tbuckley/cabot-search huggingface dataset:
Transcriptomic versus Chromosomal Prognostic Markers and Clinical Outcome in Uveal Melanoma
Authors: Lori A. Worley, Michael D. Onken, Erica Person, Diane Robirds, Julie Branson, Devron H. Char, Arie Perry, J. William Harbour
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To compare a gene expression–based classifier versus the standard genetic prognostic marker, monosomy 3, for predicting metastasis in uveal melanoma. Experimental Design: Gene expression profiling, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) were done on 67 primary uveal melanomas. Clinical and pathologic prognostic factors were also assessed. Variables were analyzed by Cox proportional hazards, Kaplan-Meier analysis, sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios. Results: The gene expression–based molecular classifier assigned 27 tumors to class 1 (low risk) and 25 tumors to class 2 (high risk). By Cox univariate proportional hazards, class 2 signature (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were the only variables significantly associated with metastasis. Only the class 2 signature was needed to optimize predictive accuracy in a Cox multivariate model. A less significant association with metastasis was observed for monosomy 3 detected by aCGH (P = 0.076) and FISH (P = 0.127). The sensitivity and specificity for the molecular classifier (84.6% and 92.9%, respectively) were superior to monosomy 3 detected by aCGH (58.3% and 85.7%, respectively) and FISH (50.0% and 72.7%, respectively). Positive and negative predictive values (91.7% and 86.7%, respectively) and positive and negative likelihood ratios (11.9 and 0.2, respectively) for the molecular classifier were also superior to those for monosomy 3. Conclusions: Molecular classification based on gene expression profiling of the primary tumor was superior to monosomy 3 and clinicopathologic prognostic factors for predicting metastasis in uveal melanoma.
Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes
Authors: Yoshikazu Nakaoka, Keigo Nishida, Yasushi Fujio, Masahiro Izumi, Kazuo Terai, Yuichi Oshima, Shoko Sugiyama, Satoshi Matsuda, Shigeo Koyasu, Keiko Yamauchi-Takihara, Toshio Hirano, Ichiro Kawase, Hisao Hirota
Journal: Circulation Research (2003)

Grb2-associated binder-1 (Gab1) is a scaffolding/docking protein and contains a Pleckstrin homology domain and potential binding sites for Src homology (SH) 2 and SH3 domains. Gab1 is tyrosine phosphorylated and associates with protein tyrosine phosphatase SHP2 and p85 phosphatidylinositol 3-kinase on stimulation with various cytokines and growth factors, including interleukin-6. We previously demonstrated that interleukin-6-related cytokine, leukemia inhibitory factor (LIF), induced cardiac hypertrophy through gp130. In this study, we report the role of Gab1 in gp130-mediated cardiac hypertrophy. Stimulation with LIF induced tyrosine phosphorylation of Gab1, and phosphorylated Gab1 interacted with SHP2 and p85 in cultured cardiomyocytes. We constructed three kinds of adenovirus vectors, those carrying wild-type Gab1 (AdGab1WT), mutated Gab1 lacking SHP2 binding site (AdGab1F627/659), and beta-galactosidase (Adbeta-gal). Compared with cardiomyocytes infected with Adbeta-gal, longitudinal elongation of cardiomyocytes induced by LIF was enhanced in cardiomyocytes infected with AdGab1WT but inhibited in cardiomyocytes infected with AdGab1F627/659. Upregulation of BNP mRNA expression by LIF was evoked in cardiomyocytes infected with Adbeta-gal and AdGab1WT but not in cardiomyocytes infected with AdGab1F627/659. In contrast, Gab1 repressed skeletal alpha-actin mRNA expression through interaction with SHP2. Furthermore, activation of extracellular signal-regulated kinase 5 (ERK5) was enhanced in cardiomyocytes infected with AdGab1WT compared with cardiomyocytes infected with Adbeta-gal but repressed in cardiomyocytes infected with AdGab1F627/659. Coinfection of AdGab1WT with adenovirus vector carrying dominant-negative ERK5 abrogated longitudinal elongation of cardiomyocytes induced by LIF. Taken together, these findings indicate that Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes through activation of ERK5.
Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication
Authors: Azra Bihorac, Lakhmir S. Chawla, Andrew D. Shaw, Ali Al-Khafaji, Danielle L. Davison, George E. DeMuth, Robert Fitzgerald, Michelle Ng Gong, Derrel D. Graham, Kyle Gunnerson, Michael Heung, Saeed Jortani, Eric Kleerup, Jay L. Koyner, Kenneth Krell, Jennifer LeTourneau, Matthew Lissauer, James Miner, H. Bryant Nguyen, Luis M. Ortega, Wesley H. Self, Richard Sellman, Jing Shi, Joely Straseski, James E. Szalados, Scott T. Wilber, Michael G. Walker, Jason Wilson, Richard Wunderink, Janice Zimmerman, John A. Kellum
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest.Objectives: We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.Methods: We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test.Measurements and Main Results: Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)2/1,000 was 92% (95% confidence interval [CI], 85–98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06–0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4–22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63–0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80–0.90 for clinical variables plus [TIMP-2]·[IGFBP7]).Conclusions: Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)2/1,000 identifies patients at risk for imminent AKI.Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).
HEPATIC CIRRHOSIS: EFFECTS OF SODIUM CHLORIDE ADMINISTRATION AND RESTRICTION AND OF ABDOMINAL PARACENTESIS ON ELECTROLYTE AND WATER BALANCE 12
Authors: George J. Gabuzda, Henry S. Traeger, Charles S. Davidson
Journal: Journal of Clinical Investigation (1954)

