tbuckley/cabot-search huggingface dataset:
SNAI1 is critical for the aggressiveness of prostate cancer cells with low E-cadherin
Authors: Gagan Deep, Anil K Jain, Anand Ramteke, Harold Ting, Kavitha C Vijendra, Subhash C Gangar, Chapla Agarwal, Rajesh Agarwal
Journal: Molecular Cancer (2014)

A better molecular understanding of prostate carcinogenesis is warranted to devise novel targeted preventive and therapeutic strategies against prostate cancer (PCA), a major cause of mortality among men. Here, we examined the role of two epithelial-to-mesenchymal transition (EMT) regulators, the adherens junction protein E-cadherin and its transcriptional repressor SNAI1, in regulating the aggressiveness of PCA cells.The growth rate of human prostate carcinoma PC3 cells with stable knock-down of E-cadherin (ShEC-PC3) and respective control cells (Sh-PC3) was compared in MTT and clonogenic assays in cell culture and in nude mouse xenograft model in vivo. Stemness of ShEC-PC3 and Sh-PC3 cells was analyzed in prostasphere assay. Western blotting and immunohistochemistry (IHC) were used to study protein expression changes following E-cadherin and SNAI1 knock-down. Small interfering RNA (siRNA) technique was employed to knock- down SNAI1 protein expression in ShEC-PC3 cells.ShEC-PC3 cells exerted higher proliferation rate both in cell culture and in athymic nude mice compared to Sh-PC3 cells. ShEC-PC3 cells also formed larger and a significantly higher number of prostaspheres suggesting an increase in the stem cell-like population with E-cadherin knock-down. Also, ShEC-PC3 prostaspheres disintegration, in the presence of serum and attachment, generated a bigger mass of proliferating cells as compared to Sh-PC3 prostaspheres. Immunoblotting/IHC analyses showed that E-cadherin knock-down increases the expression of regulators/biomarkers for stemness (CD44, cleaved Notch1 and Egr-1) and EMT (Vimentin, pSrc-tyr416, Integrin β3, β-catenin, and NF-κB) in cell culture and xenograft tissues. The expression of several bone metastasis related molecules namely CXCR4, uPA, RANKL and RunX2 was also increased in ShEC-PC3 cells. Importantly, we observed a remarkable increase in SNAI1 expression in cytoplasmic and nuclear fractions, prostaspheres and xenograft tissues of ShEC-PC3 cells. Furthermore, SNAI1 knock-down by specific siRNA strongly inhibited the prostasphere formation, clonogenicity and invasiveness, and decreased the level of pSrc-tyr416, total Src and CD44 in ShEC-PC3 cells. Characterization of RWPE-1, WPE1-NA22, WPE1-NB14 and DU-145 cells further confirmed that low E-cadherin is associated with higher SNAI1 expression and prostasphere formation.Together, these results suggest that E-cadherin loss promotes SNAI1 expression that controls the aggressiveness of PCA cells.
Electrodiffusive movements of chloride ion in sodium-free solution: a possible calcium activated chloride conductance in cultured heart cells
Authors: S. Liu, M. Lieberman
Journal: Cardiovascular Research (1994)

The aim was to demonstrate that removal of extracellular sodium (Na+o), a manoeuvre known to increase intracellular calcium (Cai2+), can activate a chloride ion conductance in cultured embryonic chick heart cells.Intracellular chloride activity (aiCl) and membrane potentials (Em) were simultaneously measured using chloride selective and 3 M KCl filled microelectrodes.In Na+o-free and K+o-free solutions, a frusemide (0.3 mM) resistant decrease in aiCl of 10 mM was recorded within 10 min, along with a 5 mV hyperpolarisation, and the calculated chloride equilibrium potential (ECl) followed the change of Em, suggesting a possibly enhanced chloride conductance. When cells were exposed to Na+o-free solution, the decrease of aiCl by approximately 10 mM was associated with an initial depolarisation, followed by a hyperpolarisation to approximately -60 mV (more negative than ECl). Subsequent removal of K+o depolarised Em to -39 mV (approximately ECl), and no further loss of aiCl occurred. Restoration of K+o caused a hyperpolarisation of Em (more negative than ECl) and a continuing decline of aiCl. Prevention of K+o induced hyperpolarisation by addition of 1 mM Ba2+ stopped the decline of aiCl (Em approximately ECl), suggesting that following Na+o removal, alteration of the driving force for chloride led to a chloride efflux via an enhanced chloride conductance. When Em depolarised to -50 mV after 3 min exposure to 0.1 mM ouabain, removal of [Cl-]o caused a further depolarisation and readdition of [Cl-]o induced an 18 mV hyperpolarisation. This chloride induced hyperpolarisation was blocked by removal of [Ca2+]o (+1 mM EGTA).The increase in chloride conductance observed under conditions that are known to raise Ca2+i supports the presence of a Ca2+i activated chloride conductance in cultured chick heart cells.
Enhanced Na(+)-Ca2+ exchange activity in cardiomyopathic Syrian hamster.
Authors: S N Hatem, J S Sham, M Morad
Journal: Circulation Research (1994)

