tbuckley/cabot-search huggingface dataset:
Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on the human mast-cell line (HMC)-1 by inflammatory mediators
Authors: B. Wedi, J. Elsner, W. Czech, J. H. Butterfield, A. Kapp
Journal: Allergy (1996)

The effect of inflammatory mediators on the expression of several surface adhesion molecules on the human mast-cell line (HMC)-1 was studied. By flow cytometry, it could be shown that among several surface adhesion molecules (ICAM-1/CD54, VLA-4/CD49d, Mac-1/CD11b, LFA-1/CD11a, LFA-2/CD2, LFA-3/CD58, VCAM-1), only the constitutively expressed immunoglobulin family member intercellular adhesion molecule-1 (ICAM-1) is modulated by proinflammatory cytokines on HMC-1 mast cells. Stimulation with tumor necrosis factor-a (TNF-alpha) and interferon-gamma (IFN-gamma) resulted, in addition to interleukin-(IL-)4, in selective upregulation of ICAM-1 expression. Costimulation of either IL-4 or IFN-gamma with TNF-alpha further increased the ICAM-1 expression as compared to the stimuli alone. In contrast, stem-cell factor (SCF), granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-10, IL-8, monocyte chemotactic and activating factor (MCAF), and the complement split product C5a failed to modulate the expression of any adhesion molecule examined. The levels of cytoplasmic free calcium in HMC-1 mast cells were not altered by cross-linking surface ICAM-1, suggesting linkage of other intracellular signaling pathways. This cytokine-induced upregulation of ICAM-1 expression might reveal a putative regulatory mechanism of mast-cell interaction with effector cells bearing the counterparts of ICAM-1 (CD54), the molecules Mac-1 (CD11b/CD18) and leukosialin (CD43), and the principal ligand LFA-1 (CD11a/CD18).
Neutrophil-derived 5′-Adenosine Monophosphate Promotes Endothelial Barrier Function via CD73-mediated Conversion to Adenosine and Endothelial A2B Receptor Activation
Authors: Paul F. Lennon, Cormac T. Taylor, Gregory L. Stahl, Sean P. Colgan
Journal: The Journal of Experimental Medicine (1998)

During episodes of inflammation, polymorphonuclear leukocyte (PMN) transendothelial migration has the potential to disturb vascular barrier function and give rise to intravascular fluid extravasation and edema. However, little is known regarding innate mechanisms that dampen fluid loss during PMN-endothelial interactions. Using an in vitro endothelial paracellular permeability model, we observed a PMN-mediated decrease in endothelial paracellular permeability. A similar decrease was elicited by cell-free supernatants from activated PMN (FMLP 10−6 M), suggesting the presence of a PMN-derived soluble mediator(s). Biophysical and biochemical analysis of PMN supernatants revealed a role for PMN-derived 5′-adenosine monophosphate (AMP) and its metabolite, adenosine, in modulation of endothelial paracellular permeability. Supernatants from activated PMN contained micromolar concentrations of bioactive 5′-AMP and adenosine. Furthermore, exposure of endothelial monolayers to authentic 5′-AMP and adenosine increased endothelial barrier function more than twofold in both human umbilical vein endothelial cells and human microvascular endothelial cells. 5′-AMP bioactivity required endothelial CD73-mediated conversion of 5′-AMP to adenosine via its 5′-ectonucleotidase activity. Decreased endothelial paracellular permeability occurred through adenosine A2B receptor activation and was accompanied by a parallel increase in intracellular cAMP. We conclude that activated PMN release soluble mediators, such as 5′-AMP and adenosine, that promote endothelial barrier function. During inflammation, this pathway may limit potentially deleterious increases in endothelial paracellular permeability and could serve as a basic mechanism of endothelial resealing during PMN transendothelial migration.
Candidate Tumor Suppressor and pVHL Partner Jade-1 Binds and Inhibits AKT in Renal Cell Carcinoma
Authors: Liling Zeng, Ming Bai, Amit K. Mittal, Wassim El-Jouni, Jing Zhou, David M. Cohen, Mina I. Zhou, Herbert T. Cohen
Journal: Cancer Research (2013)

