tbuckley/cabot-search huggingface dataset:
A HIF-1 network reveals characteristics of epithelial-mesenchymal transition in acute promyelocytic leukemia
Authors: Stefano Percio, Nadia Coltella, Sara Grisanti, Rosa Bernardi, Linda Pattini
Journal: Genome Medicine (2014)

Acute promyelocytic leukemia (APL) is a sub-type of acute myeloid leukemia (AML) characterized by a block of myeloid differentiation at the promyelocytic stage and the predominant t(15:17) chromosomal translocation. We have previously determined that cells from APL patients show increased expression of genes regulated by hypoxia-inducible transcription factors (HIFs) compared to normal promyelocytes. HIFs regulate crucial aspects of solid tumor progression and are currently being implicated in leukemogenesis.To investigate the contribution of hypoxia-related signaling in APL compared to other AML sub-types, we reverse engineered a transcriptional network from gene expression profiles of AML patients' samples, starting from a list of direct target genes of HIF-1. A HIF-1-dependent subnetwork of genes specifically dysregulated in APL was derived from the comparison between APL and other AMLs.Interestingly, this subnetwork shows a unique involvement of genes related to extracellular matrix interaction and cell migration, with decreased expression of genes involved in cell adhesion and increased expression of genes implicated in motility and invasion, thus unveiling the presence of characteristics of epithelial-mesenchymal transition (EMT). We observed that the genes of this subnetwork, whose dysregulation shows a peculiar pattern across different AML sub-types, distinguish malignant from normal promyelocytes, thus ruling out dependence on a myeloid developmental stage. Also, expression of these genes is reversed upon treatment of APL-derived NB4 cells with all-trans retinoic acid and cell differentiation.Our data suggest that pathways related to EMT-like processes can be implicated also in hematological malignancies besides solid tumors, and can identify specific AML sub-types.
Variables controlling the secretion of a somatomedin-like peptide by cultured porcine smooth muscle cells.
Authors: D R Clemmons
Journal: Circulation Research (1985)

Somatomedin-C, a peptide growth factor that is also termed insulin-like growth factor I, stimulates smooth muscle cell replication; however, these cells proliferate in somatomedin-C-deficient medium. We postulated, therefore, that these cells might release a somatomedin-like molecule into the surrounding culture medium. Porcine aortic smooth muscle cells that were exposed to serum-free Dulbecco's modified minimum essential medium for 24 hours were found to release a somatomedin-like molecule that could be detected by a specific radioimmunoassay for somatomedin-C. Several variables in the design of tissue culture conditions were found to regulate the secretion of the somatomedin-like peptide. There was an inverse relationship between somatomedin-like peptide secretion and culture density. Cultures grown to a density of 110,000 cells/well secreted 0.18 +/- 0.02 U/ml per 10(5) cells, whereas cultures grown to 38,000 cells/well secreted 0.59 +/- 0.06 U/ml per 10(5) cells (P less than 0.001). Serum deprivation and days of preincubation before initiation of an experiment were found to influence somatomedin-like peptide secretion significantly. Platelet-derived growth factor, which stimulates smooth muscle cell replication, was a potent stimulant of somatomedin-like peptide secretion. Exposure to a concentration of 500 ng/ml platelet-derived growth factor induced a 2.8-fold increase in somatomedin-like peptide secretion over basal levels, (i.e., 0.37 +/- 0.05 to 0.98 +/- 0.7 U/ml, P less than 0.001). The effect of platelet-derived growth factor was enhanced (41% increase) by concomitant incubation with 1% somatomedin-C-deficient platelet poor plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Reversal of 5-Fluorouracil-Induced Myelosuppression by Prolonged Administration of High-Dose Uridine
Authors: C.J. v. Groeningen, G.J. Peters, A. Leyva, E. Laurensse, H.M. Pinedo
Journal: JNCI Journal of the National Cancer Institute (1989)

