tbuckley/cabot-search huggingface dataset:
Disease and region-related cardiac fibroblast potassium current variations and potential functional significance
Authors: Chia Tung Wu, Xiao Yan Qi, Hai Huang, Patrice Naud, Kristin Dawson, Yung Hsin Yeh, Masahide Harada, Chi Tai Kuo, Stanley Nattel
Journal: Cardiovascular Research (2014)

Fibroblasts, which play an important role in cardiac function/dysfunction, including arrhythmogenesis, have voltage-dependent (Kv) currents of unknown importance. Here, we assessed the differential expression of Kv currents between atrial and ventricular fibroblasts from control dogs and dogs with an atrial arrhythmogenic substrate caused by congestive heart failure (CHF). Left atrial (LA) and ventricular (LV) fibroblasts were freshly isolated from control and CHF dogs (2-week ventricular tachypacing, 240 bpm). Kv currents were measured with whole-cell voltage-clamp, mRNA by quantitative polymerase chain reaction (qPCR) and fibroblast proliferation by 3H-thymidine incorporation. Robust voltage-dependent tetraethylammonium (TEA)-sensitive K+ currents (IC50 ∼1 mM) were recorded. The morphologies and TEA responses of LA and LV fibroblast Kv currents were similar. LV fibroblast Kv-current densities were significantly greater than LA, and Kv-current densities were significantly less in CHF than control. The mRNA expression of Kv-channel subunits Kv1.5 and Kv4.3 was less in LA vs. LV fibroblasts and was down-regulated in CHF, consistent with K+-current recordings. Ca2+-dependent K+-channel subunit (KCa1.1) mRNA and currents were less expressed in LV vs. LA fibroblasts. Inhibiting LA fibroblast K+ current with 1 mmol/L of TEA or KCa1.1 current with paxilline increased proliferation. Fibroblast Kv-current expression is smaller in CHF vs. control, as well as LA vs. LV. KCa1.1 current is greater in LA vs. LV. Suppressing Kv current with TEA enhances fibroblast proliferation, suggesting that Kv current might act to check fibroblast proliferation and that reduced Kv current in CHF may contribute to fibrosis. Fibroblast Kv-current remodelling may play a role in the atrial fibrillation (AF) substrate; modulating fibroblast K+ channels may present a novel strategy to prevent fibrosis and AF.
Carcinogenic properties of orthodianisidine.
Authors: D Acheson
Journal: BMJ (1967)

emerged from large studies in Texas9 and South Africa."`'12Altogether it seems unlikely that enteroviruses or adenoviruses are significant causes of uncomplicated diarrhoeal disease.Routine virological investigation by present techniques of stools from diarrhoeal patients is an unrewarding diver- sion of effort.Perhaps when the technical trick of demonstrating hepatitis virus has been discovered a new group of agents may be found responsible for that large majority of diarrhoeal illnesses in which neither viro- logical nor bacteriological tests are currently successful.-Weare, etc.,
Chronic Rejection
Authors: Martin Gasser, Ana Maria Waaga-Gasser, Joana E. Kist-van Holthe, Xueli Yuan, Susanne M. Lenhard, Kald A. Abdallah, Anil Chandraker
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The use of immunosuppressive drugs in models of chronic rejection may limit their usefulness for mechanistic studies. We have developed a new minor histocompatibility-mismatched rat kidney transplant model without the need for immunosuppression. Kidneys from LEW (RT1l) donors were transplanted to congenic WF.1L (RT1l) recipients and compared with the reversed strain combination and isogenic controls. Urinary protein excretion was measured serially in all recipients; kidneys were harvested 90, 120, and 180 d after transplantation for morphologic analysis and cytokine gene expression. In vitro lymphocytic reactivity and cytokine analysis of mixed lymphocyte reaction (MLR) culture supernatants by ELISA was also carried out. LEW into WF.1L kidney grafts developed proteinuria starting 120 d after transplantation and were associated with morphologic changes of focal segmental glomerulosclerosis together with interstitial cell infiltrates, upregulated gene expression of IL-1β, IL-2, and TNF-α/-β, as well as IL-2, IFN-γ, and TNF-α production by lymphocytes in MLR culture supernatants. WF.1L kidneys transplanted into LEW recipients did not develop chronic rejection and had upregulation of Th2 cytokines, both within the allograft and in MLR supernatant of recipient lymphocytes cultured with WF.1L cells. Furthermore, these lymphocytes produced both Th1 and Th2 cytokines when cultured with WF cells, unlike lymphocytes from the LEW isografts, which produced Th1 cytokines when challenged with WF cells. These studies show that indirect allorecognition can cause strain-dependent chronic rejection associated with Th1-like cytokine production, whereas production of Th2 cytokines is associated with protection from the development of chronic rejection.
NKT Cells Inhibit the Development of Experimental Crescentic Glomerulonephritis
Authors: Seung Hee Yang, Su Jin Kim, Nakkyung Kim, Ji Eun Oh, Jung Gil Lee, Nam Hyun Chung, Suhnggwon Kim, Yon Su Kim
Journal: Journal of the American Society of Nephrology (2008)

