tbuckley/cabot-search huggingface dataset:
Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor–Associated PDGFRAD842V Mutation
Authors: Barbara Dewaele, Bartosz Wasag, Jan Cools, Raf Sciot, Hans Prenen, Peter Vandenberghe, Agnieszka Wozniak, Patrick Schöffski, Peter Marynen, Maria Debiec-Rychter
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Activating mutations in platelet-derived growth factor receptor-α (PDGFRA) have been reported in ∼5% to 10% of patients with gastrointestinal stromal tumors (GIST). Imatinib efficiently inhibits the juxtamembrane PDGFRA mutations, whereas many tyrosine kinase domain activation loop PDGFRA mutations confer primary resistance to imatinib. In this study, we compared the efficacy of second-line tyrosine kinase inhibitors such as dasatinib, sorafenib, and nilotinib against two GIST-related PDGFRA mutants, PDGFRAD842V and PDGFRAΔDIM842-844. In addition, we sought to investigate the inhibitory effect of the heat shock protein 90 inhibitor, IPI-504, on these mutants. Experimental Design: Primary imatinib-resistant tumor cells and cell lines expressing imatinib-resistant PDGFRAD842V or imatinib-sensitive PDGFRAΔDIM842-844 mutants were treated with different concentrations of dasatinib, sorafenib, nilotinib, and IPI-504. The effect of treatment on proliferation, survival, and signaling was determined. Results: All inhibitors tested exhibited a high efficacy toward the PDGFRAΔDIM842-844 mutant. In contrast, ex vivo and in vitro assays revealed that only dasatinib potently inhibited the PDGFRAD842V isoform with an IC50 value of 62 nmol/L. Sorafenib and nilotinib were significantly less efficacious against this mutation, inhibiting the PDGFRA kinase activity at &amp;gt;1,000 and &amp;gt;5,000 nmol/L, and suppressing the proliferation of the cells expressing the PDGFRAD842V mutant with an IC50 value of 239 and 1,310 nmol/L, respectively. IPI-504 treatment potently inhibited PDGFRA kinase activity by inducing the degradation of PDGFRAD842V and PDGFRAΔDIM842-844 at 256 and 182 nmol/L, respectively. Conclusions: Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRAD842V mutant isoform.
Control of Thyroid Hormone Secretion in Normal Subjects Receiving Iodides
Authors: Apostolos G. Vagenakis, Patricia Downs, Lewis E. Braverman, Albert Burger, Sidney H. Ingbar
Journal: Journal of Clinical Investigation (1973)

The administration of exogenous iodides (saturated solution of potassium iodide, SSKI) to normal male volunteers resulted in a significant decrease in the serum concentration of thyroxine (T(4)) and triiodothyronine (T(3)) and a significant increase in serum concentration of thyrotropin (TSH). During the control period (phase I), serum concentrations of T(4) averaged 6.9+/-1.8 mug/100 ml (mean +/-SD), T(3) 106+/-15 ng/100 ml, and TSH 3.7+/-1.3 muU/ml. During the administration of 1 drop of SSKI twice daily for 11 days (phase II), there was a small but significant decrease in the serum concentration of T(4) and T(3) (5.8+/-1.6 mug/100 ml and 91+/-19 ng/100 ml, respectively) and a small but significant increase in the serum concentration of TSH (6.0+/-3.5 muU/ml). During the administration of 5 drops of SSKI twice daily (phase III) over the following 12-19 days, these changes persisted, except for a small increase in the serum concentration of T(3) (97+/-20 ng/100 ml), which was statistically significant when compared to values obtained during phase II. Values returned to control levels 14 days after withdrawal of SSKI. Almost all these observed changes took place within the limits of the normal range. It is postulated that, in euthyroid individuals, iodides specifically inhibit release of T(4) and probably of T(3). The resulting slight decrease in values for serum T(4) and T(3) elicits a small increase in TSH secretion which, it is postulated, antagonizes the inhibition of hormone release induced by iodides. As a result, a new equilibrium is reached which maintains the euthyroid state.
The Cognitive Cost of Anticholinergic Burden: Decreased Response to Cognitive Training in Schizophrenia
Authors: Sophia Vinogradov, Melissa Fisher, Heather Warm, Christine Holland, Margaret A. Kirshner, Bruce G. Pollock
Journal: American Journal of Psychiatry (2009)

