tbuckley/cabot-search huggingface dataset:
Turning on a Fuel Switch of Cancer: hnRNP Proteins Regulate Alternative Splicing of Pyruvate Kinase mRNA
Authors: Mo Chen, Jian Zhang, James L. Manley
Journal: Cancer Research (2010)

Unlike normal cells, which metabolize glucose by oxidative phosphorylation for efficient energy production, tumor cells preferentially metabolize glucose by aerobic glycolysis, which produces less energy but facilitates the incorporation of more glycolytic metabolites into the biomass needed for rapid proliferation. The metabolic shift from oxidative phosphorylation to aerobic glycolysis is partly achieved by a switch in the splice isoforms of the glycolytic enzyme pyruvate kinase. Although normal cells express the pyruvate kinase M1 isoform (PKM1), tumor cells predominantly express the M2 isoform (PKM2). Switching from PKM1 to PKM2 promotes aerobic glycolysis and provides a selective advantage for tumor formation. The PKM1/M2 isoforms are generated through alternative splicing of two mutually exclusive exons. A recent study shows that the alternative splicing event is controlled by heterogeneous nuclear ribonucleoprotein (hnRNP) family members hnRNPA1, hnRNPA2, and polypyrimidine tract binding protein (PTB; also known as hnRNPI). These findings not only provide additional evidence that alternative splicing plays an important role in tumorigenesis, but also shed light on the molecular mechanism by which hnRNP proteins regulate cell proliferation in cancer.
Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study
Authors: Ezra EW Cohen, Darren W Davis, Theodore G Karrison, Tanguy Y Seiwert, Stuart J Wong, Sreenivasa Nattam, Mark F Kozloff, Joseph I Clark, Duen-Hwa Yan, Wen Liu, Carolyn Pierce, Janet E Dancey, Kerstin Stenson, Elizabeth Blair, Allison Dekker, Everett E Vokes
Journal: The Lancet Oncology (2009)
New Tricks for Old Dogs
Authors: Cam Patterson, George A. Stouffer, Nageswara Madamanchi, Marschall S. Runge
Journal: Circulation Research (2001)

Abstract —Thrombin is a serine protease that potently activates platelets and catalyzes the conversion of fibrinogen to fibrin. Thrombin also exerts direct effects on vascular cells, such as smooth muscle cells, via interactions with members of the protease-activated receptor family. Evidence in several animal models implicates thrombin-mediated signaling events in the response to injury that typifies vascular lesion formation in atherosclerosis and restenosis. In this review, we examine the activation of protease-activated receptors by thrombin, the downstream signaling events mediated by these receptors, and the physiological role of thrombin in vascular cells and vascular disease.
Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors
Authors: David P. Ryan, Joseph P. Eder, Thomas Puchlaski, Michael V. Seiden, Thomas J. Lynch, Charles S. Fuchs, Philip C. Amrein, Darrell Sonnichsen, Jeffrey G. Supko, Jeffrey W. Clark
Journal: Clinical Cancer Research (2004)

Abstract Purpose: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. Experimental Design: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. Results: The dose of BMS-214662 was escalated from 36 to 225 mg/m2 through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m2, consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m2, the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 ± 0.27 h and a total body clearance of 21.8 ± 10.8 liters/h/m2, with a low apparent volume of distribution at steady state (31.5 ± 12.9 liters/m2). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 ± 2.94 μg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 ± 6.4% of baseline at the end of the infusion but fully recovered within 24 h. Conclusions: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.
Tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells
Authors: Wei Liao, Claes-Henrik Florén
Journal: Hepatology (1993)