CD1d is an MHC class I-like, beta2-microglobulin-associated protein, constitutively expressed by antigen-presenting cells and some epithelial cells, which is recognized by NKT cells, a subpopulation of T cells. CD1d-dependent NKT cells confer protection in immune-mediated disorders, but whether these cells modulate the development of glomerulonephritis is unknown. Experimental crescentic glomerulonephritis was induced by administering anti-glomerular basement membrane antibodies to NKT cell-deficient (CD1d(-/-)) and wild-type mice. Compared with wild-type mice, NKT cell-deficient mice had an accelerated course of glomerulonephritis measured by renal function and crescent formation, and this was abrogated by adoptive transfer of NKT cells. Reconstitution with NKT cells also attenuated intraglomerular expression of TGF-beta1 and decreased phosphorylation of the transcription factors NF-kappaB and IkappaB. Adopted transfer of fluorescence-labeled NKT cells demonstrated their distribution to glomeruli damaged by anti-glomerular basement membrane antibodies but not to the tubulointerstitium. The chemokine CXCL16, which is the ligand for CXCR6 on NKT cells, was upregulated in glomeruli after induction of glomerulonephritis, and NKT cells were present in the same glomeruli. In vitro, NKT cells inhibited LPS-stimulated proliferation of mesangial cells, an affect that was reduced by co-current treatment with an anti-CXCL16 monoclonal antibody. In summary, these findings highlight the regulatory capacity of CD1d-dependent NKT cells in experimental glomerulonephritis and suggest that CXCL16 is involved in the recruitment of these cells to the site of injury.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers
Authors: Alex A. Adjei, Roger B. Cohen, Wilbur Franklin, Clive Morris, David Wilson, Julian R. Molina, Lorelei J. Hanson, Lia Gore, Laura Chow, Stephen Leong, Lara Maloney, Gilad Gordon, Heidi Simmons, Allison Marlow, Kevin Litwiler, Suzy Brown, Gregory Poch, Katie Kane, Jerry Haney, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2008)

To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer.In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations.Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated >or= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for >or= 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles.AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.
Assessment of techniques for preventing glycolysis in cardiac muscle
Authors: J S PIROLO, D G ALLEN
Journal: Cardiovascular Research (1986)

Studies of myocardial function during ischaemic or anoxia would be assisted if it were possible to inhibit glycolysis completely and reversibly. Three methods of preventing glycolysis in isolated perfused ferret hearts were studied: (a) the removal of glucose from the perfusate followed by manoeuvres designed to deplete glycogen stores, (b) the use of 2-deoxyglucose, and (c) the use of iodoacetate. The rate of glycolysis before and after applying the three methods was assessed by measuring lactate production during short periods of anoxia. Metabolic changes associated with each method were investigated with phosphorus nuclear magnetic resonance, and other side effects associated with each method were assessed by measuring developed pressure. The results show that removal of glucose followed by glycogen depletion reduced the rate of glycolysis to any chosen extent and that the method was reversible. 2-Deoxyglucose treatment did not lead to complete inhibition of glycolysis, was not reversible, and reduced the concentrations of phosphocreatinine and adenosine triphosphate in the heart. Iodoacetate treatment completely blocked glycolysis, but it was not reversible and subsequent periods of anoxia lead to a rapid fall in adenosine triphosphate owing to the accumulation of phosphorylated glycolytic intermediates.
Host Response to Cytomegalovirus Infection as a Determinant of Susceptibility to Coronary Artery Disease
Authors: Jianhui Zhu, Gene M. Shearer, James E. Norman, Ligia A. Pinto, Francesco M. Marincola, Abhiram Prasad, Myron A. Waclawiw, Gyorgy Csako, Arshed A. Quyyumi, Stephen E. Epstein
Journal: Circulation (2000)

