tbuckley/cabot-search huggingface dataset:
Emigrated Rat Neutrophils Adhere to Cardiac Myocytes via α <sub>4</sub> Integrin
Authors: Paul H. Reinhardt, Christopher A. Ward, Wayne R. Giles, Paul Kubes
Journal: Circulation Research (1997)

Abstract Previous work has shown that neutrophils isolated from whole blood adhere to cardiac myocytes via CD18 (β 2 integrin) to cause injury to the heart cells. In vitro, we have found that upon endothelial transmigration, neutrophils can also express α 4 β 1 ; however, whether this contributes to neutrophil adhesion to parenchymal cells remains entirely unknown. Unstimulated and tumor necrosis factor-α–stimulated rat cardiac myocytes adherent to gelatin-coated coverslips supported N -formyl-Met-Leu-Phe (fMLP)–induced neutrophil (isolated from whole blood) adhesion entirely via CD18 (blocked with monoclonal antibody [mAb] WT-3). Emigrated neutrophils spontaneously adhered to cardiac myocytes also entirely via CD18. However, if fMLP was used to restimulate emigrated neutrophils, the adhesion to cardiac myocytes was entirely independent of CD18. Although an anti–α 4 integrin antibody (mAb TA-2) alone did not reduce the emigrated neutrophil-myocyte interaction, dual administration of TA-2 and WT-3 reduced adhesion by 81%. α 4 integrin was expressed in small amounts on the surface of circulating neutrophils, increased following transmigration, and then increased &gt;5-fold after restimulation of these emigrated neutrophils. In the presence of the anti-CD18 antibody, a fibronectin fragment (FN-40) but not a vascular cell adhesion molecule-1 antibody (mAb 5F10) inhibited neutrophil-myocyte interactions by 80%. Similar results were seen when the rat chemokine CINC-gro was used instead of fMLP, suggesting that the α 4 -dependent adhesion was not specific to fMLP. These data demonstrate that α 4 integrin can be physiologically induced to increase in number and avidity after neutrophil emigration and that this adhesion molecule can cause firm adhesion to fibronectin on parenchymal cells, including rat cardiac myocytes.
Development of Central Nervous System Metastases in Patients with Advanced Non–Small Cell Lung Cancer and Somatic <i>EGFR</i> Mutations Treated with Gefitinib or Erlotinib
Authors: Stephanie Heon, Beow Y. Yeap, Gregory J. Britt, Daniel B. Costa, Michael S. Rabin, David M. Jackman, Bruce E. Johnson
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non–small cell lung cancer (NSCLC). However, there are incomplete data about their impact on the development and control of CNS metastases. Experimental Design: Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. Results: Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months. Conclusions: Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients. Clin Cancer Res; 16(23); 5873–82. ©2010 AACR.
Flavopiridol Induces p53 via Initial Inhibition of Mdm2 and p21 and, Independently of p53, Sensitizes Apoptosis-Reluctant Cells to Tumor Necrosis Factor
Authors: Zoya N. Demidenko, Mikhail V. Blagosklonny
Journal: Cancer Research (2004)

Flavopiridol (FP) inhibits gene expression and causes apoptosis, and these effects cannot be explained by inhibition of cyclin-dependent kinases that govern cell cycle. The simple and established notion that FP is an inhibitor of transcription predicts its effects. Because Mdm-2 targets p53 for degradation, FP, as predicted, dramatically induced p53 by inhibiting Mdm-2. Once p53 was induced, restoration of transcription (by removal of FP) resulted in superinduction of p21 and Mdm-2. Similarly, low concentrations of FP (50 nm) induced p21 and Mdm-2 because of their initial down-regulation. A sustained decrease of Mdm-2/p21 expression and accumulation of p53 coincided with near-maximal cytotoxicity of FP at concentrations >100 nm. Induction of p53 was a marker, not a cause, of cytotoxicity. FP caused rapid apoptosis (caspase-dependent cell death) in p53-null leukemia cells. In these cells, FP-induced apoptosis was converted to growth arrest by inhibitors of caspases. In apoptosis-reluctant A549 and PC3M cancer cells, FP inhibited cell proliferation but did not cause apoptosis. Like typical inhibitors of transcription, FP sensitized cells to apoptotic stimuli, allowing tumor necrosis factor to cause rapid and massive apoptosis in otherwise apoptosis-reluctant cells. We discuss that, as a reversible inhibitor of transcription, FP can be used clinically in novel rational drug combinations.
Nasal nitric oxide screening for primary ciliary dyskinesia: systematic review and meta-analysis
Authors: Samuel A. Collins, Kerry Gove, Woolf Walker, Jane S.A. Lucas
Journal: European Respiratory Journal (2014)

