tbuckley/cabot-search huggingface dataset:
Aurora-A Kinase Regulates Breast Cancer–Associated Gene 1 Inhibition of Centrosome-Dependent Microtubule Nucleation
Authors: Satish Sankaran, Donna E. Crone, Robert E. Palazzo, Jeffrey D. Parvin
Journal: Cancer Research (2007)

Abstract Breast cancer–associated gene 1 (BRCA1) regulates the duplication and the function of centrosomes in breast cells. We have previously shown that BRCA1 ubiquitin ligase activity directly inhibits centrosome-dependent microtubule nucleation. However, there is a paradox because centrosome microtubule nucleation potential is highest during mitosis, a phase when BRCA1 is most abundant at the centrosome. In this study, we resolve this conundrum by testing whether centrosomes from cells in M phase are regulated differently by BRCA1 when compared with other phases of the cell cycle. We observed that BRCA1-dependent inhibition of centrosome microtubule nucleation was high in S phase but was significantly lower during M phase. The cell cycle–specific effects of BRCA1 on centrosome-dependent microtubule nucleation were detected in living cells and in cell-free experiments using centrosomes purified from cells at specific stages of the cell cycle. We show that Aurora-A kinase modulates the BRCA1 inhibition of centrosome function by decreasing the E3 ubiquitin ligase activity of BRCA1. In addition, dephosphorylation of BRCA1 by protein phosphatase 1α enhances the E3 ubiquitin ligase activity of BRCA1. These observations reveal that the inhibition of centrosome microtubule nucleation potential by the BRCA1 E3 ubiquitin ligase is controlled by Aurora-A kinase and protein phosphatase 1α–mediated phosphoregulation through the different phases of the cell cycle. [Cancer Res 2007;67(23):11186–94]
The Antianginal Agent Trimetazidine Does Not Exert Its Functional Benefit via Inhibition of Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase
Authors: Alan MacInnes, David A. Fairman, Peter Binding, Jo ann Rhodes, Michael J. Wyatt, Anne Phelan, Peter S. Haddock, Eric H. Karran
Journal: Circulation Research (2003)

Trimetazidine acts as an effective antianginal clinical agent by modulating cardiac energy metabolism. Recent published data support the hypothesis that trimetazidine selectively inhibits long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), thereby reducing fatty acid oxidation resulting in clinical benefit. The aim of this study was to assess whether trimetazidine and ranolazine, which may also act as a metabolic modulator, are specific inhibitors of LC 3-KAT. We have demonstrated that trimetazidine and ranolazine do not inhibit crude and purified rat heart or recombinant human LC 3-KAT by methods that both assess the ability of LC 3-KAT to turnover specific substrate, and LC 3-KAT activity as a functional component of intact cellular beta-oxidation. Furthermore, we have demonstrated that trimetazidine does not inhibit any component of beta-oxidation in an isolated human cardiomyocyte cell line. Ranolazine, however, did demonstrate a partial inhibition of beta-oxidation in a dose-dependent manner (12% at 100 micromol/L and 30% at 300 micromol/L). Both trimetazidine (10 micromol/L) and ranolazine (20 micromol/L) improved the recovery of cardiac function after a period of no flow ischemia in the isolated working rat heart perfused with a buffer containing a relatively high concentration (1.2 mmol/L) of free fatty acid. In summary, both trimetazidine and ranolazine were able to improve ischemic cardiac function but inhibition of LC 3-KAT is not part of their mechanism of action. The full text of this article is available online at http://www.circresaha.org.
Epoetin-Induced Autoimmune Pure Red Cell Aplasia
Authors: Nicole Casadevall, Kai-Uwe Eckardt, Je[Combining Acute Accent]ro[Combining Circumflex Accent]me Rossert
Journal: Journal of the American Society of Nephrology (2005)

During the first 10 yr of therapy with recombinant human erythropoietin ([EPO]), only three cases of antibody-associated pure red cell aplasia have been described in patients who were treated with EPO, whereas several millions of patients have received this treatment. Thus, the possibility for epoetin to induce the formation of anti-EPO antibodies was considered extremely low. However, since 1998, a significant increase in the number of cases of EPO-induced pure red cell aplasia has been found in patients with chronic kidney disease with a peak in 2001 and 2002. The incidence rate seems now to be back to the baseline level. The change in formulation of epoetin α sold outside the United States seems to be the cause of these antibodies.
Inhibition of p70S6K2 down-regulates Hedgehog/GLI pathway in non-small cell lung cancer cell lines
Authors: Shinji Mizuarai, Aki Kawagishi, Hidehito Kotani
Journal: Molecular Cancer (2009)

