tbuckley/cabot-search huggingface dataset:
p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes
Authors: Pu Liao, Shi-Qiang Wang, Su Wang, Ming Zheng, Meizi Zheng, Sheng-Jun Zhang, Heping Cheng, Yibin Wang, Rui-Ping Xiao
Journal: Circulation Research (2002)

p38 Mitogen-activated protein kinase (MAPK) is one of the most ancient signaling molecules and is involved in multiple cellular processes, including cell proliferation, cell growth, and cell death. In the heart, enhanced activation of p38 MAPK is associated with ischemia/reperfusion injury and the onset of heart failure. In the present study, we investigated the function of p38 MAPK in regulating cardiac contractility and its underlying mechanisms. In cultured adult rat cardiomyocytes, activation of p38 MAPK by adenoviral gene transfer of an activated mutant of its upstream kinase, MKK3bE, led to a significant reduction in baseline contractility, compared with uninfected cells or those infected with a control adenoviral vector (Adv-beta-galactosidase). The inhibitory effect of MKK3bE on contractility was largely prevented by coexpressing a dominant-negative mutant of p38 MAPK or treating cells with a p38 MAPK inhibitor, SB203580. Conversely, inhibition of endogenous p38 MAPK activity by SB203580 rapidly and reversibly enhanced cell contractility in a dose-dependent manner, without altering L-type Ca(2+) currents or Ca(2+)(i) transients. MKK3bE-induced p38 activation had no significant effect on pH(i), whereas SB203580 had a minor effect to elevate pH(i). Furthermore, activation of p38 MAPK was unable to increase troponin I phosphorylation. Thus, we conclude that the negative inotropic effect of p38 MAPK is mediated by decreasing myofilament response to Ca(2+), rather than by altering Ca(2+)(i) homeostasis and that the reduced myofilament Ca(2+) sensitivity is unlikely attributable to troponin I phosphorylation or alterations in pH(i). These findings reveal a novel function of p38 MAPK and shed a new light on our understanding of the coincidence of p38 MAPK activation and the onset of heart failure.
On the mechanism of sustained ventricular arrhythmias associated with acute myocardial infarction
Authors: E. KAPLINSKY, J. H. YAHINI, H. N. NEUFELD
Journal: Cardiovascular Research (1972)

The effects of rapid ventricular epicardial stimulation on the cardiac rhythm were studied in eight dogs, five days after coronary artery ligation, and in eight controls. Various degrees of ventricular arrhythmias were noted upon cessation of stimulation in the coronary ligated animals only. These post stimulation rhythm disorders were directly related to the frequency of stimulation. The QRS complexes of the post stimulation arrhythmias were of multiform configuration and were entirely different from the ones recorded during stimulation. Also, similar configuration of post stimulation arrhythmias could be observed following stimulation at widely separated sites. Both the mode of initiation and of termination of the post stimulation arrhythmias support the presence of circus movement around and in the infarction as the basis of sustained ventricular arrhythmias in acute myocardial infarction. The present study suggests also that the acutely damaged myocardial tissue becomes both a source for ectopic activity and an obstacle, around which re-entry circuits may be produced by these ectopic ventricular beats, and prolonged ventricular arrhythmias thus sustained.
Wegener Granulomatosis and Trimethoprim-Sulfamethoxazole
Authors: BURTON C. WEST
Journal: Annals of Internal Medicine (1987)

Wegener granulomatosis was diagnosed in a 42-year-old woman in 1965. Although a regimen of azathioprine and prednisone was helpful, the disease progressed. Cyclophosphamide was added to this regimen in 1969. On three separate occasions her disease relapsed when cyclophosphamide therapy was discontinued. In 1984, she developed cyclophosphamide-resistant disease and drug toxicity. We were able to discontinue cyclophosphamide therapy after a trimethoprim-sulfamethoxazole regimen that was begun in February 1985 led to rapid improvement, a fall in the erythrocyte sedimentation rate, and a complete remission. Her 22-year survival is the longest one reported. Because patients with Wegener granulomatosis sometimes respond to trimethoprim-sulfamethoxazole, this therapy deserves careful study and implies that Wegener granulomatosis is an as yet unidentified infection.
Role of Altered Renal Lipid Metabolism in the Development of Renal Injury Induced by a High-Fat Diet
Authors: Shinji Kume, Takashi Uzu, Shin-ichi Araki, Toshiro Sugimoto, Keiji Isshiki, Masami Chin-Kanasaki, Masayoshi Sakaguchi, Naoto Kubota, Yasuo Terauchi, Takashi Kadowaki, Masakazu Haneda, Atsunori Kashiwagi, Daisuke Koya
Journal: Journal of the American Society of Nephrology (2007)