Schizophrenia is treated with medications that raise serum anticholinergic activity and are known to adversely affect cognition. The authors examined the relationship between serum anticholinergic activity and baseline cognitive performance and response to computerized cognitive training in outpatients with schizophrenia.Fifty-five patients were randomly assigned to either computerized cognitive training or a computer games control condition. A neurocognitive battery based on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was performed at baseline and after the intervention. Serum anticholinergic activity, measured at study entry by radioreceptor assay, was available for 49 patients.Serum anticholinergic activity showed a significant negative correlation with baseline performance in verbal working memory and verbal learning and memory, accounting for 7% of the variance in these measures, independent of age, IQ, or symptom severity. Patients in the cognitive training condition (N=25) showed a significant gain in global cognition compared to those in the control condition, but this improvement was negatively correlated with anticholinergic burden. Serum anticholinergic activity uniquely accounted for 20% of the variance in global cognition change, independent of age, IQ, or symptom severity.Serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in MATRICS-based measures of verbal working memory and verbal learning and memory and is significantly associated with a lowered response to an intensive course of computerized cognitive training. These findings underscore the cognitive cost of medications that carry a high anticholinergic burden. The findings also have implications for the design and evaluation of cognitive treatments for schizophrenia.
Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial
Authors: Massimo Imazio, Riccardo Belli, Antonio Brucato, Roberto Cemin, Stefania Ferrua, Federico Beqaraj, Daniela Demarie, Silvia Ferro, Davide Forno, Silvia Maestroni, Davide Cumetti, Ferdinando Varbella, Rita Trinchero, David H Spodick, Yehuda Adler
Journal: The Lancet (2014)
Ethanol Lock and Risk of Hemodialysis Catheter Infection in Critically Ill Patients. A Randomized Controlled Trial
Authors: Bertrand Souweine, Alexandre Lautrette, Didier Gruson, Emmanuel Canet, Kada Klouche, Laurent Argaud, Julien Bohe, Maïté Garrouste-Orgeas, Christophe Mariat, François Vincent, Sophie Cayot, Olivier Cointault, Alain Lepape, Dominique Guelon, Michael Darmon, Aurélien Vesin, Nicolas Caillot, Carole Schwebel, Alexandre Boyer, Elie Azoulay, Lila Bouadma, Jean-François Timsit
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Ethanol rapidly eradicated experimental biofilm. Clinical studies of ethanol lock to prevent catheter-related infections (CRIs) suggest preventive efficacy. No such studies have been done in intensive care units (ICU).To determine whether ethanol lock decreases the risk of major CRI in patients with short-term dialysis catheters (DCs).A randomized, double-blind, placebo-controlled trial was performed in 16 ICUs in seven university hospitals and one general hospital in France between June 2009 and December 2011. Adults with insertion of a nontunneled, nonantimicrobial-impregnated double-lumen DC for an expected duration greater than 48 hours, to perform renal-replacement therapy or plasma exchange, were randomly allocated (1:1) to receive a 2-minute catheter lock with either 60% wt/wt ethanol solution (ethanol group) or 0.9% saline solution (control group) at the end of DC insertion and after each renal-replacement therapy or plasma exchange session. The main outcome was major CRI defined as either catheter-related clinical sepsis without bloodstream infection or catheter-related bloodstream infection during the ICU stay.The intent-to-treat analysis included 1,460 patients (2,172 catheters, 12,944 catheter-days, and 8,442 study locks). Median DC duration was 4 days (interquartile range, 2-8) and was similar in both groups. Major CRI incidence did not differ between the ethanol and control groups (3.83 vs. 2.64 per 1,000 catheter-days, respectively; hazard ratio, 1.55; 95% confidence interval, 0.83-2.87; P = 0.17). No significant differences occurred for catheter colonization (P = 0.57) or catheter-related bloodstream infection (P = 0.99).A 2-minute ethanol lock does not decrease the frequency of infection of DCs in ICU patients. Clinical trial registered with www.clinicaltrials.gov (NCT 00875069).
Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78
Authors: Yu Rebecca Miao, Bedrich L. Eckhardt, Yuan Cao, Renata Pasqualini, Pedram Argani, Wadih Arap, Robert G. Ramsay, Robin L. Anderson
Journal: Clinical Cancer Research (2013)