Nasal nitric oxide (nNO) concentrations are low in patients with primary ciliary dyskinesia (PCD) providing a noninvasive screening test. We conducted a systematic review of the literature to examine the utility of nNO in screening for PCD, in particular 1) different respiratory manoeuvres during sampling (velum closure, tidal breathing, etc .), 2) accuracy in screening young/uncooperative children, 3) stationary versus portable analysers, and 4) nNO in “atypical” PCD. 96 papers were assessed according to modified PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and 22 were included in this review. Meta-analysis of 11 studies comparing nNO during a velum closure breath hold gave a mean± sd nNO of 19.4±18.6 nL·min -1 in PCD (n = 478) and 265.0±118.9 nL·min -1 in healthy controls (n = 338). Weighted mean difference for PCD versus healthy controls was 231.1 nL·min -1 (95% CI 193.3–268.9; n = 338) and 114.1 nL·min -1 (95% CI 101.5–126.8; n = 415) for PCD versus cystic fibrosis. Five studies of nNO measurement during tidal breathing demonstrated that this is an acceptable manoeuvre in young children where velum closure is not possible, but the discriminatory value was reduced. Four small studies of portable NO analysers suggest these are reliable tools for screening for PCD. However, nNO must be interpreted alongside clinical suspicion. Future studies should focus on standardising sampling techniques and reporting.
Classifying sports medicine diagnoses: a comparison of the International classification of diseases 10-Australian modification (ICD-10-AM) and the Orchard sports injury classification system (OSICS-8)
Authors: K Rae, H Britt, J Orchard, C Finch
Journal: British Journal of Sports Medicine (2005)

Background: The International classification of diseases 10-Australian modification (ICD-10-AM) and the Orchard sports injury classification system (OSICS-8) are two classifications currently being used in sports injury research. Objectives: To compare these two systems to determine which was the more reliable and easier to apply in the classification of injury diagnoses of patients who presented to sports physicians in private sports medicine practice. Methods: Ten sports physicians/sports physician registrars each coded one of 10 different lists of 30 sports medicine diagnoses according to both ICD-10-AM and OSICS-8 in random order. The coders noted the time taken to apply each classification system, and allocated an ease of fit score for individual diagnoses into the systems. The 300 diagnoses were each coded twice more by “expert” coders from each system, and these results compared with those of the 10 volunteers. Results: Overall, there was a higher level of agreement between the different coders for OSICS-8 than for ICD-10-AM. On average, it was 23.5 minutes quicker to complete the task with OSICS-8 than with ICD-10-AM. Furthermore, there was also higher concordance between the three coders with OSICS-8. Subjective analysis of the codes assigned indicated reasons for disagreement and showed that, in some instances, even the “expert” coders had difficulties in assigning the most appropriate codes. Conclusions: Based on the results of this study, OSICS-8 appears to be the preferred system for use by inexperienced coders in sports medicine research. The agreement between coders was, however, lower than expected. It is recommended that changes be made to both OSICS-8 and ICD-10-AM to improve their reliability for use in sports medicine research.
Cross-Sectional and Longitudinal Changes of Glucose Effectiveness in Relation to Glucose Tolerance
Authors: Carlos Lorenzo, Lynne E. Wagenknecht, Andrew J. Karter, Anthony J.G. Hanley, Marian J. Rewers, Steven M. Haffner
Journal: Diabetes Care (2011)

