tbuckley/cabot-search huggingface dataset:
Transforming growth factor beta engages TACE/ADAM17 and ErbB3 to activate PI3K/Akt in HER2-overexpressing breast cancer and desensitizes cells to trastuzumab.
Authors: E Wang, B Xiang, MG Olivares, C Chung, CL Arteaga
Journal: Cancer Research (2009)

Abstract Abstract #35 TGFb signaling synergizes with HER2 in breast cancer progression. Exogenous TGFb or expression of an activated TGFb type I receptor (Alk5T204D) in MCF10A/HER2 and BT474 cells activated PI3K/Akt and enhanced survival and migration. In both cell types, TGFb stimulated P-EGFR and P-HER2 as well as the association of p85, the regulatory subunit of PI3K, with Y1289 P-ErbB3 which, in turn, activated PI3K/Akt. RNA interference of ErbB3 or treatment with pertuzumab, an antibody that blocks HER2-mediated activation of ErbB3, blocked TGFb-induced P-ErbB3, P-Akt, and cell motility. Treatment with TGFb or expression of Alk5TD increased protein levels of secreted TGFalpha, amphiregulin, and heregulin without a change in mRNA levels. The increase on secreted ErbB ligands without a change in mRNA levels suggested increased shedding of ErbB pro-ligands by tumor necrosis factor a-converting enzyme (TACE). Transfection of siRNA against human TACE but not control siRNA abrogated TGFb-stimulated ErbB receptor phosphorylation, P-Akt, and cell invasiveness. Transfection of full-length mouse TACE but not truncated TACE lacking the cytoplasmic domain reconstituted TGFb-induced ErbB phosphorylation in cells transfected with human TACE siRNA. TGF-b increased TACE phosphorylation in both serine and threonine as measured by P-Ser and P-Thr immunoblots of TACE pull downs. Incubation of TACE with Alk5TD in the presence of ATP in vitro resulted in both Ser and Thr phosphorylation in full-length but not truncated TACE. Further, addition of TGFb or expression of Alk5TD desensitized SKBR3 and BT474 cells to trastuzumab. Treatment with the type I TGFb receptor (Alk5) small molecule inhibitor LY2109761, the PI3K inhibitor LY294002, or siRNA against ErbB3 or TACE restored the inhibitory effect of trastuzumab. Finally, we generated an active Alk5 expression signature by selecting genes that were differentially expressed between BT474/Alk5TD and BT474/vector cells. Mapping of this signature to a previously published 295-breast tumor array (van de Vijver et al. and Chang et al.) revealed 90 of 271 genes in the Alk5TD signature with a &amp;gt;1.5-fold change from the median expression which correlated with HER2-positive and basal-like tumors and conferred a worse recurrence-free (RFS) and overall survival (OS) (RFS p=0.05, OS p=0.01). Hierarchical clustering analysis to an array data set reported by Harris et al. in 22 patients with HER2+ breast cancer treated with neoadjuvant trastuzumab and vinorelbine (Clin. Cancer Res. 2007) showed that the Alk5TD signature correlated with tumors that did not respond clinically. These data suggest that TGFb potentiates signaling downstream ErbB receptors via TACE, ErbB3, and PI3K, thus contributing to tumor progression and resistance to anti-HER2 therapies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 35.
CANCER OF THE TRANSVERSE COLON IN A SEVEN YEAR OLD BOY
Authors: Damon B. Pfeiffee
Journal: JAMA (1935)

In considering the question of cancer of the colon in children, one is dealing with an unusual condition. Although it does occur rather infrequently, one should keep it in mind in the consideration of the diagnosis of some obscure abdominal conditions. The incidence of cancer in persons under the age of 15 years is so low that reported cases are regarded as oddities.<sup>1</sup>Cases of carcinoma of the intestinal tract occurring in young persons must be looked on as extremely uncommon.<sup>2</sup>In considering the incidence of carcinoma of the large bowel in children, Philipp<sup>3</sup>stated that 28 per cent of ninety-three cases affected the intestinal tract. In 1914 Redho<sup>4</sup>was able to find but 536 cases of carcinoma during the period of youth in a review of the literature up to that date. Schamoni<sup>5</sup>performed 2,500 necropsies on children in the first ten years
Spreading cortical venous thrombosis due to infusion of hyperosmolar solution into the internal jugular vein.
Authors: R G Souter, A Mitchell
Journal: BMJ (1982)

