology (2013)

Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period. The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike's information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations. Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05). By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.
Human Medial Frontal Cortex Mediates Unconscious Inhibition of Voluntary Action
Authors: Petroc Sumner, Parashkev Nachev, Peter Morris, Andrew M. Peters, Stephen R. Jackson, Christopher Kennard, Masud Husain
Journal: Neuron (2007)

SummaryWithin the medial frontal cortex, the supplementary eye field (SEF), supplementary motor area (SMA), and pre-SMA have been implicated in the control of voluntary action, especially during motor sequences or tasks involving rapid choices between competing response plans. However, the precise roles of these areas remain controversial. Here, we study two extremely rare patients with microlesions of the SEF and SMA to demonstrate that these areas are critically involved in unconscious and involuntary motor control. We employed masked-prime stimuli that evoked automatic inhibition in healthy people and control patients with lateral premotor or pre-SMA damage. In contrast, our SEF/SMA patients showed a complete reversal of the normal inhibitory effect—ocular or manual—corresponding to the functional subregion lesioned. These findings imply that the SEF and SMA mediate automatic effector-specific suppression of motor plans. This automatic mechanism may contribute to the participation of these areas in the voluntary control of action.
Lung Uptake of Thallium as a Prognostic Indicator
Authors: Robert A. O'Rourke
Journal: New England Journal of Medicine (1987)

Visualization of regional myocardial blood flow after intravenous injection of thallium-201 near peak exercise, when performed early after exercise and several hours later, is a useful noninvasive technique for detecting myocardial ischemia (as indicated by a reversible perfusion defect), myocardial scarring (an irreversible defect), or their combination (a partially reversible defect). Thallium, like potassium, is taken up avidly by normal myocardial cells. Despite disadvantages — its long physical half-life of 73.5 hours, its suboptimal energy for imaging with a gamma camera, and the presence of artifactual "defects" due to attenuation of myocardial activity by other tissues — thallium remains the . . .
TOLERANCE TO BACTERIAL PYROGENS
Authors: Paul B. Beeson
Journal: The Journal of Experimental Medicine (1947)

In a study of the febrile responses of rabbits to repeated intravenous injections of pyrogenic substances from Eberthella typhosa, Serratia marcescens, and Pseudomonas aeruginosa, the following observations were made: 1. A characteristic pattern of response to daily injections of the same dose of pyrogenic material was noted. This consisted of a progressive diminution in febrile response during the 1st week or 10 days, after which an animal responded to each injection with approximately the same degree of fever, even when the injections were continued for several weeks. 2. Animals given injections of the same amount of pyrogenic material at semiweekly or weekly intervals showed some diminution in febrile reaction but the alteration was less pronounced than that in animals injected every day. 3. Pyrogen tolerance appeared to be lost quickly. Animals allowed to rest for approximately 3 weeks reacted to readministration of pyrogen with fever comparable with that which occurred after the first injection. 4. By gradually increasing the size of the daily dose of pyrogen a tolerance could be established such that a reduced, but still considerable, amount of pyrogen caused no fever whatever. 5. Rabbits that had been injected with S. marcescens or Ps. aeruginosa pyrogens showed a diminished febrile response to E. typhosa vaccine. 6. Passive transfer of the unresponsiveness to pyrogens could not be demonstrated. 7. Prevention of temperature elevations during the course of immunization by use of an antipyretic drug did not interfere with the development of tolerance to pyrogens. 8. A series of mechanically induced bouts of fever did not reduce the responsiveness to bacterial pyrogens.
Hidden rheumatoid factor in seronegative juvenile rheumatoid arthritis.
Authors: T Moore, R W Dorner, J Zuckner
Journal: Annals of the Rheumatic Diseases (1974)