The signaling of contraction by Ca2+ in the Syrian hamster (BIO 14.6) heart in the late stage of the cardiomyopathy (220 to 300 days old) was compared with that in age-matched healthy hamster hearts. Membrane current and cell shortening or intracellular Ca2+ transients were measured simultaneously in isolated whole-cell-clamped myocytes. The density of the L-type Ca2+ current was smaller in myopathic than in normal myocytes (2.13 +/- 0.3 versus 3.21 +/- 0.4 pA/pF at 0 mV, P &lt; .05). In both control and myopathic myocytes, the L-type Ca2+ current gated the release of Ca2+ and activation of contraction. In myopathic myocytes, activation of contraction also activated a slowly inactivating inward current of 1.73 +/- 0.2 pA/pF. The Na(+)-Ca2+ exchanger generated this current (INa-Ca), because it was suppressed by rapid replacement of Na+ with Li+ and depletion of the intracellular Ca2+ pool by caffeine. INa-Ca, activated by rapid application of caffeine, was not significantly different in both groups (3.7 +/- 0.5 pA/pF in control hearts versus 3.9 +/- 0.5 pA/pF in cardiomyopathic hearts). The activation of the inward exchanger current in myopathic myocytes coincided with a significant prolongation of contraction and the intracellular Ca2+ transient and a delay in the onset of relaxation. These results suggest that the enhanced activity of the Na(+)-Ca2+ exchanger may be related to compromised sequestration of Ca2+ in these animals.
Statins for heart failure: a potential for new treatment
Authors: N Haramaki
Journal: Cardiovascular Research (2003)

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are potent and widely used cholesterol-lowering drugs. Since the pathophysiology of atherosclerosis involves the uptake of modified low density lipoprotein (LDL) cholesterol, it has been generally assumed that the cholesterol-lowering effect of statins mediates the beneficial effects on atherosclerotic disease. Several clinical trials have demonstrated beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, subgroup analysis and meta-analysis of cholesterol-lowering trials indicated that the risk of atherosclerotic disease in patients treated with statins is significantly lower than the expected risk based on the level of serum cholesterol. These findings mostly suggest the existence of statins' beneficial effects beyond their cholesterol-lowering effects, which are termed “pleiotropic effects”. The pleiotropic effects of statins involved improvement of endothelial function, stabilization of atherosclerotic plaques, inhibition of cell migration and proliferation, and reduction of inflammation and oxidative stress. Many of these properties seem to contribute to the favorable effects of statins on atherosclerotic disease. However, in terms of pleiotropic effects, statins need not be limited to prevention of atherosclerotic disease.

Heart failure is a complex syndrome that consists not only of hemodynamic abnormalities but also of metabolic and neurohormoral alterations. Although hemodynamic stress in heart failure may play a role in the disease process, it is now believed that many other mechanisms, such as the activation of neurohormones and proinflammatory cytokines, may be more important in mediating the progression of heart failure. In particular, serum levels of proinflammatory cytokines such as tumor necrosis factor-α, interleukin 6, and C-reactive protein (CRP) are … 

*Corresponding author. Tel.: +81-942-35-3311; fax: +81-942-33-6509. Email address: haramaki{at}med.kurume-u.ac.jp
Release of angiotensin converting enzyme by the lung after Pseudomonas bacteremia in sheep.
Authors: A B Gorin, G Hasagawa, M Hollinger, J Sperry, J Zuckerman
Journal: Journal of Clinical Investigation (1981)

