tbuckley/cabot-search huggingface dataset:
Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression
Authors: Amrendra K Ajay, Ankur K Upadhyay, Sandeep Singh, Maleppillil V Vijayakumar, Ratna Kumari, Vimal Pandey, Ramanamurthy Boppana, Manoj K Bhat
Journal: Molecular Cancer (2010)

Abstract Background p53 is the most studied tumor suppressor and its overexpression may or may not cause cell death depending upon the genetic background of the cells. p53 is degraded by human papillomavirus (HPV) E6 protein in cervical carcinoma. Several stress activated kinases are known to phosphorylate p53 and, among them cyclin dependent kinase 5 (Cdk5) is one of the kinase studied in neuronal cell system. Recently, the involvement of Cdk5 in phosphorylating p53 has been shown in certain cancer types. Phosphorylation at specific serine residues in p53 is essential for it to cause cell growth inhibition. Activation of p53 under non stress conditions is poorly understood. Therefore, the activation of p53 and detection of upstream kinases that phosphorylate non-genotoxically overexpressed p53 will be of therapeutic importance for cancer treatment. Results To determine the non-genotoxic effect of p53; Tet-On system was utilized and p53 inducible HPV-positive HeLa cells were developed. p53 overexpression in HPV-positive cells did not induce cell cycle arrest or apoptosis. However, we demonstrate that overexpressed p53 can be activated to upregulate p21 and Bax which causes G2 arrest and apoptosis, by inhibiting protein phosphatase 2A. Additionally, we report that the upstream kinase cyclin dependent kinase 5 interacts with p53 to phosphorylate it at Serine20 and Serine46 residues thereby promoting its recruitment on p21 and bax promoters. Upregulation and translocation of Bax causes apoptosis through intrinsic mitochondrial pathway. Interestingly, overexpressed activated p53 specifically inhibits cell-growth and causes regression in vivo tumor growth as well. Conclusion Present study details the mechanism of activation of p53 and puts forth the possibility of p53 gene therapy to work in HPV positive cervical carcinoma.
Comparison of Simian Virus 40-Induced Mouse and Hamster Tumor-Specific Transplantation Antigens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J H Coggin
Journal: JNCI Journal of the National Cancer Institute (1979)

The tumor-specific transplantation antigen (TSTA), which appears on papovavirus-induced sarcomas of the hamster, has been demonstrated to be common in any cell type transformed by a given virus. Other studies have suggested that cell-free TSTA has been successfully Isolated from mouse sarcoma cells Induced in vitro by simian virus 40 (SV40). Considerable work has been done toward purifying and identifying this mouse TSTA. We obtained preparations from the laboratory reporting the isolation of TSTA from the SV40-induced mouse sarcoma cells as well as cell lines from which the preparations of TSTA had been derived. These extracts, as well as fresh extracts made from the appropriate SV40-induced mouse tumor line, were tested for their ability to Interrupt tumor production in mice after challenge with homologous and heterologous sarcomas and to prevent SV40 primary tumor induction in hamsters. The findings indicated that TSTA extracted from SV40-induced mouse sarcoma cells as well as from the intact irradiated mouse sarcoma cells failed to prevent SV40 oncogenesis as well as tumor transplantation in the hamster, but It was capable of preventing specific tumor transplantation when used as a vaccine in mice. Human and hamster cells transformed by SV40 were capable of interrupting SV40 oncogenesis in the hamster. These results suggested that the so-called TSTA, which is immunogenic and induces specific transplantation resistance in mice to SV40-in-duced mouse sarcomas, was not the same TSTA that appears on human, rat, and hamster cells and that is produced by SV40 in those cell types. Further, tumor antigen may be the immunizing component which others have isolated as a transplantation-like antigen from mouse sarcoma cells. An alternative explanation would be a peculiar histocompatibility (H-2) barrier in the hamster to the immunogenicity of TSTA induced in mouse cells.
Dietary Precursors and Brain Neurotransmitter Formation
Authors: J D Fernstrom
Journal: Annual Review of Medicine (1981)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Akt activation by PHLPP1 ablation prevents pathological hypertrophy by promoting angiogenesis
Authors: Mingchuan Li, Emilio Hirsch
Journal: Cardiovascular Research (2014)

This editorial refers to ‘Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy’ by C. Moc et al. , pp. 160–170, this issue. 

