tbuckley/cabot-search huggingface dataset:
Abstract 3396: Dual lineage inhibition of ETV1 and KIT disrupts the ETV1-KIT feed forward circuit and potentiates imatinib antitumor effect in GIST oncogenesis
Authors: Leili Ran, Inna Sirota, Zhen Cao, Devan Murphy, Shipra Shukla, Ferdinando Rossi, John Wongvipat, William D. Tap, Peter Besmer, Cristina R. Antonescu, Yu Chen, Ping Chi
Journal: Cancer Research (2014)

Abstract Gastrointestinal stromal tumour (GIST) is one of the most common types of human sarcoma and is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Despite the initial clinical success of imatinib that specifically target mutant KIT and PDGFRA, imatinib resistance has become the biggest challenge in the management of advanced GIST patient. Novel therapeutics that can improve the efficacy of first line imatinib therapy and/or prevent and overcome imatinib resistance is imperative. The ETS family member, ETV1, has been previously identified as a lineage-specific survival factor that cooperates with mutant KIT by ETV1 protein stabilization by active MAP kinase signaling downstream of KIT signaling in GIST oncogenesis. Here we demonstrate that ETV1 is required for GIST initiation and maintenance in vivo using compound genetically engineered mouse models (GEMM). We further identified that ETV1 forms a feed forward circuit in GIST oncogenesis where the ETV1 protein is stabilized by active MAP kinase signaling downstream of KIT and stabilized ETV1enhances KIT expression through direct binding to the KIT enhancer regions in both GIST mouse models and human GIST cell lines. The dual lineage targeting of KIT by imatinib and ETV1 by MEK162 (an MEK inhibitor) disrupts the ETV1-KIT feed forward circuit and induces more apoptosis than single agent imatinib or MEK162 in human GIST cells. The combination therapy resulted in complete tumor regression whereas single agent imatinib or MEK162 resulted in stabilization of disease in human GIST xenograft studies. Moreover, the combination therapy also induced more tumor fibrosis than single agent imatinib or MEK162 in GIST GEMM. These observations demonstrate the in vivo role of ETV1 in GIST oncogenesis and the feasibility of targeting ETV1 protein stability by inhibiting MAP kinase signaling. They also suggest that the dual lineage targeting of ETV1 and KIT by the combination therapy may provide a more effective therapeutic strategy than imatinib alone in GIST management. Citation Format: Leili Ran, Inna Sirota, Zhen Cao, Devan Murphy, Shipra Shukla, Ferdinando Rossi, John Wongvipat, William D. Tap, Peter Besmer, Cristina R. Antonescu, Yu Chen, Ping Chi. Dual lineage inhibition of ETV1 and KIT disrupts the ETV1-KIT feed forward circuit and potentiates imatinib antitumor effect in GIST oncogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3396. doi:10.1158/1538-7445.AM2014-3396
Costs associated with persistent allergic rhinitis are reduced by levocetirizine
Authors: J. Bousquet, N. Demarteau, J. Mullol, M. E. van den Akker‐van Marle, E. Van Ganse, C. Bachert
Journal: Allergy (2005)

Background: Allergic rhinitis was recently classified by the ARIA guidelines as persistent or intermittent. Levocetirizine was shown to improve symptoms and health‐related quality of life of patients with persistent allergic rhinitis in the XPERT TM study, a 6‐month randomized double blind placebo‐controlled trial. Objective: To assess the total costs of persistent allergic rhinitis, and the effect of long‐term treatment with levocetirizine on these costs from several perspectives (societal, social security system, and employers). Methods: Direct medical cost parameters (medications, physician visits and hospitalizations) and time lost parameters (workdays and Usual Daily Activities (UDA) lost) related to persistent allergic rhinitis and its comorbidities (asthma, sinusitis, otitis and upper respiratory infection) were measured. A cost analysis was performed using 2002 French costing data. Results: From a societal perspective, the total cost of persistent allergic rhinitis without long‐term treatment was estimated at €355.06/patient/month. From a social security perspective, levocetirizine treatment yielded an additional cost of €2.78/patient/month, compared to no‐treatment. However, levocetirizine reduced the total cost of persistent allergic rhinitis and its comorbidities by €152.93/patient/month from a societal perspective and by €64.70/patient/month from an employer perspective. Most gains resulted from a decrease in the lost workdays and UDA in the levocetirizine group. Conclusion: The cost of persistent allergic rhinitis is substantial. Treatment with levocetirizine reduces the cost of persistent allergic rhinitis and its comorbidities to the society by €152.93/patient/month while improving symptoms and health‐related quality of life.
Enhanced acetylcholine and P2Y-receptor stimulated vascular EDHF-dilatation in congestive heart failure
Authors: M Malmsjö
Journal: Cardiovascular Research (1999)