IpratropiumE~~~~~~~~~~~~~~~~~~~~~~~r.: mide 300 Days Case 3. Four-hourly peak expiratory flow rates before and after administration of bronchodilators before, during, and after inclusion of ipratropium bromide.this view, but the cases reported here emphasise the need for careful observation in view of the possibility of an advrerse reaction, which might be associated with increased viscosity of the sputum.4It is esssntial that a documented stable baseline of pulmonary function is obtained before ipratropium is added and that the drug is withdrawn immediately if the patient's condition deteriorates.
UNILATERAL SUBLUXATIONS OF THE CERVICAL VERTEBRAE WITHOUT ASSOCIATED FRACTURE
Authors: BARBARA B. STIMSON
Journal: JAMA (1935)

Since Jan. 1, 1929, there have been sixty-six cases of unilateral subluxation of the cervical vertebrae without associated fracture seen in the fracture service of the Presbyterian Hospital. Of these, five were seen in the first three years and thirty-nine in the past eighteen months. This sudden and spectacular increase is due not to any change in the neck structure of New York's population but to the education of the members of the staff in the recognition of the condition. We feel, therefore, that it is of value to present this group of cases not in order to describe a new condition or method of treatment but to refresh the memory of the profession at large as to the characteristic picture these patients present and to set forth our experience in their treatment. Of the sixty-six patients, thirty-six were male and thirty female. Fifty-two were between the ages of 10
Mechanism of apical and basolateral Na(+)-independent Cl-/base exchange in the rabbit superficial proximal straight tubule.
Authors: I Kurtz, G Nagami, N Yanagawa, L Li, C Emmons, I Lee
Journal: Journal of Clinical Investigation (1994)

The present study was undertaken to determine the magnitude and mechanism of base transport via the apical and basolateral Na(+)-independent Cl-/base exchangers in rabbit isolated perfused superficial S2 proximal tubules. The results demonstrate that there is an apical Na(+)-independent Cl-/base exchanger on both membranes. HCO3- fails to stimulate apical Cl-/base exchange in contrast to the basolateral exchanger. Inhibition of endogenous HCO3- production does not alter the rate of apical Cl-/base exchange in Hepes-buffered solutions. Both exchangers are inhibited by H2DIDS and furosemide; however, the basolateral anion exchanger is more sensitive to these inhibitors. The results indicate that the apical and basolateral Cl-/base exchangers differ in their transport properties and are able to transport base equivalents in the absence of formate. The formate concentration in rabbit arterial serum is approximately 6 microM and in vitro tubule formate production is < 0.6 pmol/min per mm. Formate in the micromolar range stimulates Jv in a dose-dependent manner in the absence of a transepithelial Na+ and Cl- gradient and without a measurable effect on Cl(-)-induced equivalent base flux. Apical formic acid recycling cannot be an important component of any cell model, which accounts for formic acid stimulation of transcellular NaCl transport in the rabbit superficial S2 proximal tubule. We propose that transcellular NaCl transport in this nephron segment is mediated by an apical Na+/H+ exchanger in parallel with a Cl-/OH- exchanger and that the secreted H+ and OH- ions form H2O in the tubule lumen.
Endothelin-1 is synthesized and inhibits cyclic adenosine monophosphate- dependent anion secretion by an autocrine/paracrine mechanism in gallbladder epithelial cells.
Authors: L Fouassier, T Chinet, B Robert, A Carayon, P Balladur, M Mergey, A Paul, R Poupon, J Capeau, V Barbu, C Housset
Journal: Journal of Clinical Investigation (1998)

Ion and fluid transport across the biliary epithelium contributes to bile secretion. Since endothelin (ET)-1 affects ion transport activities and is released by human gallbladder- derived biliary epithelial cells in primary culture, we examined the expression of ET peptides and ET receptors and the influence of ET-1 on ion transport in this epithelium ex vivo. In freshly isolated gallbladder epithelial cells, preproET-1, -2, and -3 mRNAs were detected by reverse transcription PCR and ET-1 isopeptide was identified by chromatography. The cells also displayed ET receptor mRNAs and high-affinity binding sites for ET-1, mostly of the ETB type. Electrogenic anion secretion across intact gallbladder mucosa was stimulated by forskolin, secretin, and exogenous ATP, as assessed by short-circuit current (Isc) increases in Ussing-type chambers. ET-1 inhibited forskolin- and secretin-induced changes in Isc, without affecting baseline Isc or ATP-induced changes. Accordingly, ET-1 significantly reduced the accumulation of intracellular cAMP elicited by forskolin and secretin in the epithelial cells, and this effect was abolished by pertussis toxin. This is the first evidence that ET-1 is synthesized and inhibits, via a Gi protein-coupled receptor, cAMP-dependent anion secretion in human gallbladder epithelium, indicating a role in the control of bile secretion by an autocrine/paracrine mechanism.
Community-acquired pneumonia during the first post-pandemic influenza season: A prospective, multicentre cohort study
Authors: Diego Viasus, Carmen Marinescu, Aroa Villoslada, Elisa Cordero, Juan Gálvez-Acebal, María C. Fariñas, Irene Gracia-Ahufinger, Anabel Fernández-Navarro, Jordi Niubó, Lucia Ortega, Elena Muñez-Rubio, María P. Romero-Gómez, Jordi Carratalà
Journal: Journal of Infection (2013)
ROENTGENOGRAMS OF THE FETAL SKELETON AS A POSITIVE SIGN OF PREGNANCY
Authors: IRVING F. STEIN
Journal: JAMA (1923)