Akt/PKB (protein kinase B) plays a central role in regulating cardiac hypertrophy and contractile function. Appropriate activation of Akt in the heart is known to protect against cardiac remodelling, but abnormal long-term Akt stimulation leads to heart failure.1 Although Akt modulation could, in principle, be exploited to promote adaptive cardiac remodelling, an efficient way to safely activate Akt has so far never been reported. Moc et al. 2 rescue pressure overload-induced cardiac hypertrophy through a safe way to activate Akt by ablation of the protein phosphatase PHLPP1 ( Figure 1 ). 



Figure 1 
Involvement of PHLPP1 in Akt-related cardiac processes. (Left) PHLPP1 dephosphorylates Akt on Ser473 and inhibits its activity. The pro-angiogenic and pro-survival Akt-dependent signalling remains low. (Right) Blocking of PHLPP1 releases the inhibition of Akt activity, enhances angiogenesis, and reduces apoptotic cell death.



In the heart, Akt regulates multiple cardiac functions, such as cardiomyocyte growth, apoptosis, angiogenesis, and contractility. Akt is at the centre of a crossroad involving a large plethora of different signalling molecules. When cells receive multiple stimulations from the environment, receptors in the cell membrane, like …
Risk factors for complicated parapneumonic effusion and empyema on presentation to hospital with community-acquired pneumonia
Authors: J D Chalmers, A Singanayagam, M P Murray, C Scally, A Fawzi, A T Hill
Journal: Thorax (2009)

<h3>Background:</h3> The aim of this study was to identify key factors on admission predicting the development of complicated parapneumonic effusion or empyema in patients admitted with community-acquired pneumonia. <h3>Methods:</h3> A prospective observational study of patients admitted with community-acquired pneumonia in NHS Lothian, UK, was conducted. Multivariate regression analyses were used to evaluate factors that could predict the development of complicated parapneumonic effusion or empyema, including admission demographics, clinical features, laboratory tests and pneumonia-specific (Pneumonia Severity Index (PSI), CURB65 (New onset confusion, urea &gt;7 mmol/l, Respiratory rate ≥30 breaths/min, Systolic blood pressure &lt; 90 mm Hg and/or diastolic blood pressure ≤60 mm Hg and age ≥65 years) and CRB65 (New onset confusion, Respiratory rate ≥30 breaths/min, Systolic blood pressure &lt;90 mm Hg and/or diastolic blood pressure ≤60 mm Hg and age ≥65 years)) and generic sepsis scoring systems (APACHE II (Acute Physiology and Chronic Health Evaluation II), SEWS (standardised early warning score) and systemic inflammatory response syndrome (SIRS)). <h3>Results:</h3> 1269 patients were included in the study and 92 patients (7.2%) developed complicated parapneumonic effusion or empyema. The pneumonia-specific and generic sepsis scoring systems had no value in predicting complicated parapneumonic effusion or empyema. Multivariate logistic regression identified albumin &lt;30 g/l adjusted odds ratio (AOR) 4.55 (95% CI 2.45 to 8.45, p&lt;0.0001), sodium &lt;130 mmol/l AOR 2.70 (1.55 to 4.70, p = 0.0005), platelet count &gt;400×10<sup>9</sup>/l AOR 4.09 (2.21 to 7.54, p&lt;0.0001), C-reactive protein &gt;100 mg/l AOR 15.7 (3.69 to 66.9, p&lt;0.0001) and a history of alcohol abuse AOR 4.28 (1.87 to 9.82, p = 0.0006) or intravenous drug use AOR 2.82 (1.09 to 7.30, p = 0.03) as independently associated with development of complicated parapneumonic effusion or empyema. A history of chronic obstructive pulmonary disease was associated with decreased risk, AOR 0.18 (0.06 to 0.53, p = 0.002). A 6-point scoring system using these combined variables had good discriminatory value: area under the receiver operator characteristic curve (AUC) 0.84 (95% CI 0.81 to 0.86, p&lt;0.0001). <h3>Conclusion:</h3> This study has identified seven clinical factors predicting the development of complicated parapneumonic effusion or empyema. Independent validation is needed.
The pattern and timing of breathing during incremental exercise: a normative study
Authors: J.A. Neder, S. Dal Corso, C. Malaguti, S. Reis, M.B. De Fuccio, H. Schmidt, J.P. Fuld, L.E. Nery
Journal: European Respiratory Journal (2003)

