tbuckley/cabot-search huggingface dataset:
Aspirin and Colorectal Cancer: Back to the Future
Authors: David Tougeron, Dan Sha, Sashidhar Manthravadi, Frank A. Sinicrope
Journal: Clinical Cancer Research (2013)

Abundant epidemiologic evidence indicates that regular and long-term use of aspirin is associated with a significant reduction in the incidence of colorectal cancer. The long duration of aspirin needed to prevent colorectal cancer is believed to be due to inhibition of precursor lesions known as adenomas, the recurrence of which is inhibited by aspirin in randomized trials. Aspirin intake has also been associated with a statistically significant improvement in patient survival after curative resection of colorectal cancer in large observational studies. In these cohorts, the survival benefit of aspirin was shown to depend upon the level of COX-2 expression in the primary colorectal cancer. More recent analysis of patient tumors from these observational cohorts suggests that the benefit of aspirin may be limited to specific molecular subtypes. Aspirin intake following colorectal cancer resection was associated with a significant improvement of survival in patients whose tumors carried mutant, but not wild-type, copies of the phosphoinositide 3-kinase (PI3KCA) gene, especially tumors that overexpressed COX-2. A mechanistic explanation is suggested by the finding that inhibition of COX-mediated prostaglandin E2 synthesis by aspirin attenuates PI3K signaling activity that is known to regulate cancer cell proliferation and survival. Aspirin has also been shown to reduce the incidence of colorectal cancers bearing wild-type, but not mutant alleles of the BRAF(V600E) oncogene. Although provocative, the potential utility of these molecular markers for predicting aspirin efficacy awaits prospective evaluation in clinical trials. If validated, these findings may support a personalized approach to using aspirin for the therapy of colorectal cancer.
Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model
Authors: R. Scott Rector, John P. Thyfault, Grace M. Uptergrove, E. Matthew Morris, Scott P. Naples, Sarah J. Borengasser, Catherine R. Mikus, Matthew J. Laye, M. Harold Laughlin, Frank W. Booth, Jamal A. Ibdah
Journal: Journal of Hepatology (2010)
Mechanisms of contraction induced by human leukocytes in normal and atherosclerotic arteries.
Authors: A Mügge, D D Heistad, R C Padgett, B J Waack, P Densen, J A Lopez
Journal: Circulation Research (1991)

Activation of leukocytes results in the release of a variety of vasoactive substances that may modulate vascular tone. We studied the effect of human polymorphonuclear (PMN) and mononuclear (MONO) leukocytes on quiescent femoral arteries in vitro. Arteries were obtained from normal and atherosclerotic cynomolgus monkeys. In normal arteries, stimulation of PMNs (3 and 5 x 10(6) cells/ml) with either thrombin (5 units/ml) or complement C5a (0.5 micrograms/ml) resulted in endothelium-independent contraction (approximately 25% of maximum contraction with 80 mM KCl). Vasocontraction was augmented in the presence of superoxide dismutase (150 units/ml) and was significantly impaired in the presence of the hydroxyl radical scavengers mannitol (20 mM) and deferoxamine (1 mM). Catalase (1,200 units/ml) or L-alanine (20 mM) did not modify this effect of PMNs. In contrast to PMNs, vasocontraction in response to MONOs was not altered by the addition of radical scavengers. Pretreatment of PMNs and MONOs with indomethacin (10 microM) or nordihydroguaiaretic acid (20 microM) did not influence vascular responses. Supernatant of thrombin-stimulated PMNs and MONOs also produced vasocontraction (approximately two thirds of the effect of intact cells). This vasocontractor factor (or factors) was heat stable (30 minutes, 95 degrees C) and had a molecular weight less than 1,000 as determined by ultrafiltration. Stimulation of MONOs or PMNs (3 and 5 x 10(6) cells/ml) produced a similar response in normal arteries. In contrast, the constrictor response in atherosclerotic arteries to MONOs (5 x 10(6) cells/ml) was significantly greater than to PMNs. We conclude that stimulated human PMNs and MONOs contract arteries in vitro by release of at least two factors. One factor appears to be heat stable, with a molecular weight less than 1,000. The vascular response to PMNs, but not to MONOs, appears to involve the generation of hydroxyl radicals. The response to MONOs is greater than the response to PMNs in atherosclerotic, but not in normal, arteries.
Inhaled corticosteroids in COPD and the risk of serious pneumonia
Authors: Samy Suissa, Valérie Patenaude, Francesco Lapi, Pierre Ernst
Journal: Thorax (2013)

Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.We formed a new-user cohort of patients with COPD treated during 1990-2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case-control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.
Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy
Authors: Teru Hideshima, Dharminder Chauhan, Yoshihito Shima, Noopur Raje, Faith E. Davies, Yu-Tzu Tai, Steven P. Treon, Boris Lin, Robert L. Schlossman, Paul Richardson, George Muller, David I. Stirling, Kenneth C. Anderson
Journal: Blood (2000)
Noninvasive Detection of <i>HER2</i> Amplification with Plasma DNA Digital PCR
Authors: Heidrun Gevensleben, Isaac Garcia-Murillas, Monika K. Graeser, Gaia Schiavon, Peter Osin, Marina Parton, Ian E. Smith, Alan Ashworth, Nicholas C. Turner
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Digital PCR is a highly accurate method of determining DNA concentration. We adapted digital PCR to determine the presence of oncogenic amplification through noninvasive analysis of circulating free plasma DNA and exemplify this approach by developing a plasma DNA digital PCR assay for HER2 copy number. Experimental Design: The reference gene for copy number assessment was assessed experimentally and bioinformatically. Chromosome 17 pericentromeric probes were shown to be suboptimal, and EFTUD2 at chromosome position 17q21.31 was selected for analysis. Digital PCR assay parameters were determined on plasma samples from a development cohort of 65 patients and assessed in an independent validation cohort of plasma samples from 58 patients with metastatic breast cancer. The sequential probability ratio test was used to assign the plasma DNA digital PCR test as being HER2-positive or -negative in the validation cohort. Results: In the development cohort, the HER2:EFTUD2 plasma DNA copy number ratio had a receiver operator area under the curve (AUC) = 0.92 [95% confidence interval (CI), 0.86–0.99, P = 0.0003]. In the independent validation cohort, 64% (7 of 11) of patients with HER2-amplified cancers were classified as plasma digital PCR HER2–positive and 94% (44 of 47) of patients with HER2-nonamplified cancers were classified as digital PCR HER2–negative, with a positive and negative predictive value of 70% and 92%, respectively. Conclusion: Analysis of plasma DNA with digital PCR has the potential to screen for the acquisition of HER2 amplification in metastatic breast cancer. This approach could potentially be adapted to the analysis of any locus amplified in cancer. Clin Cancer Res; 19(12); 3276–84. ©2013 AACR.
Abnormal vocal cord movement in asthma: Impact on the flow volume curve
Authors: Laurence Ruane, Kathy Low, Paul Guy, Kenneth Lau, Philip Bardin
Journal: European Respiratory Journal (2011)

Traditionally the “gold standard” for detecting abnormal vocal cord movement has been laryngoscopy. Novel dynamic 320-slice CT larynx has made it possible to quantify vocal cord movement non-invasively during inspiration and expiration. While spirometry has been useful in observing upper airway obstruction, little is known of its utility in identifying patients with abnormal vocal cord movement.   Aims:  To identify changes in the flow volume curve in patients with abnormal vocal cord movement (AVCM).   Methods:  Two groups comprising controls and asthmatics were recruited. Vocal cord abnormality was evaluated using 320-slice CT larynx. All patients had spirometry immediately prior to CT and relevant parameters were compared.   Results:  AVCM was not found in healthy control subjects. However, it was present in 11/23 asthmatics (50%).   Discussion:  While there was a significant difference in FEV1 between control and the two asthma groups, it identified obstruction alone. The only other discerning spirometric parameter was FIF50%/FEF50% which was significantly different between the control group and those with AVCM.   Conclusion:  Spirometric parameters appear to be poor discriminators for detecting AVCM. It may be that more sensitive lung function measures, such a resistance measured with body plethysmograph or oscillometer will be required to further discriminate between obstruction of the upper and/or lower airways.
Prognostic and Chemotherapy Predictive Value of Gene-Expression Phenotypes in Primary Lung Adenocarcinoma
Authors: Markus Ringnér, Göran Jönsson, Johan Staaf
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Primary lung adenocarcinoma remains a deadly disease. Gene-expression phenotypes (GEPs) in adenocarcinoma have potential to provide clinically relevant disease stratification for improved prognosis and treatment prediction, given appropriate clinical and methodologic validation. Experimental Design: 2,395 transcriptional adenocarcinoma profiles were assembled from 17 public cohorts and classified by a nearest centroid GEP classifier into three subtypes: terminal respiratory unit (TRU), proximal-proliferative, and proximal-inflammatory, and additionally scored by five transcriptional metagenes representing different biologic processes, including proliferation. Prognostic- and chemotherapy-predictive associations of the subtypes were analyzed by univariate and multivariate analysis using overall survival or distant metastasis-free survival as endpoints. Results: Overall, GEPs were associated with patient outcome in both univariate and multivariate analyses, although not in all individual cohorts. The prognostically relevant division was between TRU- and non-TRU–classified cases, with expression of proliferation-associated genes as a key prognostic component. In contrast, GEP classification was not predictive of adjuvant chemotherapy response. GEP classification showed stability to random perturbations of genes or samples and alterations to classification procedures (typically &amp;lt;10% of cases/cohort switching subtype). High classification variability (&amp;gt;20% of cases switching subtype) was observed when removing larger or entire fractions of a single subtype, due to gene-centering shifts not addressable by the classifier. Conclusions: In a large-scale evaluation, we show that GEPs add prognostic value to standard clinicopathologic variables in lung adenocarcinoma. Subject to classifier refinement and confirmation in prospective cohorts, GEPs have potential to affect the prognostication of adenocarcinoma patients through a molecularly driven disease stratification. Clin Cancer Res; 22(1); 218–29. ©2015 AACR.
Competitive AMPA receptor antagonists
Authors: Daniela Catarzi, Vittoria Colotta, Flavia Varano
Journal: Medicinal Research Reviews (2006)