Background —Positive and negative associations between cytomegalovirus (CMV) infection and coronary artery disease (CAD) have been reported. We postulated that the susceptibility to CMV-induced CAD might relate to patterns of inflammatory and immune responses to CMV infection and that sex might have an effect on these responses. Methods and Results —In 151 men and 87 women being evaluated for CAD, blood samples were tested for humoral (Ab+) and cellular (Tc+) responses to CMV and for C-reactive protein (CRP). In men, an elevated CRP level was a significant determinant of CAD even after adjustment for CAD risk factors (OR, 3.1; 95% CI, 1.21 to 7.97). CMV seropositivity was associated with elevated CRP levels on multivariate analysis ( P =0.006). In contrast, in women, CMV seropositivity was independently predictive of CAD (OR, 41.8; 95% CI, 4.12 to 423.74). CRP level in women with CAD was &gt;25% higher than those without CAD, but the difference did not reach statistical significance. Importantly, compared with CMV Ab−/Tc− women, CAD prevalence was higher in Ab+/Tc− and Ab+/Tc+ (13% versus 68% and 64%, both P &lt;0.005) but not in Ab−/Tc+ women (25%). There were no differences in age, smoking, diabetes, hypertension, and hypercholesterolemia among women with different types of immune responses to CMV infection. Conclusions —The mechanisms by which CMV predisposes to CAD in men and women may be different. In men, CMV appears to contribute to CAD risk, insofar as it predisposes to inflammation. In women, other mechanisms, possibly related to the type of immune response generated by the host, appear to be responsible for the proatherogenic effects of CMV.
Parametric response mapping as an indicator of bronchiolitis obliterans syndrome in HCT recipients
Authors: Craig Galban, Jennifer Boes, Maria Bule, Carrie Kitko, Daniel Couriel, Timothy Johnson, Eef Telenga, Maarten Van den Berge, Ella Kazerooni, Brian Ross, Gregory Yanik
Journal: European Respiratory Journal (2014)

The diagnosis of bronchiolitis obliterans syndrome (BOS), an obstructive lung disease that occurs following hematopoietic stem cell transplantation (HCT), is clinically challenging due to the presence of pulmonary infections. We evaluated parametric response mapping (PRM) as an indicator of BOS in HCT patients with acute pulmonary infection. PRM was performed in four subject cohorts: HCT patients diagnosed with acute infection (n=11), BOS (n=34), BOS plus infection (n=9), and age-matched, non-HCT subjects (n=23). The PRM analysis includes a 3D map and joint density histogram of voxels color-coded based on classification: green for normal, yellow for fSAD, red for emphysema and purple for parenchymal disease. Presented in the figure is the PRM analysis of a HCT recipient with BOS that was found to have extensive fSAD (yellow; PRM fSAD =40%). Significantly greater PRM fSAD  values were identified in patients with BOS (38±2%) as compared to infection alone (17±4%, p fSAD  were observed in patients with BOS, whether a concurrent infection was present or not. PRM is a useful indicator of BOS even in the presence of concurrent pulmonary infection. The PRM biomarker may provide a significant advance in the ability to definitively identify the non-emphysematous small airway obstruction characteristic of BOS.
Piloting a Novel Algorithm for Glucose Control in the Coronary Care Unit
Authors: Kara A. Nerenberg, Abhinav Goyal, Denis Xavier, Alben Sigamani, Jennifer Ng, Shamir R. Mehta, Rafael Díaz, Mikhail Kosiborod, Salim Yusuf, Hertzel C. Gerstein
Journal: Diabetes Care (2011)

