tbuckley/cabot-search huggingface dataset:
EGFR Tyrosine Kinase Inhibitors Decrease VEGF Expression by Both Hypoxia-Inducible Factor (HIF)-1–Independent and HIF-1–Dependent Mechanisms
Authors: Nabendu Pore, Zibin Jiang, Anjali Gupta, George Cerniglia, Gary D. Kao, Amit Maity
Journal: Cancer Research (2006)

Abstract Epidermal growth factor receptor (EGFR) inhibitors can decrease vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. In the current study, we investigate the molecular pathways by which this occurs using two drugs that have been used in the clinic, gefitinib (Iressa) and erlotinib (Tarceva). The decrease in VEGF expression by gefitinib in SQ20B squamous cell carcinoma cells was opposed by adenoviral expression of Akt in these cells. The hypoxia-inducible factor-1 (HIF-1) binding site located at approximately −1 kbp in the VEGF promoter was not required for down-regulation of promoter activity by gefitinib under normoxia. Furthermore, the drug decreased activity of a reporter containing the −88/+54 region. In a gel shift assay, gefitinib led to decreased retardation of a labeled DNA oligonucleotide probe corresponding to the −88/−66 region of the VEGF promoter, which contains Sp1 binding sites. These effects of gefitinib on VEGF promoter activity and DNA binding were both reversed by Akt expression. Phosphorylation of Sp1 was decreased in the presence of gefitinib. Gefitinib also decreases VEGF expression by decreasing HIF-1α expression. This occurs due to decreased protein translation without any change in the level of HIF-1α mRNA. Together, these results suggest that gefitinib decreases VEGF expression both by decreasing Sp1 binding to the proximal core VEGF promoter and by down-regulating HIF-1α expression. Similar results were obtained with erlotinib in SQ20B and gefitinib in HSC3 squamous carcinoma cells. These results indicate that there are at least two separate mechanisms by which EGFR inhibitors decrease VEGF expression. (Cancer Res 2006; 66(6): 3197-204)
A Case of Bilateral Parasternal Diaphragmatic Hernia
Authors: R. W. Brown
Journal: Thorax (1952)

<h3>Abstract</h3> 3D <i>in vitro</i> cancer models are important therapeutic and biological discovery tools, yet formation of multicellular spheroids in a throughput and highly controlled manner to achieve robust and statistically relevant data, remains challenging. Here, we developed an enabling technology consisting of a bespoke drop-on-demand 3D bioprinter capable of high-throughput printing of 96-well plates of spheroids. 3D-multicellular spheroids are embedded inside a tissue-like matrix with precise control over size and cell number. Application of 3D bioprinting for high-throughput drug screening was demonstrated with doxorubicin. Measurements showed that IC<sub>50</sub> values were sensitive to spheroid size, embedding and how spheroids conform to the embedding, revealing parameters shaping biological responses in these models. Our study demonstrates the potential of 3D bioprinting as a robust high-throughput platform to screen biological and therapeutic parameters. <h3>Significance Statement</h3> <i>In vitro</i> 3D cell cultures serve as more realistic models, compared to 2D cell culture, for understanding diverse biology and for drug discovery. Preparing 3D cell cultures with defined parameters is challenging, with significant failure rates when embedding 3D multicellular spheroids into extracellular mimics. Here, we report a new 3D bioprinter we developed in conjunction with bioinks to allow 3D-multicellular spheroids to be produced in a high-throughput manner. High-throughput production of embedded multicellular spheroids allowed entire drug-dose responses to be performed in 96-well plate format with statistically relevant numbers of data points. We have deconvoluted important parameters in drug responses including the impact of spheroid size and embedding in an extracellular matrix mimic on IC<sub>50</sub> values.
Blood Pressure Control in Diabetes
Authors: Doyle M. Cummings, Lisa Doherty, George Howard, Virginia J. Howard, Monika M. Safford, Valerie Prince, Brett Kissela, Daniel T. Lackland
Journal: Diabetes Care (2010)

