tbuckley/cabot-search huggingface dataset:
Antitumor Effects of a Combined 5-Aza-2′Deoxycytidine and Valproic Acid Treatment on Rhabdomyosarcoma and Medulloblastoma in <i>Ptch</i> Mutant Mice
Authors: Ines Ecke, Frauke Petry, Albert Rosenberger, Svantje Tauber, Sven Mönkemeyer, Ina Hess, Christian Dullin, Sarah Kimmina, Judith Pirngruber, Steven A. Johnsen, Anja Uhmann, Frauke Nitzki, Leszek Wojnowski, Walter Schulz-Schaeffer, Olaf Witt, Heidi Hahn
Journal: Cancer Research (2009)

Patched (Ptch) heterozygous mice develop medulloblastoma (MB) and rhabdomyosarcoma (RMS) resembling the corresponding human tumors. We have previously shown that epigenetic silencing of the intact Ptch allele contributes to tumor formation in this model. Here, we investigated whether targeting of epigenetic silencing mechanisms could be useful in the treatment of Ptch-associated cancers. A reduction of endogenous DNA methyltransferase1 (Dnmt1) activity significantly reduced tumor incidence in heterozygous Ptch knockout mice. A combined treatment with the Dnmt inhibitor 5-aza-2'deoxycytidine (5-aza-dC) and the histone deacetlyase (HDAC) inhibitor valproic acid (VPA) efficiently prevented MB and RMS formation, whereas monotherapies with either drug were less effective. Wild-type Ptch expression was efficiently reactivated in tumors by 5-aza-dC/VPA combination therapy. This was associated with reduced methylation of the Ptch promoter and induction of histone hyperacetylation suggesting inhibition of HDACs in vivo. However, the treatment was not effective in clinically overt, advanced stage tumors. This is a first in vivo demonstration that targeting of Dnmt and HDAC activities is highly effective in preventing formation of Ptch-associated tumors. The results suggest a novel clinical strategy for consolidation therapy of corresponding tumors in humans after completion of conventional treatment. Our data also suggest that epigenetic therapy may be less effective in treating advanced stages of tumors, at least in this tumor model.
Optical recordings of the effect of electrical stimulation on action potential repolarization and the induction of reentry in two-dimensional perfused rabbit epicardium.
Authors: S B Knisley, B C Hill
Journal: Circulation (1993)

BACKGROUND Prolonged membrane depolarization induced by an electric shock in the heart may produce propagation block leading to repetitive beats. We studied prolonged depolarization and its role in repetitive beats in a thin epicardial layer of endocardially prefrozen arterially perfused rabbit heart. METHODS AND RESULTS A laser scanner recorded optical action potentials at 63 sites within a 1-cm2 area on the left ventricle of hearts stained with potentiometric fluorescent dye. Pacing (S1) produced propagation across the myofibers; then, a 3-millisecond shock (S2) given in the S1 refractory period produced an electric field that decreased in strength with distance along the fibers. The S2 strengths at the center of the scanned region (C) were 2.1 +/- 0.2 or 5.6 +/- 0.3 V/cm (mean +/- SD, n = 4). Repetitive beats occurred in 50% of hearts when C was 2.1 V/cm and in 100% of hearts when C was 5.6 V/cm. With each occurrence of repetitive beats, prolonged depolarization of the shocked action potential occurred within 1 mm of the S2 electrode when C was 2.1 V/cm and within 3 mm when C was 5.6 V/cm. Transient block immediately after S2 occurred between tissue with prolonged depolarization (S2 strength, 6 to 9 V/cm) and tissue without prolonged depolarization (S2 strength, 1 to 3 V/cm). Propagation in the scanned region after S2 occurred first on the side of the block distal to the S2 electrode, propagated from the most recovered to the least recovered tissue, and then turned toward the S2 electrode. When C was 5.6 V/cm, reentry by retrograde propagation near the S2 electrode produced repetitive beats. The center of the reentrant circuit exhibited further transient block and small depolarizations associated with the circulating activation. CONCLUSIONS Prolonged depolarization occurs where the S2 strength is more than 6 V/cm, block occurs between regions of prolonged depolarization and no prolonged depolarization, and reentry occurs around the block. Shock-induced prolonged depolarization can be proarrhythmic and may account for electrically induced arrhythmias.
Lower SNIP value is correlated to the need of intubation in amyotrophic lateral sclerosis
Authors: Pierluigi Carratù, Anna Cassano, Giuseppina D'Alba, Vitaliano N. Quaranta, Rosa Capozzo, Felice Gadaleta, Silvano Dragonieri, Isabella L. Simone, Giancarlo Logroscino, Onofrio Resta
Journal: European Respiratory Journal (2011)

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease which usually leads to respiratory failure, requiring Noninvasive Ventilation (NIV) or tracheostomy. No data exist on predictor factors of tracheostomy at the clinical onset of disease.