We studied release of angiotensin-converting enzyme (ACE) by the lung after acute injury associated with an increase in pulmonary vascular permeability. In eight adult sheep with chronic lung lymph fistulas, we measured lymph flow (QL), and both ACE activity and total protein content in lymph and plasma under base-line conditions and during 24 h after an infusion of live pseudomonas organism. Under base-line conditions, ACE activity in plasma was 4.93 +/- 0.43 U/ml (mean +/- SEM). The [lymph]/[plasma] ([L]/[P]) ratio for ACE was 0.93 +/- 0.18, compared with a ratio of 0.79 +/- 0.08 for albumin (mean +/- SD). We estimated the molecular weight of ovine ACE to be 145,000 by gel chromatography. Predicted [L]/[P] ratio for a molecule this size is 0.51. Thus, a substantial fraction of ACE activity detected lung lymph under base-line conditions (11.1 +/- 6.2 U/h; mean +/- SD) originated in the lung, and did not diffuse passively from plasma. After pseudomonas infusion, endothelial injury was demonstrated by a rise in pulmonary vascular clearance for total protein (Crp = QL X [L]/[P]). Crp = 3.1 +/- 0.6 ml/h before pseudomonas bacteremia, and rose to 6.7 +/- 1.2 ml/h by 2 h after onset of the infusion (means +/- SEM, p less than 0.05). Crp remained significantly elevated for at least 10 h after the infusion. Release of ACE into lung lymph doubled after acute lung injury and equaled 22.3 +/- 13.8 U/h at 4 h after onset of the infusion. ACE secretion into lung lymph had returned to baseline levels by 24 h after bacteremia. We did not observe a significant rise in plasma ACE activity after acute lung injury. Pseudomonas bacteremia in sheep results in acute, reversible lung injury associated with increased pulmonary vascular permeability, and increased release of ACE by the lung. Failure to detect a rise in plasma ACE content might result from dilution in the large vascular pool or rapid catabolism of the enzyme at some site distant from the lung.
Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway
Authors: Milton W Datta, Ana Maria Hernandez, Michael J Schlicht, Andrea J Kahler, Amy M DeGueme, Rajiv Dhir, Rajal B Shah, Cindy Farach-Carson, Andrea Barrett, Sumana Datta
Journal: Molecular Cancer (2006)

Abstract Background Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 ( Perlecan ) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila . More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer. Results Here we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling. Conclusion We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects.
Morphologic changes in infarct-related plaque after coronary stent placement
Authors: Shunta Sakai, Kyoichi Mizuno, Shinya Yokoyama, Jun Tanabe, Takuroh Shinada, Koji Seimiya, Masamichi Takano, Takayoshi Ohba, Masato Tomimura, Ryota Uemura, Takahiro Imaizumi
Journal: Journal of the American College of Cardiology (2003)
Phase I Pharmacokinetic and Pharmacodynamic Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors
Authors: James P. Thomas, Rhoda Z. Arzoomanian, Dona Alberti, Rebecca Marnocha, Fred Lee, Andreas Friedl, Kendra Tutsch, Amy Dresen, Peter Geiger, James Pluda, William Fogler, Joan H. Schiller, George Wilding
Journal: Journal of Clinical Oncology (2003)

Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors.Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m2 was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m2. Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography.Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen.Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.
The malalignment syndrome: implications for medicine and sport
Authors: G Kolt
Journal: British Journal of Sports Medicine (2004)

Wolf Schamberger. London: Churchill Livingstone, 2002, £39.99, hardcover, pp 456. ISBN 0443064717

The concepts of malalignment and imbalance have gained popularity in sports medicine over the past 10 years, and have been used to explain many of the injuries with which athletes and physical activity participants present. Rather than simply treating local symptoms, sports medicine practitioners are now looking more globally for contributing factors to injuries and encouraging preventive measures that address these more global deficits. The malalignment syndrome is a comprehensive text that can assist sports medicine practitioners …
Sudden death after radiofrequency ablation of the atrioventricular node in patients with atrial fibrillation
Authors: Cevher Ozcan, Arshad Jahangir, Paul A Friedman, David L Hayes, Thomas M Munger, Robert F Rea, Margaret A Lloyd, Douglas L Packer, David O Hodge, Bernard J Gersh, Stephen C Hammill, Win-Kuang Shen
Journal: Journal of the American College of Cardiology (2002)
THE ETIOLOGY OF TEMPORARY AMNESIA
Authors: Frederic H. Leavitt
Journal: American Journal of Psychiatry (1935)