Abstract Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N ‐methyl‐ D ‐aspartic acid (NMDA), 2‐amino‐3‐(3‐hydroxy‐5‐methylisoxazol‐4‐yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo[ f ]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the “ in vivo ” action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature. © 2006 Wiley Periodicals, Inc.
Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma.
Authors: M B Atkins, J Sparano, R I Fisher, G R Weiss, K A Margolin, K I Fink, L Rubinstein, A Louie, J W Mier, R Gucalp
Journal: Journal of Clinical Oncology (1993)

PURPOSE To determine better the activity of high-dose interleukin-2 (IL-2) either alone or in combination with interferon alfa-2b (IFN; Schering-Plough, Kenilworth, NJ) in patients with metastatic renal cell carcinoma, the IL-2 Working Group initiated a randomized phase II trial. PATIENTS AND METHODS Patients were randomly assigned to receive treatment with either IL-2 (Chiron Corp, Emeryville, CA) 1.33 mg/m2 (approximately 600,000 IU/kg) alone or IL-2 0.8 mg/m2 and IFN 3 x 10(6) U/m2 administered by bolus intravenous injection every 8 hours, days 1 to 5 and 15 to 19 (maximum, 28 doses). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and normal organ function. After 28 patients were entered onto each arm, the IL-2/IFN arm was closed because of a failure to meet predetermined efficacy criteria. An additional 43 patients (total, 71) were assigned to receive IL-2 alone. RESULTS Toxicities were similar for both study arms. Hypotension requiring pressors was the most frequent dose-limiting toxicity. Only 11 of 99 patients experienced severe toxicity; there were no irreversible side effects or treatment-related deaths. Responses were seen in three of 28 patients (11%) on IL-2/IFN (three partial responses [PRs] lasting 14, 7, and 7 months) and 12 of 71 patients (17%) on IL-2 alone (four complete responses [CRs] and eight PRs). Six of the partial responders on IL-2 and two on IL-2/IFN experienced greater than 90% reduction in tumor mass. Ten of the 12 responders to IL-2 have ongoing responses of 12+ to 26+ months in duration. CONCLUSION We conclude that both IL-2 and IL-2/IFN therapy have activity in metastatic renal cell carcinoma. In particular, therapy with high-dose IL-2 alone produces meaningful and durable responses with manageable and reversible toxicity. This study supports the contention that high-dose IL-2 represents the treatment of choice in selected patients with advanced renal cell carcinoma.
<i>FUS-CREB3L2</i>/<i>L1</i>–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of <i>CD24</i> and <i>FOXL1</i>
Authors: Emely Möller, Jason L. Hornick, Linda Magnusson, Srinivas Veerla, Henryk A. Domanski, Fredrik Mertens
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS-CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS-CREB3L2–dependent, gene expression patterns to learn more about the pathogenesis of this tumor. Experimental Design: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro. Results: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS. Conclusions: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes. Clin Cancer Res; 17(9); 2646–56. ©2011 AACR.
Evolution of Modern Birds Revealed by Mitogenomics: Timing the Radiation and Origin of Major Orders
Authors: M. A. Pacheco, F. U. Battistuzzi, M. Lentino, R. F. Aguilar, S. Kumar, A. A. Escalante
Journal: Molecular Biology and Evolution (2011)