A retrospective study was designed, in a population of 71 consecutive ALS patients (39 males), to evaluate anthropometric, clinical, and functional indicators of the need of tracheostomy, including age, sex, BMI, site of onset, time of diagnosis, co-morbidities, tobacco habit, traumas, sport activity, and sleep disorder breathing markers. Arterial Blood Gas analysis and respiratory functional test, including FVC, FEV1, as well as Sniff Nasal Inspiratory Pressure (SNIP) were also measured at first ambulatory control.

We found that SNIP test, at first control, positively correlated to the need of tracheostomy (p<0.001) in the entire population observed. The mean SNIP test value of the group who was admitted to tracheostomy was 25.12 (14.25) compared to a mean SNIP value of 54 (25.46) in the group who did not undergo tracheostomy. Other anthropometric, clinical, functional, and nocturnal parameters evaluated did not correlate to the different outcome in our population of ALS patients.

In conclusion, SNIP test could be a useful early indicator of tracheostomy in ALS patients.
Predictors of Elevated Nuclear Factor-κB–dependent Genes in Obstructive Sleep Apnea Syndrome
Authors: Silke Ryan, Cormac T. Taylor, Walter T. McNicholas
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Background: Circulating nuclear factor-κB (NF-κB)–dependent genes, particularly tumor necrosis factor-α (TNF-α), are elevated in obstructive sleep apnea syndrome (OSAS) and likely contribute to cardiovascular disease. Furthermore, TNF-α is associated with excessive daytime sleepiness. We investigated the predictors of TNF-α and related genes in large, well-selected cohorts of subjects with OSAS and control subjects.Methods: We performed a prospective study of 30 subjects who did not have OSAS (22 nonsleepy normal control subjects and 8 sleepy nonapneic subjects who snored), 36 subjects with mild to moderate OSAS, and 31 subjects with severe OSAS; all subjects were male. Groups were matched for age, body mass index, and other relevant variables. Subjects had no other disease and were not regularly taking medication. All had serum for TNF-α and related assays drawn after polysomnography. A total of 49 suitable subjects were treated with continuous positive airway pressure (CPAP); sleep studies together with serum assays were repeated 6 wk later.Results: TNF-α levels were higher in subjects with OSAS than in subjects without OSAS (p < 0.001). In multivariate analysis, TNF-α was independently associated with the desaturation index (r = 0.399, p < 0.001), Epworth Sleepiness Score (r = 0.243, p = 0.005), and cholesterol (r = 0.216, p = 0.018). Furthermore, TNF-α levels were higher in sleepy nonapneic subjects who snored than in normal control subjects (p = 0.002) but lower than in subjects with OSAS (p = 0.03). CPAP therapy lowered TNF-α levels (p = 0.004). Another NF-κB–dependent cytokine, interleukin-8 (IL-8), showed similar differences between groups and after CPAP therapy, but a range of other mediators of inflammation, including IL-1, IL-6, IL-10, and IL-12, showed no differences.Conclusion: Intermittent hypoxia is the strongest predictor of TNF-α levels, supporting a role for inflammation in the cardiovascular pathophysiology of OSAS. Furthermore, TNF-α levels are independently associated with excessive daytime sleepiness.
Arginase-Producing Myeloid Suppressor Cells in Renal Cell Carcinoma Patients: A Mechanism of Tumor Evasion
Authors: Arnold H. Zea, Paulo C. Rodriguez, Michael B. Atkins, Claudia Hernandez, Sabina Signoretti, Jovanny Zabaleta, David McDermott, David Quiceno, Amanda Youmans, Anne O'Neill, James Mier, Augusto C. Ochoa
Journal: Cancer Research (2005)

