tbuckley/cabot-search huggingface dataset:
Regulation of p27 by S-Phase Kinase-Associated Protein 2 Is Associated With Aggressiveness in Non–Small-Cell Lung Cancer
Authors: Atsushi Osoegawa, Ichiro Yoshino, Shinji Tanaka, Kenji Sugio, Toshifumi Kameyama, Masafumi Yamaguchi, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2004)

The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 expression in human non-small-cell lung cancer (NSCLC).Clinicopathologic features and immunohistochemical expression of Skp2 and p27 proteins were studied in 138 patients with NSCLC. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. To analyze the role of Skp2 in vitro, NSCLC cells were transfected with an Skp2-expressing vector or small interfering RNA.Skp2 was overexpressed in males, smokers, patients with squamous cell carcinomas, and patients with poorly differentiated cancers (P = .034, < .0001, < .0001, and .002, respectively). The multivariant analysis revealed that Skp2 expression is an independent prognostic factor for survival in NSCLC. An inverse relationship of Skp2 with p27 expression was observed (P = .012), and patients with both a higher expression of Skp2 and a lower expression of p27 showed a significantly unfavorable prognosis (P = .0002). In vitro ectopic expression of Skp2 in NSCLC cells reduced the protein level of p27. Conversely, induction of Skp2 siRNA increased the protein level of p27, leading to growth inhibition in NSCLC cells.Skp2 overexpression is closely associated with the suppression of p27 and the aggressiveness in NSCLC. It also could be a therapeutic target in NSCLC.
Effects of Duty Hour Restrictions on Core Competencies, Education, Quality of Life, and Burnout Among General Surgery Interns
Authors: Ryan M. Antiel, Darcy A. Reed, Kyle J. Van Arendonk, Sean C. Wightman, Daniel E. Hall, John R. Porterfield, Karen D. Horvath, Kyla P. Terhune, John L. Tarpley, David R. Farley
Journal: JAMA Surgery (2013)

To measure the implications of the new Accreditation Council for Graduate Medical Education duty hour regulations for education, well-being, and burnout.Longitudinal study.Eleven university-based general surgery residency programs from July 2011 to May 2012.Two hundred thirteen surgical interns.Perceptions of the impact of the new duty hours on various aspects of surgical training, including the 6 Accreditation Council for Graduate Medical Education core competencies, were measured on 3-point scales. Quality of life, burnout, balance between personal and professional life, and career satisfaction were measured using validated instruments.Half of all interns felt that the duty hour changes have decreased the coordination of patient care (53%), their ability to achieve continuity with hospitalized patients (70%), and their time spent in the operating room (57%). Less than half (44%) of interns believed that the new standards have decreased resident fatigue. In longitudinal analysis, residents' beliefs had significantly changed in 2 categories: less likely to believe that practice-based learning and improvement had improved and more likely to report no change to resident fatigue (P < .01, χ2 tests). The majority (82%) of residents reported a neutral or good overall quality of life. Compared with the normal US population, 50 interns (32%) were 0.5 SD less than the mean on the 8-item Short Form Health Survey mental quality of life score. Approximately one-third of interns demonstrated weekly symptoms of emotional exhaustion (28%) or depersonalization (28%) or reported that their personal-professional balance was either "very poor" or "not great" (32%). Although many interns (67%) reported that they daily or weekly reflect on their satisfaction from being a surgeon, 1 in 7 considered giving up their career as a surgeon on at least a weekly basis.The first cohort of surgical interns to train under the new regulations report decreased continuity with patients, coordination of patient care, and time spent in the operating room. Furthermore, suboptimal quality of life, burnout, and thoughts of giving up surgery were common, even under the new paradigm of reduced work hours.
Calcineurin Regulates Myocardial Function during Acute Endotoxemia
Authors: Mandar S. Joshi, Mark W. Julian, Jennifer E. Huff, John A. Bauer, Yong Xia, Elliott D. Crouser
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Cyclosporin A (CsA) is known to preserve cardiac contractile function during endotoxemia, but the mechanism is unclear. Increased nitric oxide (NO) production and altered mitochondrial function are implicated as mechanisms contributing to sepsis-induced cardiac dysfunction, and CsA has the capacity to reduce NO production and inhibit mitochondrial dysfunction relating to the mitochondrial permeability transition (MPT).We hypothesized that CsA would protect against endotoxin-mediated cardiac contractile dysfunction by attenuating NO production and preserving mitochondrial function.Left ventricular function was measured continuously over 4 h in cats assigned as follows: control animals (n = 7); LPS alone (3 mg/kg, n = 8); and CsA (6 mg/kg, n = 7), a calcineurin inhibitor that blocks the MPT, or tacrolimus (FK506, 0.1 mg/kg, n = 7), a calcineurin inhibitor lacking MPT activity, followed in 30 min by LPS. Myocardial tissue was then analyzed for NO synthase-2 expression, tissue nitration, protein carbonylation, and mitochondrial morphology and function.LPS treatment resulted in impaired left ventricular contractility, altered mitochondrial morphology and function, and increased protein nitration. As hypothesized, CsA pretreatment normalized cardiac performance and mitochondrial respiration and reduced myocardial protein nitration. Unexpectedly, FK506 pretreatment had similar effects, normalizing both cardiac and mitochondrial parameters. However, CsA and FK506 pretreatments markedly increased protein carbonylation in the myocardium despite elevated manganese superoxide dismutase activity during endotoxemia.Our data indicate that calcineurin is a critical regulator of mitochondrial respiration, tissue nitration, protein carbonylation, and contractile function in the heart during acute endotoxemia.
Omega-3 Fatty Acids Prevent Pressure Overload–Induced Cardiac Fibrosis Through Activation of Cyclic GMP/Protein Kinase G Signaling in Cardiac Fibroblasts
Authors: Jinghai Chen, Gregory C. Shearer, Quanhai Chen, Chastity L. Healy, April J. Beyer, Vijaya B. Nareddy, A. Martin Gerdes, William S. Harris, Timothy D. O'Connell, Dajun Wang
Journal: Circulation (2011)