OBJECTIVE Despite widespread dissemination of target values, achieving a blood pressure of &amp;lt;130/80 mmHg is challenging for many individuals with diabetes. The purpose of the present study was to examine temporal trends in blood pressure control in hypertensive individuals with diabetes as well as the potential for race, sex, and geographic disparities. RESEARCH DESIGN AND METHODS We analyzed baseline data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal cohort study of 30,228 adults (58% European American and 42% African American), examining the causes of excess stroke mortality in the southeastern U.S. We calculated mean blood pressure and blood pressure control rates (proportion with blood pressure &amp;lt;130/80 mmHg) for 5,217 hypertensive diabetic participants by year of enrollment (2003–2007) using multivariable logistic regression models. RESULTS Only 43 and 30% of European American and African American diabetic hypertensive participants, respectively, demonstrated a target blood pressure of &amp;lt;130/80 mmHg (P &amp;lt; 0.001). However, a temporal trend of improved control was evident; the odds of having a blood pressure &amp;lt;130/80 mmHg among diabetic hypertensive participants of both races enrolled in 2007 (as compared with those enrolled in 2003) were ∼50% greater (P &amp;lt; 0.001) in multivariate models. CONCLUSIONS These data suggest temporal improvements in blood pressure control in diabetes that may reflect broad dissemination of tighter blood pressure control targets and improving medication access. However, control rates remain low, and significant racial disparities persist among African Americans that may contribute to an increased risk for premature cardiovascular disease.
Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties
Authors: Charles Antzelevitch, Luiz Belardinelli, Andrew C. Zygmunt, Alexander Burashnikov, José M. Di Diego, Jeffrey M. Fish, Jonathan M. Cordeiro, George Thomas
Journal: Circulation (2004)

Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations.Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol.Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.
Quantitative proteomics reveals posttranslational control as a regulatory factor in primary hematopoietic stem cells
Authors: Richard D. Unwin, Duncan L. Smith, David Blinco, Claire L. Wilson, Crispin J. Miller, Caroline A. Evans, Ewa Jaworska, Stephen A. Baldwin, Kay Barnes, Andrew Pierce, Elaine Spooncer, Anthony D. Whetton
Journal: Blood (2006)
Something Old, Something Few, Something Subjective, Something Déjà Vu
Authors: Sandra J. Horning
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIAL Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.18.114 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12506161 Something Old, Something Few, Something Subjective, Something Déjà Vu Sandra J. HorningxSandra J. HorningSearch for articles by this author Show More Stanford University, Stanford, CA https://doi.org/10.1200/JCO.2003.18.114 Full Text PDF Figures and Tables "Something Old, Something Few, Something Subjective, Something Déjà Vu." Journal of Clinical Oncology, 21(1), pp. 1–2© 2003 by American Society of Clinical Oncology
THE TREATMENT OF LICHEN PLANUS WITH UIPASIC.
Authors: J. O'D. ALEXANDER
Journal: British Journal of Dermatology (1960)

Journal Article THE TREATMENT OF LICHEN PLANUS WITH UIPASIC. Get access J. O'D. ALEXANDER, M.B.Ch.B., F.R.F.P.S.G. J. O'D. ALEXANDER, M.B.Ch.B., F.R.F.P.S.G. Glasgow Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 72, Issue 10, 1 October 1960, Pages 355–357, https://doi.org/10.1111/j.1365-2133.1960.tb13819.x Published: 01 October 1960
Abstract 115: Relationship of Body Mass Index (BMI) to Minimum Distance from Skin Surface to Myocardium: Implications for Neuromuscular Incapacitating Devices (NMID)
Authors: Gregory G Bashian, Gabriel A Wagner, Don W Wallick, Patrick J Tchou
Journal: Circulation (2007)

Introduction : It is controversial whether NMIDs can induce cardiac arrhythmias in humans. Studies in swine models have shown varying results. Two reported no induced VF, while a third showed 1 case of induced VF during epinephrine infusion. Two studies showed site sensitivity of cardiac capture depending on location of NMID electrodes. Human studies have not shown any induced arrhythmias. However, it is unclear whether electrodes were placed at the most vulnerable regions of the chest. This study sought to assess the thoracic location and range of minimum skin-to-heart distances (mSHD) and its relationship to BMI. Methods : Forty-five patients who had undergone cardiac CT scans were randomly selected for evaluation. These scans were analyzed to determine the mSHD and the location of this point on the chest surface relative to anatomic landmarks (horizontal distance from midsternum and vertical distance from sternal insertion of the lowest left rib). Linear regression analysis was performed using BMI and mSHD. Results : mSHD ranged from 1.8 cm to 6.4 cm. FIGURE 1 shows the linear regression of mSHD vs. BMI. mSHD was to the left of mid sternum (2.5 ± 2.5 cm) and slightly inferior (0.5 ± 2.0 cm) to the lowest left rib sternal insertion. The area of myocardial contact with the anterior chest wall averaged 51 ± 25 cm 2 , and was unrelated to BMI. Conclusions : In this study of adults, the average location of the site of mSHD was slightly to the left of mid sternum and just below the lowest rib insertion. There is a linear relationship between BMI and mSHD. The size of a person and the anatomic relationship of the heart to the anterior chest wall can influence the potential cardiac capture by NMIDs at the site of mSHD. Figure 1: mSHD vs. BMI
Icatibant treatment for acquired C1‐inhibitor deficiency: a real‐world observational study
Authors: A. Zanichelli, M. Bova, A. Coerezza, A. Petraroli, M. Triggiani, M. Cicardi
Journal: Allergy (2012)