Abstract Myeloid suppressor cells with high arginase activity are found in tumors and spleen of mice with colon and lung cancer. These cells, described as macrophages or immature dendritic cells, deplete arginine and impair T cell proliferation and cytokine production. Although arginase activity has been described in cancer patients, it is thought to originate from tumor cells metabolizing arginine to ornithine needed to sustain rapid cell proliferation. The goal of this study was to determine whether myeloid suppressor cells producing high arginase existed in renal cell carcinoma patients. Peripheral blood mononuclear cells from 123 patients with metastatic renal cell carcinoma, prior to treatment, were found to have a significantly increased arginase activity. These patients had a markedly decreased cytokine production and expressed low levels of T cell receptor CD3ζ chain. Cell separation studies showed that the increased arginase activity was limited to a specific subset of CD11b+, CD14−, CD15+ cells with a polymorphonuclear granulocyte morphology and markers, instead of macrophages or dendritic cells described in mouse models. Furthermore, these patients had low levels of arginine and high levels of ornithine in plasma. Depletion of the CD11b+, CD14− myeloid suppressor cells reestablished T cell proliferation and CD3ζ chain expression. These results showed, for the first time, the existence of suppressor myeloid cells producing arginase in human cancer patients. In addition, it supports the concept that blocking arginase may be an important step in the success of immunotherapy.
Autophagy Plays a Critical Role in the Degradation of Active RHOA, the Control of Cell Cytokinesis, and Genomic Stability
Authors: Amine Belaid, Michaël Cerezo, Abderrahman Chargui, Elisabeth Corcelle–Termeau, Florence Pedeutour, Sandy Giuliano, Marius Ilie, Isabelle Rubera, Michel Tauc, Sophie Barale, Corinne Bertolotto, Patrick Brest, Valérie Vouret-Craviari, Daniel J. Klionsky, Georges F. Carle, Paul Hofman, Baharia Mograbi
Journal: Cancer Research (2013)

Degradation of signaling proteins is one of the most powerful tumor-suppressive mechanisms by which a cell can control its own growth. Here, we identify RHOA as the molecular target by which autophagy maintains genomic stability. Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy. Underlying this phenotype, active RHOA is sequestered via p62 (SQSTM1) within autolysosomes and fails to localize to the plasma membrane or to the spindle midbody. Conversely, inhibition of autophagosome formation by ATG5 shRNA dramatically increases localization of active RHOA at the midbody, followed by diffusion to the flanking zones. As a result, all of the approaches we examined that compromise autophagy (irrespective of the defect: autophagosome formation, sequestration, or degradation) drive cytokinesis failure, multinucleation, and aneuploidy, processes that directly have an impact upon cancer progression. Consistently, we report a positive correlation between autophagy defects and the higher expression of RHOA in human lung carcinoma. We therefore propose that autophagy may act, in part, as a safeguard mechanism that degrades and thereby maintains the appropriate level of active RHOA at the midbody for faithful completion of cytokinesis and genome inheritance.
Membrane Estrogen Receptor Engagement Activates Endothelial Nitric Oxide Synthase via the PI3-Kinase–Akt Pathway in Human Endothelial Cells
Authors: M. Page Haynes, Diviya Sinha, Kerry Strong Russell, Mark Collinge, David Fulton, Manuel Morales-Ruiz, William C. Sessa, Jeffrey R. Bender
Journal: Circulation Research (2000)

17beta-Estradiol (E(2)) is a rapid activator of endothelial nitric oxide synthase (eNOS). The product of this activation event, NO, is a fundamental determinant of cardiovascular homeostasis. We previously demonstrated that E(2)-stimulated endothelial NO release can occur without an increase in cytosolic Ca(2+). Here we demonstrate for the first time, to our knowledge, that E(2) rapidly induces phosphorylation and activation of eNOS through the phosphatidylinositol 3 (PI3)-kinase-Akt pathway. E(2) treatment (10 ng/mL) of the human endothelial cell line, EA.hy926, resulted in increased NO production, which was abrogated by the PI3-kinase inhibitor, LY294002, and the estrogen receptor antagonist ICI 182, 780. E(2) stimulated rapid Akt phosphorylation on serine 473. As has been shown for vascular endothelial growth factor, eNOS is an E(2)-activated Akt substrate, demonstrated by rapid eNOS phosphorylation on serine 1177, a critical residue for eNOS activation and enhanced sensitivity to resting cellular Ca(2+) levels. Adenoviral-mediated EA.hy926 transduction confirmed functional involvement of Akt, because a kinase-deficient, dominant-negative Akt abolished E(2)-stimulated NO release. The membrane-impermeant E(2)BSA conjugate, shown to bind endothelial cell membrane sites, also induced rapid Akt and consequent eNOS phosphorylation. Thus, engagement of membrane estrogen receptors results in rapid endothelial NO release through a PI3-kinase-Akt-dependent pathway. This explains, in part, the reduced requirement for cytosolic Ca(2+) fluxes and describes an important pathway relevant to cardiovascular pathophysiology.
A one-dimensional viscoelastic model of cat heart muscle studied by small length perturbations during isometric contraction.
Authors: L Loeffler, K Sagawa
Journal: Circulation Research (1975)

