tbuckley/cabot-search huggingface dataset:
Ikaros controls isotype selection during immunoglobulin class switch recombination
Authors: MacLean Sellars, Bernardo Reina-San-Martin, Philippe Kastner, Susan Chan
Journal: The Journal of Experimental Medicine (2009)

Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros transcription factor results in increased and ectopic CSR to IgG2b and IgG2a, and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, transcription, and activation-induced cytidine deaminase (AID) accessibility at the γ2b and γ2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene transcription as it directly binds the Igh 3′ enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of γ2b and γ2a transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.
Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure
Authors: Kim Fox, Ian Ford, Philippe Gabriel Steg, Jean-Claude Tardif, Michal Tendera, Roberto Ferrari
Journal: New England Journal of Medicine (2014)

An elevated heart rate is an established marker of cardiovascular risk. Previous analyses have suggested that ivabradine, a heart-rate-reducing agent, may improve outcomes in patients with stable coronary artery disease, left ventricular dysfunction, and a heart rate of 70 beats per minute or more.We conducted a randomized, double-blind, placebo-controlled trial of ivabradine, added to standard background therapy, in 19,102 patients who had both stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more (including 12,049 patients with activity-limiting angina [class ≥II on the Canadian Cardiovascular Society scale, which ranges from I to IV, with higher classes indicating greater limitations on physical activity owing to angina]). We randomly assigned patients to placebo or ivabradine, at a dose of up to 10 mg twice daily, with the dose adjusted to achieve a target heart rate of 55 to 60 beats per minute. The primary end point was a composite of death from cardiovascular causes or nonfatal myocardial infarction.At 3 months, the mean (±SD) heart rate of the patients was 60.7±9.0 beats per minute in the ivabradine group versus 70.6±10.1 beats per minute in the placebo group. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96 to 1.20; P=0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction. Ivabradine was associated with an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina (P=0.02 for interaction). The incidence of bradycardia was higher with ivabradine than with placebo (18.0% vs. 2.3%, P<0.001).Among patients who had stable coronary artery disease without clinical heart failure, the addition of ivabradine to standard background therapy to reduce the heart rate did not improve outcomes. (Funded by Servier; SIGNIFY Current Controlled Trials number, ISRCTN61576291.).
Creeping Proteins in Microporous Structures: Polymer Brush‐Assisted Fabrication of 3D Gradients for Tissue Engineering
Authors: Michel Klein Gunnewiek, Andrea Di Luca, Hermannes Z. Bollemaat, Clemens A. van Blitterswijk, G. Julius Vancso, Lorenzo Moroni, Edmondo M. Benetti
Journal: Advanced Healthcare Materials (2015)

Coupling of rapid prototyping techniques and surface-confined polymerizations allows the fabrication of 3D multidirectional gradients of biomolecules within microporous scaffolds. The compositional gradients can be tailored by polymer-brush-assisted diffusion of protein solutions. This technique allows spatial control over stem cells manipulation within 3D environments.
Cancer Genomics: Technology, Discovery, and Translation
Authors: Ben Tran, Janet E. Dancey, Suzanne Kamel-Reid, John D. McPherson, Philippe L. Bedard, Andrew M.K. Brown, Tong Zhang, Patricia Shaw, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, Benjamin G. Neel, Lillian L. Siu
Journal: Journal of Clinical Oncology (2012)

In recent years, the increasing awareness that somatic mutations and other genetic aberrations drive human malignancies has led us within reach of personalized cancer medicine (PCM). The implementation of PCM is based on the following premises: genetic aberrations exist in human malignancies; a subset of these aberrations drive oncogenesis and tumor biology; these aberrations are actionable (defined as having the potential to affect management recommendations based on diagnostic, prognostic, and/or predictive implications); and there are highly specific anticancer agents available that effectively modulate these targets. This article highlights the technology underlying cancer genomics and examines the early results of genome sequencing and the challenges met in the discovery of new genetic aberrations. Finally, drawing from experiences gained in a feasibility study of somatic mutation genotyping and targeted exome sequencing led by Princess Margaret Hospital-University Health Network and the Ontario Institute for Cancer Research, the processes, challenges, and issues involved in the translation of cancer genomics to the clinic are discussed.
Adrenergic Effects on Ventricular Vulnerability
Authors: JAOK HAN, PERFECTO GARCIA DE JALON, GORDON K. MOE
Journal: Circulation Research (1964)

Effects of stimulation of the cardiac sympathetic nerves and intravenous administration of sympathomimetic amines on the multiple response or fibrillation threshold (VMRT) and on other properties of the dog ventricles were compared. Stimulation of the cardiac sympathetic nerves decreased the VMRT. Administration of sympathomimetic amines caused a brief decrease in the VMRT followed by a sustained increase. Temporal dispersion of recovery of excitability and the degree of ventricular vulnerability were closely related; the ventricle was more vulnerable to fibrillation when the dispersion was increased. The hyperkalemic effect of epinephrine was not responsible for the observed changes in ventricular vulnerability.
Deficiency in the Transcription Factor Interferon Regulatory Factor (Irf)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells
Authors: Michael Lohoff, Gordon S. Duncan, David Ferrick, Hans-Willi Mittrücker, Susi Bischof, Stefan Prechtl, Martin Röllinghoff, Edgar Schmitt, Andreas Pahl, Tak W. Mak
Journal: The Journal of Experimental Medicine (2000)

Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1−/− mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1−/− mice, IRF-2−/− mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1−/− and IRF-2−/− mice, but the underlying mechanism differs. NK (but not NK+ T) cell numbers are decreased in IRF-2−/− mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.
Perifosine Synergistically Enhances TRAIL-Induced Myeloma Cell Apoptosis via Up-Regulation of Death Receptors
Authors: Ebenezer David, Rajni Sinha, Jing Chen, Shi-Yong Sun, Jonathan L. Kaufman, Sagar Lonial
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aim of this study is to investigate the efficacy of a novel Akt inhibitor, perifosine, in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in human myeloma cells and primary patient samples. Experimental Design: The activity of perifosine in combination with TRAIL was evaluated with experiments testing the effect of perifosine on DR4/DR5 expression by the use of chimeric blocking antibodies, as well as siRNA. Results: DR4 and DR5 expression was induced by exposure to single-agent perifosine. After exposure of human myeloma cell lines or primary patient samples to increasing doses of perifosine with exogenous TRAIL, we identified synergistically enhanced apoptosis when compared with the perifosine alone, which was achieved with levels well below clinically achievable concentrations for both agents. Transfection with siRNA against DR4, and DR5 reduced the level of apoptosis induced by the combination but did not result in total abrogation of the combination effect. Overexpression of activated Akt, the proposed target for perifosine, did not inhibit the combination effect. Anti-DR4 and DR5 chimeric proteins blocked the cytotoxicity induced by the combination, and the use of c-FLICE-like interleukin protein (FLIP) siRNA enhanced the efficacy at the combination, further supporting the importance of the DR4/DR5 axis in the effect of perifosine. Conclusion: Our observation seems to be independent of the effects of perifosine on Akt signaling, and may represent an additional mechanism of action for this agent, and supports future clinical trials combining these two agents.
Protection of Glucagon-Like Peptide-1 in Cisplatin-Induced Renal Injury Elucidates Gut-Kidney Connection
Authors: Daisuke Katagiri, Yoshifumi Hamasaki, Kent Doi, Koji Okamoto, Kousuke Negishi, Masaomi Nangaku, Eisei Noiri
Journal: Journal of the American Society of Nephrology (2013)

Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.
Effect of Inhaled Iloprost Plus Oral Sildenafil in Patients With Primary Pulmonary Hypertension
Authors: Heinrike Wilkens, Angelika Guth, Jochem König, Nicole Forestier, Bodo Cremers, Benno Hennen, Michael Böhm, Gerhard W. Sybrecht
Journal: Circulation (2001)

Background The application of iloprost, a stable prostacyclin analogue, by inhalation has been shown to improve hemodynamic variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short-term effects. One potential approach to prolong and increase the vasorelaxant effects of aerosolized iloprost might be to combine use with phosphodiesterase inhibitors. Methods and Results The short-term effects of 8.4 to 10.5 μg of aerosolized iloprost, the phosphodiesterase type 5 inhibitor sildenafil, and the combination thereof were compared in 5 patients with primary pulmonary hypertension. Aerosolized iloprost resulted in a more pronounced decrease in mean pulmonary arterial pressure (PAP) than sildenafil alone (9.4±1.3 versus 6.4±1.1 mm Hg; P &lt;0.05). The reduction in mean PAP after sildenafil was maximal after the first dose (25 mg). The combination of sildenafil plus iloprost lowered mean PAP significantly more than iloprost alone (13.8±1.4 versus 9.4±1.3 mm Hg; P &lt;0.009). No significant changes in heart rate or systemic arterial pressure were observed during any treatment. The treatments were well tolerated, without major adverse effects. Conclusions Sildenafil caused a long-lasting reduction in mean PAP and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. These data suggest that small doses of a phosphodiesterase type 5 inhibitor may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension.
Effects of noninvasive ventilation on lung hyperinflation in stable hypercapnic COPD
Authors: O. Díaz, P. Bégin, B. Torrealba, E. Jover, C. Lisboa
Journal: European Respiratory Journal (2002)