Abstract Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema ( HAE ) with C1‐inhibitor (C1‐ INH ) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1‐ INH deficiency ( AAE ). Forty‐eight moderate‐to‐severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67–39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25–2.10) h and complete resolution in 6.75 (0.50–30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.
Historical perspectives on umbilical cord clamping and neonatal transition
Authors: Candice L Downey, Susan Bewley
Journal: Journal of the Royal Society of Medicine (2012)

The timing of umbilical cord clamping is contested. Many textbooks imply that ‘early’ cord clamping (Table 1) is an inevitable and normal part of the third stage of labour.1 Indeed, it is widely practised and supported.2 The National Institute for Health and Clinical Excellence (NICE) recommended early clamping in their 2007 intrapartum care guideline.3 Yet, early umbilical cord clamping can be detrimental to the newborn, leading to an increased risk of anaemia and, in the premature infant, an increased risk of intraventricular haemorrhage and respiratory complications.4,5 Delaying clamping in preterm infants decreases the need for blood transfusion4 which has been associated with neonatal necrotizing enterocolitis and death.6 In the term infant, delayed clamping improves neonatal oxygen transport and red blood cell flow and in premature infants it is associated with fewer days on oxygen and ventilation.4 The mounting evidence for deferring clamping has prompted changes to recent guidelines. The World Health Organisation (WHO) has officially endorsed the practice of so-called ‘delayed’ cord clamping.5 The International Federation of Gynaecology and Obstetrics and the International Confederation of Midwives have also removed early cord clamping from active management guidelines.4



Table 1

Examples of variable definitions of ‘early’ and ‘late’ cord clamping (adapted from Ref 4)



Despite the disadvantages, early cord clamping is still routine among maternity staff.2 When evidence for clinical practice is lacking, its history may enlighten.
Systematic review of the effectiveness of stage based interventions to promote smoking cessation
Authors: R. P. Riemsma
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To evaluate the effectiveness of interventions using a stage based approach in bringing about positive changes in smoking behaviour. <b>Design</b> Systematic review. <b>Data sources</b> 35 electronic databases, catalogues, and internet resources (from inception to July 2002). Bibliographies of retrieved references were scanned for other relevant publications, and authors were contacted if necessary. <b>Results</b> 23 randomised controlled trials were reviewed; two reported details of an economic evaluation. Eight trials reported effects in favour of stage based interventions, three trials showed mixed results, and 12 trials found no statistically significant differences between a stage based intervention and a non-stage based intervention or no intervention. Eleven trials compared a stage based intervention with a non-stage based intervention, and one reported statistically significant effects in favour of the stage based intervention. Two studies reported mixed effects, and eight trials reported no statistically significant differences between groups. The methodological quality of the trials was mixed, and few reported any validation of the instrument used to assess participants9 stage of change. Overall, the evidence suggests that stage based interventions are no more effective than non-stage based interventions or no intervention in changing smoking behaviour. <b>Conclusions</b> Limited evidence exists for the effectiveness of stage based interventions in changing smoking behaviour.
Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon
Authors: C. B. BUNKER, P. C. GOLDSMITH, T. A. LESLIE, N. HAYES, J. C. FOREMAN, P. M. DOWD
Journal: British Journal of Dermatology (1996)

It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynaud's phenomenon (RP). Both endothelin-1 (ET-1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature, and calcitonin gene-related peptide (CGRP), a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET-1 levels are raised, and there is a diminution of CGRP-containing perivascular nerves in finger skin in RP. We undertook a pharmacological study to investigate the sensitivity of the digital cutaneous microvasculature to intradermal ET-1 and CGRP. Differences were found in RP compared with normal digital skin, supporting the idea that the digital cutaneous microvasculature is actively involved in the pathogenesis of RP. In RP, the erythematous response to ET-1 was diminished at both 20 and 5 degrees C (a low temperature at which RP classically occurs) providing pharmacological support for the morphological evidence that in RP there is a deficiency of CGRP-containing nerves in the distal digital skin.
Importance of E-Selectin for Firm Leukocyte Adhesion In Vivo
Authors: Klaus Ley, Margaretta Allietta, Daniel C. Bullard, Sharon Morgan
Journal: Circulation Research (1998)

