tbuckley/cabot-search huggingface dataset:
Expression of phospho-AKT (Ser 473) is an excellent predictor of PSA failure in prostate cancer
Authors: Jeffrey I. Kreisberg, Shazli N. Malik, Thomas J. Prihoda, Roble G. Bedolla, Dean A. Troyer, Paramita M. Ghosh
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1463 

The serine/threonine protein kinase AKT (also known as Protein Kinase B), a downstream effector of phosphatidylinositol 3-kinase (PI3K), is a well-known mediator of cell survival, while ERK1/2, a member of the mitogen activated protein kinase (MAPK) family, is usually thought to be a mediator of proliferation. We previously showed by immunohistochemistry elevated expression of the phosphorylated (activated) form of AKT (Ser 473) (pAkt) and decreased expression of phosphorylated ERK1/2 (Thr202/Tyr204) (pERK), indicative of inactivation, in high Gleason grade prostate cancer (Malik et al, Clin Cancer Res, 2002, 8:1168-1171). Here we report a highly significant progressive increase in staining for the cell proliferation antigen, Ki67, with increasing Gleason scores (Pearson coefficient = 0.47, p<0.0001) in prostate tissue from 74 patients with adenocarcinoma of the prostate. Comparison of Ki67 labeling indices (Ki67-LI) with pAKT expression showed a significant positive correlation (Pearson coefficient = 0.36, p = 0.003). There was no correlation between staining for pERK and Ki67-LI. These results suggested that pAKT, but not pERK, mediated proliferation in prostate cancer. Next, we determined whether expression of pAkt or pERK predicted clinical outcome. PSA failure (detectable and rising PSA) vs. PSA non-failure (undetetectable PSA 5 years post-prostatectomy) was used as a surrogate for outcome. Prostatic tissues from cases of PSA failure vs. non-failure were stained for pAKT and pERK. Significant increase in mean pAKT staining (p<0.001) in the PSA failures vs non-failures were seen based on the Wilcoxon signed ranks test. Using the best fitting multiple logistic regression equation, a 100-point increase in pAKT resulted in a 160% increase in the odds of being a PSA failure. For pERK, there was decreased staining in PSA failures vs non-failures (p<0.08): a 100-point decrease resulted in an 80% increase in the odds of being a PSA failure. Each of these effects assumed the other biomarker was held constant. The area under the receiver operating characteristic (ROC) curve for these two biomarkers predicting PSA failure was 0.84, indicating excellent discrimination between PSA failure and non-failure cases. The Hosmer-Lemeshow goodness of fit test indicates a good fit for both models (pAKT and pERK). These data indicate that increase in pAKT and decreases in pERK are important predictors of probability of PSA failure.
Abstract 3829: Endothelial Cell Response to Hypoxia is Modulated by Microrna-210 Direct Targeting of Ephrin-A3
Authors: Pasquale Fasanaro, Yuri D’Alessandra, Valeria Di Stefano, Roberta Melchionna, Sveva Romani, Maurizio C Capogrossi, Fabio Martelli
Journal: Circulation (2008)

MicroRNAs (miRNAs) are small non-protein-coding RNAs that negatively modulate gene expression. In this study, miRNAs role in endothelial cell response to hypoxia was investigated. It was found that the expression of miR-210 progressively increased upon exposure to hypoxia. Interestingly, HIF1-alpha was necessary and sufficient for miR-210 induction, while HIF2-alpha was not necessary. miR-210 over-expression in normoxic endothelial cells increased the formation of capillary-like structures on Matrigel and VEGF-induced cell migration. Conversely, miR-210 blockade via LNA-anti-miRNA transfection decreased the formation of capillary-like structures stimulated by hypoxia and inhibited cell migration in response to VEGF. miR-210 over-expression did not affect endothelial cell growth in both hypoxia and normoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, both in normoxia and in hypoxia. We found that one relevant target of miR-210 in hypoxia was Ephrin-A3, since miR-210 was necessary and sufficient to down-regulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences: indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210, prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. A combination of proteomic and transcriptomic approaches has been undertaken, identifying potential direct and indirect targets of miR-210 action. We conclude that miR-210 induction is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration and differentiation.
Abstract 1212: Mutant p53 stabilizes and protects the transcription factor ETS2 from proteasomal degradation by the ubiquitin ligase COP1/DET1
Authors: Zunamys I. Carrero, Madhusudhan Kollareddy, Krishna M. Chauhan, Gopalakrishnan Ramakrishnan, Luis A. Martinez
Journal: Cancer Research (2015)