Objective: Congestive heart failure (CHF) is accompanied by impaired peripheral blood flow and endothelial dysfunction with decreased release of nitric oxide (NO). Strong evidence supports the existence of another vasodilatory substance, endothelium derived hyperpolarising factor (EDHF), which has not previously been studied in CHF. Method: CHF was induced by left coronary artery ligation resulting in a reproducible myocardial infarction in Sprague Dawley rats. Vasodilatory responses to acetylcholine and extracellular nucleotides (ATP, ADPβS, ADP and UTP) were examined in cylindrical segments of the mesenteric artery, precontracted with noradrenaline. The combined NO- and EDHF-dilatation (after inhibition of cyclo-oxygenase pathways) was called "total dilatation", as indomethacin had only minor effects in this system. NO-dilatation was studied in segments pretreated with indomethacin and the potassium channel inhibitors charybdotoxin (10−7.5 M) and apamin (10−6 M), while EDHF-dilatations were studied in the presence of indomethacin (10−5 M) and L-NOARG (10−3.5 M). Results: EDHF-dilatations in CHF were strongly up-regulated for ACh (36% vs. 73%; sham vs. CHF operated rats), ADPβS (10% vs. 42%), ADP (0% vs. 21%) and UTP (3% vs. 35%). These dilatations were abolished by a combination of charybdotoxin and apamin, confirming that they were mediated by EDHF. The NO-dilatations on the other hand were down-regulated in CHF as compared to sham operated rats for ACh (93% vs. 76%; sham vs. CHF operated rats), ADPβS (61% vs. 37%). ADP (60% vs. 30%), ATP (49% vs. 34%) and UTP (65% vs. 47%), while a minor decrease was seen in the total dilatation for ACh (87% vs. 75%; sham vs. CHF operated rats), ADPβS (47% vs. 42%), ADP (59% vs. 39%), ATP (52% vs. 39%) and UTP (59% vs. 44%). Conclusion: In this model of non-atherosclerotic CHF there was a minor decrease in the total dilatation and a marked down-regulation of the NO-mediated dilatation, while the EDHF-dilatation was up-regulated. Increased EDHF-activity in CHF may represent a compensatory response to decreased NO-activity to preserve endothelial function and tissue perfusion.
Diuretics and Sudden Cardiac Death
Authors: Bernhard R. Winkelmann
Journal: Annals of Internal Medicine (1996)

Letters15 August 1996Diuretics and Sudden Cardiac DeathBernhard R. Winkelmann, MDBernhard R. Winkelmann, MDHoechst AG, 65926 Frankfurt, GermanySearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-125-4-199608150-00028 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:According to the 1992 Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure, β-blockers and diuretics are the preferred drugs for treating hypertension [1]. Hoes and colleagues [2] challenge that view and report that the use of non-potassium-sparing diuretics and β-blockers is associated with increased risk for sudden death [2]. Although the authors also came to the former conclusion in a review of published studies on non-potassium-sparing diuretics [3], the latter finding is unexpected.In a recent overview, Kendall and colleagues [4] concluded that none of the available therapies is more effective than β-blockers ...References1. Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure. 5th report on the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure, JNC V. Arch Intern Med. 1993; 153:154-83. Google Scholar2. Hoes AW, Grobbee DE, Lubsen J, Veld AJ, van der Does E, Hofman A. Diuretics, β-blockers, and the risk for sudden cardiac death in hypertensive patients. Ann Intern Med. 1995; 123:481-7. Google Scholar3. Hoes AW, Grobbee DE, Peet TM, Lubsen J. Do non-potassium sparing diuretics increase the risk of sudden cardiac death in hypertensive patients? Recent evidence. Drugs. 1994; 47:711-33. Google Scholar4. Kendall MJ, Lynch KP, Hjalmarson A, Kjekshus J. β-blockers and sudden cardiac death. Ann Intern Med. 1995; 123:358-67. Google Scholar5. Yusuf S. Calcium antagonists in coronary artery disease and hypertension—time for reevaluation? Circulation. 1995; 92:1079-82. Google Scholar Author, Article, and Disclosure InformationAffiliations: Hoechst AG, 65926 Frankfurt, Germany PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 August 1996Volume 125, Issue 4Page: 347-348KeywordsAnginaCalciumCalcium antagonist therapyDiureticsDrugsHeart failureHypertensionPrimary hypertensionRisk managementSudden cardiac death Issue Published: 15 August 1996 CopyrightCopyright © 1996 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...
Zinc inhibits FPA release and increases fibrin turbidity
Authors: Gerard Marx, Pierre Hopmeier
Journal: American Journal of Hematology (1986)