The von Hippel-Lindau (VHL) tumor suppressor pVHL is lost in the majority of clear-cell renal cell carcinomas (RCC). Activation of the PI3K/AKT/mTOR pathway is also common in RCC, with PTEN loss occurring in approximately 30% of the cases, but other mechanisms responsible for activating AKT at a wider level in this setting are undefined. Plant homeodomain protein Jade-1 (PHF17) is a candidate renal tumor suppressor stabilized by pVHL. Here, using kinase arrays, we identified phospho-AKT1 as an important target of Jade-1. Overexpressing or silencing Jade-1 in RCC cells increased or decreased levels of endogenous phospho-AKT/AKT1. Furthermore, reintroducing pVHL into RCC cells increased endogenous Jade-1 and suppressed endogenous levels of phospho-AKT, which colocalized with and bound to Jade-1. The N-terminus of Jade-1 bound both the catalytic domain and the C-terminal regulatory tail of AKT, suggesting a mechanism through which Jade-1 inhibited AKT kinase activity. Intriguingly, RCC precursor cells where Jade-1 was silenced exhibited an increased capacity for AKT-dependent anchorage-independent growth, in support of a tumor suppressor function for Jade-1 in RCC. In support of this concept, an in silico expression analysis suggested that reduced Jade-1 expression is a poor prognostic factor in clear-cell RCC that is associated with activation of an AKT1 target gene signature. Taken together, our results identify 2 mechanisms for Jade-1 fine control of AKT/AKT1 in RCC, through loss of pVHL, which decreases Jade-1 protein, or through attenuation in Jade-1 expression. These findings help explain the pathologic cooperativity in clear-cell RCC between PTEN inactivation and pVHL loss, which leads to decreased Jade-1 levels that superactivate AKT. In addition, they prompt further investigation of Jade-1 as a candidate biomarker and tumor suppressor in clear-cell RCC.
Natural selection and the molecular clock.
Authors: J H Gillespie
Journal: Molecular Biology and Evolution (1986)

This paper concludes that the statistical properties of protein evolution are compatible with a particular model of evolution by natural selection. The argument begins with a statistical description of the molecular clock based on a Poisson process with a randomly varying tick rate. If the time scale of the change of the tick rate of the molecular clock is assumed to be much less than the average time between substitutions, then it is shown that the substitution process must be episodic, with bursts of substitutions being separated by long periods of time with no substitutions. This analysis generalizes the recent work of Gillespie (1984a). The second part of the argument shows that a simple model of evolution by natural selection--one that incorporates a changing environment, the molecular landscape, and a simple form of epistasis--exhibits dynamics that are identical to those inferred from the statistical analysis. This leads to the conclusion that natural selection is a viable explanation for protein evolution. In addition, a correction formula for multiple substitutions is given that does not require that the substitution process be a Poisson process, and some comments on the inability of the neutral allele theory to account for the dynamics of the substitution process are presented.
No difference in graft-versus-host disease, relapse, and survival comparing peripheral stem cells to bone marrow using unrelated donors
Authors: Mats Remberger, Oolle Ringdén, Igor-Wolfgang Blau, Hellmut Ottinger, Bernhard Kremens, Micheil G. Kiehl, Johan Aschan, Dietrich W. Beelen, Nadezda Basara, Gunilla Kumlien, Axel A. Fauser, Volker Runde
Journal: Blood (2001)
Activation of Phosphatidylinositol-3′-kinase/AKT Signaling Is Essential in Hepatoblastoma Survival
Authors: Wolfgang Hartmann, Jan Küchler, Arend Koch, Nicolaus Friedrichs, Anke Waha, Elmar Endl, Jacqueline Czerwitzki, Dagmar Metzger, Susanne Steiner, Peter Wurst, Ivo Leuschner, Dietrich von Schweinitz, Reinhard Buettner, Torsten Pietsch
Journal: Clinical Cancer Research (2009)

