tbuckley/cabot-search huggingface dataset:
Effects of ADMA upon Gene Expression: An Insight into the Pathophysiological Significance of Raised Plasma ADMA
Authors: Caroline L Smith, Shelagh Anthony, Mike Hubank, James M Leiper, Patrick Vallance
Journal: PLoS Medicine (2005)

Asymmetric dimethylarginine (ADMA) is a naturally occurring inhibitor of nitric oxide synthesis that accumulates in a wide range of diseases associated with endothelial dysfunction and enhanced atherosclerosis. Clinical studies implicate plasma ADMA as a major novel cardiovascular risk factor, but the mechanisms by which low concentrations of ADMA produce adverse effects on the cardiovascular system are unclear.We treated human coronary artery endothelial cells with pathophysiological concentrations of ADMA and assessed the effects on gene expression using U133A GeneChips (Affymetrix). Changes in several genes, including bone morphogenetic protein 2 inducible kinase (BMP2K), SMA-related protein 5 (Smad5), bone morphogenetic protein receptor 1A, and protein arginine methyltransferase 3 (PRMT3; also known as HRMT1L3), were confirmed by Northern blotting, quantitative PCR, and in some instances Western blotting analysis to detect changes in protein expression. To determine whether these changes also occurred in vivo, tissue from gene deletion mice with raised ADMA levels was examined. More than 50 genes were significantly altered in endothelial cells after treatment with pathophysiological concentrations of ADMA (2 microM). We detected specific patterns of changes that identify pathways involved in processes relevant to cardiovascular risk and pulmonary hypertension. Changes in BMP2K and PRMT3 were confirmed at mRNA and protein levels, in vitro and in vivo.Pathophysiological concentrations of ADMA are sufficient to elicit significant changes in coronary artery endothelial cell gene expression. Changes in bone morphogenetic protein signalling, and in enzymes involved in arginine methylation, may be particularly relevant to understanding the pathophysiological significance of raised ADMA levels. This study identifies the mechanisms by which increased ADMA may contribute to common cardiovascular diseases and thereby indicates possible targets for therapies.
Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells
Authors: Marie-José Blivet-Van Eggelpoël, Hamza Chettouh, Laetitia Fartoux, Lynda Aoudjehane, Véronique Barbu, Colette Rey, Sabrina Priam, Chantal Housset, Olivier Rosmorduc, Christèle Desbois-Mouthon
Journal: Journal of Hepatology (2012)
Mesothelioma presenting with pneumothorax and interlobar tumour
Authors: GP Mannes, AS Gouw, HH Berendsen, AJ Verhoeff, PE Postmus
Journal: European Respiratory Journal (1991)

A patient presented with a pneumothorax, a parahilar mass and a pleural effusion on the left side. Histology proved that this was caused by a malignant mesothelioma, epithelial type. The pneumothorax persisted, even after chest drainage and pleurodesis with talc powder and tetracycline.
Corticosteroid reversibility in COPD is related to features of asthma.
Authors: P Chanez, A M Vignola, T O'Shaugnessy, I Enander, D Li, P K Jeffery, J Bousquet
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Eosinophilic inflammation has been observed in the airways of patients with chronic obstructive pulmonary disease (COPD). A subset of patients clinically diagnosed as having COPD show a reversibility of airflow obstruction when treated with corticosteroids, and may consist of patients with features of asthma including reticular basement membrane thickening and eosinophilic inflammation. Twenty-five unselected patients clinically diagnosed as having COPD received a daily oral dose of 1.5 mg/kg body weight of prednisolone for 15 d to assess the relationships between the functional response to corticosteroids and the presence of features of asthma. Eosinophilic inflammation was characterized before the course of corticosteroid therapy by enumerating eosinophils in peripheral blood, bronchoalveolar lavage fluid (BALF), and bronchial biopsies, using EG2 monoclonal antibody, and by measurement of eosinophil cationic protein (ECP) in BALF. A response to treatment was defined by an increase in FEV1 of at least 12% from baseline values and an absolute value of 200 ml measured at the end of the treatment. Twelve of 25 patients responded to the treatment. By comparison with nonresponders, responders had a significantly larger number of eosinophils (p < 0.015), and higher levels of ECP (p = 0.013) in their BALF. The responders had a thicker reticular basement membrane than the nonresponders (p < 0.04). These results indicate that a response to prednisolone in patients diagnosed as having COPD might occur more readily in a subset of patients presenting with features of asthma.
MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype
Authors: Cherie Blenkiron, Leonard D Goldstein, Natalie P Thorne, Inmaculada Spiteri, Suet-Feung Chin, Mark J Dunning, Nuno L Barbosa-Morais, Andrew E Teschendorff, Andrew R Green, Ian O Ellis, Simon Tavaré, Carlos Caldas, Eric A Miska
Journal: Genome biology (2007)