Abstract Genetic mutations of the tumor suppressor gene TP53 contribute to a great majority of human cancers. One mechanism by which mutant TP53 (mtp53) acts is through the interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with ETS2, an ETS transcription factor, and increases its stability. This results in an increase of the expression of ETS target genes that are associated with the transition of normal cells into tumor cells. Previous studies have shown that the ubiquitin-proteasomal pathway regulates ETS2 stability. To study the mechanism of ETS2 ubiquitin-mediated degradation, we used siRNA to knockdown ubiquitin ligases known to interact with ETS2. A significant increase in ETS2 stability was observed when the ubiquitin ligase COP1 and its binding partner DET1 were knocked down. We find that ectopically expressed COP1/DET1 leads to ETS2 ubiquitination and degradation, and that a COP1 without an intact RING domain fails to degrade ETS2. Mutation of COP1 putative binding sites in ETS2 also prevented its degradation. Given that mtp53 interacts with ETS2, we assessed mtp53's role in ETS2 stability by conducting ubiquitination assays. Our data showed that mtp53 prevents COP1/DET1 from ubiquitinating ETS2, thus preventing it from being degraded. We are currently studying the mechanism of COP1/DET1 binding to ETS2 and how mtp53 interferes with this process, thus rescuing ETS2. We surmise that mtp53 disrupts the binding of COP1/DET1 to ETS2, leading to its stabilization. Through this mechanism, mtp53 can alter the balance of ETS proteins in normal cells, which results in an increased ETS2 transcriptional program that drives cancer cells to be more invasive and metastatic. Citation Format: Zunamys I. Carrero, Madhusudhan Kollareddy, Krishna M. Chauhan, Gopalakrishnan Ramakrishnan, Luis A. Martinez. Mutant p53 stabilizes and protects the transcription factor ETS2 from proteasomal degradation by the ubiquitin ligase COP1/DET1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1212. doi:10.1158/1538-7445.AM2015-1212
Abstract 19986: Rotenone-Induced Mitochondrial Oxidative Stress Corrupts Tube Formations in Human Coronary Artery Endothelial Cells by Inhibiting mTOR Signaling Pathway
Authors: Yuh Fen Pung, Christopher Kolz, William M Chilian
Journal: Circulation (2010)

The function of the heart is highly dependent on oxidative energy that is generated in mitochondria. A by-product of mitochondrial bioenergetic activity is generation of reactive oxygen species. We...
Abstract 16088: Radial Artery Free and T Graft Patency Over a 15 Year Period
Authors: Hendrick Barner, Marci Bailey, Michael Pasque, Marc Moon, Ralph Damiano, Jennifer Lawton
Journal: Circulation (2011)

Objectives: The radial artery is often utilized as the second arterial graft for coronary artery bypass grafting (CABG). Little is known about the differences in long term patency between radial fr...
Cause of Death in Resistant and Advanced Chronic Myeloid Leukemia (CML) Patients Treated with Tyrosine Kinase Inhibitors (TKIs).
Authors: Lisa J McGarry, Chakkarin Burudpakdee, Smeet Gala, Arpamas Seetasith, Merena Nanavaty, Hui Huang
Journal: Blood (2014)
UV dose and DNA repair capacity predict non-melanoma skin cancer risk
Authors: Juan M. Ramos, Abigail Ruiz, Roy A. Armstrong, Jaime L. Matta
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2892 