The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Because tumor cell dissemination is often an early event in breast cancer progression and can occur before diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose-regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which are localized at the plasma membrane.Here, we show that matched primary tumors and metastases from patients who died from advanced breast cancer also express high levels of GRP78. We used a peptidomimetic targeting strategy that uses a known GRP78-binding peptide fused to a proapoptotic moiety [designated bone metastasis targeting peptide 78 (BMTP78)] and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Furthermore, in preclinical metastasis models, we show that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases.The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide-mediated targeting of cell surface-localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated.
Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma
Authors: É. Huszár, G. Vass, É. Vizi, Zs. Csoma, E. Barát, Gy. Molnár Világos, I. Herjavecz, I. Horváth
Journal: European Respiratory Journal (2002)

Persistent airway inflammation may require the use of different markers for monitoring airway inflammation. In this study, the authors investigated whether adenosine, which may be produced in allergic inflammatory conditions, could be measured with good reproducibility in exhaled breath condensate (EBC), and whether its concentration was elevated in patients with asthma. EBC adenosine and exhaled nitric oxide (eNO), a noninvasive marker of asthmatic airway inflammation, were measured in 40 healthy volunteers and 43 patients with allergic bronchial asthma. Repeatability of adenosine measurement was checked in 20 pairs of samples collected from healthy control subjects. Adenosine was detectable in all EBC samples by the applied high-performance liquid chromatographic method. The mean difference between repeated measurements of adenosine was −0.1 nM and all differences were within the coefficient of repeatability. Adenosine concentration was higher in steroid-naive patients (n=23) compared with healthy control subjects and steroid-treated patients (n=20). In patients with worsening symptoms of asthma (n=23), adenosine concentration was elevated compared with those in a stable condition (n=20). Furthermore, adenosine concentrations were related to eNO levels in asthmatic patients. These results, showing good reproducibility of adenosine measurements and increased adenosine concentrations in steroid-naive patients and in patients with worsening of asthmatic symptoms, indicate that adenosine measurement in exhaled breath condensate might be an acceptable novel method to investigate the role of local production of adenosine in the airways.
Higher Oily Fish Consumption in Late Pregnancy Is Associated With Reduced Aortic Stiffness in the Child at Age 9 Years
Authors: Jennifer Bryant, Mark Hanson, Charles Peebles, Lucy Davies, Hazel Inskip, Sian Robinson, Philip C. Calder, Cyrus Cooper, Keith M. Godfrey
Journal: Circulation Research (2015)

Rationale: Higher pulse wave velocity (PWV) reflects increased arterial stiffness and is an established cardiovascular risk marker associated with lower long-chain n-3 polyunsaturated fatty acid intake in adults. Experimentally, maternal fatty acid intake in pregnancy has lasting effects on offspring arterial stiffness. Objective: To examine the association between maternal consumption of oily fish, a source of long-chain n-3 polyunsaturated fatty acids, in pregnancy and child’s aortic stiffness age 9 years. Methods and Results: In a mother–offspring study (Southampton Women’s Survey), the child’s descending aorta PWV was measured at the age of 9 years using velocity-encoded phase-contrast MRI and related to maternal oily fish consumption assessed prospectively during pregnancy. Higher oily fish consumption in late pregnancy was associated with lower childhood aortic PWV (sex-adjusted β=−0.084 m/s per portion per week; 95% confidence interval, −0.137 to −0.031; P =0.002; n=226). Mother’s educational attainment was independently associated with child’s PWV. PWV was not associated with the child’s current oily fish consumption. Conclusions: Level of maternal oily fish consumption in pregnancy may influence child’s large artery development, with potential long-term consequences for later cardiovascular risk.
Novel Functional Germline Variants in the VEGF Receptor 2 Gene and Their Effect on Gene Expression and Microvessel Density in Lung Cancer
Authors: Dylan M. Glubb, Elisa Cerri, Alexandra Giese, Wei Zhang, Osman Mirza, Emma E. Thompson, Peixian Chen, Soma Das, Jacek Jassem, Witold Rzyman, Mark W. Lingen, Ravi Salgia, Fred R. Hirsch, Rafal Dziadziuszko, Kurt Ballmer-Hofer, Federico Innocenti
Journal: Clinical Cancer Research (2011)