Two previous uncontrolled studies have suggested that noninvasive mechanical ventilation (NIMV) in patients with hypercapnic chronic obstructive pulmonary disease (COPD) improves arterial blood gas tensions by decreasing lung hyperinflation with the consequent reduction in inspiratory loads and changes in ventilatory pattern. The aim of this randomised placebo-controlled study was to determine whether these mechanisms play a pivotal role in the effects of NIMV on arterial blood gases. Thirty-six stable hypercapnic COPD patients were randomly allocated to NIMV or sham NIMV. A 2-week run-in period was followed by a 3-week study period, during which ventilation was applied 3 h·day −1 , 5 days a week. Arterial blood gases, spirometry, lung volumes, and respiratory mechanics were measured before and after application of NIMV. Patients submitted to NIMV showed changes (mean (95% confidence interval)) in daytime arterial carbon dioxide tension ( P a,CO 2 ) and arterial oxygen tension of −1.12 (−1.52–−0.73) kPa (−8.4 (−11.4–−5.5) mmHg) and 1.14 (0.70–1.50) kPa (8.6 (5.3–11.9) mmHg), respectively. Total lung capacity, functional residual capacity (FRC) and residual volume were found to be reduced by 10 (7–13), 25 (18–31), and 36 (27–45)% of their predicted value, respectively, whereas forced expiratory volume in one second and forced vital capacity increased by 4 (1.5–6.9) and 9 (5–13)% pred, respectively. Tidal volume ( V T ) increased by 181 (110–252) mL. All of the above changes were significant compared with sham NIMV. Changes in P a,CO 2 were significantly related to changes in dynamic intrinsic positive end-expiratory pressure, inspiratory lung impedance, V T and FRC. It was concluded that the beneficial effects of noninvasive mechanical ventilation could be explained by a reduction in lung hyperinflation and inspiratory loads.
Value-Based Cancer Care and the Excessive Cost of Drugs
Authors: Benjamin Djulbegovic
Journal: JAMA Oncology (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Histamine bronchial challenge: effect on regional ventilation and aerosol deposition.
Authors: H Clague, D Ahmad, M J Chamberlain, W K Morgan, S Vinitski
Journal: Thorax (1983)

We studied regional changes in ventilation and aerosol deposition after histamine challenge in six patients with asthma and two with rhinitis and a history of wheezing. All were known to have bronchial hyperreactivity and all showed an increased response to histamine. Ventilation and aerosol deposition studies, using xenon-133 and an aerosol of sulphur colloid tagged with technetium 99m, were performed while they were sitting. Before administration of histamine radioaerosol scintiscans were abnormal in five of six patients; after histamine challenge all were abnormal and central deposition was significantly greater in all of them. The decrease in aerosol penetration correlated with the percentage decrease in FEV1, indicating that the efficiency of aerodynamic filtration depends on the degree of airway narrowing. In six of the eight subjects the distribution of ventilation changed from predominantly basal to predominantly apical after histamine, which suggests the airways response was greater, at least initially, in the better ventilated regions. This indicates a close relationship between regional ventilation and the site of histamine deposition and has implications for the delivery of aerosolised agents in general.
Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction
Authors: Tomasz J. Guzik, Nyssa E. Hoch, Kathryn A. Brown, Louise A. McCann, Ayaz Rahman, Sergey Dikalov, Jorg Goronzy, Cornelia Weyand, David G. Harrison
Journal: The Journal of Experimental Medicine (2007)

Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1−/− mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)–salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II–dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase–deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4−CD8−). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) α, and treatment with the TNFα antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure.
Glucagon-Like Peptide 1 Attenuates the Acceleration of Gastric Emptying Induced by Hypoglycemia in Healthy Subjects
Authors: Mark P. Plummer, Karen L. Jones, Chris E. Annink, Caroline E. Cousins, Juris J. Meier, Marianne J. Chapman, Michael Horowitz, Adam M. Deane
Journal: Diabetes Care (2014)

Exogenous GLP-1 slows gastric emptying in health and diabetes leading to diminished glycemic excursions. Gastric emptying is markedly accelerated by hypoglycemia. The primary objective was to determine whether GLP-1 attenuates the acceleration of gastric emptying induced by hypoglycemia.Ten healthy volunteers were studied on four separate days in a randomized double-blind fashion. Blood glucose was stabilized using a glucose/insulin clamp at hypoglycemia (2.6 mmol/L on two occasions [hypo]) or euglycemia (6.0 mmol/L on two occasions [eu]) between T = -15 and 45 min before clamping at 6.0 mmol/L until 180 min. During hypoglycemia and euglycemia, subjects received intravenous GLP-1 (1.2 pmol/kg/min) or placebo. At T = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq (99m)Tc-sulfur-colloid and 3 g of 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from T = 0 to 180 min and serum 3-OMG taken at 15-min intervals. The areas under the curve for gastric emptying and 3-OMG concentration were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests.Gastric emptying was accelerated during hypoglycemia (hypo/placebo vs. eu/placebo; P < 0.001), as was glucose absorption (P < 0.03). GLP-1 slowed emptying during euglycemia (eu/placebo vs. eu/GLP-1; P < 0.001). However, hypoglycemia-induced acceleration of gastric emptying on placebo was markedly diminished by GLP-1 (hypo/placebo vs. hypo/GLP-1; P < 0.008), as was glucose absorption (P < 0.01).Acute administration of exogenous GLP-1 attenuates, but does not abolish, the acceleration of gastric emptying by insulin-induced hypoglycemia in healthy subjects.
The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone
Authors: Pierrick G.J. Fournier, Patricia Juárez, Guanglong Jiang, Gregory A. Clines, Maria Niewolna, Hun Soo Kim, Holly W. Walton, Xiang Hong Peng, Yunlong Liu, Khalid S. Mohammad, Clark D. Wells, John M. Chirgwin, Theresa A. Guise
Journal: Cancer Cell (2015)