Non-melanoma skin cancer (NMSC) is the most common cancer worldwide. UV radiation is an important risk factor for NMSC. UVA and UVB can cause DNA damage and promote carcinogenesis. Cancer risk is partly determined by the capacity of the body to repair DNA damage. DNA repair capacity (DRC) is an independent risk factor for the development of both NMSC and melanoma. A 3.5-year clinical case-control retrospective study was performed in Puerto Rico to develop a model of how environmental and lifestyle factors (UV exposure and use of sunblock) and genetic factors (DRC and skin type) influence the risk of NMSC. UVA and UVB measurements were obtained over a 5-year continuous period using a Biospherical Instruments GUV-511 radiometer. All participants (n=550) provided informed consent and completed a questionnaire that elicited information on risk factors including UV exposure in hours per month. DRC was measured in peripheral blood lymphocytes using a host cell reactivation assay with luciferase reporter gene. The contribution of each risk factor was determined by age-adjusted multivariate logistic regression analysis. Monthly averages of daily UV radiation fluxes ranged from 569 to 1504 kJ•m2•d^-1 . UV fluxes were 24% higher from March–September when compared with the October-February period. Persons with NMSC had a significantly lower DRC (42%) compared with controls. Significant risk or protective factors (p<0.05) included a minimum of 3-hour weekly cumulative UV dose (OR=1.90, 95% CI=1.08-3.17), skin type I and II (OR=6.2, 95% CI=3.66-10.31), and the use of sunblock (OR=0.30, 95% CI=0.18-0.51). A high DRC level (highest 10%) reduced NMSC risk 5.5-fold (OR=0.18, 95% CI=0.09-0.42) and a low DRC (lowest 33%) increased risk by 3.3-fold (OR=3.3, 95% CI=1.83-5.94). Overall, for every 1% decrease in DRC, the risk of developing NMSC increased by 20%. For each year of increasing age, NMSC risk increased 6%. Our findings suggest that NMSC risk is influenced by an interaction between genes and environment. Genetic factors and their interactions have a more pronounced influence than environmental factors alone although both types have a profound influence on NMSC risk. If our findings can be validated by others, these data may be useful for designing NMSC prevention programs. Supported by NIH-RCMI grant 2G12RR03050-19 to J.M.
Methods of surveying patients' satisfaction
Authors: K. T Gavin, M. J Turner, R. Fielding, A. Hedley, J. Cheang, A. Lee
Journal: BMJ (1997)

Data are not now collected by ethnic group in South AfricaEditor-Claire Hilton notes that since April 1995 British hospitals have had to collect data on each patient's ethnic group. 1 In the United States this is standard practice.In the Morbidity and Mortality Weekly Report data on numerous variables relating to the health and ill health of black and white people are regularly given 2 -as also, on occasion, are data on Hispanics, American Indians, Inuits, and Pacific Islanders.In South Africa precisely the converse has occurred.Ethnic subdivisions have stopped appearing in reports from the Central Statistics Services, and thus mortalities are no longer given for the constituent populations (black, Asian, coloured (Eur-African-Malay), and white), only for the combined population.Additionally, in our big cities annual reports from public health departments provide only combined data on morbidity and mortality.Disadvantages are many.Recently, colleagues and I reviewed changes in the total death rate and the death rate from coronary heart disease in South African populations. 3 We found that, from 1978 to 1989, mortality from coronary heart disease fell by 56% in the white population and by 36% in each of the Indian and coloured populations.Because changes in mortality from this foremost "killer" are continuing we intended to update our information.But this is now precluded.Currently, desegregation does not apply to our national cancer registry.But if it did how, for example, could benefits from Papanicolaou smear tests be assessed?The incidences of cervical cancer in the black and coloured populations are among the highest in the world.The constituent populations of South Africa have a wider divergence in the occurrence of a variety of diseases than occurs in any other country: coronary heart disease, appendicitis, colon cancer, and hip fractures.Interethnic differences in the occurrence of disease, reactivity, and metabolism are well known elsewhere. 4 In South Africa the change to using combined data will make it harder to identify and quantify the target populations who are in most need of help, as well as severely stultifying research on the occurrence of disease and on combating it.Hilton is right, of course, that the level of treatment is affected by ethnic group.Recently, in the United States the effect of race and income on mortality and the use of services among beneficiaries of Medicare was investigated; both race and income were shown as having substantial prejudicial effects, that of race being much more pronounced than that of income. 5This is a matter of universal shame.
Molecular Basis of Blood Diseases.
Authors: Peter T. Rowley
Journal: Annals of Internal Medicine (1988)