The positive signs of pregnancy are those objective signs referable to the fetus appearing after the quickening, any one of which can definitely establish the diagnosis of pregnancy. They become positive only when elicited by the examining physician, to wit: (1) the fetal heart tones, heard by the physician; (2) fetal movement, felt by the physician, and (3) fetal parts palpated and differentiated by the physician. Some of the recent textbooks, such as that of De Lee, mention roentgen-ray examination of the fetal skeleton in the last trimester as an additional sign, but place very little emphasis on its value or range of usefulness. A final sign, the presence of chorionic villi in uterine scrapings, is also a positive sign, but obviously does not concern us in this presentation. Granted that the fetal roentgenogram is a positive sign, what is its practical value? Several articles have appeared on this subject
STUDIES OF PROTEIN METABOLISM IN INTESTINAL EPITHELIAL CELLS*
Authors: Martin Lipkin, Henry Quastler
Journal: Journal of Clinical Investigation (1962)

Some aspects of intracellular protein metab- olism can be studied with radioactive amino acids.Most previous studies of intestinal cells have involved measurements of incorporation of amino acids into fractions of the entire mucosa (1) and have provided composite measurements of protein synthesis in the tissues.The gastrointestinal mu- cosa contains numerous connective tissue ele- ments, blood cells, smooth muscle and nerve cells, and several kinds of epithelial cells.In the small bowel the epithelial cells are of four types: Paneth, argentaffine, principal, and goblet cells; the prin- cipal cells themselves include proliferating, and differentiating or mature cells.All of these ele- ments synthesize protein, but they synthesize dif- ferent kinds of protein at different rates.It is desirable to define amino acid incorporation and protein synthesis with respect to particular tissue elements.This can be done by autoradiographic methods.The feasibility and value of this ap- proach have been demonstrated by Leblond, Everett and Simmons (2), using radioactive methionine.In the present study leucine has been used, labeled with tritium for autoradio- graphic studies, and with C14 for concomitant radiochemical analyses.The kinetics of incorpo- ration, the differences in rate of uptake between cells as well as within cells, and the further fate of incorporated leucine have been studied in some detail.Normal mice were used, as well as mice subjected to protein starvation and to ster- oid treatment. METHODSAdult male C57 Brown mice were maintained on a standard nutritional diet (3).
Abstract P1-13-09: Sensitive liquid chromatography-tandem mass spectrometry method for serum estradiol and estrone assessment without derivatisation, overcoming cross reactivity with exemestane
Authors: A Lintermans, S Pauwels, P Vermeersch, I Jans, J Billen, K Van Asten, D Vanderschueren, P Neven
Journal: Cancer Research (2013)