The formation of ascites and edema by patients with chronic liver disease can be controlled by rigid dietary sodium restriction (1-5).When sodium is administered, ascites formation re-commences while sodium excretion usually remains minimal.These facts have not yet been integrated with the factors usually considered contributory to the formation of ascites and edema, viz.: ele- vated portal pressure (6, 7), reduced serum albu- min concentration and colloid osmotic pressure (8-12), increased anti-diuretic activity (13), al- tered membrane permeability (4, 14), or altered renal tubular function (15).However, whatever the pathogenetic factors operating, fluid retention is readily conditioned by the sodium content of the diet.The observations reported here concern patients with cirrhosis of the liver with ascites and edema in whom the alterations in electrolyte and water balance attributable to abdominal paracenteses and to sodium chloride administration and restriction were studied under controlled conditions of food, water, and sodium chloride intake.
Evidence from bioassay studies indicating a role for adenosine in cardiac ischemic and hypoxic dilation in the dog.
Authors: J B Scott, W T Chen, B T Swindall, J M Dabney, F J Haddy
Journal: Circulation Research (1979)

Previous studies using bioassay demonstrated the presence of a vasoactive substance or substances in coronary sinus blood during myocardial reactive hyperemia which had, on bioassay, characteristics of adenosine and/or AMP. In the present studies, specific blockers were applied to an improved bioassay system to define more precisely the nature of the substance or substances and to determine whether it also appears during local cardiac hypoxia. In the anesthetized dog, coronary sinus blood was bioassayed in an isolated autologous kidney during reactive and hypoxic dilation. During reactive dilation, the bioassay kidney responded with a large resistance increase which was blocked by theophylline and adenosine deaminase and converted to a decrease by adenosine autoblockade. The same was true for hypoxic dilation, except in this instance, only adenosine deaminase reduced the response (40%). Theophylline and adenosine autoblockade eliminated responses of the bioassay organ to both exogenous adenosine and exogenous AMP, but adenosine deaminase was specific for adenosine. These results confirm that one or more vasoactive substances appear in sinus blood in vasoactive quantities during cardiac reactive dilation, and that the peak concentration correlates roughly with the peak flow. In addition, they show that this also is the case for hypoxic dilation. More importantly, they demonstrate that the substance almost certainly is adenosine in the case of reactive dilation, and that increased adenosine levels also are present during hypoxic dilation, but in addition, suggest that AMP sometimes appears in coronary sinus blood during severe cardiac hypoxia in the dog heart.
PREPARATION AND HOST-REACTIVE PROPERTIES OF ENDOTOXIN WITH LOW CONTENT OF NITROGEN AND LIPID
Authors: Edgar Ribi, Willard T. Haskins, Maurice Landy, Kelsey C. Milner
Journal: The Journal of Experimental Medicine (1961)

