tbuckley/cabot-search huggingface dataset:
Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin
Authors: S. H. Oh, J. K. Woo, Y. D. Yazici, J. N. Myers, W.-Y. Kim, Q. Jin, S. S. Hong, H.-J. Park, Y.-G. Suh, K.-W. Kim, W. K. Hong, H.-Y. Lee
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundThe molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor 1α (HIF-1α) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90.
The Free Hormone Hypothesis: A Physiologically Based Mathematical Model*
Authors: CARL M. MENDEL
Journal: Endocrine Reviews (1989)

The free hormone hypothesis states that the biological activity of a given hormone is affected by its unbound (free) rather than protein-bound concentration in the plasma. The fundamental mathematical and physiological principles relating to this hypothesis are reviewed, along with experimental data that shed light on its validity. It is shown that whether or not this hypothesis is likely to be valid for any given hormone will depend largely on which step in the tissue uptake process (plasma flow, dissociation from plasma binding proteins, influx, or intracellular elimination) is rate-limiting to the net tissue uptake of that hormone. It is further shown that the free hormone hypothesis could hold even if tissue uptake of hormone occurred by a mechanism that acted directly on one or more circulating protein-bound pools of hormone. Indeed, many of the data previously interpreted as being inconsistent with the free hormone hypothesis are in fact readily consistent with it when its predictions are fully understood. Nevertheless, the free hormone hypothesis is not likely to be valid for all hormones with respect to all tissues. It is likely to be valid with respect to all tissues for the thyroid hormones, for cortisol, and for the hydroxylated metabolites of vitamin D. For many of the other steroid hormones, however, it is likely to be valid with respect to some tissues, but not with respect to others (in particular, the liver). And for some of the steroid hormones (in particular, progesterone) it may not hold at all.
The politics of moving beyond prejudice
Authors: Caroline Howarth, Wolfgang Wagner, Shose Kessi, Ragini Sen
Journal: Behavioral and Brain Sciences (2012)

Dixon et al. have highlighted the importance of a political conceptualisation of intergroup relations that challenges individualising models of social change. As important as this paper is for the development of critical debates in psychology, we can detect at least three issues that warrant further discussion: (a) the cultural and historical conditions of structural inequality and its perception, (b) the marginalisation of post-colonial works on collective mobilisation, and (c) acknowledging the complex perspectives and politics of those targeted by prejudice.
Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis
Authors: Giovanni Sotgiu, Rosella Centis, Lia D'Ambrosio, Jan-William C. Alffenaar, Holly A. Anger, Jose A. Caminero, Paolo Castiglia, Saverio De Lorenzo, Giovanni Ferrara, Won-Jung Koh, Giesela F. Schecter, Tae S. Shim, Rupak Singla, Alena Skrahina, Antonio Spanevello, Zarir F. Udwadia, Miquel Villar, Elisabetta Zampogna, Jean-Pierre Zellweger, Alimuddin Zumla, Giovanni Battista Migliori
Journal: European Respiratory Journal (2012)

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21–90) and 61 (29–119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg versus &gt;600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.
Prevalence and effects of malnutrition in COPD patients referred for pulmonary rehabilitation
Authors: Melissa G.S. Ng, Samantha S.C. Kon, Jane L. Canavan, Amy L. Clark, Claire M. Nolan, Sarah E. Jones, Michael I. Polkey, Marinos Elia, William D.-C. Man
Journal: European Respiratory Journal (2013)

Background 

Disease-related malnutrition is common in patients with COPD and is associated with adverse prognosis. Pulmonary rehabilitation (PR) is an opportunity to identify patients at risk of malnutrition. The Malnutrition Universal Screening Tool (MUST) is a simple validated tool, but little data exists in patients with COPD.

Aims 

To determine the prevalence of malnutrition in COPD patients referred for PR; describe lung function, fat free mass (FFM), quadriceps muscle strength, exercise capacity, and dyspnoea in patients stratified by the MUST.