Abstract Objective Measuring serum estrogen levels in postmenopausal women on oral aromatase inhibitors is important but challenging. Direct immunoassays are the most widely used techniques for measuring serum estradiol (E2) in research and clinical laboratories. Unfortunately, commercially available immunoassays for E2 lack precision and accuracy in the low range (&amp;lt;20 ng/l) and are susceptible to interference. In addition, particularly in exemestane users biochemical monitoring of E2 is problematic because exemestane metabolites cross react in most immunoassays for E2. We developed a sensitive, routinely applicable liquid chromatography-tandem mass spectrometry (LC-MSMS) method for E2 and estrone (E1) quantification in human serum without the need for derivatization or an extended extraction protocol. Materials and methods Serum E2 levels, assessed with LC-MSMS and electrochemiluminescence estradiol assay (ECLIA) on Modular E170 from Roche Diagnostics, of 10 breast cancer patients treated with exemestane were compared. Limit of quantification (LOQ) was 1.3 ng/l for LC-MSMS (coefficient of variation &amp;lt;20% and signal-to-noise ratio &amp;gt; 10, own validation) and 5 pg/ml for ECLIA (Roche, according to manufacturer). Results Patients treated with exemestane showed much higher E2 levels when measured by ECLIA compared to E2 levels determined by LC-MSMS (Table 1). All patients, but one, had E2 values below LOQ when assessed with LC-MSMS whereas ECLIA measurements showed higher levels with a large variety (mean: 16.5 ng/l; range: 7-33 ng/l). Results for E2 via ECLIA and LC-MSMS for patients treated with exemestanePatientE2 LC-MSMS ng/lE2 ECLIA ng/l1&amp;lt;1.3212&amp;lt;1.373&amp;lt;1.3124&amp;lt;1.3335&amp;lt;1.3156&amp;lt;1.3227&amp;lt;1.398&amp;lt;1.32692.51010&amp;lt;1.310 Conclusion E2 levels in exemestane users measured with ECLIA from Roche are overestimated, probably due to cross reactivity of its metabolites. Therefore, this assay can not be used in these patients. Here, we demonstrate that this hurdle can be overcome by assessment of estrogen values with LC-MSMS. Our group was able to develop such a sensitive method, without derivatization. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-09.
Monitoring of Endotoxin-Induced Pulmonary Inflammation In Vivo in NF-kB Luciferase Transgenic Mice
Authors: P.S. Thorne, S. Hadina, K. Kulhankova, C. Wohlford-Lenane, P.B. McCray, J.P. Weiss
Journal: Journal of Allergy and Clinical Immunology (2006)
Preoperative Echocardiography for Noncardiac Surgery
Authors: Herman O. Klein
Journal: Annals of Internal Medicine (1997)

Letters1 June 1997Preoperative Echocardiography for Noncardiac SurgeryHerman O. Klein, MDHerman O. Klein, MDSapir Medical Center, Kfar-Saba, IsraelSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-126-11-199706010-00027 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I found Halm and colleagues' research interesting [1], but it is remarkable that an article that bases most of its conclusions on echocardiographic ejection fraction that was “assessed visually” was accepted for publication by the Annals. How happy must be the echocardiographers who can, without fail, differentiate visually whether left ventricular ejection fraction is less than or greater than 30%! Ditto for the editors who believe this and do not require more objective data.REFERENCE1. Halm EA, Browner WS, Tubau JF, Tateo IM, Mangano DT. Echocardiography for assessing cardiac risk in patients having noncardiac surgery. The Study of Perioperative Ischemia Research Group. Ann Intern Med. 1996; 125:433-41. Google Scholar Author, Article, and Disclosure InformationAuthors: Herman O. Klein, MDAffiliations: Sapir Medical Center, Kfar-Saba, Israel PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 June 1997Volume 126, Issue 11Page: 919KeywordsEchocardiographyEjection fractionLeft ventricular ejection fractionSurgery ePublished: 15 August 2000 Issue Published: 1 June 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
IDEAL framework for surgical innovation 1: the idea and development stages
Authors: P. McCulloch, J. A. Cook, D. G. Altman, C. Heneghan, M. K. Diener
Journal: BMJ (2013)

IDEAL is a framework for evaluations of surgical innovations, which follow a distinct development pathway differing from the approach developed for pharmacological interventions. Many pathway and evaluation challenges are shared by other interventional therapies, requiring individual therapist skills and customisation of treatment to the individual, partly through medical devices. This paper provides an overview of the IDEAL framework and recommendations, and focuses on the first two stages: idea and development.
A safer poxvirus vaccine
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

The smallpox virus has been eradicated thanks to widespread vaccinations with the vaccinia virus. But because live vaccinia virus is used, some vaccine recipients, particularly those who are immune compromised, have experienced fatal infections. Xu et al. (page 981) now offer up an alternative that might side-step the pitfalls of the old vaccine.

Killed vaccinia virus does not induce antibodies against proteins that trigger smallpox, forcing researchers to look for alternative strategies. Xu et al. considered designing vaccines that target virulence proteins that mute the immune response. They reasoned that a vaccine that did not include the entire virus would be safer, while antibodies against virulence proteins, known as immune response modifiers (IRMs), would prevent disease even if they did not neutralize the virus.

The group now identifies an IRM that is the major target of protective antibodies in a mouse model of smallpox. This IRM prevents the antiviral cytokine interferon-α from activating its receptor on immune cells. Deletion of the IRM from the mousepox virus, the group found, caused a 107-fold decrease in its virulence and prevented lethality.