Background— Omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) from fish oil ameliorate cardiovascular diseases. However, little is known about the effects of ω-3 polyunsaturated fatty acids on cardiac fibrosis, a major cause of diastolic dysfunction and heart failure. The present study assessed the effects of ω-3 polyunsaturated fatty acids on cardiac fibrosis. Methods and Results— We assessed left ventricular fibrosis and pathology in mice subjected to transverse aortic constriction after the consumption of a fish oil or a control diet. In control mice, 4 weeks of transverse aortic constriction induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation (proliferation and transformation into myofibroblasts). Dietary supplementation with fish oil prevented transverse aortic constriction–induced cardiac dysfunction and cardiac fibrosis and blocked cardiac fibroblast activation. In heart tissue, transverse aortic constriction increased active transforming growth factor-β1 levels and phosphorylation of Smad2. In isolated adult mouse cardiac fibroblasts, transforming growth factor-β1 induced cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid increased cyclic GMP levels and blocked cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid blocked phospho-Smad2/3 nuclear translocation. DT3, a protein kinase G inhibitor, blocked the antifibrotic effects of eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid increased phosphorylated endothelial nitric oxide synthase and endothelial nitric oxide synthase protein levels and nitric oxide production. Conclusion— Omega-3 fatty acids prevent cardiac fibrosis and cardiac dysfunction by blocking transforming growth factor-β1–induced phospho-Smad2/3 nuclear translocation through activation of the cyclic GMP/protein kinase G pathway in cardiac fibroblasts.
Frontotemporal dementia and its subtypes: a genome-wide association study
Authors: Raffaele Ferrari, Dena G Hernandez, Michael A Nalls, Jonathan D Rohrer, Adaikalavan Ramasamy, John B J Kwok, Carol Dobson-Stone, William S Brooks, Peter R Schofield, Glenda M Halliday, John R Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R A Mackenzie, Ging-Yuek R Hsiung, David M A Mann, Jordan Grafman, Christopher M Morris, Johannes Attems, Timothy D Griffiths, Ian G McKeith, Alan J Thomas, P Pietrini, Edward D Huey, Eric M Wassermann, Atik Baborie, Evelyn Jaros, Michael C Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B Rowe, Johannes C M Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M Van Deerlin, Murray Grossman, John Q Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano F Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E Nielsen, Lena E Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N Rossor, Nick C Fox, Jason D Warren, Maria Grazia Spillantini, Huw R Morris, Patrizia Rizzu, Peter Heutink, Julie S Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, David Knopman, Keith A Josephs, Bradley F Boeve, Joseph E Parisi, William W Seeley, Bruce L Miller, Anna M Karydas, Howard Rosen, John C van Swieten, Elise G P Dopper, Harro Seelaar, Yolande A L Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B Singleton, John Hardy, Parastoo Momeni
Journal: The Lancet Neurology (2014)
MRI-informed electrical impedance tomography from phantom to thorax
Authors: Ross Little, John Davidson, Josephine Naish, Paul Wright, Alexandra Morgan, Ron Kikinis, Hugh McCann, Geoff Parker
Journal: European Respiratory Journal (2012)

Electrical impedance tomography (EIT) has the potential to provide non-invasive, high temporal resolution, long term lung function monitoring. We present an instrument capable of volumetric data acquisition applied to a male torso, show an MRI-informed reconstruction, and correspondence of EIT measurements with high resolution MRI.