Methods 

Over 3 years, 778 COPD patients referred for PR had a MUST, FEV1, body mass index (BMI), FFM (BodyStat1500®), quadriceps maximum voluntary contraction (QMVC), MRC and incremental shuttle walk (ISW) measured. Patients were stratified according to risk of malnutrition (MUST: 0=low risk,1=medium risk,≥2=high risk), and ANOVA, Kruskal Wallis or Chi-square were used to make comparisons between groups.

Results 

Overall prevalence of malnutrition was 11% (6% medium risk, 5% high risk).

View this table:

Clinical characteristics stratified according to MUST





Conclusions 

The prevalence of malnutrition in stable COPD patients referred for PR is 11%. The MUST is a valid tool in COPD and identifies decreasing FEV1, BMI, QMVC, FFM, worsening breathlessness and exercise capacity with increasing risk of malnutrition.
Confronting Complexity: Strategies for Understanding the Microcircuitry of the Retina
Authors: Richard H. Masland, Elio Raviola
Journal: Annual Review of Neuroscience (2000)

The mammalian retina contains upward of 50 distinct functional elements, each carrying out a specific task. Such diversity is not rare in the central nervous system, but the retina is privileged because its physical location, the distinctive morphology of its neurons, the regularity of its architecture, and the accessibility of its inputs and outputs permit a unique variety of experiments. Recent strategies for confronting the retina’s complexity attempt to marry genetic approaches to new kinds of anatomical and electrophysiological techniques.
PWE-146 The Newcastle Varices In Pbc (nvp) Score – A Validation Study
Authors: L Chinnappan, T Cross, P Richardson, K Martin, I Patanwala
Journal: Gut (2014)

<h3>Introduction</h3> The NVP score<sup>1</sup> is a simple, non- invasive externally validated tool which aims to predict variceal risk in patients with primary biliary cirrhosis based on serum albumin levels, platelet count and serum alkaline phosphatase level. A easy accessible online tool is available where values can be entered and score greater than 50% is considered to predict the presence of varices, thereby warranting oesophago-gastro-duodenoscopy (OGD). The aim of this study was to validate this score in an external validation cohort from Liverpool. <h3>Methods</h3> Retrospective study involving 80 PBC patients under follow up at a university hospital. Of them, patients who had undergone a OGD for any clinical reason were identified and findings of the OGD noted. Results of blood tests to allow calculation of the NVP score were recorded. An NVP probability of 0.5 was used as the cut-off to analyse the performance of the score. <h3>Results</h3> Patients involved in the study had mean albumin levels of 36, platelets of 260 with an ALP ranging between 58 and 811. 97% were female and median age of patients was 67 years. 30 PBC patients who had an OGD were identified. 10 of the 30 patients had varices on endoscopy. The NVP Score performed well in identifying those in whom varices were absent in this cohort (sensitivity of 100%, specificity 69%, Negative Predictive Value 100% and Positive Predictive Value 10%; overall accuracy 84.5%) and had a good discriminating power with AUROC 0.89. <h3>Conclusion</h3> The NVP Score proved to be a highly sensitive tool to discriminate patients with PBC who do not have varices and in whom OGD is unnecessary in our cohort. The study therefore strongly supports the view that prospectively applying the score in patients with PBC will help to direct endoscopic evaluation in the right category of patients thereby ensuring effective use of resources. <h3>Reference</h3> Patanwala I, <i>et al</i>. <i>J Hepatol</i>. 2013 Aug;59(2):32735 doi:10.1016/j.jhep.2013.04:010 <h3>Disclosure of Interest</h3> None Declared.
Autologous survival of cyanate‐treated cryopreserved sickle erythrocytes
Authors: Oswaldo Castro, Sohall R. Rana, William N. Poillon
Journal: American Journal of Hematology (1986)