Abstract Physiologic concentrations of Zn(II) (4–40 μM) can increase the rate of thrombin‐induced fibrin clot formation (decreased clotting time, CT) and increase the turbidity of the fibrin gel. Both the initial and ultimate turbidity (Abs 600 mm ) of fibrin gels are increased in the presence of Zn(II). Two techniques were used to elaborate the mechanisms of Zn +2 procoagulant effect. Analytical ultracentrifugation indicates that Zn(II) does not induce the formation of fibrinogen multimers. Radioimmunoassay for FPA indicates that thrombin activation of fibrinogen is decreased by Zn(II), with 50% inhibition of FPA release observed at 35 μM Zn(II). These experiments indicate that the critical feature of Zn(II) procoagulant effect is not due to the induction of fibrinogen proteolysis by thrombin, which is actually decreased. Rather, it appears that Zn(II) accelerates the polymerization step of fibrin assembly and concomitantly modifies fibrin gel structure.
Abstract 5259: Application of HT-RNAi-based functional genomics in neuroblastoma
Authors: Irma M. Gonzales, Shilpi Arora, Javed Khan, David O. Azorsa
Journal: Cancer Research (2010)

Abstract Neuroblastoma is the most common extra-cranial solid cancer in children. About 70% of patients with neuroblastoma have metastatic disease at the time of diagnosis. Children with favorable disease characteristics and younger than one year of age (stages I and II) have a higher likelihood of disease-free survival. However, older children with advanced disease (stages III and IV) have only a 30% chance of survival even with aggressive therapy. Additionally, amplification of the MYC-N gene has been associated with stage III and IV tumors, thus establishing it as a poor prognostic marker. Current treatment primarily consists of combinations of surgery, radiation, and chemotherapy. Newer regimens also include the topoisomerase I inhibitor topotecan, which has been found to be effective against recurrent disease. In order to identify “Achilles heel” targets that modulate growth of neuroblastoma, we applied a functional genomics approach using High Throughput RNA interference (HT-RNAi). Furthermore, by treatment of cells with low dose topotecan, we hope to identify genes the can improve the response to this current therapy. We first identified optimal siRNA transfection conditions for the four neuroblastoma cell lines; MYC-N amplified, IMR-5 and IMR-32 and MYC-N non-amplified, SK-N-AS and NB-EB. Since these cell lines can be difficult to transfect with siRNA, several cationic lipids were tested at varying lipid:siRNA ratios to obtain the optimal reagent and ratio for each cell line. Next, we determined the optimal low dose (IC10-30) of topotecan for each cell line. Following these optimizations, HT-RNAi assays were conducted on the four neuroblastoma cell lines using a kinase siRNA library targeting 572 kinases and a siRNA library targeting 532 apoptosis associated genes treated with vehicle or low dose topotecan. These HT-RNAi screens identified genes whose silencing decreased neuroblastoma cell growth and genes whose silencing improved topotecan response. We are currently in the process of validating these results. After validation, we hope to develop these molecular targets into innovative therapeutics for children affected with this disease. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5259.
IMMUNOLOGIC RELATIONSHIP OF DONOVANIA GRANULOMATIS TO GRANULOMA INGUINALE
Authors: Katherine Anderson, E. W. Goodpasture, W. A. DeMonbreun
Journal: The Journal of Experimental Medicine (1945)