The effect of high-dose uridine on 5-fluorouracil (5-FU)-induced toxicity was investigated. Nine patients were treated weekly with 5-FU at increasing dosages. Five patients developed dose-limiting leukopenia, and four patients developed thrombocytopenia. At dose-limiting toxicity, 5-FU treatment was repeated and followed after 3 hours by intermittent iv infusion of uridine (2 g/m2 per hr) during 72 hours. Leukopenia was reversed for several weeks but thrombocytopenia was not. Side effects consisted of mild rises in body temperature. The pharmacokinetics of uridine were similar to those observed with single-agent uridine. Our data indicate that high-dose uridine can reduce the severity of 5-FU-induced myelosuppression.
Endothelial Activation and Increased Heparan Sulfate Expression in Cystic Fibrosis
Authors: Nicola Solic, John Wilson, Susan J. Wilson, Janis K. Shute
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Pulmonary disease in cystic fibrosis (CF) is characterized by an exaggerated interleukin (IL)-8-driven, neutrophilic, inflammatory response to infection. Binding of IL-8 to heparan sulfate (HS)-containing proteoglycans (HSPG) facilitates binding of the chemokine to its specific receptor, stabilizes and prolongs IL-8 activity, and protects it from proteolysis. We hypothesized that increased expression of HSPG contributes to the sustained inflammatory response in CF bronchial tissue.Our objectives were to analyze the distribution and abundance of IL-8 and HS, in intact and cleaved forms, in bronchial tissue from adult patients with CF or chronic obstructive pulmonary disease (COPD) and a control group without inflammatory airway disease.Immunostaining and quantitative image analysis were applied to ethanol-fixed and paraffin-embedded tissue obtained at transplant in patients with CF or COPD, or postmortem in the control group.Quantitative immunohistochemical analysis demonstrated significant disease-related differences. Intact HS was significantly more abundant in epithelial and endothelial basement membranes in CF than in COPD or the control group. Conversely, cleaved HS was significantly more abundant in COPD than the other groups. More IL-8-positive blood vessels were observed in CF and COPD compared with the control group, whereas more extensive IL-8 expression in the epithelium was observed in CF compared with COPD.Sustained neutrophil recruitment in the CF airway may therefore be related not only to increased IL-8 expression but also to the increased stability and prolonged activity and retention of IL-8 when it is bound to HSPG in bronchial tissue.
The PPARγ-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction
Authors: Craig A Lygate, Karen Hulbert, Mina Monfared, Mark A Cole, Kieran Clarke, Stefan Neubauer
Journal: Cardiovascular Research (2003)

Peroxisome proliferator-activated receptor gamma (PPARgamma) activators may be beneficial in heart failure due to their metabolic and antihypertrophic effects, but these agents can cause oedema. We hypothesized that, on balance, the PPARgamma activator rosiglitazone would be beneficial in heart failure post-myocardial infarction.Rosiglitazone (3 mg/kg/day p.o.) given to male Wistar rats for 14 days, caused a 31% increase in left ventricular (LV) dP/dt(max) (P<0.05 vs. placebo). A separate group of rats was subjected to sham (SH) or coronary artery ligation and randomised to: untreated (UT); rosiglitazone 3 mg/kg/day (R); captopril, 2 g/l in drinking water (C); captopril+rosiglitazone (C+R). Mean LV infarct sizes were similar for all groups at 40+/-2%. After 8 weeks, echocardiographic ejection fractions were 82+/-3, 40+/-3, 50+/-2*, 49+/-2, 50+/-3% for SH, UT, R, C and C+R groups, respectively (*P<0.05 vs. UT). Captopril prevented LV dilatation, but rosiglitazone did not. In vivo hemodynamics showed that only UT had significantly elevated LV end-diastolic pressures and reduced +dP/dt(max), with R partially, and C and C+R almost completely preventing the increase in LVEDP. Captopril, but not rosiglitazone, significantly reduced LV hypertrophy [LV/bw; 1.97+/-0.09 (SH), 2.15+/-0.04 (UT), 2.10+/-0.05 (R), 1.81+/-0.04* (C), 1.88+/-0.07 (C+R); *(P<0.05 vs. UT)]. Rosiglitazone increased 8-week mortality, which was 26% for R and 19% for C+R compared with 0% for UT and C (P=0.03 vs. UT).Rosiglitazone did not modulate LV remodeling, but was associated with increased mortality post-myocardial infarction (MI) in rats. The mechanisms require further study, but these results caution against use of PPARgamma activators in post-MI heart failure in non-diabetics.
Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents
Authors: Lorenzo M. Leoni, Brandi Bailey, Jack Reifert, Heather H. Bendall, Robert W. Zeller, Jacques Corbeil, Gary Elliott, Christina C. Niemeyer
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
Autoantibodies against CD74 in spondyloarthritis
Authors: N T Baerlecken, S Nothdorft, G H Stummvoll, J Sieper, M Rudwaleit, S Reuter, T Matthias, R E Schmidt, T Witte
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Establishing the diagnosis is often difficult, since abnormalities in conventional X-ray develop with a latency of several years and only HLA-B27 is used as a laboratory marker. The goal of our study was to identify new autoantibodies as diagnostic markers of SpA. <h3>Methods</h3> Protein array technology was used to screen for new autoantigens in ankylosing spondylitis. Then, the results were confirmed by ELISA using Class II-associated invariant chain peptide domain of CD74 as antigen. Sera for the ELISA were obtained from 216 patients with axial (n=156) and peripheral (n=60) SpA. Sera of patients with psoriatic arthritis without axial involvement as another subtype of peripheral SpA, rheumatoid arthritis, systemic lupus erythematosus, HIV infection and blood donors served as controls. All donors provided informed consent for the study which was approved by the local ethics committee (project number 4928). <h3>Results</h3> Using protein arrays, we detected IgG antibodies against CD74 in SpA sera. Using ELISA technology on sera that had previously been frozen for several years, IgG autoantibodies against CD74 were found in 67% of the SpA patients and were even more frequent in patients with a short disease duration. In the controls, the prevalence of the new autoantibodies was 18/40 (45%) in psoriatic arthritis without axial involvement, 9/80 (11%) in rheumatoid arthritis, 6/40 (15%) in systemic lupus erythematosus, 1/40 (2.5%) in HIV and 1/125 (0.8%) in blood donors. <h3>Conclusions</h3> Antibodies against CD74 could provide an important additional tool for diagnosis of SpA.
Nifedipine and cardioplegia: rat heart studies with the St Thomas' cardioplegic solution
Authors: F. YAMAMOTO, A. S MANNING, M. V BRAIMBRIDGE, D. J HEARSE
Journal: Cardiovascular Research (1983)