Abstract The effects of carbamylation and frozen storage on the autologous 51 Cr survival and metabolic features of sickle erythrocytes (S‐RBCs) were determined. Red cells from four patients with sickle hemoglobinopathies were treated with 50 mM sodium cyanate for 2 hr (37°C), glycerolized and frozen (−30°C) for 62‐153 days. The mean in vitro loss of S‐RBCs from the combination of cyanate treatment and cryopreservation was 23.6% (±3.5 SD). The 2, 3‐diphosphoglycerate content of the thawed cells did not change significantly. However, ATP levels decreased to about 50% of the corresponding values in fresh, untreated S‐RBCs. Despite this decrease in ATP, the mean intravascular survival of the frozen cyanated cells nearly doubled. At the high concentration of cyanate used, the oxygen affinity of S‐RBCs increased markedly: Their mean P50 was 13.1 mm Hg (± 1.9SD). The gelation of HbS at zero pO 2 was also markedly inhibited in the one sample of cyanate‐treated S‐RBCs examined. Clinical studies to determine the efficacy of autologous transfusions with extensively carbamylated, cryopreserved S‐RBCs should be considered.
A science of intentional change and the prospects for a culture of peace
Authors: Michael Allen Fox
Journal: Behavioral and Brain Sciences (2014)

Abstract Have humans evolved as violent and warlike? Studies of peaceful societies, historical trends of warfare and violence, and cooperation say otherwise. Evolution is not destiny; human choices are important interventions in the process. A science of intentional change, using alternative learning techniques that support human interactions based on nonviolence and peaceful coexistence, might help to evolve a culture of peace.
Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region
Authors: Jeffrey C Barrett, James C Lee, Charles W Lees, Natalie J Prescott, Carl A Anderson, Anne Phillips, Emma Wesley, Kirstie Parnell, Hu Zhang, Hazel Drummond, Elaine R Nimmo, Dunecan Massey, Kasia Blaszczyk, Timothy Elliott, Lynn Cotterill, Helen Dallal, Alan J Lobo, Craig Mowat, Jeremy D Sanderson, Derek P Jewell, William G Newman, Cathryn Edwards, Tariq Ahmad, John C Mansfield, Jack Satsangi, Miles Parkes, Christopher G Mathew, Peter Donnelly, Leena Peltonen, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Nicholas John Craddock, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Mark I McCarthy, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Nilesh Samani, Richard C Trembath, Ananth C Viswanathan, Nicholas Wood, Chris C A Spencer, Céline Bellenguez, Daniel Davison, Colin Freeman, Amy Strange, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Marc L Perez, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Antony P Attwood, Jonathan Stephens, Jennifer Sambrook, Willem H Ouwehand, Wendy L McArdle, Susan M Ring, David P Strachan
Journal: Nature Genetics (2009)
Mitogen-Activated Protein Kinase Kinase Inhibition Enhances Nuclear Proapoptotic Function of p53 in Acute Myelogenous Leukemia Cells
Authors: Kensuke Kojima, Marina Konopleva, Ismael J. Samudio, Vivian Ruvolo, Michael Andreeff
Journal: Cancer Research (2007)