Metabolic syndrome is associated with increased risk of chronic kidney disease, and the renal injury in patients with metabolic syndrome may be a result of altered renal lipid metabolism. We fed wild-type or insulin-sensitive heterozygous peroxisome proliferator-activated receptor gamma-deficient (PPARgamma(+/-)) mice a high-fat diet for 16 weeks. In wild-type mice, this diet induced core features of metabolic syndrome, subsequent renal lipid accumulation, and renal injury including glomerulosclerosis, interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated, determined by increased renal mRNA expression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase (ACC) and by increased ACC activity. In addition, renal lipolysis was suppressed, determined by reduced mRNA expression of the lipolytic enzyme carnitine palmitoyl acyl-CoA transferase 1 and by reduced activity of AMP-activated protein kinase. In PPARgamma(+/-) mice, renal injury, systemic metabolic abnormalities, renal accumulation of lipids, and the changes in renal lipid metabolism were attenuated. Thus, a high-fat diet leads to an altered balance between renal lipogenesis and lipolysis, subsequent renal accumulation of lipid, and renal injury. We suggest that renal lipid metabolism could serve as a new therapeutic target to prevent chronic kidney disease in patients with metabolic syndrome.
Denosumab for Patients With Persistent or Relapsed Hypercalcemia of Malignancy Despite Recent Bisphosphonate Treatment
Authors: M. I. Hu, I. Glezerman, S. Leboulleux, K. Insogna, R. Gucalp, W. Misiorowski, B. Yu, W. Ying, R. K. Jain
Journal: JNCI Journal of the National Cancer Institute (2013)

Hypercalcemia of malignancy (HCM), caused primarily by tumor-induced bone resorption, may lead to renal failure, coma, and death. Although HCM can be treated with intravenous bisphosphonates, patients may not respond or may relapse on therapy. Denosumab binds the bone resorption mediator RANKL. In this single-arm, open-label, proof-of-concept study, HCM patients with albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL (Common Terminology Criteria for Adverse Events grade ≥3) despite recent intravenous bisphosphonate treatment received subcutaneous denosumab on days 1, 8, 15, and 29, and then every 4 weeks. The primary endpoint was the proportion of patients with CSC 11.5mg/dL or less (grade ≤1) within 10 days of denosumab initiation. In a prespecified interim analysis, 15 patients received denosumab (median CSC = 13.6mg/dL). Time to response and response duration were analyzed with Kaplan–Meier methods. All statistical tests were two-sided. By day 10, 12 patients (80%; 95% exact confidence interval [CI] = 52% to 96%) responded (CSC ≤11.5mg/dL); median response duration was 26 days. Ten patients (67%; 95% exact CI = 38% to 88%) had complete responses (CSC ≤10.8mg/dL) by day 10. Denosumab may offer a new treatment option for HCM. Clinicaltrials.gov identifier: NCT00896454.
Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of <i>RIG-I</i> Signaling
Authors: Maya Shmulevitz, Lu-Zhe Pan, Katy Garant, Da Pan, Patrick W.K. Lee
Journal: Cancer Research (2010)

Abstract Reovirus is the first naturally occurring human virus reported to exploit activated Ras signaling in the host cell for infection, and is currently undergoing clinical trials as a cancer therapeutic. Recent evidence suggests that Ras transformation promotes three reoviral replication steps during the first round of infection: uncoating of the incoming virion, generation of progeny viruses with enhanced infectivity, and virus release through enhanced apoptosis. Whether oncogenic Ras also enhances reovirus spread in subsequent rounds of infection through other mechanisms has not been examined. Here, we show that compared with nontransformed cells, Ras-transformed cells are severely compromised not only in their response to IFN-β, but also in the induction of IFN-β mRNA following reovirus infection. Defects in both IFN-β production and response allow for efficient virus spread in Ras-transformed cells. We show that the MEK/ERK pathway downstream of Ras is responsible for inhibiting IFN-β expression by blocking signaling from the retinoic acid–inducible gene I (RIG-I) which recognizes viral RNAs. Overexpression of wild-type RIG-I restores INF-β expression in reovirus-infected Ras-transformed cells. In vitro–synthesized viral mRNAs also invoke robust RIG-I–mediated IFN-β production in transfected nontransformed cells, but not in Ras-transformed cells. Collectively, our data suggest that oncogenic Ras promotes virus spread by suppressing viral RNA–induced IFN-β production through negative regulation of RIG-I signaling. Cancer Res; 70(12); 4912–21. ©2010 AACR.
Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes
Authors: A. Nicole Desch, Sophie L. Gibbings, Rajni Goyal, Raivo Kolde, Joe Bednarek, Tullia Bruno, Jill E. Slansky, Jordan Jacobelli, Robert Mason, Yoko Ito, Elise Messier, Gwendalyn J. Randolph, Miglena Prabagar, Shaikh M. Atif, Elodie Segura, Ramnik J. Xavier, Donna L. Bratton, William J. Janssen, Peter M. Henson, Claudia V. Jakubzick
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