To develop a model of heart muscle, we studied cat papillary muscle contracting in a quasi-isometric condition under a fixed inotropic state. The properties of resting muscle were determined by using a step stretch of less than 1.2% of Lmax for initial lengths from 85 to 100% Lmax. The passive force response suggested the model of the passive branch (Fig. 1). All five parameters were small at muscle lengths below 95% of Lmax but increased markedly at longer lengths. The properties of contracting muscle were studied with a sinusoidal length change (amplitude less than 0.15% of Lmax, frequency 0.1-35.0 Hz). The frequency response of active (total minus passive) stiffness suggested the model of the active branch (Fig. 1). We determined the dependency of the elastic elements (K, Ks) and the viscous element (C) on length and time by recording the frequency response at various combinations of length and time Ks varied linearly with active force (FA). K and C exhibited time courses that paralleled FA up to 0.6tmax, and they maintained their values until 1.4tmax. K then fell toward zero, whereas C exhibited a secondary rise before it fell toward zero. K was dependent of length up to 95% of Lmax and then began to decline, but C varied in proportion to muscle length.
Chemokines and cardiovascular diseases
Authors: S Sasayama
Journal: Cardiovascular Research (2000)

See article by Damas et al. [16] ( pages 428 -436) inty may result in their adsorption onto endothelial cell this issue.lining of the blood vessels, connective tissues and cell matrices.Thus, chemokines immobilized on tissue or matrix surfaces may induce ''haptotactic'' migration of
Pseudomonas aeruginosa accentuates epithelial-to-mesenchymal transition in the airway
Authors: L. A. Borthwick, S. S. Sunny, V. Oliphant, J. Perry, M. Brodlie, G. E. Johnson, C. Ward, K. Gould, P. A. Corris, A. De Soyza, A. J. Fisher
Journal: European Respiratory Journal (2010)

Epithelial-to-mesenchymal transition (EMT) has been implicated in the dysregulated epithelial wound repair that contributes to obliterative bronchiolitis (OB) after lung transplantation. Acquisition of <i>Pseudomonas aeruginosa</i> in the transplanted airway has been shown to be a risk factor for the development of OB. We investigated the potential of <i>P. aeruginosa</i> to drive EMT in primary bronchial epithelial cells (PBECs) isolated from lung transplant recipients. Changes in the expression of epithelial and mesenchymal markers was assessed in cells challenged with clinical isolates of <i>P. aeruginosa</i> or co-cultured with <i>P. aeruginosa</i>-activated monocytic cells (THP-1) in the presence or absence of transforming growth factor (TGF)-β1. <i>P. aeruginosa</i> did not drive or accentuate TGF-β1-driven EMT directly. Co-culturing <i>P. aeruginosa</i>-activated THP-1 cells with PBECs did not drive EMT. However, co-culturing <i>P. aeruginosa</i>-activated THP-1 cells with PBECs significantly accentuated TGF-β1-driven EMT. <i>P. aeruginosa</i>, <i>via</i> the activation of monocytic cells, can accentuate TGF-β1-driven EMT. These <i>in vitro</i> observations may help explain the <i>in vivo</i> clinical observation of a link between acquisition of <i>P. aeruginosa</i> and an increased risk of developing OB.
Community-acquired pneumonia in pediatric patients: New diagnostic priorities
Authors: Zoia Nesterenko, Olena Ivanina
Journal: European Respiratory Journal (2012)