Abstract Activation of the Raf/MEK/ERK pathway and inactivation of wild-type p53 by Mdm2 overexpression are frequent molecular events in acute myelogenous leukemia (AML). We investigated the interaction of Raf/MEK/ERK and p53 pathways after their simultaneous blockades using a selective small-molecule antagonist of Mdm2, Nutlin-3a, and a pharmacologic MEK-specific inhibitor, PD98059. We found that PD98059, which itself has minimal apoptogenic activity, acts synergistically with Nutlin-3a to induce apoptosis in wild-type p53 AML cell lines OCI-AML-3 and MOLM-13. Interestingly, PD98059 enhanced nuclear proapototic function of p53 in these cells. In accordance with the activation of transcription-dependent apoptosis, PD98059 treatment promoted the translocation of p53 from the cytoplasm to the nucleus in OCI-AML-3 cells, in which p53 primarily initiates transcription-independent apoptosis when cells are treated with Nutlin-3a alone. The critical role of p53 localization in cells with increased p53 levels was supported by enhanced apoptosis induction in cells cotreated with Nutlin-3a and the nuclear export inhibitor leptomycin B. PD98059 prevented p53-mediated induction of p21 at the transcriptional level. The repressed expression of antiapototic p21 also seemed to contribute to synergism between PD98059 and Nutlin-3a because (a) the synergistic apoptogenic effect was preserved in G1 cells, (b) p53-mediated induction of p21 was preferentially seen in G1 cells, (c) PD98059 strongly antagonized p21 induction by Nutlin-3a, and (d) cells with high p21 levels were resistant to apoptosis. This is the first report showing that the Raf/MEK/ERK pathway regulates the subcellular localization of p53 and the relative contribution of transcription-dependent and transcription-independent pathways in p53-mediated apoptosis. [Cancer Res 2007;67(7):3210–9]
Molecular Cloning and Characterization of the Intermediate-Conductance Ca <sup>2+</sup> -Activated K <sup>+</sup> Channel in Vascular Smooth Muscle
Authors: Craig B. Neylon, Richard J. Lang, Ying Fu, Alex Bobik, Peter H. Reinhart
Journal: Circulation Research (1999)

Abstract —Recent evidence suggests that functional diversity of vascular smooth muscle is produced in part by a differential expression of ion channels. The aim of the present study was to examine the role of Ca 2+ -activated K + channels (K Ca channels) in the expression of smooth muscle cell functional phenotype. We found that smooth muscle cells exhibiting a contractile function express predominantly large-conductance (≈200 pS) K Ca (BK) channels. In contrast, proliferative smooth muscle cells express predominantly K Ca channels exhibiting a much smaller conductance (≈32 pS). These channels are blocked by low concentrations of charybdotoxin (10 nmol/L) but, unlike BK channels, are insensitive to iberiotoxin (100 nmol/L). To determine the molecular identity of this K + channel, we cloned a 1.9-kb cDNA from an immature-phenotype smooth muscle cell cDNA library. The cDNA contains an open reading frame for a 425 amino acid protein exhibiting sequence homology to other K Ca channels, in particular with mIK1 and hIK1. Expression in oocytes gives rise to a K + -selective channel exhibiting intermediate-conductance (37 pS at −60 mV) and potent activation by Ca 2+ ( K d 120 nmol/L). Thus, we have cloned and characterized the vascular smooth muscle intermediate-conductance K Ca channel (SMIK), which is markedly upregulated in proliferating smooth muscle cells. The differential expression of these K Ca channels in functionally distinct smooth muscle cell types suggests that K Ca channels play a role in defining the physiological properties of vascular smooth muscle. The full text of this article is available at http://www.circresaha.org.
Atoh1 Inhibits Neuronal Differentiation and Collaborates with Gli1 to Generate Medulloblastoma-Initiating Cells
Authors: Olivier Ayrault, Haotian Zhao, Frederique Zindy, Chunxu Qu, Charles J. Sherr, Martine F. Roussel
Journal: Cancer Research (2010)

Abstract The morphogen and mitogen Sonic Hedgehog (Shh) activates a Gli1-dependent transcription program that drives proliferation of granule neuron progenitors (GNP) within the external germinal layer of the postnatally developing cerebellum. Medulloblastomas with mutations activating the Shh signaling pathway preferentially arise within the external germinal layer, and the tumor cells closely resemble GNPs. Atoh1/Math1, a basic helix-loop-helix transcription factor essential for GNP histogenesis, does not induce medulloblastomas when expressed in primary mouse GNPs that are explanted from the early postnatal cerebellum and transplanted back into the brains of naïve mice. However, enforced expression of Atoh1 in primary GNPs enhances the oncogenicity of cells overexpressing Gli1 by almost three orders of magnitude. Unlike Gli1, Atoh1 cannot support GNP proliferation in the absence of Shh signaling and does not govern expression of canonical cell cycle genes. Instead, Atoh1 maintains GNPs in a Shh-responsive state by regulating genes that trigger neuronal differentiation, including many expressed in response to bone morphogenic protein-4. Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development. Cancer Res; 70(13); 5618–27. ©2010 AACR.
Transcapillary escape rate of albumin and right atrial pressure in chronic congestive heart failure before and after treatment.
Authors: B Hesse, H H Parving, H Lund-Jacobsen, I Noer
Journal: Circulation Research (1976)