Abstract Background MicroRNAs (miRNAs), a class of short non-coding RNAs found in many plants and animals, often act post-transcriptionally to inhibit gene expression. Results Here we report the analysis of miRNA expression in 93 primary human breast tumors, using a bead-based flow cytometric miRNA expression profiling method. Of 309 human miRNAs assayed, we identify 133 miRNAs expressed in human breast and breast tumors. We used mRNA expression profiling to classify the breast tumors as luminal A, luminal B, basal-like, HER2+ and normal-like. A number of miRNAs are differentially expressed between these molecular tumor subtypes and individual miRNAs are associated with clinicopathological factors. Furthermore, we find that miRNAs could classify basal versus luminal tumor subtypes in an independent data set. In some cases, changes in miRNA expression correlate with genomic loss or gain; in others, changes in miRNA expression are likely due to changes in primary transcription and or miRNA biogenesis. Finally, the expression of DICER1 and AGO2 is correlated with tumor subtype and may explain some of the changes in miRNA expression observed. Conclusion This study represents the first integrated analysis of miRNA expression, mRNA expression and genomic changes in human breast cancer and may serve as a basis for functional studies of the role of miRNAs in the etiology of breast cancer. Furthermore, we demonstrate that bead-based flow cytometric miRNA expression profiling might be a suitable platform to classify breast cancer into prognostic molecular subtypes.
Apoptosis of Endothelial Cells Precedes Myocyte Cell Apoptosis in Ischemia/Reperfusion Injury
Authors: Tiziano Scarabelli, Anastasis Stephanou, Neil Rayment, Evasio Pasini, Laura Comini, Salvatore Curello, Roberto Ferrari, Richard Knight, David Latchman
Journal: Circulation (2001)

Apoptosis contributes to cell loss after ischemia/reperfusion injury in the heart. This study describes the time course and level of apoptosis in different cell types in the intact heart during ischemia/reperfusion injury.Isolated Langendorff-perfused rat hearts were subjected to perfusion alone (control) or to 35 minutes of regional ischemia, either alone or followed by 5, 60, or 120 minutes of reperfusion. Sections were stained by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and propidium iodide and with anti-von Willebrand factor, anti-desmin, or anti-active caspase 3 antibodies; they were then visualized by confocal microscopy. Sections were also examined by electron microscopy. No TUNEL-positive cells were seen in control hearts or hearts exposed to ischemia alone. Early in reperfusion, TUNEL staining was colocalized with endothelial cells from small coronary vessels. Endothelial apoptosis peaked at 1 hour of reperfusion and, at this time, there was clear perivascular localization of apoptotic cardiac myocytes, whose number was inversely proportional to their distance from a positive vessel. After 2 hours of reperfusion, apoptotic cardiac myocytes assumed a more homogeneous distribution. Active caspase 3 labeling was seen independent of DNA fragmentation during ischemia alone, but it colocalized with TUNEL staining over the 3 time points of reperfusion. Immunocytochemical findings were confirmed by electron microscopy and Western blotting.In the very early stages of reperfusion, apoptosis is first seen in the endothelial cells from small coronary vessels. The radial spread of apoptosis to surrounding cardiac myocytes suggests that reperfusion induces the release of soluble pro-apoptotic mediators from endothelial cells that promote myocyte apoptosis.
Removal of foreign bodies by rigid bronchoscopy technique in children - The end of an era?
Authors: Dirk Schramm, Julia Delißen, Antje Schuster
Journal: European Respiratory Journal (2012)