Tumor necrosis factor mediates most biological activities of endotoxin and also, in part, mediates endotoxin-induced disturbances in lipid metabolism. In this study, the effect of tumor necrosis factor on low-density lipoprotein receptor activity was investigated in cells of HepG2, a well-differentiated human hepatoma cell line. Pretreatment of the cells with tumor necrosis factor leads to enhanced binding, uptake and degradation of 125I-labeled low-density lipoprotein. This effect of tumor necrosis factor was dose and time dependent. Tumor necrosis factor-stimulated enhancement of low-density lipoprotein binding occurred at all stages of cell growth. However, addition of an excess of unlabeled low-density lipoprotein, to down-regulate low-density lipoprotein receptors before exposure to tumor necrosis factor of the cells, completely abolished the effects of tumor necrosis factor. Competition experiments using unlabeled low-density lipoprotein and blockage experiments with a monoclonal low-density lipoprotein receptor antibody showed that tumor necrosis factor-stimulated low-density lipoprotein binding takes place through stimulation of low-density lipoprotein receptors. Comparison of the kinetics of specific low-density lipoprotein binding in the unstimulated cells and in the tumor necrosis factor-stimulated cells indicated that tumor necrosis factor caused a 30% increase in maximum velocity with no significant change in Michaelis constant, suggesting that tumor necrosis factor increases the number of low-density lipoprotein receptors on the cells rather than changing binding affinity. Preincubation of the cells with cycloheximide or actinomycin D totally abolished the up-regulatory effect of tumor necrosis factor on low-density lipoprotein receptors. Tumor necrosis factor did not stimulate proliferation of HepG2 cells, as judged by cell protein determination or by [3H]thymidine incorporation. In conclusion, this study suggests that tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells by stimulation of de novo synthesis of receptors, independent of cell growth.
Prognostic value of<i>TP53</i>,<i>KRAS</i>and<i>EGFR</i>mutations in nonsmall cell lung cancer: the EUELC cohort
Authors: Chiara Scoccianti, Aurélien Vesin, Ghislaine Martel, Magali Olivier, Elisabeth Brambilla, Jean-François Timsit, Luca Tavecchio, Christian Brambilla, John K. Field, Pierre Hainaut
Journal: European Respiratory Journal (2012)

Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in the TP53 , KRAS and EGFR genes. The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues. TP53 mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p&lt;0.0001). TP53 mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second primary lung cancer or recurrence/metastasis (progressive disease). EGFR mutations were almost exclusively found in never-smoking females (p=0.0067). KRAS mutations were detected in 18.5% of cases, mainly ADC (p&lt;0.0001), and showed a tendency toward association with progressive disease status. These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception of KRAS mutation, which may have a prognostic value in ADC.
Classical Hodgkin lymphoma is characterized by high constitutive expression of activating transcription factor 3 (ATF3), which promotes viability of Hodgkin/Reed-Sternberg cells
Authors: Martin Janz, Michael Hummel, Matthias Truss, Brigitte Wollert-Wulf, Stephan Mathas, Korinna Jöhrens, Christian Hagemeier, Kurt Bommert, Harald Stein, Bernd Dörken, Ralf C. Bargou
Journal: Blood (2005)
Effect of different physiotherapy devices on ventilation distribution in adults with cystic fibrosis
Authors: Markus Wettstein, Thomas Riedel
Journal: European Respiratory Journal (2013)

Background: Respiratory Physiotherapy (RPT) is a mainstay in the treatment of cystic fibrosis. In a previous study we showed distinct differences in ventilation distribution between RPT devices in healthy adults. (Roelli A. et al. Eur Respir J 2010; 36 (Suppl 54) abstract) 

Aim: The main aim of the present study was to compare the effect of different RPT devices on gravity-dependent ventilation distribution in adults with cystic fibrosis (CF) and in healthy adults (healthy).

Methods: In 9 adults with CF and in 11 healthy adults electrical impedance tomography (EIT) measurements were performed during spontaneous breathing, continuous positive airway pressure (CPAP) and positive expiratory pressure (PEP) in upright and right lateral position. Spatial ventilation distribution was assessed.

Results: In upright position the right and the left lung were equally ventilated in both groups (right lung: mean (SD) 51% (1%) healthy, 53% (10%) CF). During spontaneous breathing in right lateral position the proportion of ventilation directed to the right, dependent lung significantly increased to 64%(2%) (p<0.01) in healthy and to 65%(16%) (p<0.01) in CF. This effect was enhanced with CPAP (70% (7%) (p<0.05) healthy, 74% (15%) (p=0.05) CF). but neutralized with PEP (49% (5%) (p<0.01) healthy, 58% (16%) (p<0.01) CF).