Hepatoblastoma represents the most frequent malignant liver tumor in childhood. The phosphatidylinositol-3'-kinase (PI3K)/AKT pathway is crucial in downstream signaling of multiple receptor tyrosine kinases of pathogenic importance in hepatoblastoma. Increased PI3K/AKT signaling pathway activity and activating mutations of PIK3CA, encoding a PI3K catalytic subunit, have been reported in different childhood tumors. The current study was done to analyze the role of PI3K/AKT signaling in hepatoblastoma.Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT protein, its targets p-(Ser9)-GSK-3beta and p-(Ser2448)-mTOR, as well as the cell cycle regulators Cyclin D1, p27(KIP1), and p21(CIP1) were done and the PIK3CA gene was screened for mutations. In vitro, two hepatoblastoma cell lines treated with the PI3K inhibitor LY294002 were analyzed for AKT and GSK-3beta phosphorylation, cell proliferation, and apoptosis. Additionally, simultaneous treatments of hepatoblastoma with LY294002 and cytotoxic drugs were carried out.Most tumors strongly expressed p-AKT, p-GSK-3beta, and p-mTOR; subgroups showed significant Cyclin D1, p27(KIP1), and p21(CIP1) expression. One hepatoblastoma carried an E545A mutation in the PIK3CA gene. In vitro, PI3K inhibition diminished hepatoblastoma cell growth being accompanied by reduced AKT and GSK-3beta phosphorylation. Flow cytometry and 4', 6-diamidino-2-phenylindole stainings showed that PI3K pathway inhibition leads to a substantial increase in apoptosis and a decrease in cellular proliferation linked to reduced Cyclin D1 and increased p27(KIP1) levels. Simultaneous treatment of hepatoblastoma cell lines with LY294002 and cytotoxic drugs resulted in positive interactions.Our findings imply that PI3K signaling plays an essential role in growth control of hepatoblastoma and might be successfully targeted in multimodal therapeutic strategies.
Validation Study of the Accuracy of a Postoperative Nomogram for Recurrence After Radical Prostatectomy for Localized Prostate Cancer
Authors: Markus Graefen, Pierre I. Karakiewicz, Ilias Cagiannos, Eric Klein, Patrick A. Kupelian, David I. Quinn, Susan M. Henshall, John J. Grygiel, Robert L. Sutherland, Phillip D. Stricker, Jean de Kernion, Thomas Cangiano, Fritz H. Schröder, Mark F. Wildhagen, Peter T. Scardino, Michael W. Kattan
Journal: Journal of Clinical Oncology (2002)

PURPOSE: A postoperative nomogram for prostate cancer was developed at Baylor College of Medicine. This nomogram uses readily available clinical and pathologic variables to predict 7-year freedom from recurrence after radical prostatectomy. We evaluated the predictive accuracy of the nomogram when applied to patients of four international institutions. PATIENTS AND METHODS: Clinical and pathologic data of 2,908 patients were supplied for validation, and 2,465 complete records were used. Nomogram-predicted probabilities of 7-year freedom from recurrence were compared with actual follow-up in two ways. First, the area under the receiver operating characteristic curve (AUC) was calculated for all patients and stratified by the time period of surgery. Second, calibration of the nomogram was achieved by comparing the predicted freedom from recurrence with that of an ideal nomogram. For patients in whom the pathologic report does not distinguish between focal and established extracapsular extension (an input variable of the nomogram), two separate calculations were performed assuming one or the other. RESULTS: The overall AUC was 0.80 when applied to the validation data set, with individual institution AUCs ranging from 0.77 to 0.82. The predictive accuracy of the nomogram was apparently higher in patients who were operated on between 1997 and 2000 (AUC, 0.83) compared with those treated between 1987 and 1996 (AUC, 0.78). Nomogram predictions of 7-year freedom from recurrence were within 10% of an ideal nomogram. CONCLUSION: The postoperative Baylor nomogram was accurate when applied at international treatment institutions. Our results suggest that accurate predictions may be expected when using this nomogram across different patient populations.
Effect of Meal Eating Compared to Nibbling upon Atherosclerosis in Chickens
Authors: CLARENCE COHN, RUTH PICK, LOUIS N. KATZ
Journal: Circulation Research (1961)

Both the production and regression of experimental atherosclerosis, as influenced by eating habits, were studied in the chicken. Birds were either allowed free access to food 24 hours/day ("nibblers") or only for two one-hour periods per day ("meal eaters"). In the induction experiments, it was found that the meal eaters exhibited double the serum cholesterol levels and seven times the severity of coronary atherosclerosis as the nibblers. In studies designed to explore the effects of these eating habits on the regression of established atherosclerosis, lesions were induced in the usual way by feeding an atherogenic diet under the conditions of meal eating. Then the birds were put on regular mash and divided into two groups: meal eaters and nibblers. Meal eating a regular mash diet was associated with (a) slower rate of fall of serum cholesterol levels to normal, and (b) a marked decrease in the rate of healing of the coronary lesions as compared to nibbling. It is concluded that the manner of ingestion of the diet plays a significant role in accentuating the production and in inhibiting the regression of experimental atherosclerosis.
Human myocardial Na,K-ATPase — quantification, regulation and relation to Ca
Authors: Thomas A Schmidt, Keld Kjeldsen
Journal: Cardiovascular Research (1998)

Time for primary review 26 days.