1. The investigation showed that many etiological factors may underlie the production of amnesia and loss of identity. 2. In the 104 cases studied, the great classifications were organic brain disease, functional mental disease, the psychoneuroses, exogenous and endogenous toxæmias, epilepsy, and malingering. 3. Males constituted the great bulk of the cases, with the exception of the psychoneurosis-hysteria and the malingering group, where females predominated. 4. Among the negro race, females constituted the great majority of the patients, very few negro males developing amnesia. 5. The most melodramatic and interesting cases were those that were of an hysterical or epileptic genesis. 6. In children, the condition occurred only when constitutional mental inferiority was present. 7. The ratio of amnesia cases to total cases admitted in an acute psychopathic hospital service was 1:120.
Primary metastatic (stage IV) Ewing tumor: Survival analysis of 171 patients from the EICESS studies
Authors: M. Paulussen, S. Ahrens, S. Burdach, A. Craft, B. Dockhorn-Dworniczak, J. Dunst, B. Fröhlich, W. Winkelmann, A. Zoubek, H. Jürgens
Journal: Annals of Oncology (1998)
The Evolution of Aerobic Fermentation in Schizosaccharomyces pombe Was Associated with Regulatory Reprogramming but not Nucleosome Reorganization
Authors: Zhenguo Lin, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2010)

Aerobic fermentation has evolved independently in two yeast lineages, the Saccharomyces cerevisiae and the Schizosaccharomyces pombe lineages. In the S. cerevisiae lineage, the evolution of aerobic fermentation was shown to be associated with transcriptional reprogramming of the genes involved in respiration and was recently suggested to be linked to changes in nucleosome occupancy pattern in the promoter regions of respiration-related genes. In contrast, little is known about the genetic basis for the evolution of aerobic fermentation in the Sch. pombe lineage. In particular, it is not known whether respiration-related genes in Sch. pombe have undergone a transcriptional reprogramming or changes in nucleosome occupancy pattern in their promoter regions. In this study, we compared genome-wide gene expression profiles of Sch. pombe with those of S. cerevisiae and the aerobic respiration yeast Candida albicans. We found that the expression profile of respiration-related genes in Sch. pombe is similar to that of S. cerevisiae, but different from that of C. albicans, suggesting that their transcriptional regulation has been reprogrammed during the evolution of aerobic fermentation. However, we found no significant nucleosome organization change in the promoter of respiration-related gene in Sch. pombe.
EPIDEMIOLOGY OF LYMPHOCYTIC CHORIOMENINGITIS IN A MOUSE STOCK OBSERVED FOR FOUR YEARS
Authors: Erich Traub
Journal: The Journal of Experimental Medicine (1939)

A small mouse stock in which lymphocytic choriomeningitis is endemic has been observed over a period of 4 years. The disease has persisted during that time, but it has become so mild that it can no longer be recognized by clinical observation. In spite of this fact, all of the stock mice tested, both young and old, carried considerable amounts of virus in their organs and blood. The females readily transmit the infection to their offspring. Intrauterine infection has become the only mode of transmission of the disease in contrast to the situation in 1935 when a certain number of mice were born virus-free and became infected by contact shortly after birth. The present mildness of the disease appears to be due to two factors, namely, the change in its mode of transmission just mentioned, and a shift in the severity of the disease with regard to the age of the host at the time of infection. This shift has occurred gradually since 1935 when the mice infected in utero were the only ones to become sick. Since 1937, however, the virus is quite harmless for such animals and produces symptoms only in suckling mice from the virus-free stock exposed to contact infection. Evidence is presented which suggests that the shift in the severity of the disease was caused by a decrease of the pathogenicity of the virus for embryonic mouse tissue and a concurrent increase of the resistance to intrauterine infection of the mice from the infected stock. Another change noted concerned the communicability of the experimental disease. In contrast to observations made in 1935 the experimental infection of mature mice from the virus-free colony is now very rarely transmitted by contact to healthy mice, young or old. Suckling mice from the same stock infected by intranasal instillation of virus, however, readily transmit the disease and continue to do so as they grow up. The same is true for mice infected naturally. The reason for this discrepancy has not been ascertained, but it has been shown that naturally infected mice capable of transmitting the disease in general discharge large amounts of virus through the nose for a longer period of time than mature mice infected experimentally which fail to transmit their infection. It may likewise be of significance in this connection that the virus can lose its communicability by animal passage. A marked change (chiefly climatic and dietary) in the environmental conditions of the infected stock failed to influence the course and character of the epidemic.