Conclusions: PEP shows distinct differences to CPAP and spontaneous breathing with respect to their impact on gravitational ventilation distribution in CF similar to healthy adults. Different RPT devices cannot be used interchangeably. CF shows a higher inter-subject variability in ventilation distribution most likely due to differences in severity of the lung disease.
Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains
Authors: Daniel Sauter, Michael Schindler, Anke Specht, Wilmina N. Landford, Jan Münch, Kyeong-Ae Kim, Jörg Votteler, Ulrich Schubert, Frederic Bibollet-Ruche, Brandon F. Keele, Jun Takehisa, Yudelca Ogando, Christina Ochsenbauer, John C. Kappes, Ahidjo Ayouba, Martine Peeters, Gerald H. Learn, George Shaw, Paul M. Sharp, Paul Bieniasz, Beatrice H. Hahn, Theodora Hatziioannou, Frank Kirchhoff
Journal: Cell Host & Microbe (2009)
THE TREATMENT OF CARVERNOUS HAEMANGIOMA WITH TOPICAL BETAMETHASONE 17 VALERATE
Authors: G. Weber
Journal: British Journal of Dermatology (1973)

Journal Article THE TREATMENT OF CARVERNOUS HAEMANGIOMA WITH TOPICAL BETAMETHASONE 17 VALERATE Get access G. Weber G. Weber Skin Clinic City Hospital 85 Nurnberg 5 Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 89, Issue 6, 1 December 1973, Pages 649–651, https://doi.org/10.1111/j.1365-2133.1973.tb07596.x Published: 01 December 1973
Expressed Sequence Tag-Linked Microsatellites as a Source of Gene-Associated Polymorphisms for Detecting Signatures of Divergent Selection in Atlantic Salmon (Salmo salar L.)
Authors: Anti Vasemägi, Jan Nilsson, Craig R. Primmer
Journal: Molecular Biology and Evolution (2005)

The prediction that selection affects the genome in a locus-specific way also affecting flanking neutral variation, known as genetic hitchhiking, enables the use of polymorphic markers in noncoding regions to detect the footprints of selection. However, as the strength of the selective footprint on a locus depends on the distance from the selected site and will decay with time due to recombination, the utilization of polymorphic markers closely linked to coding regions of the genome should increase the probability of detecting the footprints of selection as more gene-containing regions are covered. The occurrence of highly polymorphic microsatellites in the untranslated regions of expressed sequence tags (ESTs) is a potentially useful source of gene-associated polymorphisms which has thus far not been utilized for genome screens in natural populations. In this study, we searched for the genetic signatures of divergent selection by screening 95 genomic and EST-derived mini- and microsatellites in eight natural Atlantic salmon, Salmo salar L., populations from different spatial scales inhabiting contrasting natural environments (salt-, brackish, and freshwater habitat). Altogether, we identified nine EST-associated microsatellites, which exhibited highly significant deviations from the neutral expectations using different statistical methods at various spatial scales and showed similar trends in separate population samples from different environments (salt-, brackish, and freshwater habitats) and sea areas (Barents vs. White Sea). We consider these ESTs as the best candidate loci affected by divergent selection, and hence, they serve as promising genes associated with adaptive divergence in Atlantic salmon. Our results demonstrate that EST-linked microsatellite genome scans provide an efficient strategy for discovering functional polymorphisms, especially in nonmodel organisms.
ABVD in Older Patients With Early-Stage Hodgkin Lymphoma Treated Within the German Hodgkin Study Group HD10 and HD11 Trials
Authors: Boris Böll, Helen Görgen, Michael Fuchs, Annette Pluetschow, Hans Theodor Eich, Mario J. Bargetzi, Eckhart Weidmann, Christian Junghanß, Richard Greil, Alexander Scherpe, Oliver Schmalz, Dennis A. Eichenauer, Bastian von Tresckow, Achim Rothe, Volker Diehl, Andreas Engert, Peter Borchmann
Journal: Journal of Clinical Oncology (2013)