![Figure][1] 



EIT data were acquired using two planes of 16 electrodes on the Manchester fEITER system, a BS EN 60601-1:2006 compliant system, followed by MRI acquired using fast field echo on a 1.5 T Philips Achieva. The data were coaligned using the open source medical image platform 3D-Slicer. Figure 1(a)-(c) shows an MRI axial slice of the torso, coalignment with EIT, and EIT alone.

The system acquired volume data using 32 electrodes in two planes. The EIT was reconstructed using a torso boundary-only model derived from the MRI. This should produce a more faithful reconstruction than a generic model, allowing investigation of sensitivity of EIT measurements using increasingly precise models.

At 100 fps, the EIT provides excellent temporal resolution. For example, it shows different temporal sequences of lung ventilation (dorsal versus ventral) within the breathing cycle for an upright subject as compared with supine. Current analyses of EIT data for lung function monitoring use sub-cycle statistics and time differentials; the (minimum) 3-fold increase in frame rate provided by fEITER will improve these methods substantially.

 [1]: pending:yes
IL-23 and Autoimmunity: New Insights into the Pathogenesis of Inflammatory Bowel Disease
Authors: Clara Abraham, Judy H. Cho
Journal: Annual Review of Medicine (2008)

The intestinal immune system has the challenge of maintaining both a state of tolerance toward intestinal antigens and the ability to combat pathogens. This balance is partially achieved by reciprocal regulation of proinflammatory, effector CD4(+) T cells and tolerizing, suppressive regulatory T cells. Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have linked CD to a number of IL-23 pathway genes, notably IL23R (interleukin 23 receptor). Similar associations in IL-23 pathway genes have been observed in UC. IL23R is a key differentiation feature of CD4(+) Th17 cells, effector cells that are critical in mediating antimicrobial defenses. However, IL-23 and Th17 cell dysregulation can lead to end-organ inflammation. The differentiation of inflammatory Th17 cells and suppressive CD4(+) Treg subsets is reciprocally regulated by relative concentrations of TGFbeta, with the concomitant presence of proinflammatory cytokines favoring Th17 differentiation. The identification of IL-23 pathway and Th17 expressed genes in IBD pathogenesis highlights the importance of the proper regulation of the IL-23/Th17 pathway in maintaining intestinal immune homeostasis.
Mechanical Control of Tissue Morphogenesis
Authors: Parth Patwari, Richard T. Lee
Journal: Circulation Research (2008)

Mechanical forces participate in morphogenesis from the level of individual cells to whole organism patterning. This article reviews recent research that has identified specific roles for mechanical forces in important developmental events. One well defined example is that dynein-driven cilia create fluid flow that determines left-right patterning in the early mammalian embryo. Fluid flow is also important for vasculogenesis, and evidence suggests that fluid shear stress rather than fluid transport is primarily required for remodeling the early vasculature. Contraction of the actin cytoskeleton, driven by nonmuscle myosins and regulated by the Rho family GTPases, is a recurring mechanism for controlling morphogenesis throughout development, from gastrulation to cardiogenesis. Finally, novel experimental approaches suggest critical roles for the actin cytoskeleton and the mechanical environment in determining differentiation of mesenchymal stem cells. Insights into the mechanisms linking mechanical forces to cell and tissue differentiation pathways are important for understanding many congenital diseases and for developing regenerative medicine strategies.
CASE OF ACROMEGALY
Authors: W. B. Hunter
Journal: BMJ (1903)

an officer must be invalided and this is serious to a man near the time when he may receive command of his battalion.The result of inquiries as to specific trouble was negative.'His condition was as bad as could be, the breathlessness was very great and attended by anginal attacks.Whlen tested by Hill and Barnard's sphygmometer the maximum swing of the needle was at 200 Hg, the effects of back pressure being seen in the oedema of the legs and the ~siz-e of the liver.The heart was failing, and the constant 7paiii and the breathlessness were very trying.I gave mnorphine sulph., guarded by a dose of atrop.sulph., to check the restlessness, and regular doses of nitro-glycerine to lessen the resistance ahead, and so let the blood get away; hypo- dermics of strychninie to brace ihe heart muscle, an occa- -sional blue pill and seidlitz.By the time Sir William Broadbent saw him the dose of morphine was gr.W a dav.Thle condition of hiis heart is described in the note follow- mang,
Circulating high sensitivity troponin T in severe sepsis and septic shock: distribution, associated factors, and relation to outcome
Authors: Helge Røsjø, Marjut Varpula, Tor-Arne Hagve, Sari Karlsson, Esko Ruokonen, Ville Pettilä, Torbjørn Omland
Journal: Intensive Care Medicine (2010)