The Na,K-ATPase (sodium, potassium adenosine triphosphatase) or the Na,K-pump is an ubiquitous enzyme which performs the active transport of Na and K across the cell membrane [1]. Thus, by hydrolysing ATP the Na,K-ATPase pumps 3 Na ions out of the cell and 2 K ions into the cell. Hence, Na,K-ATPase is of importance for the characteristic distribution of these cations across the cell membrane and for generation of the membrane potential; thus optimum Na,K-ATPase function is required to ensure excitability and conduction. By generating the Na gradient across the sarcolemma, Na,K-ATPase creates a driving force for active Ca extrusion via the Na — Ca exchanger embedded in the membrane. Together with the Ca-ATPase located in the sarcolemma and in the membrane of the sarcoplasmic reticulum, the Na-Ca exchanger is of importance for maintaining low diastolic Ca concentration [2]. When muscular cells are depolarized intracellular Ca rises as much as 10 fold to around 1 μmol×litre−1 [3]. Subsequently Ca binds to troponin C triggering the force generating interaction between actin and myosin. Thus, Na,K-ATPase has the capacity for influencing muscular force generation. It might be noted that whereas the Na,K-pump utilizes around 4% of myocardial energy expenditure to maintain Na,K gradients, as much as 30% is used to fuel the Ca-ATPase [4].

Cardiac glycosides bind to the Na,K-ATPase in a 1: 1 ratio [5], and myocardial Na,K-ATPase is generally accepted to be the target for its positive inotropic action eliciting an increase in the availability of Ca to the contractile proteins in heart cells [6]. Cardiac glycosides bind with high affinity and specificity to an inhibitory site on the α subunit of Na,K-ATPase facing the outside of the cell, resulting in the complete inhibition of Na and K … 

* Corresponding author. Tel. (+45) 3545 2871; Fax: (+45) 3138 3186.
Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells
Authors: Keiichi Hishikawa, Barry S. Oemar, Felix C. Tanner, Toshio Nakaki, Tomoko Fujii, Thomas F. Lüscher
Journal: Circulation (1999)

Connective tissue growth factor (CTGF) is expressed at very high levels particularly in the shoulder of human atherosclerotic lesions but not in normal blood vessels. Thus, CTGF may be important in the regulation of vascular smooth muscle cell function in atherosclerosis, but its precise role remains elusive.Full-length CTGF cDNA driven by a cytomegalovirus promoter was transiently transfected into cultured human aortic smooth muscle cells (HASCs). Northern and Western analysis demonstrated that CTGF was overexpressed in these cells 48 hours after transfection. The effects of CTGF overexpression on cell proliferation were evaluated by [(3)H]thymidine uptake and cell count in quiescent HASCs or those stimulated with platelet-derived growth factor (PDGF). Although mock transfection showed no effect, CTGF overexpression significantly inhibited cell proliferation in cells stimulated by PDGF. Moreover, CTGF overexpression, but not mock transfection, significantly increased apoptosis as assessed by DNA fragmentation associated with histone, TdT-mediated dUTP biotin nick end-labeling, and appearance of hypodiploid cells by flow cytometry.Our results for the first time demonstrate that CTGF can also act as a growth inhibitor in human aortic smooth muscle cells at least in part by inducing apoptosis. This may be important for the formation and composition of lesions and plaque stability in atherosclerosis.
Clouding of Surgeons' Spectacles
Authors: R. W. Power
Journal: BMJ (1948)

Design and reporting of trialsTrials should improve on three main aspects: interventions, choice of outcomes, and reporting of results.Firstly, because systemic glucocorticoids are now the standard treatment of children and adolescents with severe exacerbations they should be systematically given with 2 agonists in future trials.Conversely, in children and adolescents with mild to moderate exacerbations trials are needed to evaluate the potential benefit of systematically adding anticholinergics to every 2 agonist inhalation, titrating the number of inhalations to patients' response.Secondly, as admission and relapse rates are relatively gross measures of efficacy, subject to practice variation, future trials should include more sensitive and reliable endpoints such as quality of life, duration of hospitalisation, and duration of symptoms following discharge.Finally, there is a need for consistent reporting of baseline severity, glucocorticoid use, and admission and relapse rates.
Azithromycin for cystic fibrosis
Authors: K.W. Southern
Journal: European Respiratory Journal (2004)