Endotoxins of low lipid content prepared from S. enteritidis by the aqueous ether method have been further treated to remove bound lipid by non-hydrolytic procedures. Such endotoxins, containing as little as 2 per cent lipid A, were as potent in stimulating a variety of physiological responses as those prepared by the well known phenol-water or Boivin procedures which yield products containing as much as 30 per cent lipid A. To verify the difference in lipid content between the aqueous ether preparations and other types of endotoxins, three different methods of lipid analysis were employed: determination of chloroform-soluble material released by hydrolysis with hydrochloric acid (lipid A) or with acetic acid (lipid W), and estimation of total bound fatty acids. These methods were in accord in showing the magnitude of the difference. No more than one-half of the fatty acids present in endotoxin were associated with the fraction designated lipid A. Methods are described for the preparation of potent endotoxins with analytical values for nitrogen, phosphorus, hexosamine, carbohydrate, and fatty acid which do not differ appreciably from those of the classical, non-toxic, haptenic polysaccharides.
Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group
Authors: Markus Joerger, Alwin D.R. Huitema, Dick J. Richel, Christian Dittrich, Nikolas Pavlidis, Evangelos Briasoulis, Jan B. Vermorken, Elena Strocchi, Andrea Martoni, Roberto Sorio, Henk P. Sleeboom, Miguel A. Izquierdo, Duncan I. Jodrell, Hilary Calvert, Alan V. Boddy, Harry Hollema, Regine Féty, Wjf J.F. Van der Vijgh, Georg Hempel, Etienne Chatelut, Mats Karlsson, Justin Wilkins, Brigitte Tranchand, Ad H.G.J. Schrijvers, Christian Twelves, Jos H. Beijnen, Jan H.M. Schellens
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC &amp;gt; 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC &amp;gt; 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC &amp;gt; 0.05 &amp;gt; 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC &amp;gt; 0.05 &amp;lt; 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC &amp;gt; 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P &amp;lt; 10−4). Conclusions: In this group of patients, paclitaxel tC &amp;gt; 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
Bayesian Selection of Nucleotide Substitution Models and Their Site Assignments
Authors: Chieh-Hsi Wu, Marc A. Suchard, Alexei J. Drummond
Journal: Molecular Biology and Evolution (2012)

Probabilistic inference of a phylogenetic tree from molecular sequence data is predicated on a substitution model describing the relative rates of change between character states along the tree for each site in the multiple sequence alignment. Commonly, one assumes that the substitution model is homogeneous across sites within large partitions of the alignment, assigns these partitions a priori, and then fixes their underlying substitution model to the best-fitting model from a hierarchy of named models. Here, we introduce an automatic model selection and model averaging approach within a Bayesian framework that simultaneously estimates the number of partitions, the assignment of sites to partitions, the substitution model for each partition, and the uncertainty in these selections. This new approach is implemented as an add-on to the BEAST 2 software platform. We find that this approach dramatically improves the fit of the nucleotide substitution model compared with existing approaches, and we show, using a number of example data sets, that as many as nine partitions are required to explain the heterogeneity in nucleotide substitution process across sites in a single gene analysis. In some instances, this improved modeling of the substitution process can have a measurable effect on downstream inference, including the estimated phylogeny, relative divergence times, and effective population size histories.
Alexander Mavor Knox
Authors: C H Cameron
Journal: BMJ (2003)

Former general practitioner Kelso, Roxburghshire (b Stonehaven 1923; q Aberdeen 1945), d 12 January 2003.

After working as a house physician in a hospital in Hackney, he was drafted into the Royal Army Medical Corps, serving in Italy, Egypt, Palestine, Kenya, and Nyasaland. After discharge, hospital posts in Aberdeen and Aylesbury were followed by assistantships in Glamis, and Kelso, where he became a partner in 1954. The amalgamation of the two Kelso practices in 1966 was cemented by the building of Edenside Surgery, which, for the time, was architecturally exciting, and in whose planning Mavor had had a significant hand. He and his wife, Win, also a partner in the practice, shared a love of roses, Italian art, and northwest Scotland. He leaves Win and five children.
Hypoxia Selectively Activates the CREB Family of Transcription Factors in the <i>In Vivo</i> Lung
Authors: Martin O. Leonard, Katherine Howell, Stephen F. Madden, Christine M. Costello, Desmond G. Higgins, Cormac T. Taylor, Paul McLoughlin
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation.To identify transcription factor pathways uniquely activated in the lung in response to hypoxia.After exposure to environmental hypoxia (10% O(2)) for varying periods (3 h to 2 wk), lungs and systemic organs were isolated from groups of adult male mice. Bioinformatic examination of genes the expression of which changed in the hypoxic lung (assessed using microarray analysis) identified potential lung-selective transcription factors controlling these changes in gene expression. In separate further experiments, lung-selective activation of these candidate transcription factors was tested in hypoxic mice and by comparing hypoxic responses of primary human pulmonary and cardiac microvascular endothelial cells in vitro.Bioinformatic analysis identified cAMP response element binding (CREB) family members as candidate lung-selective hypoxia-responsive transcription factors. Further in vivo experiments demonstrated activation of CREB and activating transcription factor (ATF)1 and up-regulation of CREB family-responsive genes in the hypoxic lung, but not in other organs. Hypoxia-dependent CREB activation and CREB-responsive gene expression was observed in human primary lung, but not cardiac microvascular endothelial cells.These findings suggest that activation of CREB and AFT1 plays a key role in the lung-specific responses to hypoxia, and that lung microvascular endothelial cells are important, proximal effector cells in the specific responses of the pulmonary circulation to hypoxia.
Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes
Authors: Hermann Haller, Sadayoshi Ito, Joseph L. Izzo, Andrzej Januszewicz, Shigehiro Katayama, Jan Menne, Albert Mimran, Ton J. Rabelink, Eberhard Ritz, Luis M. Ruilope, Lars C. Rump, Giancarlo Viberti
Journal: New England Journal of Medicine (2011)

Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria.
Adipocyte Fatty Acid–Binding Protein Suppresses Cardiomyocyte Contraction
Authors: Valéria Lamounier-Zepter, Christiane Look, Julio Alvarez, Torsten Christ, Ursula Ravens, Wolf-Hagen Schunck, Monika Ehrhart-Bornstein, Stefan R. Bornstein, Ingo Morano
Journal: Circulation Research (2009)

Adipocyte fatty acid-binding protein (FABP4) is a member of the intracellular lipid-binding protein family and is predominantly expressed in adipose tissue. Emerging evidence suggests that FABP4 plays a role in some aspects of the metabolic syndrome including the development of type 2 diabetes and atherosclerosis. We have recently reported that secretory products from human adipocytes directly and acutely depressed cardiac contractile function.The purpose of this study was to identify this adipocyte-derived cardiodepressant factor.Through mass spectrometry and immunoblotting, we have identified this cardiodepressant factor as FABP4. FABP4 represents 1.8% to 8.1% of total protein secreted by adipocytes in extracellular medium. FABP4 acutely depressed shortening amplitude as well as intracellular systolic peak Ca(2+) in a dose-dependent manner in isolated rat cardiomyocytes. Heart-specific FABP isoform (FABP3) revealed a similar cardiodepressant effect. The N-terminal amino acids 1 to 20 of FABP4 could be identified as the most effective cardiodepressive domain. We could exclude any effect of FABP4 on action potential duration and L-type Ca(2+) current, suggesting a reduced excitation-contraction gain caused by FABP4 as the main inhibitory mechanism.We conclude that the release of FABP4 from adipocytes may be involved in the development of cardiac contractile dysfunction of obese subjects.
Molecular sequelae of histone deacetylase inhibition in human malignant B cells
Authors: Nicholas Mitsiades, Constantine S. Mitsiades, Paul G. Richardson, Ciaran McMullan, Vassiliki Poulaki, Galinos Fanourakis, Robert Schlossman, Dharminder Chauhan, Nikhil C. Munshi, Teru Hideshima, Victoria M. Richon, Paul A. Marks, Kenneth C. Anderson
Journal: Blood (2003)
Ribavirin Treatment Effects on Breast Cancers Overexpressing eIF4E, a Biomarker with Prognostic Specificity for Luminal B-Type Breast Cancer
Authors: Filippa Pettersson, Christina Yau, Monica C. Dobocan, Biljana Culjkovic-Kraljacic, Hélène Retrouvay, Rachel Puckett, Ludmila M. Flores, Ian E. Krop, Caroline Rousseau, Eftihia Cocolakis, Katherine L. B. Borden, Christopher C. Benz, Wilson H. Miller
Journal: Clinical Cancer Research (2011)

We have evaluated the eukaryotic translation initiation factor 4E (eIF4E) as a potential biomarker and therapeutic target in breast cancer. eIF4E facilitates nuclear export and translation of specific, growth-stimulatory mRNAs and is frequently overexpressed in cancer.Breast cancer cells were treated with ribavirin, an inhibitor of eIF4E, and effects on cell proliferation and on known mRNA targets of eIF4E were determined. eIF4E expression was assessed, at the mRNA and protein level, in breast cancer cell lines and in skin biopsies from patients with metastatic disease. Additionally, pooled microarray data from 621 adjuvant untreated, node-negative breast cancers were analyzed for eIF4E expression levels and correlation with distant metastasis-free survival (DMFS), overall and within each intrinsic breast cancer subtype.At clinically relevant concentrations, ribavirin reduced cell proliferation and suppressed clonogenic potential, correlating with reduced mRNA export and protein expression of important eIF4E targets. This effect was suppressed by knockdown of eIF4E. Although eIF4E expression is elevated in all breast cancer cell lines, variability in ribavirin responsiveness was observed, indicating that other factors contribute to an eIF4E-dependent phenotype. Assessment of the prognostic value of high eIF4E mRNA in patient tumors found that significant discrimination between good and poor outcome groups was observed only in luminal B cases, suggesting that a specific molecular profile may predict response to eIF4E-targeted therapy.Inhibition of eIF4E is a potential breast cancer therapeutic strategy that may be especially promising against specific molecular subtypes and in metastatic as well as primary tumors.