Abstract Background The Hedgehog (HH) pathway promotes tumorigenesis in a diversity of cancers. Activation of the HH signaling pathway is caused by overexpression of HH ligands or mutations in the components of the HH/GLI1 cascade, which lead to increased transactivation of GLI transcription factors. Although negative kinase regulators that antagonize the activity of GLI transcription factors have been reported, including GSK3β, PKA and CK1s, little is known regarding positive kinase regulators that are suitable for use on cancer therapeutic targets. The present study attempted to identify kinases whose silencing inhibits HH/GLI signalling in non-small cell lung cancer (NSCLC). Results To find positive kinase regulators in the HH pathway, kinome-wide siRNA screening was performed in a NSCLC cell line, A549, harboring the GLI regulatory reporter gene. This showed that p70S6K2-silencing remarkably reduced GLI reporter gene activity. The decrease in the activity of the HH pathway caused by p70S6K2-inhibition was accompanied by significant reduction in cell viability. We next investigated the mechanism for p70S6K2-mediated inhibition of GLI1 transcription by hypothesizing that GSK3β, a negative regulator of the HH pathway, is activated upon p70S6K2-silencing. We found that phosphorylated-GSK3β (Ser9) was reduced by p70S6K2-silencing, causing a decreased level of GLI1 protein. Finally, to further confirm the involvement of p70S6K2 in GLI1 signaling, down-regulation in GLI-mediated transcription by PI3KCA-inhibition was confirmed, establishing the pivotal role of the PI3K/p70S6K2 pathway in GLI1 cascade regulation. Conclusion We report herein that inhibition of p70S6K2, known as a downstream effector of the PI3K pathway, remarkably decreases GLI-mediated transactivation in NSCLC by reducing phosphorylated-GSK3β followed by GLI1 degradation. These results infer that p70S6K2 is a potential therapeutic target for NSCLC with hyperactivated HH/GLI pathway.
Performance of forced expiratory manoeuvre in children
Authors: E. D'angelo, V. Carnelli, E D'angelo, J Milic-Emili
Journal: European Respiratory Journal (2000)

The negative expiratory pressure (NEP) method has been previously used to assess the performance of forced vital capacity (FVC) manoeuvre in normal adults. The aim of the present study is to assess whether flow limitation is achieved during FVC manoeuvres in children aged 6-14 yrs. NEP (-10 cmH2O) was successfully applied in 177 normal children, the portion of FVC over which expiratory flow did or did not change with NEP being taken as effort-dependent and effort-independent, respectively. In all children peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) increased with NEP, indicating that PEF was in the effort-dependent portion of FVC. This portion decreased significantly with age (50-20% of FVC from 6-14 yrs). It is suggested that this mainly reflects the poorer coordination of specialized motor acts in younger children because of incomplete morphological and functional maturation of the relevant central nervous system (CNS) mechanisms. The results indicate that most unexperienced children aged 6-14 yrs can perform acceptable forced vital capacity manoeuvres, eventually achieving flow limitation over a portion of the forced vital capacity that increases with age. The negative expiratory pressure method can be used for online assessment of the performance of forced vital capacity manoeuvres and evaluation of treatment-related effects.
A STUDY OF THE BEHAVIOR OF FOWL POX VIRUS MODIFIED BY INTRACEREBRAL PASSAGE
Authors: G. John Buddingh
Journal: The Journal of Experimental Medicine (1938)

1. Intracerebral transfer in chicks of fowl pox virus produces marked changes in its behavior when studied in the chorio-allantoic membrane of chick embryos and in the skin of baby chicks. 2. A great and persistent increase in virulence for epithelial cells, characterized by rapid necrosis instead of proliferation and hyperplasia, is acquired by the virus propagated intracerebrally. 3. An affinity for cells of mesodermal origin including endothelial cells of blood vessels, and an increase in affinity for entodermal cells is acquired by the virus propagated intracerebrally. 4. The intracerebral virus causes a uniform morphological change in all types of cells, in that the infected cells rapidly become spherical in shape, detached, and desquamated followed by necrosis. 5. One intracerebral passage is sufficient to produce this change in the virus.
Different Patterns of Interatrial Conduction in Clockwise and Counterclockwise Atrial Flutter
Authors: Joseph E. Marine, Victoria J. Korley, Ogundu Obioha-Ngwu, Jane Chen, Peter Zimetbaum, Panos Papageorgiou, Paul Milliez, Mark E. Josephson
Journal: Circulation (2001)