Journal Article Nifedipine and cardioplegia: rat heart studies with the St Thomas' cardioplegic solution Get access FUMIO YAMAMOTO, FUMIO YAMAMOTO From The Heart Research Unit, The Rayne Institute, The St Thomas' Hospital, London SE1, United Kingdom †Address for reprint requests: Dr D J Hearse, The Rayne Institute, The St Thomas' Hospital, London SE1, UK. Search for other works by this author on: Oxford Academic PubMed Google Scholar ALLAN S MANNING, ALLAN S MANNING From The Heart Research Unit, The Rayne Institute, The St Thomas' Hospital, London SE1, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar MARK V BRAIMBRIDGE, MARK V BRAIMBRIDGE From The Heart Research Unit, The Rayne Institute, The St Thomas' Hospital, London SE1, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar DAVID J HEARSE DAVID J HEARSE From The Heart Research Unit, The Rayne Institute, The St Thomas' Hospital, London SE1, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 17, Issue 12, December 1983, Pages 719–727, https://doi.org/10.1093/cvr/17.12.719 Published: 01 December 1983
Anatomy and physiology of collateral respiratory pathways
Authors: L Delaunois
Journal: European Respiratory Journal (1989)

When complete obstruction of an airway occurs, ventilation and gas exchange distal to the obstruction can be preserved if "collateral ventilation" exists. Three collateral pathways have been described: the interalveolar, the bronchioloalveolar and the interbronchiolar communications. The various techniques used to measure collateral flow, resistance, compliance and time constant are described, with particular attention to those trying to separate the resistances of intrasegmental and collateral pathways. The various techniques used to measure collateral flow, resistance, compliance and time constant are described, with particular attention to those trying to separate the resistances of intrasegmental and collateral pathways. The relative importance of collateral ventilation in humans and animals is shown; factors affecting this ventilation are described: type of flow, lung volume, surface tension, alveolar CO2, pulmonary circulation and oedema, cholinergic and adrenergic receptors, histamine, interdependence. Parenchymal diseases disturb collateral flow; on the other hand, collateral channels can provide alternative pathways in various human pathologies.
Transport of <sup>14</sup> C-4-Cholesterol between Serum and Wall in the Perfused Dog Common Carotid Artery
Authors: COLIN G. CARO, ROBERT M. NEREM
Journal: Circulation Research (1973)

The transport of certain materials between the blood and the wall in arteries appears to be dependent on wall shear rate with shear rate-enhancing flux; however, the mechanism is unclear. If the transport is diffusional, it must involve three steps: diffusion across a boundary layer, uptake at the blood-wall interface, and transport within the wall. If the first step is rate controlling, if wall shear rate is spatially uniform, and if a diffusion boundary layer commences upstream at the junction between the vessel and an impermeable tube, then flux will be proportional to the cube root of wall shear rate divided by distance and will depend on the species diffusion coefficient. A dog's common carotid artery was perfused with serum containing 14 C-4-cholesterol linked with lipoprotein; the fluid mechanics resembled those described above. In 20 experiments, there was no spatial dependence of uptake of the label, flux was lower by a factor of about a hundred than that predicted, and there was a suggestion (statistically nonsignificant) of shear dependence. The first two findings are inconsistent with transport controlled by the diffusion boundary layer. An uptake-controlled transport could be shear dependent.
Enzyme inhibitory autoantibodies to pyruvate dehydrogenase complex in primary biliary cirrhosis differ for mammalian, yeast and bacterial enzymes: Implications for molecular mimicry
Authors: Khay-Lin Teoh, Ian R. Mackay, Merrill J. Rowley, Shelley P. M. Fussey
Journal: Hepatology (1994)