The transcapillary escape rate of albumin (TERalb), i.e., the fraction of intravascular mass of albumin that passes to the extravascular space per unit of time, was determined from the disappearance of intravenously injected 125I-labeled human serum albumin during the first 60 minutes after injection in 10 subjects with chronic right heart failure. The investigation was repeated after sodium and water depletion. Before treatment TERalb was significantly elevated (mean 8.3 +/- 1.6% (SD)/hour, in comparison to values for normal subjects (mean 5.4 +/- 1.1%/hour, P less than 0.001). With treatment TERalb decreased significantly (mean 5.9 +/- 1.2%/hour, P less than 0.01). Right atrial pressure decreased from an average of 10 mm Hg to 6 mm Hg during treatment. A statistically significant, positive correlation was found between TERalb and right atrial pressure (r = 0.77, P less than 0.001). Our results best can be explained by increased filtration, mainly through the venous end of the microvasculature, due to the increased venous pressure in heart failure.
Atu027 Prevents Pulmonary Metastasis in Experimental and Spontaneous Mouse Metastasis Models
Authors: Ansgar Santel, Manuela Aleku, Nadine Röder, Kristin Möpert, Birgit Durieux, Oliver Janke, Oliver Keil, Jens Endruschat, Sibylle Dames, Christian Lange, Mona Eisermann, Kathrin Löffler, Melanie Fechtner, Gerald Fisch, Christiane Vank, Ute Schaeper, Klaus Giese, Jörg Kaufmann
Journal: Clinical Cancer Research (2010)

Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node metastasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the pharmacologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four different preclinical mouse models.Atu027 compared with vehicle or control small interfering RNA lipoplexes was tested in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous metastasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules (repeated low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. Primary tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistochemistry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to provide an insight into molecular changes on depletion of PKN3, in support of efficacy results.Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formation of spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well as in mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an increase in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change endothelial function, resulting in reduced colonization and micrometastasis formation.Atu027 can be considered as a potent drug for preventing lung metastasis formation, which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy.
Blanching the airways: steroid effects in asthma
Authors: A. J Knox, K. Deacon, R. Clifford
Journal: Thorax (2007)

An important effect of steroids on angiogenesis in asthma

The vascular changes which occur in airways diseases such as asthma are starting to attract considerable attention from the respiratory research community. In addition to the vascular engorgement which occurs as part of the acute inflammatory process, several groups have demonstrated increased new vessel formation (angiogenesis) in chronic asthma.1–3 Not only does this occur in adult asthma, but recent studies suggest it is a prominent feature of childhood asthma, suggesting that vascular remodelling may occur relatively early in the asthmatic process.4 The increased airway wall thickening produced by the expanded vasculature causes enhanced airway narrowing on stimulation with constrictor agents, thereby contributing to bronchial hyper-responsiveness. Furthermore, the increased blood flow may increase inflammatory cell trafficking and exudation and transudation of cytokines and mediators and contribute to airway hyper-responsiveness by supporting the increased airway smooth muscle mass which is a key feature of asthma histopathology.5

There are a number of candidate angiogenic factors for these changes, perhaps the most important of which are vascular endothelial growth factor (VEGF) and angiopoietin-1, distinct molecules which act together at different stages of angiogenic processes in several biological systems.6,7,8,9,10,11,12,13, …