The recent application of the techniques of molecular biol- ogy to the study of human diseases has made it possible to obtain information unavailable-and, in some instances, unimaginable-a decade ago.Because of the rapidity with which developments have occurred, many clinicians and scientists may be unaware of them and of the insights they provide into the origin of diseases.To address the needs of this audience, four noted authorities in the field, George Stamatoyannopoulos, Arthur Nienhuis, Philip Leder, and Philip Majerus, have recruited 27 of their colleagues to describe what is currently known about the molecular basis of blood diseases.The first chapter introduces the reader to the methods of molecular cloning and analysis of gene structure that have generated much of the information pre- sented subsequently.Several chapters then describe gene structure, expression, and regulation, using the globin genes as a model.After this general introduction, specific groups of diseases are addressed.Each area of classic hematology-the red cell, the white cell (both normal and malignant), and the soluble and cellular components of the hemostatic system (including hemostasis, thrombosis, and fibrinolysis)-is taken up in turn.In addition, three chap- ters present immunological topics-immunoglobulin and T-cell receptor genes (as well as lymphocyte differentia- tion), enzyme deficiencies associated with immunological disorders, and molecular mechanisms of complement ac-
Abstract 20238: The Oncogenic Axis STAT3/Pim1 is a New Therapeutic Target for Human Pulmonary Arterial Hypertension
Authors: Roxane Paulin, Audrey Courboulin, Eric Dumas de La Roque, Jolyane Meloche, Sebastien Bonnet
Journal: Circulation (2010)

Pulmonary arterial hypertension (PAH) is a proliferative remodeling disease characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis. The sustainabili...
Abstract 1991: Paramedic Prehospital Cath Lab Activation for STEMI, Without ECG Transmission, Dramatically Reduces Door To Balloon Time
Authors: Fouad Bachour, Stephen W Smith, David Hildebrandt, Mengistu Simegn, Richard W Asinger
Journal: Circulation (2007)

BACKGROUND: By using a team-based approach, and ED staff activating the cath lab, our mean Door-Balloon Time (DBT) was <90 min. OBJECTIVE: Further improve our DBT through paramedic prehospital cath...
Kwashiorkor
Authors: M. K. Sandozai, A. H. Haquani, V. Rajeshvari, J. Kaur
Journal: BMJ (1963)

HYPOCHROMIC ANAEMIA with a similar anaemia in a sibling which was refractory to pyridoxine.In the second, several members suffered from varying combinations of refractory hypochromic anaemia with hyperferricaemia, pigmentation, and duodenal ulceration.The similarities between pyridoxine-responsive anaemia and other cases of hypochromic iron-loading anaemia refractory to treatment are emphasized.An apparent association of duodenal ulceration or dyspepsia and pig- mentation with this group of anaemias is noted and contrasted with the dissociation of these features in our second family.Our thanks are due to Mr. D.
Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study
Authors: EA Sausville, D Headlee, M Stetler-Stevenson, ES Jaffe, D Solomon, WD Figg, J Herdt, WC Kopp, H Rager, SM Steinberg
Journal: Blood (1995)
Service is valuable for evaluating murmurs too
Authors: P. S C Wong, S. Doshi
Journal: BMJ (1995)

EDITOR,--For the past 10 months we have been offering general practitioners in the Brighton area an open access echocardiography service similar to those in Edinburgh1 and Nottingham.2 Ours differs principally in that we encourage referral for the evaluation of murmurs as well as heart failure.

