tbuckley/cabot-search huggingface dataset:
Microarray-Assisted Pathway Analysis Identifies Mitogen-Activated Protein Kinase Signaling as a Mediator of Resistance to the Green Tea Polyphenol Epigallocatechin 3-Gallate in Her-2/neu–Overexpressing Breast Cancer Cells
Authors: Shangqin Guo, Jun Lu, Aravind Subramanian, Gail E. Sonenshein
Journal: Cancer Research (2006)

Abstract Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor and induction of multiple downstream signaling pathways, including the Akt kinase to nuclear factor-κB (NF-κB) cascade that is associated with poor prognosis. Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu–driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-κB activities. Interestingly, upon prolonged culture in the presence of EGCG, cells resistant to the polyphenol could be isolated. Here, we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-κB activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray studies of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis pathway assessment, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG. (Cancer Res 2006; 66(10): 5322-9)
Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure
Authors: H.-B. Zhang, R.-C. Li, M. Xu, S.-M. Xu, Y.-S. Lai, H.-D. Wu, X.-J. Xie, W. Gao, H. Ye, Y.-Y. Zhang, X. Meng, S.-Q. Wang
Journal: Cardiovascular Research (2013)

Chronic heart failure is a complex clinical syndrome with impaired myocardial contractility. In failing cardiomyocytes, decreased signalling efficiency between the L-type Ca2+ channels (LCCs) in the plasma membrane (including transverse tubules, TTs) and the ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) underlies the defective excitation–contraction (E–C) coupling. It is therefore intriguing to know how the LCC–RyR signalling apparatus is remodelled in human heart failure. Stereological analysis of transmission electron microscopic images showed that the volume densities and the surface areas of TTs and junctional SRs were both decreased in heart failure specimens of dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). The TT–SR junctions were reduced by ∼60%, with the remaining displaced from the Z-line areas. Moreover, the spatial span of individual TT–SR junctions was reduced by ∼17% in both DCM and ICM tissues. In accordance with these remodelling, junctophilin-2 (JP2), a structural protein anchoring SRs to TTs, was down-regulated, and miR-24, a microRNA that suppresses JP2 expression, was up-regulated in both heart failure tissues. Human heart failure of distinct causes shared similar physical uncoupling between TTs and SRs, which appeared attributable to the reduced expression of JP2 and increased expression of miR-24. Therapeutic strategy against JP2 down-regulation would be expected to protect patients from cardiac E–C uncoupling.
Involvement of Phosphorylation in Doxorubicin-Mediated Myofibril Degeneration
Authors: Mark A. Sussman, Sarah F. Hamm-Alvarez, Patricia M. Vilalta, Sara Welch, Larry Kedes
Journal: Circulation Research (1997)

Loss of myofilaments has been observed in both adaptive cardiac responses (ie, hypertrophy) as well as in chemotheraputic use of antineoplastic drugs with cardiotoxic side effects (ie, doxorubicin). An understanding of the degenerative process is a prerequisite for determining approaches to limit the cardiomyopathic changes associated with chronic heart disease or long-term chemotheraputic treatments. However, little is known about the specific events and molecular changes that initiate the degenerative process. To study this process, neonatal rat cardiomyocytes were treated with doxorubicin, which induced rapid and widespread thin-filament degeneration as observed by fluorescence confocal microscopy. which demonstrated deterioration of sarcomeric thin-filament structure. Changes in the spontaneous beating of cardiomyocytes corresponding with myofibrillar degeneration were apparent using differential interference contrast video microscopy. After finding induction of kinase activity by doxorubicin in cultured cardiomyocytes, the protective effects of specific inhibitors of kinase activity were assessed for their ability to inhibit doxorubicin-induced myofibrillar breakdown. Doxorubicin-induced changes appeared similar to the degeneration observed after treatment with a protein kinase activator (phorbol 12-myristate 13-acetate) or a serine-threonine protein phosphatase inhibitor (okadaic acid). Collectively, these results indicate that activation of protein kinase is an important event in the initiation of myofibrillar degeneration by doxorubicin. Further analyses of myofibrillar proteins with respect to biochemical modifications will be necessary to determine if phosphorylation events transmit signal(s) to initiate degeneration.
Cultured rat aortic vascular smooth muscle cells digest naturally produced extracellular matrix. Involvement of plasminogen-dependent and plasminogen-independent pathways.
Authors: G Sperti, R T van Leeuwen, P H Quax, A Maseri, C Kluft
Journal: Circulation Research (1992)