1. A washed bacterial suspension of Donovan microorganisms cultivated in the yolk of chick embryos was used as an antigen in intracutaneous tests in 6 cases of granuloma inguinale in the active stage of the disease. These injections were responded to by an extensive erythematous and edematous reaction that reached its height in 24 hours and disappeared within 48 hours later. Four control cases without granuloma inguinale did not react to the injection to any greater extent than would be expected from the slight trauma incident to them. The skin of the reacting patients responded in a similar manner but to a lesser extent to a filtrate of infected yolk. Simultaneous control injections of filtered normal yolk demonstrated that sensitivity to normal yolk was not responsible for the reactions. 2. A mucoid material present in infected yolk, soluble in N/100 NaOH, and precipitable by N/100 HCl was recovered and purified by repeated acid precipitation, extraction with ether, washing in distilled water, and dissolution in N/100 NaOH. We regard this material to be of capsular origin. 3. The presumptive capsular material injected intradermally elicited a somewhat different and milder reaction in patients with active granuloma inguinale, but we regard it as specific. 4. The "capsularrdquo; material in suitable dilution elicited distinct precipitation reactions when mixed with the serum from 18 of 19 cases of active granuloma inguinale. Serum from 1 active case showed no precipitation. Sixty-four serums, including 6 from lymphopathia venereum patients and 18 from Wassermann- or Kahn-positive patients, and 1 from an early chancroid failed to precipitate. Two serums from a total of 66 used as controls showed a precipitate in the presence of the capsular material. These patients gave no history or evidence of granuloma inguinale. 5. The "capsular" material fixed complement in the presence of serum from patients with granuloma inguinale. Serum from 12 of 15 cases of granuloma inguinale demonstrated complement fixation. Three failed to fix complement. Of 19 control serums 18 failed to fix complement in the presence of the capsular material and 1 fixed only a very slight amount of complement. None of these serums nor the capsular material itself was anticomplementary. 6. The high proportion of precipitation and complement fixation reactions obtained from patients with active granuloma inguinale is indicative of a specific immunological relationship of the Donovan microorganism cultivated in embryonic yolk to the disease, granuloma inguinale. 7. We suggest that one or all of these methods might be so standardized as to be of distinct diagnostic value.
Genital herpes infection and non-specific urethritis.
Authors: S Jeansson, L Molin
Journal: BMJ (1971)

malabsorption of vitamin B12 and four of these had abnormally low serum levels of the vitamin.We have data on 114 diabetic patients who have had at least 2 g of met- formin daily for at least two years and of these no less than 17-5% had serum levels
178 DE NOVO EXTRAHEPATIC MALIGNANCIES IN A COHORT OF CIRRHOTIC PATIENTS
Authors: M. Montealegre Barrejon, J.M. Moreno Planas, A. Caramuto Martins, A.B. Galera Rodenas, E. Cascales Martinez, M. Vargas Travaglini, D.F. Garcia Nuñnez, A.J. Velasco Valcarcel, M.D.M. Vicente Gutiérrez, R. Pérez Flores
Journal: Journal of Hepatology (2010)
An apple a day does not keep the doctor away, US study finds
Authors: M. McCarthy
Journal: BMJ (2015)

Eating an apple a day is not associated with fewer visits to the doctor, a US study published by JAMA Internal Medicine has found.1

The researchers said that they conducted the study because the claim that “An apple a day keeps the doctor away” had never been rigorously examined. The saying is derived from an earlier one, “Eat an apple on going to bed and you’ll keep the doctor from earning his bread,” first cited in Wales in 1866.2

The researchers wrote, “Although some may jest, considering the relatively low cost of apples (currently $1.13 [£0.76; €1.05] per pound of …
Teenager died after surgeon "lost his temper"
Authors: C. Dyer
Journal: BMJ (2001)

A consultant surgeon standing trial at Exeter crown court for the manslaughter of a teenage patient caused her death through negligence after losing his temper during the operation, the court was told last week.

Kenneth Woodburn, aged 39, of Idless, near Truro, Cornwall, pleaded not guilty to the manslaughter of 16 year old Kelly Dent at Treliske Hospital, Truro, in September 1998.

The teenager, who had acute myeloid leukaemia, was added to Mr Woodburn's operating list at short notice, after attempts by her own consultant to insert a Hickman line had failed.