Glucose effectiveness (S(G)), the capacity of glucose to enhance its own disposition, is an independent predictor of future diabetes. However, there are data on cross-sectional and longitudinal changes of S(G) and its components, basal insulin effect on S(G) (BIE) and S(G) at zero insulin (GEZI), but the natural course of S(G) has not been described in a large population.S(G) was measured at baseline in 1,265 participants (aged 40-69 years) and at the 5-year examination in 827 participants in the Insulin Resistance Atherosclerosis Study (IRAS) using the frequently sampled intravenous glucose tolerance test. None of these participants were treated with glucose-lowering agents.In cross-sectional analyses, S(G), BIE, and GEZI deteriorated with worsening of glucose tolerance (P < 0.001 for all three associations). In longitudinal analyses among subjects with normal glucose tolerance (NGT) at baseline, S(G), BIE, and GEZI declined in those who progressed to impaired glucose tolerance (IGT) or diabetes (P < 0.001 for all three measures). More modest longitudinal changes were demonstrated in individuals with IGT. The transition back to NGT (as opposed to no change) compared with the transition to diabetes was statistically significant for S(G) (P = 0.049) and BIE (P = 0.042) and was not a statistically significant trend for GEZI (P = 0.332). In individuals with diabetes, only BIE had a significant decline (P = 0.003).S(G), BIE, and GEZI decline in subjects whose glycemic status worsens. S(G) and GEZI deteriorate more in the initial stages of the disease process.
Pregnancy outcomes in pulmonary arterial hypertension in the modern management era
Authors: Xavier Jaïs, Karen M. Olsson, Joan A. Barbera, Isabel Blanco, Adam Torbicki, Andrew Peacock, C. Dario Vizza, Peter Macdonald, Marc Humbert, Marius M. Hoeper
Journal: European Respiratory Journal (2012)

Previous studies have reported mortality rates of up to 56% associated with pregnancy in pulmonary arterial hypertension (PAH) but the management of this disease has changed considerably in recent years. We compiled a multinational, prospective registry to examine the contemporary outcome of pregnancies in patients with PAH. During a 3-yr period, the 13 participating centres reported 26 pregnancies. Three (12%) females died and one (4%) developed right heart failure requiring urgent heart–lung transplantation. There were eight abortions; two spontaneous and six induced. 16 (62%) pregnancies were successful, i.e. the females delivered healthy babies without complications. These females had well controlled PAH (pulmonary vascular resistance (PVR) 500±352 dyn·s·cm −5 ); eight of them were long-term responders to calcium channel blockers. In contrast, the females who died or required transplantation had poorly controlled PAH (PVR 1,667±209 dyn·s·cm −5 ). Pregnancy remains associated with a substantial mortality rate in PAH. However, our results indicate that the outcome of pregnancy in PAH has improved, at least when PAH is well controlled, and particularly in long-term responders to calcium channel blockers. These data must be confirmed by larger series before the general recommendation to avoid pregnancy in all patients with PAH is reconsidered.
Use of Four Biomarkers to Evaluate the Risk of Breast Cancer Subtypes in the Women's Contraceptive and Reproductive Experiences Study
Authors: Huiyan Ma, Yaping Wang, Jane Sullivan-Halley, Linda Weiss, Polly A. Marchbanks, Robert Spirtas, Giske Ursin, Ronald T. Burkman, Michael S. Simon, Kathleen E. Malone, Brian L. Strom, Jill A. McDonald, Michael F. Press, Leslie Bernstein
Journal: Cancer Research (2010)