Clinical evaluation of the pattern and timing of breathing during submaximal exercise can be valuable for the identification of the mechanical ventilatory consequences of different disease processes and for assessing the efficacy of certain interventions. Sedentary individuals (60 male/60 female, aged 20-80 yrs) were randomly selected from >8,000 subjects and submitted to ramp incremental cycle ergometry. Tidal volume (VT)/resting inspiratory capacity, respiratory frequency, total respiratory time (Ttot), inspiratory time (TI), expiratory time (TE), duty cycle (TI/Ttot) and mean inspiratory flow (VT/TI) were analysed at selected submaximal ventilatory intensities. Senescence and female sex were associated with a more tachypnoeic breathing pattern during isoventilation. The decline in Ttot was proportional to the TI and TE reductions, i.e. TI/Ttot was remarkably constant across age strata, independent of sex. The pattern, but not timing, of breathing was also influenced by weight and height; a set of demographically and anthropometrically based prediction equations are therefore presented. These data provide a frame of reference for assessing the normality of some clinically useful indices of the pattern and timing of breathing during incremental cycle ergometry in sedentary males and females aged 20-80 yrs.
Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes: Autoantibodies, Autoantigens, and Their Applicability in Diagnosis and Disease Prediction
Authors: Corrado Betterle, Chiara Dal Pra, Franco Mantero, Renato Zanchetta
Journal: Endocrine Reviews (2002)

Abstract Recent progress in the understanding of autoimmune adrenal disease, including a detailed analysis of a group of patients with Addison’s disease (AD), has been reviewed. Criteria for defining an autoimmune disease and the main features of autoimmune AD (history, prevalence, etiology, histopathology, clinical and laboratory findings, cell-mediated andhumoral immunity, autoantigens and their autoepitopes, genetics, animal models, associated autoimmune diseases, pathogenesis, natural history, therapy) have been described. Furthermore, the autoimmune polyglandular syndromes (APS) associated with AD (revised classification, animal models, genetics, natural history) have been discussed. Of Italian patients with primary AD (n = 317), 83% had autoimmune AD. At the onset, all patients with autoimmune AD (100%) had detectable adrenal cortex and/or steroid 21-hydroxylase autoantibodies. In the course of natural history of autoimmune AD, the presence of adrenal cortex and/or steroid 21-hydroxylase autoantibodies identified patients at risk to develop AD. Different risks of progression to clinical AD were found in children and adults, and three stages of subclinical hypoadrenalism have been defined. Normal or atrophic adrenal glands have been demonstrated by imaging in patients with clinical or subclinical AD. Autoimmune AD presented in four forms: as APS type 1 (13% of the patients), APS type 2 (41%), APS type 4 (5%), and isolated AD (41%). There were differences in genetics, age at onset, prevalence of adrenal cortex/21-hydroxylase autoantibodies, and associated autoimmune diseases in these groups. “Incomplete” forms of APS have been identified demonstrating that APS are more prevalent than previously reported. A varied prevalence of hypergonadotropic hypogonadism in patients with AD and value of steroid-producing cells autoantibodies reactive with steroid 17α-hydroxylase or P450 side-chain cleavage enzyme as markers of this disease has been discussed. In addition, the prevalence, characteristic autoantigens, and autoantibodies of minor autoimmune diseases associated with AD have been described. Imaging of adrenal glands, genetic tests, and biochemical analysis have been shown to contribute to early and correct diagnosis of primary non-autoimmune AD in the cases of hypoadrenalism with undetectable adrenal autoantibodies. An original flow chart for the diagnosis of AD has been proposed.
The Influence of Body Mass Index on Severe Neutropenia with Dose-Dense Paclitaxel/Carboplatin in Ovarian Cancer Patients
Authors: N. Takase, M. Tanioka, T. Onoe, A. Kitao, Y. Kikukawa, K. Matsumoto, S. Yamaguchi, K. Fujiwara, S. Negoro
Journal: Annals of Oncology (2013)
Inhibition of Hypoxia Inducible Factor-1α by Dihydroxyphenylethanol, a Product from Olive Oil, Blocks Microsomal Prostaglandin-E Synthase-1/Vascular Endothelial Growth Factor Expression and Reduces Tumor Angiogenesis
Authors: Erika Terzuoli, Sandra Donnini, Antonio Giachetti, Miguel A. Iñiguez, Manuel Fresno, Giovanni Melillo, Marina Ziche
Journal: Clinical Cancer Research (2010)