Background — The terms counterclockwise (CC) and clockwise (C) atrial flutter (Afl) are used to describe right atrial activation around the tricuspid valve in the left anterior oblique view. The manner in which the left atrium is activated, as reflected by coronary sinus (CS) recordings, has not been systematically evaluated. Methods and Results — Nine patients with both CC and C Afl underwent electrophysiological study with CS recordings during both rhythms with the use of a decapolar catheter with the tip placed in the distal CS. Patterns of CS activation during each type of Afl as well as during during sinus rhythm were categorized into 1 of 3 patterns: sequential proximal-to-distal, sequential distal-to-proximal, and fused, indicating activation from different directions. In 7 of 9 patients, the pattern of CS activation in CC Afl and C Afl differed, with a proximal-to-distal pattern in CC Afl and a fused pattern in C Afl. In 2 patients, pacing the high right atrial septum near the presumed site of Bachmann’s bundle in sinus rhythm showed a similar fused pattern of CS activation. Conclusions — These results demonstrate different patterns of CS activation in CC Afl and C Afl in the majority of patients and are consistent with a model in which the left atrium is activated predominantly over Bachmann’s bundle during C Afl and over the CS os in CC Afl. These findings may have implications for maintenance of Afl, interpretation of flutter wave morphology on surface ECG, and left atrial mechanical function in Afl.
Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences
Authors: Francesc Coll, Ruth McNerney, Mark D Preston, José Afonso Guerra-Assunção, Andrew Warry, Grant Hill-Cawthorne, Kim Mallard, Mridul Nair, Anabela Miranda, Adriana Alves, João Perdigão, Miguel Viveiros, Isabel Portugal, Zahra Hasan, Rumina Hasan, Judith R Glynn, Nigel Martin, Arnab Pain, Taane G Clark
Journal: Genome Medicine (2015)

Abstract Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.
[1] DURABLE SUSTAINED VIROLOGICAL RESPONSE AFTER TREATMENT WITH PEGINTERFERON α-2a (PEGASYS®) ALONE OR IN COMBINATION WITH RlBAVlRlN (COPEGUS®): 5-YEAR FOLLOW-UP AND THE CRITERIA OF A CURE
Authors: M.G. Swain, M.-Y. Lai, M.L. Shiftman, W.G.E. Cooksley, A. Abergel, A. Lin, E. Connell, M. Diago
Journal: Journal of Hepatology (2007)
Late-breaking abstract: Pre-clinical efficacy of RP5090 in PI3Kδ mediated airway disorders
Authors: Kasiviswanath Routhu, Kanthikiran Varanasi, Sridhar Veeraraghavan, Meyyappan Muthuppalaniappan, G. Babu, Srikant Viswanadha, Swaroop Vakkalanka
Journal: European Respiratory Journal (2011)

Introduction:  PI3Kδ plays a pivotal role in airway remodelling processes that include recruitment and activation of inflammatory cells, cytokine release, mast cell activation and vascular permeability. Given the established criticality of PI3Kδ in airway inflammation, inhibitors specifically targeting this isoform would attenuate progression of asthma and COPD.   Methods:  Specificity of RP5090 towards PI3Kδ, suppression of pAKT in THP-1 cells, elastase exocytosis and migration in neutrophils, and IgE-induced mast cell degranulation were determined. Pre-clinical efficacy of RP5090 was confirmed in animal models of airway disorders, namely, LPS-induced pulmonary neutrophilia in rat as well as in acute and chronic eosinophilia models in Guinea Pig.   Results:  RP5090 demonstrated significant potency against PI3Kδ (18.5 nM) with several fold selectivity over other isoforms with subsequent inhibition of pAKT. Additionally, the compound inhibited neutrophil functionality and mast-cell degranulation at nanomolar concentrations. RP5090 displayed excellent efficacy in inhibiting LPS-induced neutrophilia in SD rat (65% at 20 mg/kg b.wt). Besides, the compound decreased eosinophil infiltration into the lungs upon induction by PAF (>80% @ 10 mg/kg) or OVA (>60% @ 1 mg/kg) in Guinea pigs. Consistent with  in vitro  findings, the compound caused a significant inhibition of mast cell degranulation manifested by a reduction in histamine release.   Conclusions:  Results demonstrate the therapeutic potential of RP5090 in asthma and related airway disorders acting via the PI3Kδ pathway. Further in vivo studies are in progress to evaluate the efficacy of the compound in airway hyper-responsiveness prior to the initiation of clinical trials.
Reduced Adiponectin Concentration in Women With Gestational Diabetes
Authors: Ravi Retnakaran, Anthony J.G. Hanley, Nuryt Raif, Philip W. Connelly, Mathew Sermer, Bernard Zinman
Journal: Diabetes Care (2004)