Epidemiologic studies suggest that some hormone-related risk factors in breast cancer differentially influence risk for disease subtypes classified by the status of the estrogen and progesterone receptors (ER/PR). However, it remains unclear whether human epidermal growth factor receptor 2 (HER2) or p53 expression status further differentiates these exposure-risk group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1,197 population-based cases and 2,015 controls from the Los Angeles County or Detroit components of the Women's Contraceptive and Reproductive Experiences Study. Case-control comparisons by ER/PR/HER2/p53 status were conducted by multivariable polychotomous unconditional logistic regression methods. We found that OC use was not associated with any breast cancer subtype as defined by ER/PR/HER2/p53 status, except for a 2.9-fold increased risk of so-called triple-negative tumors (ER(-)/PR(-)/HER2(-)) among women of 45 to 64 years of age who started OC use before age 18. Parity was associated with a decreased risk of luminal A (ER(+) or PR(+), HER2(-)), luminal B (ER(+) or PR(+)/HER2(+)), and ER(-)/PR(-)/HER2(+) tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple-negative tumors. Long duration of breast-feeding lowered the risk of triple-negative and luminal A tumors. p53 status did not define further differential risk patterns. Our findings offer evidence of differences in the hormone-related risk factors between triple-negative cancers and other ER/PR/HER2-defined subtypes of breast cancer.
The use of benzodiazepines could be a protective factor for community-acquired pneumonia (CAP) in ≤60-year-old subjects: Table 1
Authors: Jordi Almirall, Mateu Serra-Prat, Francisco Baron, Elisabet Palomera, Ignasi Bolíbar
Journal: Thorax (2013)

The use of benzodiazepines could be a protective factor for community-acquired pneumonia (CAP) in 60-year-old subjectsWe have read with interest the study of Obiora et al 1 regarding the effect of benzodiazepines (BZs) on the risk of community-acquired pneumonia (CAP).It is concluded that the use of BZs was associated with an increased risk for CAP and CAP-related mortality.However, the effect of BZs in patients with CAP is still a matter of debate.We would like to contribute to this unsolved question, with new data from a previously published populationbased case-control study carried out in a sample of 2662 subjects (1336 CAP patients and 1326 controls). 2In fact, not only the use of BZs was not statistically associated with CAP in the overall study population, but also a protective effect for CAP was observed in the subgroup of patients aged 60 years or younger (see table 1), with an OR of 0.54 ( p=0.012) in the bivariate analysis and an OR of 0.53 (95% CI 0.31 to 0.91) in the multivariate analysis after adjusting for asthma, chronic 964
MOLECULAR GRADIENTS AND DEVELOPMENT OF RETINOTOPIC MAPS
Authors: Todd McLaughlin, Dennis D.M. O'Leary
Journal: Annual Review of Neuroscience (2005)

Gradients of axon guidance molecules have long been postulated to control the development of the organization of neural connections into topographic maps. We review progress in identifying molecules required for mapping and the mechanisms by which they act, focusing on the visual system, the predominant model for map development. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, remain the only molecules that meet all criteria for graded topographic guidance molecules, although others fulfill some criteria. Recent reports further define their modes of action and new roles for them, including EphB/ephrin-B control of dorsal-ventral mapping, bidirectional signaling of EphAs/ephrin-As, bifunctional action of ephrins as attractants or repellents in a context-dependent manner, and complex interactions between multiple guidance molecules. In addition, spontaneous patterned neural activity has recently been shown to be required for map refinement during a brief critical period. We speculate on additional activities required for map development and suggest a synthesis of molecular and cellular mechanisms within the context of the complexities of map development.
Feasibility of Real-Time Magnetic Resonance Imaging for Catheter Guidance in Electrophysiology Studies
Authors: Saman Nazarian, Aravindan Kolandaivelu, Menekhem M. Zviman, Glenn R. Meininger, Ritsushi Kato, Robert C. Susil, Ariel Roguin, Timm L. Dickfeld, Hiroshi Ashikaga, Hugh Calkins, Ronald D. Berger, David A. Bluemke, Albert C. Lardo, Henry R. Halperin
Journal: Circulation (2008)