VEGF receptor 2 (VEGFR-2) plays a crucial role in mediating angiogenic endothelial cell responses via the VEGF pathway, and angiogenesis inhibitors targeting VEGFR-2 are in clinical use. As angiogenesis is a host-driven process, functional heritable variation in KDR, the gene encoding VEGFR-2, may affect VEGFR-2 function and, ultimately, the extent of tumor angiogenesis.We resequenced KDR using 24 DNAs each from healthy Caucasian, African American, and Asian groups. Nonsynonymous genetic variants were assessed for function by phosphorylation assays. Luciferase reporter gene assays were used to examine effects of variants on gene expression. KDR mRNA and protein expression and microvessel density (MVD) were measured in non-small cell lung cancer (NSCLC) tumor samples, and matching patient DNA samples were genotyped to test for associations with variants of interest.KDR resequencing led to the discovery of 120 genetic variants, of which 25 had not been previously reported. Q472H had increased VEGFR-2 protein phosphorylation and associated with increased MVD in NSCLC tumor samples. -2854C and -2455A increased luciferase expression and associated with higher KDR mRNA levels in NSCLC samples. -271A reduced luciferase expression and associated with lower VEGFR-2 levels in NSCLC samples. -906C and 23408G associated with higher KDR mRNA levels in NSCLC samples.This study has defined KDR genetic variation in 3 populations and identified common variants that impact on tumoral KDR expression and vascularization. These findings may have important implications for understanding the molecular basis of genetic associations between KDR variation and clinical phenotypes related to VEGFR-2 function.
Errors in the Guaiac Test For Occult Blood
Authors: H. David Markman
Journal: JAMA (1967)

<h3>To the Editor:—</h3> During a lecture and clinical demonstration, I performed a guaiac test for occult blood on a stool specimen that appeared tarry, and obtained a negative reaction. In order to illustrate how a positive reaction should appear, I repeated the test with a specimen containing fresh blood. To my discomfiture, this too, produced a negative result. This communication is written to call attention to some of the causes of such false reactions. As is well known, the guaiac test is usually performed by smearing a small quantity of stool on a piece of filter paper. Two drops of each of the following reagents are added in succession and mixed with the stool: glacial acetic acid, saturated alcoholic solution of gum guaiac, and 3% hydrogen peroxide. The presence of occult blood is indicated by the appearance of a deep blue color within one minute.<sup>1</sup> What is less known,
ROS Generation by Nonphagocytic NADPH Oxidase
Authors: Jian-Mei Li, Ajay M. Shah
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Oxidative stress has emerged as an important pathogenic factor in the development of long-term complications, such as atherosclerosis and nephropathy, in patients with diabetes. Whereas multiple enzymes and processes can contribute to oxidative stress, recent studies indicate that a multicomponent phagocyte-type NADPH oxidase is a major source of reactive oxygen species (ROS) production in many nonphagocytic cells, including fibroblasts, vascular smooth muscle cells, endothelial cells, renal mesangial cells, and tubular cells. Under physiologic conditions, nonphagocytic NADPH oxidases have very low-level constitutive activity. However, enzyme activity can be upregulated both acutely and chronically in response to stimuli such as growth factors, cytokines, high glucose, and hyperlipidemia. ROS production by the oxidase may serve a signaling role or may lead to oxidative damage. This article reviews current knowledge of the nonphagocyte-NADPH oxidases at both structural and biochemical levels and discusses the possible role of these enzymes in the pathophysiology of diabetic nephropathy. E-mail: [email protected]
Direct analysis of HLA/HER-2 peptide epitopes
Authors: Andrea Patterson, Wilfried Bardet, Ken Jackson, Jon Weidanz, William Hildebrand
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts T cells recognize cancer cells via human leukocyte antigen (HLA)/peptide complexes, and class I HLA restricted tumor infiltrating T cells correspond to favorable prognoses in several cancers, including ovarian cancer. Cancer-specific HLA/peptide complexes therefore represent tumor
Altered expression of small proteoglycans, collagen, and transforming growth factor-beta 1 in developing bleomycin-induced pulmonary fibrosis in rats.
Authors: G Westergren-Thorsson, J Hernnäs, B Särnstrand, A Oldberg, D Heinegård, A Malmström
Journal: Journal of Clinical Investigation (1993)