“Sadly, what should have been a reasonably simple …
Value of partial ejection fraction, volume increment, and regional wall motion in identifying patients with clinically significant coronary artery disease.
Authors: F H Sheehan, H T Dodge, E L Bolson, H W Woo, G R Caputo, D K Stewart
Journal: Circulation (1983)

Recent studies suggest that the partial ejection fraction (EF) in early systole is a more sensitive index of left ventricular (LV) dysfunction than the holosystolic EF. We examined LV volume, partial EF, and volume increment at each of 12 time points in systole to determine which parameter best distinguishes normal subjects from patients with coronary artery disease (CAD). Contrast ventriculograms, obtained either in the right anterior oblique projection (60 frames/sec) or in the biplane projection (30 frames/sec), of 58 normal subjects and 68 patients with CAD were studied. The endocardial contour in each frame of a sinus beat was traced to derive a volume curve. At each twelfth of systole, LV volume was extrapolated from the curve and the partial EF was calculated. The increment in volume between successive time points was also calculated. Both partial EF and LV volume in patients with CAD became progressively more abnormal with time; peak abnormality occurred at end-systole. In a subgroup of patients with CAD who had normal holosystolic EF, both partial EF and volume were normal throughout systole. The increment in volume with each twelfth of systole in patients with CAD deviated less than 1 SD from normal throughout systole. Thus, maximum abnormality in partial EF and volume occurs at end-systole. Of the parameters of global LV function tested, holosystolic EF best distinguishes patients with CAD from normal subjects. However, regional wall motion measured in the area of interest is more sensitive to localized abnormality, the severity of which may be overestimated or underestimated by the EF due to hyperkinesis or hypokinesis in other regions of the left ventricle.
Blocking the 4 integrin paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site
Authors: C. C. Feral
Journal: Journal of Clinical Investigation (2006)

Antagonists to alpha4 integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of alpha4 integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in alpha4 integrin [alpha4(Y991A) mice], which blocks paxillin binding and inhibits alpha4 integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of alpha4 integrin-null mice, mice bearing the alpha4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. Alpha4 integrins are essential for definitive hematopoiesis; however, the alpha4(Y991A) mice had intact lymphohematopoiesis and, with the exception of reduced Peyer's patches, normal architecture and cellularity of secondary lymphoid tissues. We conclude that interference with alpha4 integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of alpha4 integrins in development and hematopoiesis.
Faculty Response to Student Confrontation
Authors: THEODORE SHAPIRO, WILLIAM A. FROSCH
Journal: American Journal of Psychiatry (1970)

A psychiatric faculty was confronted with the need for change by discontented first-year medical students. A description of the events and some of the factors involved in the faculty response to the student demands is presented. There were a number of irrational and emotional factors influencing faculty attitudes; these variously reinforced prior tendencies in favor of or against change. Recognition of these irrational tendencies is essential if we are to prevent polarization and promote cooperation and problem solving.
Renal receptors and effects of atrial natriuretic factor in compensatory renal hypertrophy
Authors: Deborah A. Price, Juraj Okolicany, Thomas Maack
Journal: Kidney International (1992)

In the present study we investigated the in vivo and in vitro renal responsiveness to ANF, and the adaptation of ANF receptors in compensatory renal hypertrophy in the rat. One week after left nephrectomy (UNx), plasma levels of immunoreactive ANF, blood pressure (MAP), hematocrit (Hct), and urine flow rate (V) were unaltered compared to control (C) rats. Baseline GFR and potassium excretion (UKV) were significantly higher, and sodium excretion (UNaV) tended to be elevated in UNx rats. Administered ANF led to similar dose-related decreases in MAP and increases in Hct in UNx and C rats. However, at each dose of infused ANF, absolute values and the increase in GFR and UNaV were higher in UNx than in C rats. Hypertrophied (H) kidneys were removed from UNx and perfused in vitro to determine distribution and density of ANF receptors, responsiveness to ANF, and receptor-mediated organ clearance of 125I-ANF1-28. The density of ANF receptors in cortex, outer medulla, and papilla of H kidneys was not significantly different from that in C kidneys. In H isolated kidneys, ANF led to dose-related increases in GFR, V, UNaV, and UKV that were indistinguishable (P greater than 0.05) from those in C kidneys. Receptor-mediated organ clearance of 125I-ANF1-28 in isolated H kidneys was 2.8 +/- .02 ml/min, a value not significantly different (P greater than 0.05) from that in C kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)