Adiponectin, a novel protein secreted exclusively by adipocytes, has emerged as an important potential mediator of the insulin resistance that is so characteristic of obesity, type 2 diabetes, and atherosclerotic cardiovascular disease (1,2). Consistent with the established inverse relationship between plasma adiponectin concentration and insulin resistance, hypoadiponectinemia has been documented in patients with each of these pathologic conditions (3–7). Moreover, in the Pima Indian population, low baseline adiponectin concentration predicts the subsequent development of insulin resistance (8), whereas conversely, elevated baseline adiponectin levels have been shown to be protective against the future development of type 2 diabetes (9). Taken together, these observations suggest that hypoadiponectinemia may be an important factor in the development of insulin resistance and the pathophysiology of type 2 diabetes. Gestational diabetes mellitus (GDM) identifies a population of young women at high risk of developing type 2 diabetes (10), representing an early stage in the natural history of the disease. Thus, we hypothesized that hypoadiponectinemia may be associated with GDM. The present study investigated the relationship between adiponectin and glucose tolerance in pregnancy.

The study design, protocol, and laboratory methods have been fully described previously (11). The study protocol was approved by the research ethics board at Mount Sinai Hospital, and all subjects gave written informed …
Performance Goals for Dispatcher-Assisted Cardiopulmonary Resuscitation
Authors: Joseph P. Ornato
Journal: Circulation (2013)

A n estimated 600 000 Americans are victims of sud- den, unexpected out-of-hospital cardiac arrests each year. 1 Emergency medical services (EMS) providers attempt resuscitation in 360 000 of these "EMS-treated" individuals.EMS crews declare another 240 000 victims dead on arrival because the cardiac arrest was unwitnessed and the victim's body shows physical signs that death has not just occurred.Approximately 9.5% of EMS-treated cardiac arrest victims survive to hospital discharge.However, if one includes the 240 000 victims in whom EMS does not even attempt resuscitation, the likelihood of surviving an out-of-hospital cardiac arrest in the United States is only 5.7%.Stated differently, only 1 in every 18 out-of-hospital cardiac arrest victims in the United States will survive to hospital discharge.
Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current
Authors: Markus B. Sikkel, Thomas P. Collins, Christina Rowlands, Mit Shah, Peter O'Gara, Alan J. Williams, Sian E. Harding, Alexander R. Lyon, Kenneth T. MacLeod
Journal: Cardiovascular Research (2013)