Vascular smooth muscle (VSM) cell migration and proliferation play a major role in the development of atherosclerotic lesions, graft occlusion, and restenosis after angioplasty. Cell migration implies the digestion of the surrounding extracellular matrix. Cell-associated proteolysis has been extensively studied in neoplastic and inflammatory cells, but very little is known about the proteolytic properties of VSM. We have evaluated the ability of rat cultured VSM cells to solubilize [3H]amino acid-labeled extracellular matrices produced by bovine VSM. When plated at a density of 30,000 cells per well in 24 multiwell plates, VSM cells were able to solubilize 63.3 +/- 7.0% of the extracellular matrix after 10 days in culture. Extracellular matrix digestion occurred also when the cells were cultured in plasminogen-depleted serum but was higher in the presence of 10 micrograms/ml purified plasminogen (net percent digestion after the subtraction of the appropriate control, 8.6 +/- 3.0% versus 21.2 +/- 3.5% after 3 days in culture, p less than 0.005, respectively). The involvement of other enzymes in addition to plasmin is confirmed by the ability of VSM cells to degrade extracellular matrices from which the plasmin-sensitive component was removed with plasmin pretreatment. Rat VSM cells were able to solubilize 52.3 +/- 2.0% of this residual extracellular matrix-associated radioactivity after 6 days in culture versus 26.1 +/- 1.5% in the control dishes (p less than 0.01, n = 5). Cell contact was required for extracellular matrix degradation: cell-conditioned medium did not have any effect on extracellular matrix digestion.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of osteoprotegerin and osteoprotegerin ligand on osteoclast formation by arthroplasty membrane derived macrophages
Authors: I Itonaga
Journal: Annals of the Rheumatic Diseases (2000)

Osteoprotegerin ligand (OPGL) is a newly discovered molecule, which is expressed by osteoblasts/bone stromal cells. This ligand and M-CSF are now known to be essential for osteoclast differentiation from marrow and circulating precursors. This study examined whether OPGL and its soluble receptor osteoprotegerin (OPG), influenced osteoclast formation from human arthroplasty derived macrophages, to determine if the effects of OPGL and OPG on these cells could contribute to the osteolysis of aseptic loosening.OPGL (+/- dexamethasone/M-CSF) was added to cultures of macrophages isolated from the pseudomembrane of loosened hip arthroplasties incubated on glass coverslips and dentine slices. OPG was added to cocultures of arthroplasty derived macrophages and UMR106 osteoblast-like cells. Osteoclast differentiation in long term cultures was assessed by expression of macrophage (CD14) and osteoclast markers (tartrate resistant acid phosphatase (TRAP), vitronectin receptor (VNR) and lacunar resorption).In the absence of osteoblastic cells, the addition of OPGL alone was sufficient to induce differentiation of macrophages (CD14(+), TRAP(-), VNR(-)) into TRAP(+) and VNR(+) multinucleated cells, capable of extensive lacunar resorption. OPG was found to inhibit osteoclast formation by arthroplasty macrophages in a dose dependent manner. OPG (100 ng/ml) more than halved the formation of TRAP(+) and VNR(+) cells and the extent of lacunar resorption in co-cultures of UMR106 cells and arthroplasty macrophages.This study has shown that macrophages, isolated from the pseudomembrane surrounding loose arthroplasty components, are capable of differentiating into osteoclastic bone resorbing cells and that OPGL is required for this to occur. OPG inhibits this process, most probably by interrupting the cell-cell interaction between osteoblasts and mononuclear phagocyte osteoclast precursors present in the pseudomembrane.
Interaction between Single Nucleotide Polymorphisms in Selenoprotein P and Mitochondrial Superoxide Dismutase Determines Prostate Cancer Risk
Authors: Matthew L. Cooper, Hans-Olov Adami, Henrik Grönberg, Fredrik Wiklund, Fiona R. Green, Margaret P. Rayman
Journal: Cancer Research (2008)