BACKGROUND/HYPOTHESIS: Recommendations regarding management of foreign body (FB) aspiration in childhood have not substantially been modified since 1897 when Gustav Kilian first described the technique how to extract FBs by rigid bronchoscopy. Many paediatric pulmonology centers have adapted a two-step-procedure: First, to explore the airways by flexible bronchoscopy in case of suspicion of a FB aspiration, and then, if confirmed, to switch to rigid bronchoscopy for FB removal. In recent years, instruments have been developed especially for FB removal by flexible bronchoscopy. We hypothesize that it is no longer necessary to routinely pursue the two-step procedure.  CASE: We present the case of a 2-year-old boy who aspirated a peanut. In order to exemplarily share our experiences regarding the modern technique, we display serial photographs from the video taken during the procedure of FB removal by specialized instruments for flexible bronchoscopy. In our center, this flexible technique has developed into the usual method of choice; only in rare cases it is necessary to switch to a rigid bronchoscopy procedure.  DISCUSSION: There are only few reports on the novel flexible method for FB removal in children. A safe one-step procedure with flexible bronchoscopy offering both a diagnostic and a therapeutic potential appears to be an advantageous method for the management of our young patients. We suggest to compile and analyze paediatric pulmonologists9 experiences with the new technique, in order to finally formulate recommendations for the most advisable first-line procedure of bronchial FB removal in children.
Clinical Study of Recurrence Rate and Survival Time of Patients with Carcinoma of the Breast Treated by Biopsy Excision without any Other Therapy<sup>1</sup>
Authors: A C V Montgomery, W P Greening, A L Levene
Journal: Journal of the Royal Society of Medicine (1978)

We report the recurrence rate and survival time in 31 patients with carcinoma of the breast who were treated by limited excision of the primary tumour and no other therapy. At three years the overall recurrence rate in the breast was 28%. One patient was found to have systemic disease and two died of other causes. The overall recurrence rate in the breast at five years was 33%. One patient died of disseminated disease at 6 years 4 months.
Oral adeno-associated virus-sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice
Authors: Hong Ma, Yanxin Liu, Shilian Liu, Ruian Xu, Dexian Zheng
Journal: Hepatology (2005)

The extracellular domain of the tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) may function as a soluble cytokine to selectively kill various cancer cells without toxicity to most normal cells. We constructed a series of recombinant adeno-associated virus (AAV) vectors expressing the extracellular domain of human TRAIL fused with signal peptides of human insulin, interferon, human growth hormone, and serum albumin and designated them as AAV-ISN-T, AAV-IFN-T, AAV-HGH-T, and AAV-Alb-T, respectively. Transduction of human SMMC-7721 liver cancer cells with AAV-ISN-T led to higher levels of TRAIL95-281 protein expression in the cell culture media and produced more apoptosis of the cells in vitro than those with AAV-IFN-T, AAV-HGH-T, and AAV-Alb-T. The therapeutic potential of AAV-ISN-T was then evaluated in a transplanted mouse model established by injection of human liver cancer SMMC-7721 cells subcutaneously. Subsequent oral or intraperitoneal administration of AAV-ISN-T resulted in a rapid, high level and long time expression of soluble TRAIL in the sera and livers of the animals, as well as effective suppression of tumor growth, with no toxicity to normal hepatocytes. These data strongly suggest that it is possible to increase soluble TRAIL expression to make full use of tumoricidal activity of TRAIL as a therapeutic strategy. In conclusion, we provide evidence that oral administration of AAV-TRAIL might be an important alternative route with practical significance for cancer gene therapy. (HEPATOLOGY 2005;42:1355–1363.)
Composition of Carotid Atherosclerotic Plaque Is Associated With Cardiovascular Outcome
Authors: Willem E. Hellings, Wouter Peeters, Frans L. Moll, Sebastiaan R.D. Piers, Jessica van Setten, Peter J. Van der Spek, Jean-Paul P.M. de Vries, Kees A. Seldenrijk, Peter C. De Bruin, Aryan Vink, Evelyn Velema, Dominique P.V. de Kleijn, Gerard Pasterkamp
Journal: Circulation (2010)