The pulmonary mononuclear phagocyte system is a critical host defense mechanism composed of macrophages, monocytes, monocyte-derived cells, and dendritic cells. However, our current characterization of these cells is limited because it is derived largely from animal studies and analysis of human mononuclear phagocytes from blood and small tissue resections around tumors.
Renal dysfunction in African patients with acute heart failure
Authors: Mahmoud U. Sani, Beth A Davison, Gad Cotter, Karen Sliwa, Christopher Edwards, Licette Liu, Albertino Damasceno, Bongani M Mayosi, Okechukwu S. Ogah, Charles Mondo, Anastase Dzudie, Dike B. Ojji, Adrian A. Voors
Journal: European Journal of Heart Failure (2014)
Studies of the Cerebral Circulation with Labeled Erythrocytes in Healthy Man
Authors: GUSTAV NYLIN, SVEN HEDLUNG, OLOF REGNSTRÖM
Journal: Circulation Research (1961)

A thorough investigation of 10 healthy males, 26 to 46 years old, has been performed. One and a half ml. of their own erythrocytes, labeled with P 32 , was injected intravenously and dilution curves obtained simultaneously from one carotid artery and the two jugular bulbs. Thereafter, the same amount of labeled blood was injected into both carotid arteries, following one another, and dilution curves from the two jugular bulbs were simultaneously obtained. A total of seven dilution curves was collected in each case. The percutaneous punctures of the carotids were high enough in the neck so that it is highly probable that the injections were made into the internal carotid arteries. Calculations of the cerebral blood flow and the cerebral blood volume in absolute values were performed. The mean value of the cerebral blood flow amounted to 876 ml/min., i.e., 11.4 per cent of the cardiac output. The pool of the brain was calculated to about 100 ml. When a carotid artery was injected, the appearance and peak concentration times estimated from the dilution curves obtained from the ipsilateral bulbs were the same whether the injection was performed in the right or left side. The corresponding times for the dilution curves obtained from the contralateral bulb agreed, whichever the side on which the injection was performned. They were, however, one second longer than the ipsilateral ones. The determination of circulation time is of diagnostic value, according to an earlier publication. A simplified bloodless method has also been tried.
Phase I Trial of a Novel Intradermal Idiotype Vaccine in Patients with Advanced B-Cell Lymphoma: Specific Immune Responses Despite Profound Immunosuppression
Authors: Cristina Bertinetti, Katja Zirlik, Kristina Heining-Mikesch, Gabriele Ihorst, Heide Dierbach, Cornelius F. Waller, Hendrik Veelken
Journal: Cancer Research (2006)

Abstract The immunoglobulin receptor of B-cell lymphomas constitutes a specific tumor antigen (idiotype) and a target for active immunotherapy. Encouraging results have been reported in phase II trials after s.c. vaccination of follicular lymphoma patients during clinical remission with idiotype produced from eukaryotic cell lines and coupled to an immunogenic carrier macromolecule. We have developed a good manufacturing protocol for rapid expression of idiotype vaccines as recombinant Fab fragments in Escherichia coli. The objectives of this trial were to show safety and feasibility of intradermal immunization with this vaccine and to investigate whether immune responses were induced by this immunization route. Patients (n = 18) with advanced B-cell malignancies received repetitive intradermal vaccinations with 0.5 to 1.65 mg recombinant idiotype Fab fragment mixed with lipid-based adjuvant in combination with 150 μg granulocyte macrophage colony-stimulating factor s.c. at the same location. The patients' immune status was assessed by flow cytometry of peripheral blood lymphocytes and concomitant hepatitis B vaccination. Cellular and humoral immune responses to the vaccine were assessed by enzyme-linked immunospot and ELISA. Side effects of a total of 65 vaccinations were mild and did not affect the immunization schedule. No patient developed hepatitis B surface antibodies (anti-HBs) after two hepatitis B immunizations. Of 17 evaluable patients, five developed specific anti-vaccine antibodies, and eight developed anti-Fab T-cell responses. T-cell reactivity was independent of the cellular immune status and was idiotype specific as shown by statistical regression analysis (P = 0.0024) and epitope mapping studies. Intradermal administration of uncoupled recombinant idiotype with appropriate adjuvants may overcome profound clinical immunosuppression and induce specific immune responses. (Cancer Res 2006; 66(8): 4496-502)
The Autopsy: Obtaining Quality Assurance of Treatment
Authors: M. S. Salamat
Journal: Neuro-Oncology (2001)