The development of bleomycin-induced pulmonary fibrosis in rats was studied over a period of 21 d after an intratracheal instillation of bleomycin. The expression of three small proteoglycans (biglycan, decorin, and fibromodulin), collagen III and TGF-beta 1 was studied by RNA-transfer blot analysis. The proteoglycans were also studied by SDS-polyacrylamide gel electrophoresis and Western blots. TGF-beta 1 mRNA increased threefold already on day 3 and remained elevated until day 10. After the increase of TGF-beta 1 mRNA the messages for biglycan and collagen III steadily increased to reach a maximum 10 d after bleomycin instillation. The mRNA for biglycan increased maximally fourfold and that of collagen III 2.5-fold. Decorin mRNA, in contrast to biglycan decreased and reached 20% of control on day 10. The message for fibromodulin remained constant throughout the study period. The amounts of biglycan and decorin in the tissue changed in accordance with the mRNA levels. The results corroborate and extend previous in vitro studies concerning the effect of TGF-beta 1 on the metabolism of small proteoglycans and show that these macromolecules are regulated differently also in vivo. The marked alterations of biglycan and decorin during the development of fibrosis suggests that these proteoglycans have a regulating role in this process.
Atorvastatin Improves the Course of Ischemic Acute Renal Failure in Aging Rats
Authors: Massimo Sabbatini, Antonio Pisani, Francesco Uccello, Vittorio Serio, Rosalba Serù, Roberto Paternò, Bruno Cianciaruso, Giorgio Fuiano, Michele Andreucci
Journal: Journal of the American Society of Nephrology (2004)

Statins increase the production of nitric oxide (NO) and have beneficial effects on the course of acute renal failure (ARF) in young rats. The effects of a short-term treatment with atorvastatin (ATO) on ischemic ARF in old rats, characterized by a great susceptibility to ischemia, was tested. No difference was found in renal dynamics between young (Y, 3 mo old) and old (O, 18 mo old) rats in normal conditions (CON) or after ATO treatment (12 mg/kg/d for 14 d). Twenty-four hours after clamping of both renal arteries, a more pronounced decrease in GFR was observed in O rats versus Y rats after a greater renal vasoconstriction and hypoperfusion of aging animals. Pretreatment with ATO mitigated renal vasoconstriction in O rats and restored GFR values to Y rats. Nitrate excretion was enhanced in Y rats after ARF but was not further modified by ATO; in O rats, ARF did not increase nitrate excretion, which was raised after ATO treatment. This reflected the increase in endothelial NO synthase (eNOS)-mRNA expression and eNOS protein observed in old ATO-treated animals with ARF. ATO treatment had also a significant protective effect against the cell injury at tubular level in O, but not Y, rats. The Ras system was not influenced by ATO in O rats, whereas the activation of Rho proteins was partially inhibited by ATO. Low-dose treatment with ATO enhances NO availability in aging rats, improving renal dynamics and conferring a peculiar histologic protection at tubular level after ischemia.
LUPUS ERYTHEMATOSUS: A SIMPLE METHOD OF TREATMENT
Authors: WILLIAM D.D. SMALL
Journal: British Journal of Dermatology (1919)

Journal Article LUPUS ERYTHEMATOSUS: A SIMPLE METHOD OF TREATMENT Get access WILLIAM D.D. SMALL, M.D., F.R.C.P. Edin. WILLIAM D.D. SMALL, M.D., F.R.C.P. Edin. Honorary Physician to the Edinburgh Dispensary for Diseases of the Skin Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 31, Issue 3, 1 July 1919, Pages 136–137, https://doi.org/10.1111/j.1365-2133.1919.tb09705.x Published: 01 July 1919
Biology of pancreatic cancer.
Authors: G J Poston, J Gillespie, P J Guillou
Journal: Gut (1991)

Pancreatic cancer is the fifth leading cause of death from malignant disease in Western society. Apart from the fortunate few patients who present with a resectable small pancreatic adenocarcinoma, conventional treatment offers no hope of cure and has little palliative value. Over the past two decades major steps have been made in our understanding of the biology of pancreatic growth and neoplasia. This review sets out to explore these advances, firstly in the regulation of normal pancreatic growth, and secondly the mechanism which may be involved in malignant change of the exocrine pancreas. From an understanding of this new biology, new treatment strategies may be possible for patients with pancreatic cancer.