To assess the clinical utility of a recently developed highly sensitive cardiac troponin T (hs-cTnT) assay for providing prognostic information on patients with sepsis.cTnT levels were measured by the novel hs-cTnT assay at two time points (inclusion and 72 h thereafter) in a subgroup of patients from the FINNSEPSIS study and associations with clinical outcomes were examined. Results for the hs-cTnT assay were compared to those of the established fourth-generation cTnT assay.cTnT measured by the fourth-generation and hs-cTnT assay was detectable in 124 (60%) and 207 (100%) patients, respectively, on inclusion in this study. hs-cTnT levels on inclusion correlated with several indices of risk in sepsis, including the simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) scores. The level of hs-cTnT on inclusion was higher in hospital non-survivors (n = 47) than survivors (n = 160) (median 0.054 [Q1-3, 0.022-0.227] versus 0.035 [0.015-0.111] μg/L, P = 0.047), but hs-cTnT level was not an independent predictor of in-hospital mortality. hs-cTnT levels on inclusion were also higher in patients with septic shock during the hospitalization (0.044 [0.024-0.171] versus 0.033 [0.012-0.103] μg/L, P = 0.03), while this was not the case for the fourth-generation cTnT assay or NT-proBNP levels.Circulating hs-cTnT is present in patients with severe sepsis and septic shock, associates with disease severity and survival, but does not add to SAPS II score for prediction of mortality. hs-cTnT measurement could still have a role in sepsis as an early marker of shock.
Response to H Zeidler's comments on the CONCERTO study
Authors: Gerd R Burmester, Alan Kivitz, Hartmut Kupper, Udayasankar Arulmani, Stefan Florentinus, Sandra L Goss, Suchitrita S Rathmann, Roy M Fleischmann
Journal: Annals of the Rheumatic Diseases (2014)

We thank Dr Zeidler for his interest in our manuscript,1 expressed in his recent letter to the editor.2 While Dr Zeidler raises interesting questions regarding methotrexate (MTX) bioavailability and the differences between oral and subcutaneous formulations of MTX, these are outside the scope of the CONCERTO study. Thus, it is important to reiterate that the objective of the study was to assess the oral dose of (MTX), which when co-administered with the tumour necrosis factor inhibitor, adalimumab (ADA), is required to optimise the benefit:risk profile in patients with early rheumatoid arthritis (RA), who were MTX naive. We agree with Dr Zeidler that this is not the usual course, nor one generally recommended by the European League Against Rheumatism (EULAR), of initiating a biological therapy for the treatment of RA; however, it was critical to assess …
Acupuncture for Chronic Low Back Pain
Authors: Brian M. Berman, Helene M. Langevin, Claudia M. Witt, Ronald Dubner
Journal: New England Journal of Medicine (2010)

A 45-year-old man with a 7-year history of low back pain asks his physician for a referral to a licensed acupuncturist. Acupuncture involves the insertion of fine metallic needles into the body at specific sites. Clinical trials of acupuncture for chronic low back pain have shown higher rates of symptom improvement with either acupuncture or sham acupuncture than with usual care.
Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel
Authors: B Walker
Journal: Cardiovascular Research (2000)

Objective: To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related (HERG) channel. Methods: HERG was stably transfected into Chinese hamster ovary (CHO-K1) cells and currents were measured using a whole cell, voltage-clamp technique. Results: Azimilide had a 'dual effect', inhibiting current at voltage steps above −40 mV and augmenting current at −40 and −50 mV. Tail current inhibition following a step to +30 mV did not vary with temperature (IC50 610 nM at 22°C and 560 nM at 37°C). The agonist effect at −50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V1/2 of activation (r = 0.98, P<0.05). Time constants of inactivation were faster and there was a −10 mV shift in the V1/2 of steady state inactivation suggestive of open and inactivated state binding. By comparison, ambasilide inhibited HERG channels with lower potency (IC50 3.6 μM), in a voltage- and time-dependent but frequency-independent manner (0.03–1 Hz). Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state. The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential. Conclusions: Inhibition of HERG channels by azimilide and ambasilide exhibits a similar time and voltage-dependence. While both exhibit affinity for the open state, azimilide also binds to inactivated channels.
Src Inhibition Ameliorates Polycystic Kidney Disease
Authors: William E Sweeney, Rodo O von Vigier, Philip Frost, Ellis D Avner
Journal: Journal of the American Society of Nephrology (2008)

Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60(c-Src)) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation. With the use of the nonorthologous BPK murine model and the orthologous PCK rat model of ARPKD, greater Src activity was found to correlate with disease progression. Inhibition of Src activity with the pharmacologic inhibitor SKI-606 resulted in amelioration of renal cyst formation and biliary ductal abnormalities in both models. Furthermore, the effects of Src inhibition in PCK kidneys suggest that the ErbB2 and B-Raf/MEK/ERK pathways are involved in Src-mediated signaling in ARPKD and that this occurs without reducing elevated cAMP. These data suggest that Src inhibition may provide therapeutic benefit in PKD.