During what is a relatively barren time for new therapies for cystic fibrosis (CF), azithromycin has received a lot of attention as a potential treatment for CF lung disease. Laboratory studies suggest that azithromycin may have indirect actions, including anti-inflammatory, in addition to the standard antibacterial properties. The unique pharmacokinetics of azithromycin sets it aside from other macrolide antibiotics, but may result in increased resistance patterns. Three well-designed randomised controlled trials have demonstrated a small but significant improvement in respiratory function (forced expiratory volume in one second) with azithromycin compared with placebo. These trial results are confirmed by a recent meta-analysis. Mild adverse events (wheeze, diarrhoea and nausea) were significantly increased in one trial. There is no clear consensus regarding the correct dose and length of treatment with azithromycin. The present review discusses the role of azithromycin in the management of cystic fibrosis and the need for close monitoring of patients started on this drug. In addition, clinics should liaise closely with their microbiology departments and monitor resistance patterns.
The Role of EXT1 in Nonhereditary Osteochondroma: Identification of Homozygous Deletions
Authors: L. Hameetman, K. Szuhai, A. Yavas, J. Knijnenburg, M. van Duin, H. van Dekken, A. H. M. Taminiau, A.-M. Cleton-Jansen, J. V. M. G. Bovee, P. C. W. Hogendoorn
Journal: JNCI Journal of the National Cancer Institute (2007)

Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However, 85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare, but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas. Eight nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic hybridization (array-CGH) analysis for chromosome 8q. The array-CGH results were validated by subjecting tumor DNA to multiple ligation-dependent probe amplification (MLPA) analysis for EXT1. EXT1 locus–specific fluorescent in situ hybridization (FISH) was performed on nuclei isolated from the three tissue components of osteochondroma (cartilage cap, perichondrium, bony stalk) to examine which parts of the tumor are of clonal origin. Array-CGH analysis of tumor DNA revealed that all eight osteochondromas had a large deletion of 8q; five tumors had an additional small deletion of the other allele of 8q that contained the EXT1 gene. MLPA analysis of tumor DNA confirmed these findings and identified two additional deletions that were smaller than the limit of resolution of array-CGH. FISH analysis of the cartilage cap, perichondrium, and bony stalk showed that these homozygous EXT1 deletions were present only in the cartilage cap of osteochondroma. EXT1 functions as a classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas.
Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: randomised clinical trial
Authors: A. M. F. Porto, I. C. Coutinho, J. B. Correia, M. M. R. Amorim
Journal: BMJ (2011)

<b>Objectives</b> To determine the effectiveness of corticosteroids in reducing respiratory disorders in infants born at 34-36 weeks’ gestation. <b>Design </b>Randomised triple blind clinical trial. <b>Setting </b>A large tertiary teaching hospital in northeast of Brazil. <b>Participants </b>Women at 34-36 weeks of pregnancy at risk of imminent premature delivery. <b>Interventions </b>Betamethasone 12 mg or placebo intramuscularly for two consecutive days. <b>Main outcomes measures </b>Primary outcome was the incidence of respiratory disorders (respiratory distress syndrome and transient tachypnoea of the newborn). Secondary outcomes included the need for ventilatory support, neonatal morbidity, and duration of stay in hospital. <b>Results</b> 320 women were randomised, 163 of whom were assigned to the treatment group and 157 to the controls. Final analysis included 143 and 130 infants, respectively. The rate of respiratory distress syndrome was low (two (1.4%) in the corticosteroid group; one (0.8%) in the placebo group; P=0.54), while the rate of transient tachypnoea was high in both groups (34 (24%) <i>v</i> 29 (22%); P=0.77). There was no reduction in the risk of respiratory morbidity with corticosteroid use even after adjustment for subgroups of gestational age (34-34<sup>+6</sup> weeks, 35-35<sup>+6</sup> weeks, and ≥36 weeks). The adjusted risk of respiratory morbidity was 1.12 (95% confidence interval 0.74 to 1.70). The need for ventilatory support was around 20% in both groups. There was no difference in neonatal morbidity (88 (62%) <i>v</i> 93 (72%); P=0.08) or in the duration of stay in hospital between the two groups (5.12 <i>v</i> 5.22 days; P=0.87). Phototherapy for jaundice was required less often in babies whose mothers received corticosteroids (risk ratio 0.63, 0.44 to 0.91). <b>Conclusions</b> Antenatal treatment with corticosteroids at 34-36 weeks of pregnancy does not reduce the incidence of respiratory disorders in newborn infants. <b>Trial registration</b> Clinical Trials NCT00675246.