Primary biliary cirrhosis is a chronic autoimmune disease in which serum autoantibodies against the mitochondrial 2-oxo acid dehydrogenase enzyme complexes (M2 antibodies) are regularly present. Molecular mimicry of host proteins by bacterial counterparts is a suggested explanation for the origin of these autoantibodies. We tested this hypothesis by measuring the functional reactivity of serum autoantibodies by means of an enzyme inhibition assay against pyruvate dehydrogenase complex from different sources: mammalian, Saccharomyces cerevisiae and Escherichia coli. The 10 primary biliary cirrhosis sera all reacted on immunofluorescence study for M2 antibodies and on immunoblotting with the pyruvate dehydrogenase complex E2 subunit from each of the three enzymes, but there were strikingly different inhibitory capacities. The primary biliary cirrhosis sera were highly inhibitory for mammalian pyruvate dehydrogenase complex (10 of 10 inhibitory; mean level of inhibition, 99%), moderately inhibitory for yeast pyruvate dehydrogenase complex (10 of 10 inhibitory; mean level, 70%) and weakly inhibitory for Escherichia coli pyruvate dehydrogenase complex (4 of 10 inhibitory; mean level, 26%). Thus, with a functional assay that depends on epitope recognition of primary biliary cirrhosis sera, cross-reactivity between mammalian and bacterial pyruvate dehydrogenase complex enzymes is low and molecular mimicry, at least at the B-lymphocyte level, is not supported.
Quantitative analysis of peripheral allergen‐specific B lymphocytes in asthma
Authors: S. E. Burastero, D. Fenoglio, E. Crimi, V. Brusasco, G. A. Rossi
Journal: Allergy (1994)

We have recently shown that the number of peripheral allergen‐specific T cells can, in part, predict, together with methacholine hyperresponsiveness, the bronchial response to inhaled allergen in asthmatic patients. This study was designed to explore the role of blood B cells committed to produce allergen‐specific IgE in asthma. Twenty‐three asthmatic patients sensitized to Dermatophagoides pteronyssinus and 11 control subjects were studied. Peripheral blood B cells, committed to produce allergen‐specific IgE, were enumerated by limiting dilution microcultures of Epstein‐Barr virus (EBV)‐transformed B cells. An allergen inhalation challenge was performed in all asthmatic subjects. No difference was found in the frequency of B cells committed to produce allergen‐specific IgE either between asthmatic patients and controls or between asthmatic patients with or without late‐phase bronchial response to allergen. No correlation was found between the frequency of B cells committed to produce allergen‐specific IgE and the bronchial response to the allergen inhalation challenge. We conclude that, in quantitative terms, peripheral allergen‐specific B cells are not as relevant as T cells to the development of the asthmatic response in the model of provoked asthma.
Vorapaxar in the Secondary Prevention of Atherothrombotic Events
Authors: David A. Morrow, Eugene Braunwald, Marc P. Bonaca, Sebastian F. Ameriso, Anthony J. Dalby, Mary Polly Fish, Keith A.A. Fox, Leslie J. Lipka, Xuan Liu, José Carlos Nicolau, A.J. Oude Ophuis, Ernesto Paolasso, Benjamin M. Scirica, Jindrich Spinar, Pierre Theroux, Stephen D. Wiviott, John Strony, Sabina A. Murphy
Journal: New England Journal of Medicine (2012)

Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).
Updated safety and efficacy results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of pancreatic neuroendocrine tumors (NET).
Authors: P. Niccoli, J. Raoul, Y. Bang, I. Borbath, C. Lombard-Bohas, J. W. Valle, S. Patyna, D. Lu, R. C. Chao, E. Raymond
Journal: Journal of Clinical Oncology (2010)

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Evidence for Adult Lung Growth in Humans
Authors: James P. Butler, Stephen H. Loring, Samuel Patz, Akira Tsuda, Dmitriy A. Yablonskiy, Steven J. Mentzer
Journal: New England Journal of Medicine (2012)

A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human.