Background: High incidence of childhood community-acquired pneumonia (CAP), changes in CAP manifestations, reduced significance of classical diagnostic criteria, leading to inadequate treatment, work against lowering risk of complications and mortality.  Aim: To study the features of actual clinical course of pediatric CAP.  Methods: 64 patients aged 1-18 years, with clinically and radiographically diagnosed CAP with detection of serum antibodies against intracellular pathogens, were followed up for 12 months. Patients were divided into two age groups: aged 1-4 (group A, n = 24) and 5-18 (group B, n= 40). All patients had numerous phenotypic signs of heritable connective tissue disorders (HCTD).  Results: All patients had indistinct clinical manifestations. Recurrent course of CAP was in 54(84.4%) patients. CAP caused by Chlamydophila pneumonia (Cp) was more frequent in group A – in 23 patients (95.9% of the group), by Mycoplasma pneumonia (Mp) - in group B, in 37 patients (92.5% of the group).  Asthma was diagnosed in 29(45.3%) patients mainly of group B, with recurrent CAP in 34.5% of asthmatic patients; 62.1% of them had pulmonary hypertension (PH), 6.7% - CT signs of bullous emphysema (BE).  Conclusions: 1. Close relationship between HCTD and CAP is revealed. 2. Cp-CAP was more frequent in pediatric patients up to 4 years old, Mp-CAP - in children 5 years and older. 3. Recurrent CAP was the cause of asthma exacerbation in one-third of patients with asthma and CAP. 4. Asthma in children with CAP and HCTD was more severe with development of PH, BE.
Prevalence of Self-reported Skin Complaints and Avoidance of Common Daily Life Consumer Products in Selected European Regions
Authors: Luigi Naldi, Simone Cazzaniga, Margarida Gonçalo, Thomas Diepgen, Magnus Bruze, Peter Elsner, Peter J. Coenraads, Åke Svensson, Paola Bertuccio, Robert Ofenloch
Journal: JAMA Dermatology (2014)

IMPORTANCESkin disorders are common in the general population, and they may be associated with significant disability.The use of daily skin products may affect the appearance and severity of skin conditions.OBJECTIVES To assess the prevalence of reported itchy rash lasting longer than 3 days among the general population and to evaluate lifetime avoidance of different types of consumer products because of skin problems. DESIGN, SETTING, AND PARTICIPANTSThe European Dermato-Epidemiology Network (EDEN) Fragrance Study comprised a large descriptive epidemiological survey of the general population conducted in 6 European regions from August 20, 2008, to October 10, 2011.Participants were a random sample of individuals aged 18 to 74 years, based on electoral precincts.The participants were interviewed using a standardized questionnaire.EXPOSURES Lifetime exposure to products of common use was considered, including toiletry items that remained on the skin or were rinsed off and household and functional items. MAIN OUTCOMES AND MEASURESThe 1-month, 1-year, and lifetime age-standardized prevalence rates of itchy rash that lasted longer than 3 days. RESULTSIn total, 12 377 individuals (53.9% female; median age, 43 years) were interviewed.The overall prevalences of itchy rash were 19.3% (95% CI, 18.6%-20.0%)during the month preceding the interview, 31.8% (95% CI, 31.0%-32.6%)during the preceding year, and 51.7% (95% CI, 50.8%-52.6%)over a lifetime.In addition, the percentage of individuals who reported avoidance of any product varied from 37.0% for products intended to be left on the skin to 17.7% for household or functional products.CONCLUSIONS AND RELEVANCE Our findings confirmed the magnitude of skin problems among the general population reported in other surveys.Although itchy rash is a nonspecific manifestation, it may be considered in epidemiological surveys to reflect a constellation of skin conditions and to summarize the burden of these conditions on general health.
Deubiquitinase Inhibition by Small-Molecule WP1130 Triggers Aggresome Formation and Tumor Cell Apoptosis
Authors: Vaibhav Kapuria, Luke F. Peterson, Dexing Fang, William G. Bornmann, Moshe Talpaz, Nicholas J. Donato
Journal: Cancer Research (2010)

Abstract Recent evidence suggests that several deubiquitinases (DUB) are overexpressed or activated in tumor cells and many contribute to the transformed phenotype. Agents with DUB inhibitory activity may therefore have therapeutic value. In this study, we describe the mechanism of action of WP1130, a small molecule derived from a compound with Janus-activated kinase 2 (JAK2) kinase inhibitory activity. WP1130 induces rapid accumulation of polyubiquitinated (K48/K63-linked) proteins into juxtanuclear aggresomes, without affecting 20S proteasome activity. WP1130 acts as a partly selective DUB inhibitor, directly inhibiting DUB activity of USP9x, USP5, USP14, and UCH37, which are known to regulate survival protein stability and 26S proteasome function. WP1130-mediated inhibition of tumor-activated DUBs results in downregulation of antiapoptotic and upregulation of proapoptotic proteins, such as MCL-1 and p53. Our results show that chemical modification of a previously described JAK2 inhibitor results in the unexpected discovery of a novel DUB inhibitor with a unique antitumor mechanism. Cancer Res; 70(22); 9265–76. ©2010 AACR.