Compared with fluoroscopy, the current imaging standard of care for guidance of electrophysiology procedures, magnetic resonance imaging (MRI) provides improved soft-tissue resolution and eliminates radiation exposure. However, because of inherent magnetic forces and electromagnetic interference, the MRI environment poses challenges for electrophysiology procedures. In this study, we sought to test the feasibility of performing electrophysiology studies with real-time MRI guidance.An MRI-compatible electrophysiology system was developed. Catheters were targeted to the right atrium, His bundle, and right ventricle of 10 mongrel dogs (23 to 32 kg) via a 1.5-T MRI system using rapidly acquired fast gradient-echo images (approximately 5 frames per second). Catheters were successfully positioned at the right atrial, His bundle, and right ventricular target sites of all animals. Comprehensive electrophysiology studies with recording of intracardiac electrograms and atrial and ventricular pacing were performed. Postprocedural pathological evaluation revealed no evidence of thermal injury to the myocardium. After proof of safety in animal studies, limited real-time MRI-guided catheter mapping studies were performed in 2 patients. Adequate target catheter localization was confirmed via recording of intracardiac electrograms in both patients.To the best of our knowledge, this is the first study to report the feasibility of real-time MRI-guided electrophysiology procedures. This technique may eliminate patient and staff radiation exposure and improve real-time soft tissue resolution for procedural guidance.
Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature
Authors: Tracy A Briggs, Gillian I Rice, Sarah Daly, Jill Urquhart, Hannah Gornall, Brigitte Bader-Meunier, Kannan Baskar, Shankar Baskar, Veronique Baudouin, Michael W Beresford, Graeme C M Black, Rebecca J Dearman, Francis de Zegher, Emily S Foster, Camille Francès, Alison R Hayman, Emma Hilton, Chantal Job-Deslandre, Muralidhar L Kulkarni, Martine Le Merrer, Agnes Linglart, Simon C Lovell, Kathrin Maurer, Lucile Musset, Vincent Navarro, Capucine Picard, Anne Puel, Frederic Rieux-Laucat, Chaim M Roifman, Sabine Scholl-Bürgi, Nigel Smith, Marcin Szynkiewicz, Alice Wiedeman, Carine Wouters, Leo A H Zeef, Jean-Laurent Casanova, Keith B Elkon, Anthony Janckila, Pierre Lebon, Yanick J Crow
Journal: Nature Genetics (2011)
Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification
Authors: Estella Matutes, Winfried F. Pickl, Mars van't Veer, Ricardo Morilla, John Swansbury, Herbert Strobl, Andishe Attarbaschi, Georg Hopfinger, Sue Ashley, Marie Christine Bene, Anna Porwit, Alberto Orfao, Petr Lemez, Richard Schabath, Wolf-Dieter Ludwig
Journal: Blood (2011)
A High-Throughput Fluorimetric Assay for 2-Hydroxyglutarate Identifies Zaprinast as a Glutaminase Inhibitor
Authors: Adnan Elhammali, Joseph E. Ippolito, Lynne Collins, Jan Crowley, Jayne Marasa, David Piwnica-Worms
Journal: Cancer Discovery (2014)

Abstract Recently identified isocitrate dehydrogenase (IDH) mutations lead to the production of 2-hydroxyglutarate (2HG), an oncometabolite aberrantly elevated in selected cancers. We developed a facile and inexpensive fluorimetric microplate assay for the quantitation of 2HG and performed an unbiased small-molecule screen in live cells to identify compounds capable of perturbing 2HG production. Zaprinast, a phosphodiesterase 5 inhibitor, was identified as an efficacious modulator of 2HG production and confirmed to lower 2HG levels in vivo. The mechanism of action was not due to cGMP stabilization, but rather, profiling of metabolites upstream of mutant IDH1 pointed to targeted inhibition of the enzyme glutaminase (GLS). Zaprinast treatment reversed histone hypermethylation and soft-agar growth of IDH1-mutant cells, and treatment of glutamine-addicted pancreatic cancer cells reduced growth and sensitized cells to oxidative damage. Thus, Zaprinast is efficacious against glutamine metabolism and further establishes the therapeutic linkages between GLS and 2HG-mediated oncogenesis. Significance: Gain-of-function IDH mutations are common events in glioma, acute myelogenous leukemia, and other cancer types, which lead to the accumulation of the oncometabolite 2HG. We show that the drug Zaprinast is capable of reducing cellular 2HG levels by inhibiting the upstream enzyme GLS, thus identifying a new strategy to target 2HG production in selected IDH-mutant cancers. Cancer Discov; 4(7); 828–39. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 745