Elevated glucose levels are common after an acute myocardial infarction (AMI) and increase the risk of death. Prior trials of glucose control after AMI have been inconsistent in their ability to lower glucose levels and have reported mixed effects on mortality. We developed a paper-based glucose-lowering algorithm and assessed its feasibility and safety in the setting of AMI.A total of 287 participants with an acute ST segment elevation myocardial infarction (STEMI) and a capillary glucose level ≥8.0 mmol/L were randomly allocated to glucose management with intravenous glulisine insulin using this algorithm in the coronary care unit (CCU), followed by once-daily subcutaneous insulin glargine for 30 days versus standard glycemic approaches. The primary outcome was a difference in mean glucose levels at 24 h. Participants were followed for clinical outcomes through 90 days.At 24 h, the mean glucose level was 1.41 mmol/L (95% CI 0.69-2.13) lower in the insulin (6.53 vs. 7.94 mmol/L). Differences in glucose levels were maintained at 72 h and 30 days. A total of 22.7% of the insulin group versus 4.4% of the standard group had biochemical hypoglycemia (with neither signs nor symptoms) in the CCU because of lower glycemic goals. However, there were no differences in symptomatic hypoglycemia or clinical outcomes between the groups.A paper-based insulin algorithm targeting glucose levels of 5.0-6.5 mmol/L (90-117 mg/dL) can be feasibly implemented in the CCU. A cardiovascular outcomes trial using this approach can determine whether targeted glucose lowering improves patient outcomes.
Fractalkine Upregulates Intercellular Adhesion Molecule-1 in Endothelial Cells Through CX3CR1 and the Jak–Stat5 Pathway
Authors: Xiao Ping Yang, Subhendra Mattagajasingh, Shaobo Su, Guibin Chen, Zheqing Cai, Karen Fox-Talbot, Kaikobad Irani, Lewis C. Becker
Journal: Circulation Research (2007)

Fractalkine (FKN) is a membrane-bound chemokine that can be released by proteolysis to produce soluble FKN (s-FKN). FKN and its receptor, CX3CR1, are believed to be important factors in atherosclerosis and may play a role in acute inflammatory responses. Although FKN is expressed on endothelial cells (ECs), CX3CR1 is reported to reside mainly on certain leukocyte populations. RT-PCR and Western blotting demonstrated that both human coronary artery and umbilical vein ECs expressed CX3CR1 mRNA and protein. Confocal microscopy showed that CX3CR1 was located at the cell membrane and to a lesser extent in the cytoplasm. Following exposure of both types of ECs to hypoxia and reoxygenation, FKN expression increased rapidly and s-FKN was shed into the culture medium. The addition of s-FKN protein to cultured ECs resulted in a dose-dependent increase in intercellular adhesion molecule (ICAM)-1 mRNA. Perfusion of mouse hearts with s-FKN protein increased expression of ICAM-1 protein in vascular endothelium. Transfection of ECs with CX3CR1-interfering RNA to knockdown the receptor resulted in decreased ICAM-1 expression after s-FKN stimulation. In addition, when ECs were stimulated with s-FKN, greater adhesion of human neutrophils to the ECs was observed. This increase was ICAM-1 dependent and was blocked by CX3CR1 knockdown. Following exposure to s-FKN, ECs exhibited increased phosphorylation of Jak2 and Stat5 and the ICAM-1 expression induced by s-FKN was blocked by silencing of Stat5 with small interfering RNA. Vascular ECs express both FKN and its receptor CX3CR1. s-FKN is shed from ECs following hypoxia/reoxygenation and acts through CX3CR1 on ECs to increase ICAM-1 expression and promote neutrophil adhesion through activation of the Jak-Stat5 pathway.
Macrophage Role in the Anti-Prostate Cancer Response to One Class of Antiangiogenic Agents
Authors: I. B. J. K. Joseph, J. T. Isaacs
Journal: JNCI Journal of the National Cancer Institute (1998)