Ca2+ waves are thought to be important in the aetiology of ventricular tachyarrhythmias. There have been conflicting results regarding whether flecainide reduces Ca2+ waves in isolated cardiomyocytes. We sought to confirm whether flecainide inhibits waves in the intact cardiomyocyte and to elucidate the mechanism. We imaged spontaneous sarcoplasmic reticulum (SR) Ca2+ release events in healthy adult rat cardiomyocytes. Variation in stimulation frequency was used to produce Ca2+ sparks or waves. Spark frequency, wave frequency, and wave velocity were reduced by flecainide in the absence of a reduction of SR Ca2+ content. Inhibition of INa via alternative pharmacological agents (tetrodotoxin, propafenone, or lidocaine) produced similar changes. To assess the contribution of INa to spark and wave production, voltage clamping was used to activate contraction from holding potentials of −80 or −40 mV. This confirmed that reducing Na+ influx during myocyte stimulation is sufficient to reduce waves and that flecainide only causes Ca2+ wave reduction when INa is active. It was found that Na+/Ca2+-exchanger (NCX)-mediated Ca2+ efflux was significantly enhanced by flecainide and that the effects of flecainide on wave frequency could be reversed by reducing [Na+]o, suggesting an important downstream role for NCX function. Flecainide reduces spark and wave frequency in the intact rat cardiomyocyte at therapeutically relevant concentrations but the mechanism involves INa reduction rather than direct ryanodine receptor (RyR2) inhibition. Reduced INa results in increased Ca2+ efflux via NCX across the sarcolemma, reducing Ca2+ concentration in the vicinity of the RyR2.
Bilateral globus pallidus stimulation for severe Tourette's syndrome: a double-blind, randomised crossover trial
Authors: Zinovia Kefalopoulou, Ludvic Zrinzo, Marjan Jahanshahi, Joseph Candelario, Catherine Milabo, Mazda Beigi, Harith Akram, Jonathan Hyam, Jennifer Clayton, Lewis Kass-Iliyya, Monty Silverdale, Julian Evans, Patricia Limousin, Marwan Hariz, Eileen Joyce, Thomas Foltynie
Journal: The Lancet Neurology (2015)
Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma
Authors: Angelo Vacca, Claudio Scavelli, Guido Serini, Giulia Di Pietro, Teresa Cirulli, Francesca Merchionne, Domenico Ribatti, Federico Bussolino, Diego Guidolin, Giovanna Piaggio, Andrea Bacigalupo, Franco Dammacco
Journal: Blood (2006)
Second hand smoke exposure is associated with worse survival in early stage non-small cell lung cancer
Authors: T F Paul McKeagney
Journal: Thorax (2007)

▴ Zhou W, Heist RS, Liu G, et al . Second hand smoke exposure and survival in early-stage non-small cell lung cancer patients. Clin Cancer Res2006;12:7187–93.

[OpenUrl][1][Abstract/FREE Full Text][2]



This study examines the possible association between the extent of second hand smoke (SHS) exposure prior to diagnosis of early stage non-small cell lung cancer (stages Ia-IIb) and survival after treatment. The 393 Massachusetts General Hospital patients were grouped into …

 [1]: {openurl}?query=rft.jtitle%253DClinical%2BCancer%2BResearch%26rft.stitle%253DClin.%2BCancer%2BRes.%26rft.issn%253D1078-0432%26rft.aulast%253DZhou%26rft.auinit1%253DW.%26rft.volume%253D12%26rft.issue%253D23%26rft.spage%253D7187%26rft.epage%253D7193%26rft.atitle%253DSecond%2BHand%2BSmoke%2BExposure%2Band%2BSurvival%2Bin%2BEarly-Stage%2BNon-Small-Cell%2BLung%2BCancer%2BPatients%26rft_id%253Dinfo%253Adoi%252F10.1158%252F1078-0432.CCR-06-1460%26rft_id%253Dinfo%253Apmid%252F17145845%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
 [2]: /lookup/ijlink?linkType=ABST&journalCode=clincanres&resid=12/23/7187&atom=%2Fthoraxjnl%2F62%2F5%2F437.atom
Hip replacement surgery in patients with ankylosing spondylitis
Authors: Tone Wikene Nystad, Ove Furnes, Leif Ivar Havelin, Arne Kristian Skredderstuen, Stein Atle Lie, Bjørg-Tilde Svanes Fevang
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Although TNF-α inhibitors’ striking effect on clinical symptoms have revolutionised the treatment of ankylosing spondylitis (AS), no certain influence on the development of spinal ankylosis and joint destruction has been documented. We wished to investigate whether improved treatment has affected the use of hip arthroplasty surgery. <h3>Methods</h3> Using the Norwegian Arthroplasty Register, we selected hip prosthesis procedures performed in patients with AS in 1988–2010 (n=534), and compared the trend in the number of procedures being performed annually in 1988–2002 versus 2003–2010. Patients with osteoarthritis (OA) (n=95094) were used as a control group. <h3>Results</h3> The frequency of hip prosthesis surgery increased significantly in both groups up until 2002. In 2003–2010, although not statistically significant (p=0.087), there was a trend towards a reduced frequency in the AS group when compared with the expected continued increase as was seen among patients with OA. Mean age at surgery increased significantly (p&lt;0.001) from 49.9 years to 56.4 years when comparing patients with AS up until and after 2002. <h3>Conclusions</h3> TNF-α inhibitors were introduced to patients with AS in Norway in 2000–2003, and our findings suggest that they may have altered the prognosis by inhibiting or slowing large joint arthritis and thus reducing the need for hip replacement surgery.