Abstract —Leukocyte adhesion under flow is preferentially mediated by the selectins. In this study we used intravital microscopy to investigate whether E-selectin may promote firm leukocyte adhesion in vivo. E-Selectin is expressed by endothelial cells activated with tumor necrosis factor-α (TNF-α) and causes slow leukocyte rolling. Microinjection of formyl-methionyl-leucyl-phenylalanine (fMLP) or macrophage inflammatory protein-2 (MIP-2) next to a venule of the TNF-α–treated mouse cremaster muscle significantly increased the number of adherent leukocytes. In gene-targeted mice homozygous for a null mutation in the E-selectin gene or in wild-type mice treated with an E-selectin monoclonal antibody (mAb), this response was significantly attenuated (by &gt;80%). No such defect was seen in intercellular adhesion molecule-1 (ICAM-1)–deficient mice. E-Selectin–null mice showed more rapid leukocyte rolling than wild-type or ICAM-1–deficient mice, resulting in significantly shortened leukocyte transit times through venules. Topical application of fMLP onto the whole cremaster muscle generated the same number of adherent leukocytes in wild-type and E-selectin–deficient mice. We conclude that slow leukocyte rolling through E-selectin results in long transit times, which are essential for efficient leukocyte adhesion in response to a local chemotactic stimulus.
α2HS-glycoprotein, an Antagonist of Transforming Growth Factor β <b> <i>In vivo</i> </b>, Inhibits Intestinal Tumor Progression
Authors: Carol J. Swallow, Emily A. Partridge, Jennifer C. Macmillan, Tania Tajirian, Gianni M. DiGuglielmo, Kazy Hay, Melanie Szweras, Willi Jahnen-Dechent, Jeff L. Wrana, Mark Redston, Steven Gallinger, James W. Dennis
Journal: Cancer Research (2004)

Abstract Transforming growth factor (TGF)-β1 is associated with tumor progression and resistance to chemotherapy in established cancers, as well as host immune suppression. Here, we show that the serum glycoprotein α2-HS-glycoprotein (AHSG) blocks TGF-β1 binding to cell surface receptors, suppresses TGF-β signal transduction, and inhibits TGF-β-induced epithelial-mesenchymal transition, suggesting that AHSG may play a role in tumor progression. In 66 consecutive sporadic human colorectal cancer specimens, we observed a 3-fold depletion of ASHG in tumor compared with normal tissue, whereas levels of other abundant plasma proteins, albumin and transferrin, were equivalent. Using the Multiple intestinal neoplasia/+ (Min/+) mouse model of intestinal tumorigenesis, we found twice as many intestinal polyps overall, twice as many large polyps (&amp;gt;3 mm diameter), and more progression to invasive adenocarcinoma in Min/+ Ahsg−/− mice than in littermates expressing Ahsg. Phosphorylated Smad2 was more abundant in the intestinal mucosa and tumors of Min/+ mice lacking Ahsg, demonstrating increased TGF-β signaling in vivo. Furthermore, TGF-β-mediated suppression of immune cell function was exaggerated in Ahsg−/− animals, as shown by inhibition of macrophage activation and reduction in 12-O-tetradecanoylphorbol 13-acetate–induced cutaneous inflammation. Reconstitution of Ahsg−/− mice with bovine Ahsg suppressed endogenous TGF-β-dependent signaling to wild-type levels, suggesting that therapeutic enhancement of AHSG levels may benefit patients whose tumors are driven by TGF-β.
Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog.
Authors: T J Hougen, B L Lloyd, T W Smith
Journal: Circulation Research (1979)

The effects of digoxin on monovalent cation active transport were determined in cardiac tissue obtained from dogs given inotropic, toxic, or lethal doses of digoxin. In hemodynamically monitored dogs, active uptake of the K+ analogue Rb+ was determined in vitro in a control myocardial biopsy, and then in serial biopsies from the same dog after the infusion of [3H]digoxin in doses sufficient to cause a sustained positive inotropic effect in the absence of toxicity, and finally after additional doses to induce overt toxicity. Nontoxic digoxin doses producing a mean increase of 20% in left ventricular (LV) dP/dt significantly reduced Rb+ active transport by 25% below control values. At the onset of digoxin-induced arrhythmias, maximal LV dP/dt was 53% above control whereas active Rb+ transport was reduced by 60% below baseline values (P less than 0.001). Control dogs given vehicle alone showed no significant change in contractility or in monovalent cation active transport. In another group of dogs given a lethal dose of digoxin, Rb+ active transport was reduced 59% below control levels at the onset of overt toxicity and was further reduced 80% below control at the time of onset of a fatal rhythm disturbance. When dogs were given high affinity digoxin-specific IgG or Fab fragments at the onset of overt toxicity, toxicity was rapidly reversed, and monovalent cation active transport increased to 51% of control at the time of restoration of sinus rhythm. Twenty-four hours after antibody reversal of arrhythmias, monovalent cation transport values approximated normal control levels. These data provide quantitative estimates of the extent of inhibition of monovalent cation transport by digoxin at inotropic, toxic, and lethal endpoints. Similar degrees of transport inhibition were present at the time of onset of digoxin-induced arrhythmias and at the time or arrhythmia reversal by digoxin-specific antibodies.