Identification of patients at risk for primary and secondary manifestations of atherosclerotic disease progression is based mainly on established risk factors. The atherosclerotic plaque composition is thought to be an important determinant of acute cardiovascular events, but no prospective studies have been performed. The objective of the present study was to investigate whether atherosclerotic plaque composition is associated with the occurrence of future vascular events.Atherosclerotic carotid lesions were collected from patients who underwent carotid endarterectomy and were subjected to histological examination. Patients underwent clinical follow-up yearly, up to 3 years after carotid endarterectomy. The primary outcome was defined as the composite of a vascular event (vascular death, nonfatal stroke, nonfatal myocardial infarction) and vascular intervention. The cumulative event rate at 1-, 2-, and 3-year follow-up was expressed by Kaplan-Meier estimates, and Cox proportional hazards regression analyses were performed to assess the independence of histological characteristics from general cardiovascular risk factors. During a mean follow-up of 2.3 years, 196 of 818 patients (24%) reached the primary outcome. Patients whose excised carotid plaque revealed plaque hemorrhage or marked intraplaque vessel formation demonstrated an increased risk of primary outcome (risk difference=30.6% versus 17.2%; hazard ratio [HR] with [95% confidence interval]=1.7 [1.2 to 2.5]; and risk difference=30.0% versus 23.8%; HR=1.4 [1.1 to 1.9], respectively). Macrophage infiltration (HR=1.1 [0.8 to 1.5]), large lipid core (HR=1.1 [0.7 to 1.6]), calcifications (HR=1.1 [0.8 to 1.5]), collagen (HR=0.9 [0.7 to 1.3]), and smooth muscle cell infiltration (HR=1.3 [0.9 to 1.8]) were not associated with clinical outcome. Local plaque hemorrhage and increased intraplaque vessel formation were independently related to clinical outcome and were independent of clinical risk factors and medication use.The local atherosclerotic plaque composition in patients undergoing carotid endarterectomy is an independent predictor of future cardiovascular events.
Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions Potential for pharmacological interventions
Authors: W Stanley
Journal: Cardiovascular Research (1997)

It is now clear that the availability of different metabolic substrates can have a profound influence on the extent of damage incurred during episodes of cardiac ischaemia, and on cardiac functional recovery on reperfusion following ischaemia. In particular, increases in fatty acid availability and oxidation, compared to glucose oxidation, under such conditions leads to a worsening of outcome. Therefore metabolic interventions aimed at enhancing glucose utilisation and pyruvate oxidation at the expense of fatty acid oxidation is a valid therapeutic approach to the treatment of myocardial ischaemia. In particular, the development of agents which will promote full glucose oxidation as opposed to glycolysis alone, offer clear advantages. This can be accomplished by different means, including direct or indirect inhibition of CPT-I or inhibition of fatty acid beta-oxidation, or by direct or indirect activation of PDH. It is not yet clear which of these approaches offers the best treatment of cardiac ischaemia. To date, trimetazidine and carnitine have received limited approval in Europe for the treatment of angina; large scale clinical trials with the other agents mentioned above have not been completed. The increasing availability of agents affecting these specific sites, and the increasingly sophisticated techniques for assessing myocardial metabolism, should allow elucidation of the optimum metabolic targets and development of novel pharmacological agents for the treatment of ischaemic heart disease.
Mechanism Underlying Accelerated Arterial Oxygen Desaturation during Recurrent Apnea
Authors: Scott A. Sands, Bradley A. Edwards, Vanessa J. Kelly, Elizabeth M. Skuza, Malcolm R. Davidson, Malcolm H. Wilkinson, Philip J. Berger
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Brief recurrent apneas in preterm infants and adults can precipitate rapid and severe arterial O2 desaturation for reasons that remain unclear.Objectives: We tested a mathematically derived hypothesis that when breathing terminates apnea, mixed–venous hypoxemia continues into the subsequent apnea; as a result, there is a surge in pulmonary O2 uptake that rapidly depletes the finite alveolar O2 store, thereby accelerating arterial O2 desaturation.Methods: Recurrent apneas were simulated in an experimental lamb model. Pulmonary O2 uptake was calculated from continuously measured arterial and mixed–venous O2 saturation and cardiac output.Measurements and Main Results: Direct measurements revealed that asynchrony in the desaturation and resaturation of arterial and venous blood gave rise to dips and surges in O2 uptake. After desaturation to 50%, a typical nadir in preterm infants, O2 uptake surged to a peak of 176.9 ± 7.8% of metabolic rate. During subsequent apneas, desaturation rate was increased two- to threefold greater than during isolated apneas, in direct proportion to the magnitude of the surge in O2 uptake (P < 0.001; R2 = 0.897). Application of our mathematical model to a published recording of cyclic apneas in a preterm infant precisely reproduced the accelerated desaturation rates of up to 15% · s−1 observed clinically.Conclusions: Rapid depletion of alveolar O2 stores by surges in O2 uptake almost completely explains the acceleration of desaturation that occurs during recurrent apnea. This powerful mechanism is likely to explain the severity of intermittent hypoxemia that is associated with neurocognitive and cardiovascular morbidities in preterm infants and adults.
Concordant and discordant effects on cardiovascular risks exerted by oestrogen and progestogen in women using oral contraception and hormone replacement therapy
Authors: P. Crosignani
Journal: Human Reproduction Update (1999)