concerted effort to obtain autopsy permits for our terminal tumor patients. The success rate of the attainment of autopsies for patients with neurodegenerative diseases and the development of multiple neurodegenerative brain tissue banks in this country and around the world are testaments to the effectiveness of protocols and educational materials for caregivers who come in contact with these patients. We need to develop guidelines, some to be built into therapeutic protocols, that allow for a more systematic and successful approach to requesting an autopsy when the end nears for our CNS tumor patients.
The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study
Authors: Jesper Lindhardsen, Ole Ahlehoff, Gunnar Hilmar Gislason, Ole Rintek Madsen, Jonas Bjerring Olesen, Christian Torp-Pedersen, Peter Riis Hansen
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To examine in a nationwide cohort whether the risk of myocardial infarction (MI) in patients with rheumatoid arthritis (RA) is comparable to the risk in patients with diabetes mellitus (DM). Methods The study included the entire Danish population followed from 1 January 1997 until 31 December 2006. Through individual level-linkage of nationwide administrative registers, the authors identified subjects who developed RA and DM. The risk of MI was analysed using multivariable Poisson regression models including data on cardioprotective drugs, comorbidity and socioeconomic status. Results From a total of 4 311 022 individuals included in the cohort, 10 477 and 130 215 individuals developed RA and DM respectively. The overall incidence rate ratio (IRR) of MI in RA was 1.7 (95% CI 1.5 to 1.9), which was similar to the risk in DM (1.7 (1.6 to 1.8); p=0.64 for difference). The risk was significantly increased in all groups when stratifying on age and gender, with higher RRs in younger patients. This was especially pronounced in women &lt;50 years with RA or DM, who were subject to a sixfold increase in RR. The RA-related risk of MI was unaffected by the duration of pharmacological RA treatment and corresponded to the overall risk of MI observed in non-RA subjects, who were on the average 10 years older. Conclusions RA is associated with the same risk of MI as DM, and the risk of MI in RA patients generally corresponded to the risk in non-RA subjects 10 years older.
Adenosine Inhibits Lipopolysaccharide-Induced Cardiac Expression of Tumor Necrosis Factor-α
Authors: Daniel R. Wagner, Alain Combes, Charles McTiernan, Virginia J. Sanders, Bonnie Lemster, Arthur M. Feldman
Journal: Circulation Research (1998)

Tumor necrosis factor-alpha (TNF-alpha) is elevated in the failing heart. Very little is known about regulation of TNF-alpha in cardiomyocytes. TNF-alpha expression by macrophages is diminished by adenosine. Therefore, we hypothesized that a similar mechanism might occur in the heart. Neonatal rat myocytes were stimulated with lipopolysaccharide (LPS), and TNF-alpha was measured by ELISA. In the absence of LPS, myocytes did not release TNF-alpha in the medium. After exposure to LPS, TNF-alpha increased to 70.1+/-3.5 pg/mL at 6 hours. Immunofluorescent staining confirmed that TNF-alpha was expressed in myocytes. Adenosine decreased TNF-alpha in a dose-dependent manner (1 to 100 micromol/L, 37% to 65% decrease, P<.01). Adenosine also decreased TNF-alpha in cell homogenates by 78% (P<.0001). The effect of adenosine could be replicated by the A2 agonist PD-125944 (DPMA), by cAMP agonists 8-bromo-cAMP, forskolin, and Ro 20-1724, but not by A1 and A3 agonists. Conversely, the effect of adenosine could be suppressed by the adenylate cyclase inhibitor MDL-12,330. Adenosine also inhibited TNF-alpha in adult rat ventricular myocytes (-60%, P<.005) and rat papillary muscles (-55%, P<.05). In neonatal myocytes, adenosine normalized LPS-induced calcium changes and improved LPS-induced negative inotropic (P<.01) and negative lusitropic (P<.01) effects. Our results demonstrate that adenosine can significantly diminish TNF-alpha levels in the heart. The effect appears to be mediated by the A2 receptor and transduced through a G protein-adenylyl cyclase pathway. These results may explain some cardioprotective effects of adenosine and provide a novel pharmacological intervention in congestive heart failure.
PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of β1-adrenergic preconditioning
Authors: A ROBINET, G HOIZEY, H MILLART
Journal: Cardiovascular Research (2005)