In total, 106 patients (43 male, 63 female), have been referred: 49 with heart failure with or without murmurs (mean age …
Abstract 894: Leptin Potentiates the Angiogenic Properties of Endothelial Progenitor Cells In Vitro and In Vivo
Authors: Nana-Maria Heida, Marco R Schroeter, I-Fen Cheng, Elena I Deryugina, Thomas Korff, James P Quigley, Zaverio M Ruggeri, Jan-Peter Mueller, Gerd Hasenfuss, Stavros Konstantinides, Katrin Schaefer
Journal: Circulation (2007)

Endothelial progenitor cells (EPC) have been reported to contribute to neovascularization. We have previously shown that the adipocytokine leptin may enhance the adhesive properties of EPC by upregulating specific integrins. To investigate whether the angiogenic effects of leptin may be mediated by modulation of EPC function, mononuclear cells were isolated from healthy human volunteers and cultivated under endothelial cell conditions for 7 days. In the matrigel assay, pretreatment of EPC with recombinant leptin for 24 hours dose-dependently enhanced their incorporation into tubular structures provided by mature endothelial cells. For example, 138.3 ± 7.6% (P = 0.001) and 145.3 ± 5.5% (P = 0.0001) CM-DiI-labeled EPC were detected after stimulation with 10 and 100 ng/mL leptin, respectively (control-treated EPC defined as 100%). Furthermore, in the spheroid angiogenesis assay, stimulation of EPC with 10 ng/mL leptin increased the number of sprouts (P &lt; 0.0001) and tube length (P &lt; 0.0001) of coincubated mature endothelial cells, and the outgrowth of EPC (P &lt; 0.0001). Addition of 100-fold excess of leptin-neutralizing or leptin-receptor-binding antibodies completely reversed these effects. Moreover, EPC adhesion onto endothelial cell tubules could be reduced by addition of RGD peptides (from 159 ± 13.7% to 101.8 ± 14.6%; P = 0.02), or of neutralizing antibodies against αvβ3 (from 165.3 ± 11.8% to 103.8 ± 13.3%; P = 0.006) or αvβ5 (to 93.5 ± 15.8%; P = 0.005). Further experiments using specific signal transduction inhibitors (10 μM of LY294002, PD98059, or SB203580), as well as Western blot analysis, revealed that leptin signaling in EPC involves phosphoinositide-3 kinase and p42/44, but not by p38 MAP kinase. The effects of leptin could also be confirmed under in vivo conditions. Stimulation of EPC with 100 ng/mL leptin potentiated the insprout of newly formed avian vessels into collagen onplants placed on the chorion allantoic membrane of chicken embryos (angiogenic index, 0.58 ± 0.24) compared to control-treated EPC (0.44 ± 0.27; P = 0.07) and endothelial basal medium alone (0.31 ± 0.26; P = 0.0007). Thus, our in vitro and in vivo results suggest that the angiogenic effects of leptin may partly depend on its specific interaction with endothelial progenitor cells.
Activation of Slit2-Robo1 signaling promotes liver fibrosis
Authors: Jianlan Chang, Tian Lan, Changzheng Li, Xiaoqian Ji, Lingyun Zheng, Hongju Gou, Yitao Ou, Teng Wu, Cuiling Qi, Qianqian Zhang, Jiangchao Li, Quliang Gu, Dingwen Wen, Liu Cao, Liang Qiao, Yanqing Ding, Lijing Wang
Journal: Journal of Hepatology (2015)
Abstract 13902: Using CHADS2 Score "Backwards" plus Echo Abnormalities Suggests Occult Undiagnosed Atrial Fibrillation in 63% of Cryptogenic Stroke Patients
Authors: Nishant Gupta, Jacob I Haft, Rupen Parikh, Sharad Bajaj, Isha Gupta, Chris Lau
Journal: Circulation (2010)