Selenium may affect prostate cancer risk via its plasma carrier selenoprotein P which shows dramatically reduced expression in prostate cancer tumors and cell lines. The selenoprotein P (SEPP1) Ala234 single nucleotide polymorphism (SNP) allele is associated with lower plasma selenoprotein P in men, reducing the concentration/activity of other antioxidant selenoproteins. Selenium status also modifies the effect of the mitochondrial superoxide dismutase (SOD2) SNP Ala16Val on prostate cancer risk. We investigated the relationship of these SNPs with prostate cancer risk. DNA from 2,975 cases and 1,896 age-matched controls from the population-based Prostate Cancer in Sweden study were genotyped using TaqMan assays. Cases were designated aggressive or nonaggressive prostate cancers at diagnosis by clinical criteria. Association with prostate cancer was investigated by logistic regression; gene-gene interaction using a general linear model. The mean plasma selenium concentration measured in 169 controls was relatively low (76.0 +/- 17.2 microg/L). SNP genotype distributions were in Hardy-Weinberg equilibrium. SOD2-Ala16+ men were at a greater risk of prostate cancer [odds ratios (OR), 1.19; 95% confidence intervals (CI), 1.03-1.37] compared with SOD2-Val16 homozygotes. Men homozygous for SEPP1-Ala234 who were also SOD2-Ala16+ had a higher risk of prostate cancer (OR, 1.43; 95% CI, 1.17-1.76) and aggressive prostate cancer (OR, 1.60; 95% CI, 1.22-2.09) than those who were SOD2-Val16 homozygotes (interaction, prostate cancer P = 0.05; aggressive prostate cancer P = 0.01). This interaction was stronger in ever-smokers: SOD2-Ala16+ men homozygous for SEPP1-Ala234 had an almost doubled risk of prostate cancer (OR, 1.97; 95% CI, 1.33-2.91; interaction P = 0.001). In a low-selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at an increased risk of prostate cancer/aggressive prostate cancer especially if ever-smokers, because they are likely to produce more mitochondrial H(2)O(2) that they cannot remove, thereby promoting prostate tumor cell proliferation and migration.
<i>Brucella</i>Evades Macrophage Killing via VirB-dependent Sustained Interactions with the Endoplasmic Reticulum
Authors: Jean Celli, Chantal de Chastellier, Don-Marc Franchini, Javier Pizarro-Cerda, Edgardo Moreno, Jean-Pierre Gorvel
Journal: The Journal of Experimental Medicine (2003)

The intracellular pathogen Brucella is the causative agent of brucellosis, a worldwide zoonosis that affects mammals, including humans. Essential to Brucella virulence is its ability to survive and replicate inside host macrophages, yet the underlying mechanisms and the nature of the replicative compartment remain unclear. Here we show in a model of Brucella abortus infection of murine bone marrow-derived macrophages that a fraction of the bacteria that survive an initial macrophage killing proceed to replicate in a compartment segregated from the endocytic pathway. The maturation of the Brucella-containing vacuole involves sustained interactions and fusion with the endoplasmic reticulum (ER), which creates a replicative compartment with ER-like properties. The acquisition of ER membranes by replicating Brucella is independent of ER-Golgi COPI-dependent vesicular transport. A mutant of the VirB type IV secretion system, which is necessary for intracellular survival, was unable to sustain interactions and fuse with the ER, and was killed via eventual fusion with lysosomes. Thus, we demonstrate that live intracellular Brucella evade macrophage killing through VirB-dependent sustained interactions with the ER. Moreover, we assign an intracellular function to the VirB system, as being required for late maturation events necessary for the biogenesis of an ER-derived replicative organelle.
S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis
Authors: Michal Tomcik, Katrin Palumbo-Zerr, Pawel Zerr, Jerome Avouac, Clara Dees, Barbora Sumova, Alfiya Distler, Christian Beyer, Lucie Andres Cerezo, Radim Becvar, Oliver Distler, Mariam Grigorian, Georg Schett, Ladislav Senolt, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc). <h3>Methods</h3> The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4<sup>−/−</sup>) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes. <h3>Results</h3> The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4<sup>−/−</sup> mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model. <h3>Conclusions</h3> We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.
The key to top-level endurance running performance: a unique example
Authors: Alejandro Lucia, Jesús Oliván, Jerónimo Bravo, Marta Gonzalez-Freire, Carl Foster
Journal: British Journal of Sports Medicine (2007)