Purpose Older patients with Hodgkin lymphoma (HL) account for approximately 20% of all HL patients. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy is regarded as standard of care in these patients. However, little is known on feasibility and efficacy of ABVD in this age group. Patients and Methods We analyzed the feasibility and efficacy of four cycles of ABVD in older patients age 60 to 75 years with early-stage HL who were treated within the German Hodgkin Study Group (GHSG) HD10 and HD11 trials; results were compared with those of younger patients treated within these trials. Results In total, 1,299 patients received four cycles of ABVD, and 117 of those patients were older than age 60 years (median, 65 years). In 14% of older patients, treatment was not administered according to protocol, mainly because of excessive toxicity. The mean delay of treatment was twice as high in the older patients (2.2 v 1.2 weeks). Fifty-nine percent of older patients achieved a relative dose-intensity of at least 80% compared with 85% of younger patients. Major toxicity (WHO grade 3 and 4), including leucopenia, nausea, infection, and others, was documented in 68% of older patients with a treatment-related mortality of 5%. Complete response was achieved in 89% of older patients, 3% had progressive disease, and 11% relapsed. At a median observation time of 92 months, 28% of the patients had died, and the 5-year progression-free survival estimate was 75% (95% CI, 66% to 82%). Conclusion In patients age ≥ 60 years with HL, four cycles of ABVD is associated with substantial dose reduction, treatment delay, toxicity, and treatment-related mortality.
N-terminal domain of soluble epoxide hydrolase negatively regulates the VEGF-mediated activation of endothelial nitric oxide synthase
Authors: Hsin-Han Hou, Bruce D. Hammock, Kou-Hui Su, Christophe Morisseau, Yu Ru Kou, Susumu Imaoka, Ami Oguro, Song-Kun Shyue, Jin-Feng Zhao, Tzong-Shyuan Lee
Journal: Cardiovascular Research (2011)

The mammalian soluble epoxide hydrolase (sEH) has both an epoxide hydrolase and a phosphatase domain. The role of sEH hydrolase activity in the metabolism of epoxyeicosatrienoic acids (EETs) and the activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) has been well defined. However, far less is known about the role of sEH phosphatase activity in eNOS activation. In the present study, we investigated whether the phosphatase domain of sEH was involved in the eNOS activation in ECs. The level of eNOS phosphorylation in aortas is higher in the sEH knockout (sEH−/−) mice than in wild-type mice. In ECs, pharmacological inhibition of sEH phosphatase or overexpressing sEH with an inactive phosphatase domain enhanced vascular endothelial growth factor (VEGF)-induced NO production and eNOS phosphorylation. In contrast, overexpressing the phosphatase domain of sEH prevented the VEGF-mediated NO production and eNOS phosphorylation at Ser617, Ser635, and Ser1179. Additionally, treatment with VEGF induced a c-Src kinase-dependent increase in transient tyrosine phosphorylation of sEH and the formation of a sEH–eNOS complex, which was abolished by treatment with a c-Src kinase inhibitor, PP1, or the c-Src dominant-negative mutant K298M. We also demonstrated that the phosphatase domain of sEH played a key role in VEGF-induced angiogenesis by detecting the tube formation in ECs and neovascularization in Matrigel plugs in mice. In addition to epoxide hydrolase activity, phosphatase activity of sEH plays a pivotal role in the regulation of eNOS activity and NO-mediated EC functions.
Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury
Authors: Leo Timmers, José P.S. Henriques, Dominique P.V. de Kleijn, J. Hans DeVries, Hans Kemperman, Paul Steendijk, Cees W.J. Verlaan, Marjolein Kerver, Jan J. Piek, Pieter A. Doevendans, Gerard Pasterkamp, Imo E. Hoefer
Journal: Journal of the American College of Cardiology (2009)
Aclidinium inhibits human lung fibroblast to myofibroblast transition
Authors: Javier Milara, Adela Serrano, Teresa Peiró, Amadeu Gavaldà, Montserrat Miralpeix, Esteban Jesús Morcillo, Julio Cortijo
Journal: Thorax (2011)