Introduction: Various clinical schema have been devised to predict which pts with atrial fibrillation (Afib) would benefit from warfarin anticoagulation to prevent strokes. One of the most accepted...
Abstract 14044: The Presence of PVCs After Endocardial and/or Epicardial Ablation Predicts Recurrence at Follow-up in Patients Undergoing Catheter Ablation of Ventricular Arrhythmias for Right Ventricular Dysplasia
Authors: Luigi Di Biase, J. David Burkhardt, Pasquale Santangeli, Luis Carlos Saenz, Miguel Vacca, Atul Verma, Prasant Mohanty, Javier E. Sanchez, Rodney Horton, Rong Bai, Sanghamitra Mohanty, Richard Hongo, Salwa Beheiry, Steven Hao, Antonio Dello Russo, Michela Casella, Gemma Pelargonio, Pietro Santarelli, G. Joseph Gallinghouse, Claudio Tondo, Andrea Natale
Journal: Circulation (2010)
Abstract 3773: Myotrophin and the p53 Signaling Cascade in Cardiac Hypertrophy/Heart Failure
Authors: Biswajit Das, David Young, Amit Vasanji, Sudhiranjan Gupta, Zoran Popovic, Subha Sen
Journal: Circulation (2008)

Myotrophin (Myo), a 12-kDa protein, stimulates myocyte growth and is a factor in initiating cardiac hypertrophy (CH). Cardiospecific overexpression of Myo in transgenic mice (Myo-Tg) induces hypertrophy that progresses to heart failure (HF). Oligonucleotide gene array revealed upregulation of a p53 homologue gene (EST- AI843106 ) in Myo-Tg mice during HF, indicating that p53 plays an important role during the transition of hypertrophy to HF. To dissect out the mechanisms of p53-mediated Myo-induced CH/HF, we developed a double-transgenic mouse line (p53 −/− /myo +/+ ) by crossing Myo-Tg mice with p53-null mice. The double transgenic mice showed a significant attenuation of cardiac mass compared to Myo-Tg mice (heart weight:body weight ratio; 5.2 ± 0.21 vs. 7.9 ± 0.58, p &lt; 0.001) associated with improved cardiac function and downregulation of ANF expression, suggesting that hypertrophy induced by Myo overexpression is indeed mediated through p53. To elucidate the relationship between p53 and Myo-induced hypertrophy, we performed a Reverse-Transcription Real-Time PCR pathway array on heart tissues from p53 −/− /myo +/+ vs. Myo-Tg mice. A bioinformatic approach, Ingenuity Pathway Analysis TM (IPA), was used to analyze the selected up-/downregulated genes. The IPA network showed that among the up-/downregulated genes, Bcl2, Brca1, Cdkn1a and Myc occupy the nodal position, whereas E2f1 , Pmaip1 , Gadd45a and Pttg1 function as peripheral candidates. The expression profiles of some genes of the p53 pathway were validated by immunoblot analysis. Functional assignment of these selected candidate genes showed that Bcl2, E2f1 and FasL are related to CH/HF, but the function of Gadd45a, Pmaip1, and Vcan is still unknown. Apart from these p53 cascade members, we also found that other molecules (e.g., Jnk, Ras, NF-kB, Cyclin L, and Mek) may be involved in an intricate interplay to stimulate p53-mediated Myo-induced CH. Suppression of NF-kB activity (by electrophoresis mobility shift assay) in p53 −/− /myo +/+ mice compared to Myo-Tg mice indicated involvement of NF-kB, as predicted by IPA, in Myo/p53 cross-talk. Our data suggest that the p53 signaling cascade actively participates in progression of hypertrophy to HF, triggered by overexpression of myotrophin.