Endurance  performance depends on a complex interplay of factors, including: (1) a high maximal oxygen uptake (VO2max); (2) the ability to sustain a high percentage of VO2max for long periods of time (fractional utilisation of VO2max); and (3) the ability to move efficiently (ie,  of  or running economy).1 2 Although VO2max and fractional utilisation of VO2max have been extensively studied as determinants of  performance, by comparison,  economy has been relatively ignored in the scientific literature, though it may be the critical factor determining endurance  performance.1 Differences amongst elite athletes in a variety of endurance sporting events other than  (particularly road cycling) have also been shown to be highly related to differences in economy (or efficiency).3 The physiological index of endurance performance that improved most in seven-time winner of the Tour de France Lance Armstrong as he matured from age 21 to 28 years was gross mechanical efficiency (+8%), whereas his VO2max remained relatively unchanged.4

Black athletes of East African origin (Kenyans and Ethiopians) dominate most endurance  events, from the 5000 m track event to the marathon. Many of the best performances in these events have been achieved by Kenyans (49%) and Ethiopians (15%). In recent years, other African endurance runners (from South Africa, Tanzania, Zimbabwe and, more recently, Eritrea) have also attained excellent results in international competition. A lower cost of running, that is, better economy, has been demonstrated in some top-level East African runners5 6 and in runners from other parts of Africa compared to their Caucasian counterparts.7 This phenomenon could account, at least in part, for their superior competition performance.

The Cross-Country World Championship provides an …
Kinase Pathway Dependence in Primary Human Leukemias Determined by Rapid Inhibitor Screening
Authors: Jeffrey W. Tyner, Wayne F. Yang, Armand Bankhead, Guang Fan, Luke B. Fletcher, Jade Bryant, Jason M. Glover, Bill H. Chang, Stephen E. Spurgeon, William H. Fleming, Tibor Kovacsovics, Jason R. Gotlib, Stephen T. Oh, Michael W. Deininger, Christian Michel Zwaan, Monique L. Den Boer, Marry M. van den Heuvel-Eibrink, Thomas O'Hare, Brian J. Druker, Marc M. Loriaux
Journal: Cancer Research (2012)

Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options.
Factors associated with fatigue in patients with systemic lupus erythematosus
Authors: I. N Bruce, V. C Mak, D. C Hallett, D. D Gladman, M. B Urowitz
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> To examine the relation between fatigue, disease activity, damage, and quality of life measures in patients with systemic lupus erythematosus (SLE). <h3>METHODS</h3> Consecutive patients attending the University of Toronto Lupus Clinic were studied. Disease activity was assessed using the SLEDAI and SLAM-R and damage using the SLICC/ACR Damage index. Fatigue was measured by the Fatigue Severity Score (FSS) and health status by the SF-36 questionnaire. In all cases a tender point count was also performed. <h3>RESULTS</h3> 81 patients were studied. Their mean (SD) age and disease duration were 43 (12.5) years and 12.7 (8.0) years respectively. The FSS did not correlate with the SLEDAI nor with the SLAM-R. There was no correlation with the SLICC damage index. Fatigue severity correlated with the tender point count (SCC <i>r</i>=0.46, p&lt;0.001), and negatively with all domains of the SF36 (<i>r</i> values −0.50 to −0.82). Disease activity and damage accounted for only 4.8% and 4% respectively of the variance in fatigue severity reported by patients. <h3>CONCLUSION</h3> In an outpatient population of SLE patients, fatigue severity correlates with poor health status and a higher tender point count. In patients with SLE, factors associated with quality of life and fibromyalgia seem to have a greater influence on the severity of reported fatigue than does the level of current disease activity.
Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors
Authors: Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus, Emily Bergsland, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2008)

Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients.Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed.Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment.Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.