<h3>Background</h3> Fibroblast to myofibroblast transition is believed to contribute to airway remodelling in lung diseases such as asthma and chronic obstructive pulmonary disease. This study examines the role of aclidinium, a new long-acting muscarinic antagonist, on human fibroblast to myofibroblast transition. <h3>Methods</h3> Human bronchial fibroblasts were stimulated with carbachol (10<sup>−8</sup> to 10<sup>−5</sup> M) or transforming growth factor-β1 (TGF-β1; 2 ng/ml) in the presence or absence of aclidinium (10<sup>−9</sup> to 10<sup>−7</sup> M) or different drug modulators for 48 h. Characterisation of myofibroblasts was performed by analysis of collagen type I and α-smooth muscle actin (α-SMA) mRNA and protein expression as well as α-SMA microfilament immunofluorescence. ERK1/2 phosphorylation, RhoA-GTP and muscarinic receptors (M) 1, 2 and 3 protein expression were determined by western blot analysis and adenosine 3′-5′ cyclic monophosphate levels were determined by ELISA. Proliferation and migration of fibroblasts were also assessed. <h3>Results</h3> Collagen type I and α-SMA mRNA and protein expression, as well as percentage α-SMA microfilament-positive cells, were upregulated in a similar way by carbachol and TGF-β1, and aclidinium reversed these effects. Carbachol-induced myofibroblast transition was mediated by an increase in ERK1/2 phosphorylation, RhoA-GTP activation and cyclic monophosphate downregulation as well as by the autocrine TGF-β1 release, which were effectively reduced by aclidinium. TGF-β1 activated the non-neuronal cholinergic system. Suppression of M1, M2 or M3 partially prevented carbachol- and TGF-β1-induced myofibroblast transition. Aclidinium dose-dependently reduced fibroblast proliferation and migration. <h3>Conclusion</h3> Aclidinium inhibits human lung fibroblast to myofibrobast transition.
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis
Authors: Nanna B Finnerup, Nadine Attal, Simon Haroutounian, Ewan McNicol, Ralf Baron, Robert H Dworkin, Ian Gilron, Maija Haanpää, Per Hansson, Troels S Jensen, Peter R Kamerman, Karen Lund, Andrew Moore, Srinivasa N Raja, Andrew S C Rice, Michael Rowbotham, Emily Sena, Philip Siddall, Blair H Smith, Mark Wallace
Journal: The Lancet Neurology (2015)
Circuit weight training and cardiac morphology: a trial with magnetic resonance imaging
Authors: M D Camargo, R Stein, J P Ribeiro, P R Schvartzman, M O Rizzatti, B D Schaan
Journal: British Journal of Sports Medicine (2007)

Aerobic training (AT) and circuit weight training (CWT) improve peak oxygen uptake (VO(2)peak). During CWT the circulatory system is exposed to higher pressure, which could induce left ventricle morphological adaptations, possibly distinct from those derived from aerobic training.To compare the effects of aerobic training and CWT upon morphological and functional cardiac adaptations detected by magnetic resonance imaging.Twenty healthy sedentary individuals were randomly assigned to participate in a 12-week programme of aerobic training (n = 6), CWR (n = 7) or no intervention (n = 7, controls). Training programmes consisted of 36 sessions, 35 min each, 3 times per week, at 70% of maximal heart rate, and CWT included series of resistance exercises performed at 60% of 1 maximal repetition. Cardiopulmonary exercise testing and cardiac magnetic resonance imaging were performed before and after the intervention.There was a similar improvement in VO(2)peak following aerobic training (mean (SD) increment: 12 (4)%) and CWT (12 (4)%), while there was no change in the control group. Aerobic training (12 (6)%) and CWT (16 (5)%) improved strength in the lower limbs, and only CWT resulted in improvement of 13 (4)% in the strength of the upper limbs. However, there were no detectable changes in left ventricular mass, end-diastolic volume, stroke volume or ejection fraction.In previously sedentary individuals, short-term CWT and aerobic training induce similar improvement in functional capacity without any adaptation in cardiac morphology detectable by cardiac magnetic resonance imaging.