Abstract Purpose: 2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity. Experimental Design: To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1β (IL-1β) and prostaglandin E-2 (PGE-2). Results: DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 μmol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1β–mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1α. Moreover, DPE blocked mPGEs-1–dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1α, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal–related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1α expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1α translation. Conclusions: We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1α/mPGEs-1/VEGF axis. Clin Cancer Res; 16(16); 4207–16. ©2010 AACR.
On the origins of esterases.
Authors: M Myers, R C Richmond, J G Oakeshott
Journal: Molecular Biology and Evolution (1988)

Comparisons among the primary sequences of five cloned eukaryotic esterases reveal two distinct lineages, neither bearing any significant overall sequence similarity to the functionally related serine protease multigene family. We have not eliminated the possibility that the esterases may have residual conformational similarities to the serine proteases. However, our profile analysis and analyses of the predicted conformations of the esterases reveal little similarity to the serine proteases. Four of the esterase proteins share 27%-53% overall sequence similarity and evidence of a catalytic mechanism involving the same Arg-Asp-Ser or His-Asp-Ser charge relay. We propose that these four esterases, three of them cholinesterases, form part of a multigene family essentially separate from the serine proteases.
Elevated Heat Shock Protein 60 Levels Are Associated With Higher Risk of Coronary Heart Disease in Chinese
Authors: Xiaomin Zhang, Mei'an He, Longxian Cheng, Ying Chen, Li Zhou, Hesong Zeng, A. Graham Pockley, Frank B. Hu, Tangchun Wu
Journal: Circulation (2008)

Background— Although heat shock protein 60 (Hsp60) is implicated in the pathogenesis of atherosclerosis, its role in coronary heart disease (CHD) is uncertain. This study explored the influence of circulating Hsp60 on CHD in a large case-control study, as well as the impact of acute myocardial infarction on Hsp60 levels in a prospective study. Methods and Results— Plasma Hsp60 and anti-Hsp60 antibody levels were determined by immunoassay. In the case-control study (1003 patients with CHD, 1003 matched control subjects), Hsp60 levels were higher in patients with CHD and were related to CHD (OR comparing extreme quartiles=4.14, P &lt;0.0001). This association remained after adjustment for traditional risk factors ( P for trend &lt;0.0001). Individuals having high levels of Hsp60 (greater than the median of 160.24 ng/mL) and anti-Hsp60 antibody (greater than the median of 38.42 U/mL) were at a greater risk of CHD than those with low levels (OR 2.30, P &lt;0.0001). Stronger additive effects (OR 14.04, P &lt;0.0001) were apparent at higher Hsp60 and anti-Hsp60 antibody levels (&gt;1000 ng/mL and greater than the median of 38.42 U/mL, respectively). The simultaneous presence of high Hsp60 and anti-Hsp60 antibody levels, current smoking, hypertension, and diabetes were cumulatively associated with CHD. Individuals who had any 4 or more of these 5 factors had an OR of 38.61 for CHD ( P &lt;0.0001) compared with individuals who had none of these factors. For the prospective study, blood was drawn from 20 patients immediately after admission for acute myocardial infarction and 2, 3, and 7 days thereafter. Hsp60 levels were significantly higher on the day of and the day after arrival than 7 days after an acute myocardial infarction ( P =0.011 and P =0.026, respectively). Conclusions— Elevated Hsp60 levels are associated with an increased risk for CHD, and Hsp60 and anti-Hsp60 antibody levels combine to increase this risk. In addition, acute myocardial infarction induces Hsp60 release.
Hemodynamic effects of α-adrenergic blockade with prazosin in cirrhotic patients with portal hypertension
Authors: Agustin Albillos, Jose Luis Lledó, Rafael Bañares, Irma Rossi, Jerónimo Iborra, Jose Luis Calleja, Aurelio Garrido, Pedro Escartin, Jaime Bosch
Journal: Hepatology (1994)