The incidence of rheumatoid factor (RF) in juvenile rheumatoid arthritis (JRA) has been studied and correlated with clinical findings by Bywaters, Carter, and Scott (1959), Cassidy and Valkenburg (1967), and Hanson, Drexler, and Kornreich (1969).It is generally accepted that about 20 per cent. of patients with JRA have RF in their serum compared to 75 per cent.or more of patients with rheumatoid arthritis of adult onset.The discovery by Allen and Kunkel (1966), subsequently extended by Bluestone, Goldberg, and Cracchiolo (1969) and Cracchiolo, Bluestone, and Goldberg (1970), that certain apparently seronegative patients with rheumatoid arthritis have 'hidden' RF in their serum suggested the investigation of sero- negative patients with JRA for the possible presence of 'hidden' RF.Allen and Kunkel (1966) had con- sidered this possibility, but their 'initial studies with these techniques on serum from children with JRA failed to uncover agglutinating activity'.The present data show that about 40 per cent.ofJRA patients had 'hidden' RF in their sera.* Rheumatoid factor by latex test at a dilution of 1:20 or less was considered negative.t Patients 8 and 9 were tested twice, i.e. in
Clinical features and determinants of COPD exacerbation in the Hokkaido COPD cohort study
Authors: Masaru Suzuki, Hironi Makita, Yoichi M. Ito, Katsura Nagai, Satoshi Konno, Masaharu Nishimura
Journal: European Respiratory Journal (2013)

Exacerbations are among the major factors that may affect the natural history of chronic obstructive pulmonary disease (COPD). The aim was to investigate the clinical characteristics and determinants of COPD exacerbations in our 5-year observational cohort study which had a very low exacerbation frequency. A total of 279 patients with COPD participated in the Hokkaido COPD cohort study, and 268 subjects who had clinical data for multiple visits were analysed. Exacerbation was defined in multiple ways: the patient’s subjective complaint, symptom definition, requiring prescription change, requiring antibiotic treatment, or requiring hospital admission. Exacerbation frequency (events per person per year) was 0.78±1.16, 0.24±0.47, 0.20±0.43, 0.13±0.28 and 0.06±0.19 for subjective complaint and symptom, prescription, antibiotic and hospital admission definitions, respectively. Exacerbation events did not significantly affect the annual decline in forced expiratory volume in 1 s. A high St George’s Respiratory Questionnaire total score, especially activity score, and a low body mass index were strongly associated with exacerbation-free survival, exacerbation frequency and development of recurrent exacerbations. Despite the low exacerbation frequency in our cohort, impaired health-related quality of life and weight loss were found to be independent risk factors for COPD exacerbations.
13-cis-Retinoic Acid Plus Interferon -2a: Highly Active Systemic Theraphy for Squamous Cell Carcinoma of the Cervix
Authors: S. M. Lippman, J. J. Kavanagh, M. Paredes-Espinoza, F. Delgadillo-Madrueno, P. Paredes-Casillas, W. K. Hong, E. Holderner, I. H. Krakoff
Journal: JNCI Journal of the National Cancer Institute (1992)

Background : Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Com–plete plus partial (overall) response rates of 15% -35% (complete response rate, < 5% ) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60% -70% (complete response rates, 10% -20% ) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally ad–vanced disease. However, the lack of clear evidence that existing chemo–therapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease. Purpose : In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-α (IFN-α) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease. Methods : Twenty-six patients with un–treated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/ kg) and subcutaneous recombinant human IFN α -2a (6 mil–lion units). In 21 patients (81% ), the disease was stage II or higher. Results : Thirteen patients (50% ) experienced major responses (tumor regression ≥ 50% ) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension ≥ 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal. Conclusion : These preliminary results indicate that systemic 13-cRA plus IFN α -2a is a highly active, well-tolerated therapy for locally advanced cervical cancer. [J Natl Cancer Inst 84:241– 245, 1992]
Oxygen Supply and Neoplastic Conversion of Mouse Embryo Cells &lt;italic&gt;In Vitro&lt;/italic&gt;
Authors: Katherine K. Sanford, Ram Parshad
Journal: JNCI Journal of the National Cancer Institute (1968)