Mice that were injected with the IRM alone were protected against a later challenge with the wild-type virus. The IRM, the type I interferon binding protein, is well-conserved among poxviruses that infect mice and men, so the hope is that the recombinant IRM protein might be an effective poxvirus vaccine for humans as well.
Analysis of ACPA positivity and ACPA fine specificities in a large Swedish twin cohort (TwinGene)
Authors: Aase Haj Hensvold, Patrik K E Magnusson, Monika Hansson, Lena Israelsson, Cecilia Carlens, Rikard Holmdahl, Per-Johan Jakobsson, Johan Askling, Tomas Ekström, Vivianne Malmström, Lars Klareskog, Anca Irinel Catrina
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Genetic factors play a significant role in the variance of susceptibility for anticitrullinated protein antibodies (ACPA)-positive RA (Woude <i>et al</i> 2009). The authors wanted to study ACPA positivity as an entity and aimed to investigate the influence of genetic and environmental factors for ACPA positivity using a twin study approach. <h3>Methods</h3> The authors used a subset of the Swedish twin registry, including 12 594 monozygotic (MZ) and dizygotic (DZ) twins born 1958 or earlier. Serum samples were analysed for ACPA using a commercial ELISA (cyclic citrullinated peptides 2). Positive samples were also run for corresponding cyclic arginine peptide. Next, the ACPA-positive samples were investigated for ACPA fine specificities against native and citrullinated forms of α-enolase, collagen type II, vimentin and fibrinogen peptides. RA was verified by data from national care registers and/or by reviewing medical records. 6252 twins were defined as smokers according to information from questionnaire. Epigenetic changes such as DNA methylation, were measured in peripheral blood DNA from 20 monozygotic RA discordant twin pairs using the ‘whole genome CHARM approach’. <h3>Results</h3> 387 of 12 594 tested individuals (3.1%) were positive for ACPA (≥25 AU/ml). 202 of the 387 displayed high titres (3× above cut off). High reactivity to arginine (optical density &gt;0.4) were detected in 14 twins. Almost half (45%) of the ACPA positive samples had reactivity to any of the tested citrullinated peptides. Reactivity against Cit-enolase and Cit-vimentin were most common, detected in 39% respectively 23%. Among the ACPA-positive, 313 twin complete pairs were available, 7 concordant (all same sexed) and 306 ACPA discordant pairs. Concordance for ACPA was 4% among MZ and 3% among DZ twin pairs, with no significant tetrachoric correlation (r MZ twins 0.17, 95% CI 0.10 to 0.44, and r DZ twins 0.14, 95% CI 0.10 to 0.36). Concordance for high titre positivity was 5% among MZ and 3% among DZ twins. The concordance rate for Cit-enolase, based on the data from the ACPA positive subgroup, was 11% among MZ and 5% among DZ twins. Smokers had an increased risk of developed ACPA as compared with non-smokers (OR 1.33, 95% CI 1.08 to 1.63). Preliminary results from epigenetic study of monozygotic ACPA positive RA-positive twins compared to a healthy co twin identified 50 genes associated with differentially methylated regions (false discovery rate &lt;0,05). <h3>Conclusions</h3> Our results indicate that environment may be more important than genetics in determining which individuals will develop ACPA.
Withdrawal symptoms after discontinuation of long-acting brompheniramine maleate
Authors: G.M. Kavanagh, M.R. Charlwood, R.D. Peachey
Journal: British Journal of Dermatology (1994)

Journal Article Withdrawal symptoms after discontinuation of long‐acting brompheniramine maleate Get access G.M. Kavanagh, G.M. Kavanagh Departments of Dermatology, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.R. Charlwood, M.R. Charlwood Pharmacy, Bristol Royal Infirmary, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar R.D. Peachey R.D. Peachey Departments of Dermatology, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 131, Issue 6, 1 December 1994, Pages 913–914, https://doi.org/10.1111/j.1365-2133.1994.tb08605.x Published: 01 December 1994
THE MECHANISM OF STREPTOCOCCUS INFECTION.
Authors: GUSTAV F. RUEDIGER
Journal: JAMA (1905)

<h3>INTRODUCTION.</h3> Although a great deal of work has been done on the mechanism of streptococcus infection, both with normal and with immunized animals, many points are still left entirely in the dark. In the experiments described in this paper, an attempt is made to throw additional light on some of these points, but on account of the many inherent difficulties, the results which I have achieved by no means exhaust the problem. Shortly after the publication of his classical paper on phagocytosis in daphnia, Metchnikoff<sup>1</sup>made a study of phagocytosis of streptococci in the human body, in cases of erysipelas. He concluded from his observations that streptococci gain entrance through abrasions of the skin, multiply and set up an inflammation.