This study was aimed at investigating whether the blockade of alpha 1-adrenergic receptors could reduce portal pressure in cirrhosis. Splanchnic and systemic hemodynamics were measured in 12 cirrhotic patients with esophageal varices at baseline and 1 hr after oral administration of 2 mg of prazosin (acute study). Measurements were repeated in 10 of these 12 patients after a 3-mo course of 5 mg/12 hr of prazosin (long-term study). Short-term prazosin significantly lowered the hepatic venous pressure gradient from 20.1 +/- 1.3 to 14.4 +/- 0.9 mm Hg (-25.7%) (p < 0.01), and chronic prazosin reduced it to 16.5 +/- 1.3 mm Hg (-19.1%) (p < 0.01). Hepatic blood flow was increased, thus changes in the hepatic venous pressure gradient resulted from a reduction in the estimated hepatic vascular resistance. Reductions in hepatic venous pressure gradient achieved after short-term and long-term prazosin were not significantly different. Reductions in mean arterial pressure and systemic vascular resistance were significantly greater after short-term than after long-term prazosin. Long-term prazosin was associated with significant increases in hepatic and intrinsic hepatic clearances of indocyanine green. This therapy also led to an increase in pulmonary capillary pressure (+ 28.6%, p < 0.05) and body weight (+ 3.06%, p < 0.01) and a decrease in hematocrit (-6.1%, p < 0.05) and urinary sodium excretion (-22.6%, p < 0.05). In contrast, there were no hemodynamic changes in a group of six cirrhotic patients receiving placebo. In cirrhotic patients, short-term prazosin lowers portal pressure by decreasing hepatic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine
Authors: Dieter Rosskopf, Martin C. Michel
Journal: Pharmacological Reviews (2008)

Agonists and antagonists of G protein-coupled receptors are important drugs for the treatment of cardiovascular disease, but the therapeutic response of any given patient remains difficult to predict because of large interindividual variability. Among the factors potentially contributing to such variability, we have reviewed the evidence for a role of pharmacodynamic pharmacogenetics (i.e., polymorphisms in the cognate receptors for such drugs as well as other proteins potentially modifying their action). Based upon the availability of data and the prevalence of use, we have focused on ligands at adrenergic and angiotensin II receptors (including the indirectly acting angiotensin-converting enzyme inhibitors). The vast majority of gene polymorphisms reviewed here have shown only inconsistent effects on drug action, which does not make these polymorphisms useful genetic markers to predict treatment responses. We conclude that considerable additional research, partly involving other types of study than those available now, will be necessary to allow a definitive judgment whether pharmacodynamic pharmacogenetic markers are useful in an individualized approach to cardiovascular therapy. Moreover, we predict that even such additional research will result in only few cases where the promise of tailored treatment can be fulfilled; however, some of these few cases may be of major clinical relevance.
Further characterization of IgE‐binding antigens in horse dander, with particular emphasis on glycoprotein allergens
Authors: T. K. Johnsen, D. B. Thanh, Q. Ly, B. Smestad Paulsen, J. K. Wold
Journal: Allergy (1996)

IgE‐binding components in an extract of horse dander were analyzed, especially with regard to the glycoprotein allergens. After SDS‐PAGE under reducing conditions and blotting, several of the glycoprotein IgE‐binding components, including two distinct bands of 27 and 31 kDa, were detected. Together with several other bands, they were shown to bind to the lectins Sambucus nigra agglutinin (SNA) and Datura stramonium agglutinin (DSA), indicating terminal sialic acid linked α2→6 to galactose, and galactose linked β1→ 4 to N‐acetylglucosamine, respectively. Carbohydrate analysis after SDS‐PAGE and blotting showed the presence of mannose, galactose, N‐ acetylglucosamine, and N ‐acetyl neuraminic acid in the 27‐kDa band. The 14.4‐kDa glycoprotein component lost its IgE‐binding activity after periodate oxidation. Minor differences in allergenic activity in the other glycoprotein allergenic components were also detected, indicating that the carbohydrate part of the molecule seems to play a role in the IgE‐binding activity. Two‐dimensional electrophoresis and subsequent immunoblotting were performed to estimate the approximate number, molecular mass, and pI of IgE‐binding components. This resulted in a cluster of such components on the blot membrane.