Mitochondrial (mt) genes and genomes are among the major sources of data for evolutionary studies in birds.This places mitogenomic studies in birds at the core of intense debates in avian evolutionary biology.Indeed, complete mt genomes are actively been used to unveil the phylogenetic relationships among major orders, whereas single genes (e.g., cytochrome c oxidase I [COX1]) are considered standard for species identification and defining species boundaries (DNA barcoding).In this investigation, we study the time of origin and evolutionary relationships among Neoaves orders using complete mt genomes.First, we were able to solve polytomies previously observed at the deep nodes of the Neoaves phylogeny by analyzing 80 mt genomes, including 17 new sequences reported in this investigation.As an example, we found evidence indicating that columbiforms and charadriforms are sister groups.Overall, our analyses indicate that by improving the taxonomic sampling, complete mt genomes can solve the evolutionary relationships among major bird groups.Second, we used our phylogenetic hypotheses to estimate the time of origin of major avian orders as a way to test if their diversification took place prior to the Cretaceous/Tertiary (K/T) boundary.Such timetrees were estimated using several molecular dating approaches and conservative calibration points.Whereas we found time estimates slightly younger than those reported by others, most of the major orders originated prior to the K/T boundary.Finally, we used our timetrees to estimate the rate of evolution of each mt gene.We found great variation on the mutation rates among mt genes and within different bird groups.COX1 was the gene with less variation among Neoaves orders and the one with the least amount of rate heterogeneity across lineages.Such findings support the choice of COX 1 among mt genes as target for developing DNA barcoding approaches in birds.
Rapid cooling preserves the ischaemic myocardium against mitochondrial damage and left ventricular dysfunction
Authors: R. Tissier, N. Couvreur, B. Ghaleh, P. Bruneval, F. Lidouren, D. Morin, R. Zini, A. Bize, M. Chenoune, M.-F. Belair, C. Mandet, M. Douheret, J.-L. Dubois-Rande, J. C. Parker, M. V. Cohen, J. M. Downey, A. Berdeaux
Journal: Cardiovascular Research (2009)

We investigated whether rapid cooling instituted by total liquid ventilation (TLV) improves cardiac and mitochondrial function in rabbits submitted to ischaemia-reperfusion. Rabbits were chronically instrumented with a coronary artery occluder and myocardial ultrasonic crystals for assessment of segment length-shortening. Two weeks later they were re-anaesthetized and underwent either a normothermic 30-min coronary artery occlusion (CAO) (Control group, n = 7) or a comparable CAO with cooling initiated by a 10-min hypothermic TLV and maintained by a cold blanket placed on the skin. Cooling was initiated after 5 or 15 min of CAO (Hypo-TLV and Hypo-TLV15′ groups, n = 6 and 5, respectively). A last group underwent normothermic TLV during CAO (Normo-TLV group, n = 6). Wall motion was measured in the conscious state over three days of reperfusion before infarct size evaluation and histology. Additional experiments were done for myocardial sampling in anaesthetized rabbits for mitochondrial studies. The Hypo-TLV procedure induced a rapid decrease in myocardial temperature to 32–34°C. Throughout reperfusion, segment length-shortening was significantly increased in Hypo-TLV and Hypo-TLV15′ vs. Control and Normo-TLV (15.1 ± 3.3%, 16.4 ± 2.3%, 1.8 ± 0.6%, and 1.1 ± 0.8% at 72 h, respectively). Infarct sizes were also considerably attenuated in Hypo-TLV and Hypo-TLV15′ vs. Control and Normo-TLV (4 ± 1%, 11 ± 5%, 39 ± 2%, and 42 ± 5% infarction of risk zones, respectively). Mitochondrial function in myocardial samples obtained at the end of ischaemia or after 10 min of reperfusion was improved by Hypo-TLV with respect to ADP-stimulated respiration and calcium-induced opening of mitochondrial permeability transition pores (mPTP). Calcium concentration opening mPTP was, e.g., increased at the end of ischaemia in the risk zone in Hypo-TLV vs. Control (157 ± 12 vs. 86 ± 12 µM). Histology and electron microscopy also revealed better preservation of lungs and of cardiomyocyte ultrastructure in Hypo-TLV when compared with Control. Institution of rapid cooling by TLV during ischaemia reduces infarct size as well as other sequelae of ischaemia, such as post-ischaemic contractile and mitochondrial dysfunction.