Background . Tumor-associated macrophages (TAMs) can either promote angiogenesis (i.e., the formation of new blood vessels) in tumors by secreting tumor necrosis factor-α (TNF-α) or inhibit angiogenesis by producing granulocyte-macrophage colony-stimulating factor (GM-CSF), which in turn stimulates production of the antiangiogenic protein plasminogen activator inhibitor type 2 (PAI-2). We tested, alone or in combination, the anti-prostate cancer activity of agents that perturb macrophage function. Methods: By use of enzyme- linked immunosorbent assays, we measured the effects of Linomide® (roquinimex), thalidomide, pentoxifylline, and genistein on TNF-α and GM-CSF production in vitro by virally transformed RAW 264.7 mouse macrophages and on PAI-2 production in vitro by human macrophages. The antitumor effects of these agents were tested in vivo on transplanted Dunning R-3327 MAT-Lu rat prostate cancers; TAM numbers and blood vessel densities in these cancers were determined by use of immunocytochemistry. Results: Linomide selectively inhibited mouse macrophage secretion of TNF-α but not of GM-CSF; however, thalidomide, pentoxifylline, and genistein inhibited the production of both cytokines. Linomide, but not thalidomide or pentoxifylline, increased production of PAI-2 by human macrophages. When administered to rats bearing MAT-Lu tumors, each of the tested agents reduced TAM numbers (Linomide, by 46%; thalidomide, by 94%; pentoxifylline, by 71%; and genistein, by 96%). However, all of the agents reduced tumor blood vessel density and tumor growth, with Linomide being the most effective (44% reduction in blood vessel density and 69% inhibition of tumor growth). None of the other agents potentiated Linomide's antitumor effect. Conclusions: Linomide is unique among the antiangiogenic agents tested, in that it inhibits the stimulatory effects of TAMs on tumor angiogenesis without eliminating their antiangiogenic effects, and may thus prove to be more effective against prostate cancer.
Abstract 475: uPAR and cathepsin B knockdown inhibits radiation-induced PKC integrated integrin signaling to the cytoskeleton and migration of glioma initiating cells
Authors: Kiranmai Alapati, Venkata Ramesh Dasari, Sreelatha Gopinath, Rama Rao Malla, Meena Gujrati, Jasti S. Rao
Journal: Cancer Research (2012)

Abstract Glioblastoma (GBM) remains one of the most fatal and least successfully treated solid tumors. It is evident that some cancer cells with stem cell properties (known as glioma initiating cells; GICs) survive conventional treatments and are involved in the recurrence of tumors. In the present study, CD133+ GICs were isolated from established U251 and 5310 glioma cell lines and subjected to radiation and transfection with shRNA against uPAR and cathepsin B so that we could study the events related to cell migration. Simultaneous downregulation of uPAR and cathepsin B (pUC) caused the disruption of radiation-induced complex formation of pPKC∈/α:integrinβ1 and PKC∈:integrinβ1 in glioma cells as well as in GICs as was observed by immunoprecipitation analysis. Further, pUC treatment also inhibited the PKC/integrin signal through FAK by disintegrating the association of FAK and the cytoskeletal molecules vinculin and α-actinin. It was also observed that inhibition of radiation-induced ERK phosphorylation by pUC directed a negative feedback mechanism over the FAK signaling molecules that led to an extensive reduction in the cytoskeletal organization, and thereby generating a migratory arrest. Further confirmation was obtained by treating the cells with U0126 (10 µM), a MEK inhibitor, and rottlerin (200 µM), a PKC inhibitor. pUC treatment efficiently inhibited the co-localization of pPKC∈/α/integrinβ1, PKC∈/integrinβ1, FAK/vinculin and FAK/α-actinin in the brain tumor sections of mice implanted with glioma cells and GICs. In conclusion, shRNA-mediated knockdown of uPAR and cathepsin B could be an effective treatment strategy for controlling highly invasive glioma cells and treatment-resistant glioma initiating cells. 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 475. doi:1538-7445.AM2012-475