Using an isolated non-working rat heart model, this study investigated the mechanisms of pharmacological preconditioning (PC) induced by transient beta1-adrenoreceptor (beta1-AR) stimulation with xamoterol (XA).After 6-hydroxydopamine (6-OHDA) pretreatment and a 20-min stabilization period, hearts were perfused at constant pressure for 20 min then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R, Ctrl); exposed to 0.01 microM XA for 5 min with or without 10 microM atenolol (ATE), a specific antagonist of beta1-AR, followed by a 15-min XA-free perfusion before I/R (PC, ATE-PC, respectively); treated during 20 min with either phosphoinositide (PI) 3-kinase inhibitors, LY-294002 (LY, 15 microM), or wortmaninn (WO, 0.1 microM); protein kinase C (PKC) inhibitor, GF-109203X (GF, 4 nM); or protein kinase A (PKA) inhibitor, H89 (H89, 1 microM), with an infusion starting 3 min before XA (LY-PC, WO-PC, GF-PC, and H89-PC, respectively). The main endpoints were the mean coronary flow (MCF), the left ventricular end-diastolic pressure (LVEDP), rate-pressure product (RPP), and creatine kinase (CK) release.XA induced an increase in the MCF after I/R (t 105 min) and a protective effect on the LVEDP, which were blocked by ATE and abolished with the different inhibitors. The transient increase in RPP following XA infusion was blocked by ATE and was not modified by the inhibitors except for H89. Recovery of RPP, measured 25 min after reperfusion, was improved by XA, blocked by ATE, and decreased with the different inhibitors. Fifteen minutes after the end of ischemia, CK release reached maximal values in all groups. XA provided significant protection whereas ATE and the four inhibitors suppressed XA-induced protection.The transient preischemic exposure to nanomolar concentrations of a beta1-AR agonist is protective against I/R. PI 3-kinase, PKC, and PKA are implicated in the trigger phase of PC. These observations were confirmed by Western blots.
SG-04 * THE eEF2 KINASE, A MEDIATOR OF MEDULLOBLASTOMA ADAPTATION TO METABOLIC STRESS, SUPPORTS FATTY ACID OXIDATION
Authors: G. Leprivier, R. Teperino, A. Kristensen, M. Remke, S. Pfister, M. D. Taylor, J. A. Pospisilik, P. H. Sorensen
Journal: Neuro-Oncology (2015)

During tumour progression, brain tumour cells are exposed to nutrient deprivation due to defective tumour vasculature. The ability of brain tumour cells to adapt to reduced nutrient availability favours selection for aggressive clones. The molecular pathways supporting such metabolic adaptation are still poorly defined. We previously reported that the translation elongation factor 2 kinase (eEF2K), which controls mRNA translation at the step of elongation, is an evolutionarily conserved mediator of the response to nutrient deprivation. Gene expression analysis show that eEF2K expression is upregulated in the most aggressive subgroup of medulloblastoma (MB), namely group 3, and that high eEF2K expression is strongly associated with poor survival in both MB. In addition, genetic targeting of eEF2K significantly increases sensitivity of MB cells to nutrient deprivation, supporting a role for eEF2K in facilitating adaptation of MB to nutrient stress. To decipher the basis for eEF2K protective functions under nutrient deprivation, we performed gene expression analysis of eEF2K proficient versus deficient cells under nutrient-deprived conditions. Gene set enrichment analysis (GSEA) highlighted fatty acid oxidation (FAO) as one of the biological pathways most dramatically deregulated upon eEF2K loss. Remarkably, many genes involved in FAO are downregulated in eEF2K deficient cells under starvation, including genes encoding acyl-coA synthetases and acyl-coA dehydrogenases. Furthermore, cells lacking eEF2K are deficient in metabolizing exogenous palmitate to produce ATP, strongly supporting a role for eEF2K in stimulating FAO activity. Finally, our data show that pharmacological induction of FAO in eEF2K deficient cells using bezafibrate was sufficient to rescue cell death occurring under nutrient depleted conditions. The molecular basis for eEF2K-mediated regulation of the FAO transcriptional program is under investigation. Together, our work supports a critical role for eEF2K in driving FAO activity under nutrient deprivation, which could profoundly impact medulloblastoma adaptation to nutrient stress and therefore emergence of aggressive phenotypes.