C3Hf mouse-embryo cells were dissociated and carried in cultures exposed to continuous intermittent gassing with humidified gas mixtures containing different oxygen concentrations. The purpose of these long-term experiments was to test whether continuous exposure to 60 or 40% oxygen concentration could prevent or delay neoplastic conversion of cells grown in medium NCTC 135 with 10% horse serum, or whether continuous exposure to 2 or 1% oxygen could induce or accelerate neoplastic change in cells cultured in fetal calf or horse serum-supplemented medium 135. Although the high oxygen concentrations inhibited cell proliferation, 40% O2 did not prevent or consistently delay neoplastic conversion. Nor did the low O2 supply accelerate or induce neoplastic conversion in either the horse serum or fetal calf serum-supplemented medium. Thus it appears that O2 supply is not a determining or influencing factor in these conversions.
Purification of functional, determinant-specific, idiotype-bearing murine T cells
Authors: GK Lewis, JW Goodman
Journal: The Journal of Experimental Medicine (1978)

Strain A/J mice immunized with azobenzenearsonate (ABA)-mouse IgG conjugates develop suppression for anti-trinitrophenyl(TNP) responses to doubly conjugated (ABA,TNP) proteins. This suppression is specific for the ABA epitope and is mediated by T cells in cell transfer experiments. ABA-binding T cells from suppressed animals were purified by a two-stage procedure in which B cells were removed from spleen cell populations by adherence to plastic surfaces coated with anti-mouse Ig antibody, followed by binding the nonadherent population (more 95 percent Thy-1-positive) to surfaces coated with ABA-protein conjugates. Approximately 90 percent of the cells recovered by temperature-dependent elution from the ABA plates (similar to 2 percent of the spleen cells) bound antigen immediately afterward, and up to 50 percent of the cells bound anti-cross-reactive idiotype antibody. On the other hand, the nonadherent T-cell population was completely negative in the antigen- binding and idiotype assays. Another distinguishing feature of the two T-cell populations was that 78 percent of the adherent cells, but only 2 percent of the nonadherent cells, were Ia positive, although the specific I-region marker(s) expressed on the cells was not identified. The biological function of the antigen-binding T cells was investigated using a standard cell transfer protocol. Suppressor cells were enriched in the adherent population by a factor of at least 25, establishing that functional, epitope-specific, idiotype-bearing T cells can be significantly purified by this procedure. Note Added in Proof. We have recently isolated two types of ABA-binding molecules biosynthetically labeled with (35)S-methionine from NP-40 lysates of purified antigen-specific T cells. The molecules were purified by adsorption onto an ABA-Sepharose immunoadsorbent followed by elution with 9 M urea. Autoradiograms of SDS-PAGE of the eluates revealed components with tool wt of approximately 60,000 and 33,000 dahons. These molecules were not present in eluates from a bovine IgG-Sepharose control immunoadsorbent and thus represent specific ABA-binding products synthesized by T cells.
IκB Kinase-α Regulates Endothelial Cell Motility and Tumor Angiogenesis
Authors: Laura M. DeBusk, Pierre P. Massion, P. Charles Lin
Journal: Cancer Research (2008)

Abstract The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in many types of cancers and has been implicated in gene expression important for angiogenesis, tumor growth, progression, and metastasis. Here, we show that the NF-κB activator, IκB kinase-α (IKKα), but not IKKβ, promotes endothelial cell motility and tumor angiogenesis. IKKα is elevated in tumor vasculature compared with normal endothelium. Overexpression of IKKα in endothelial cells promoted cell motility and vascular tubule formation in a three-dimensional culture assay, and conversely, knockdown of IKKα in endothelial cells inhibited cell motility, compared with controls. Interestingly, blocking NF-κB activation totally abolished IKKα-induced angiogenic function. Furthermore, using a tumor and endothelial cell cotransplantation model, we show that overexpression of IKKα in endothelial cells significantly increased tumor vascular formation compared with controls, which contributed to increased tumor growth and tumor cell proliferation, and decreased tumor cell apoptosis. Collectively, these findings have identified a new function for IKKα through the canonical NF-κB pathway in tumor angiogenesis. [Cancer Res 2008;68(24):10223–8]