The major indications for the clinical use of oestrogen and progestogen are oral contraception (OC) in young women, and hormonal replacement therapy (HRT) in menopause. Over the past few years, epidemiological data have associated the use of these hormones to different cardiovascular conditions such as myocardial infarction, cerebrovascular disease and venous thromboembolism. This review summarizes the data discussed and the conclusions achieved by the ESHRE Capri Workshop Group, recently published in Human Reproduction.
Enhancement of basophil histamine release by interleukinl‐3: reduced effect in atopic subjects
Authors: A. Miadonna, C. Salmaso, M. Cottini, N. Milazzo, A. Tedeschi
Journal: Allergy (1996)

The inducing and enhancing effects of interleukin‐3 (IL‐3) on basophil histamine release in patients with respiratory allergy ( n = 28) and in normal subjects ( n = 22) were compared. Leukocyte suspensions. prepared by dextran sedimentation, were stimulated with anti‐IgE (1/5000), N ‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP, 1 μM), and IL‐3 (0.1–10 ngiml), and histamine concentration was measured by an automated fluorometric method. A trend toward highef histamine release after challenge with anti‐IgE, FMLP, and IL‐3 was found in atopic subjects. Preincubation of basophils with IL‐3 resulted in a dose‐dependent increase of anti‐IgE‐ and FMLP‐induced histamine release, with a more marked effect in nonatopic than in atopic subjects. Mean net enhancement of anti‐IgE‐induced histamine release by 10 ng/ml IL‐3 was 2.5±5% in atopic subjects and 29.6±4.2% in nonatopic subjects ( P&lt; 0.001). The enhancement of FMLP‐induced histamine release by IL‐3 was 10.3 ± 3.9% in atopic patients and 29±2.4% in nonatopic subjects ( P&lt;0.01 ). In atopic subjects, a negative correlation was found between anti‐IgE‐ or FMLP‐induced histamine release and net enhancement by IL‐3 (r= ‐0.45, P&lt;0.02; r= ‐0.48, P&lt;0.01, respectively). The results of this study indicate that in atopic subjects IgE‐mediated histamine release can scarcely be enhanced by a basophil response modifier such as IL‐3. It is conceivable that the frequent basophil stimulation in atopic patients leads to a reduced sensitivity to the enhancing effect of IL‐3.
An Autosomal Analysis Gives No Genetic Evidence for Complex Speciation of Humans and Chimpanzees
Authors: Masato Yamamichi, Jun Gojobori, Hideki Innan
Journal: Molecular Biology and Evolution (2011)

There have been conflicting arguments as to what happened in the human–chimpanzee speciation event. Patterson et al. (2006, Genetic evidence for complex speciation of humans and chimpanzees. Nature 441:1103–1108) proposed a hypothesis that the human–chimpanzee speciation event involved a complicated demographic process: that is, the ancestral lineages of humans and chimpanzees experienced temporal isolation followed by a hybridization event. This hypothesis stemmed from two major observations: a wide range of human–chimpanzee nucleotide divergence across the autosomal genome and very low divergence in the X chromosome. In contrast, Innan and Watanabe (2006, The effect of gene flow on the coalescent time in the human-chimpanzee ancestral population. Mol Biol Evol. 23:1040–1047) demonstrated that the null model of instantaneous speciation fits the genome-wide divergence data for the two species better than alternative models involving partial isolation and migration. To reconcile these two conflicting reports, we first reexamined the analysis of autosomal data by Patterson et al. (2006). By providing a theoretical framework for their analysis, we demonstrated that their observation is what is theoretically expected under the null model of instantaneous speciation with a large ancestral population. Our analysis indicated that the observed wide range of autosomal divergence is simply due to the coalescent process in the large ancestral population of the two species. To further verify this, we developed a maximum likelihood function to detect evidence of hybridization in genome-wide divergence data. Again, the null model with no hybridization best fits the data. We conclude that the simplest speciation model with instantaneous split adequately describes the human–chimpanzee speciation event, and there is no strong reason to involve complicated factors in explaining the autosomal data.speciation, isolation, hybridization, coalescent, human, chimpanzee.