tbuckley/cabot-search huggingface dataset:
Genome-wide RNAi synthetic lethality profiling to identify genetic determinants of Enzastaurin response
Authors: Holly Yin, Gopinath Ganji, Yue Li, Quick Que, Michelle Kassner, Pinar Tuzmen, Chris Sereduk, Leslie Gwinn, Sukru Tuzmen, Christian Beaudry, Wu Song, Libin Ma, Caroline Wilson, Connie Poh Nee, Mahesh Kumar, Yang Xiang, Jagatheswari Virayah, Jeff Keifer, David Azorsa, Michael Barrett, Kerry Blanchard, Spyro Mousses, Greg Tucker-Kellogg
Journal: Clinical Cancer Research (2007)

B56   The genetic aberrations acquired during the development of tumors represent both the drivers of disease and the opportunities for tailored therapeutics in cancer. Patients with genes and pathways altered in specific tumor types may respond differently to targeted therapies; understanding these genetic determinants of drug sensitivity as early as possible in the discovery process can help to improve and accelerate decisions regarding clinical indications, patient stratification and combination studies. We used a cell-based druggable genome-wide (~7000 targets) siRNA screen to determine enhancers of drug response for Enzastuarin, a late stage clinical candidate undergoing trials in various cancers. Assay development, validation, high throughput screening, and follow-up studies were performed in four cell lines - Calu6 (lung), HCT116 (colon), U87MG (glio) and MCF7 (breast) - representing different tumor types and varied genetic backgrounds. A variety of integrative approaches were developed for robust hit selection and prioritization. Several interesting sensitizers have thus been identified that potentiate drug effect by synthetic lethal chemogenetic interactions. Followup work is underway to translate these findings into clinically useful biomarkers and targets for combination therapy. A few preliminary examples will be shown and discussed. This approach has significant translational potential and when successfully implemented, would provide a novel opportunity to tailor therapy and improve clinical success of targeted agents.
Hydrogen peroxide and hydroxyl radical mediation of activated leukocyte depression of cardiac sarcoplasmic reticulum. Participation of the cyclooxygenase pathway.
Authors: G T Rowe, N H Manson, M Caplan, M L Hess
Journal: Circulation Research (1983)

Human peripheral blood leukocytes, activated by phorbol myristate acetate, disrupt canine sarcoplasmic reticulum calcium transport, in vitro, by an oxygen-derived free radical mechanism. Activated leukocytes significantly depress Ca++ uptake activity and Ca++ -stimulated, Mg++ -dependent ATPase activity. The depression is completely inhibited by sodium-azide (0.1 mM) or the combination of superoxide dismutase (10 micrograms/ml) and catalase (10 micrograms/ml). Exogenous hydrogen peroxide (0.441-4.41 mM) uncoupled Ca++ uptake activity from ATP hydrolysis, and this effect was inhibited by catalase. Mannitol alone did not inhibit the effects of activated leukocytes, but superoxide plus mannitol (20-100 mM) resulted in normal ATPase activity, while Ca++ uptake remained depressed. In the presence of indomethacin and ibuprofen, activated leukocytes depressed Ca++ uptake and had no effect on ATPase activity. 2-Amino-methyl-4-t-butyl-6-iodophenol (MK-447) further depressed Ca++ uptake and partially inhibited the effect on ATPase activity. Indomethacin plus catalase completely inhibited the effects of activated leukocytes on cardiac sarcoplasmic reticulum. We conclude, first, that activated leukocytes depress canine cardiac sarcoplasmic reticulum Ca++ transport by an oxygen-free radical mechanism with the generation of hydrogen peroxide and hydroxyl radical. In addition to the classical membrane NADPH oxidase system, significant oxygen radical generation can occur through the cyclooxygenase pathway of arachidonic acid metabolism, and seems to be responsible for the generation of the hydroxyl radical.
Response to Letter Regarding Article, “Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas”
Authors: Scott D. Solomon, Marc A. Pfeffer, Peter V. Finn, Monica M. Bertagnolli, John J.V. McMurray, Bernard Levin, Craig Eagle, Maria Jose Lechuga, Ernest Hawk, Ann G. Zauber, Nadir Arber, Rob Fowler, Janet Wittes
Journal: Circulation (2007)
A case-control study of deaths from asthma.
Authors: H H Rea, R Scragg, R Jackson, R Beaglehole, J Fenwick, D C Sutherland
Journal: Thorax (1986)

A population based case control-study was initiated in 1981 to identify risk factors for death from asthma. Over a two year period all deaths in the Auckland population possibly due to asthma, in people less than 60 years of age, were investigated. From the 47 people who died from asthma 44 who had useful reversibility of airways obstruction (records showing greater than 20% variability of peak flow or a history indicating equivalent variability of shortness of breath) before death were selected as cases for the study. Both hospital and community based controls were used. The cases were more likely than were the community controls to have had severe disease, a hospital admission or visits to a hospital emergency department in the previous year (odds ratios 4.4, 16.0, 8.5 respectively). The asthmatic patients who died were more likely than either group of controls to have had a previous life threatening asthma attack. Poor management of the disease and poor compliance on the part of the patient increased the risk of death. In addition, use of three or more types of asthma drug within the past year was associated with an increased risk of dying that was independent of disease severity. Of interest was a similarity between asthmatic patients admitted to hospital and those who died. Nevertheless, a history of a previous life threatening attack and a recent admission to hospital identified a group at high risk.
Revising the definition of Alzheimer's disease: a new lexicon
Authors: Bruno Dubois, Howard H Feldman, Claudia Jacova, Jeffrey L Cummings, Steven T DeKosky, Pascale Barberger-Gateau, André Delacourte, Giovanni Frisoni, Nick C Fox, Douglas Galasko, Serge Gauthier, Harald Hampel, Gregory A Jicha, Kenichi Meguro, John O'Brien, Florence Pasquier, Philippe Robert, Martin Rossor, Steven Salloway, Marie Sarazin, Leonardo C de Souza, Yaakov Stern, Pieter J Visser, Philip Scheltens
Journal: The Lancet Neurology (2010)
Inhibition of liver regeneration by chronic alcohol administration.
Authors: L Duguay, D Coutu, C Hetu, J G Joly
Journal: Gut (1982)

Liver regeneration is the common mechanism whereby a patient recovers form a liver injury. In the western world, ethanol is the single most important aetiological factor associated with liver disease, and it appears crucial to determine if ethanol interferes with liver regeneration. We studied the response to a 70% hepatectomy in 240 rats receiving a nutritionally adequate diet containing 36% of their calories as ethanol for three weeks and their pair-fed controls receiving a liquid diet where ethanol is isocalorically replace with carbohydrates. Criteria of liver regeneration were: incorporation of 3H-thymidine in hepatocyte DNA (cpm/10 microgram DNA) and number of hepatocyte labelled nuclei on autoradiography per 100 high power fields. Controls displayed the usual response with peak activity of liver regeneration at 24 hours. Consumption of ethanol was associated with a statistically significant reduction of liver regeneration by both criteria for up to 72 hours after a 70% hepatectomy and delayed the peak of regenerative activity by 24 hours. This inhibiting effect was not related to the presence of alcohol in blood nor to hepatic microsomal enzyme induction by ethanol nor to widespread necrosis of hepatocytes. This effect was reversible after one week of abstinence. This impairment of liver cell renewal by ethanol may be of major significance in the severity and outcome of alcohol-related liver injury.
Family size, infection and atopy: the first decade of the 'hygiene hypothesis'
Authors: D. Strachan
Journal: Thorax (2000)

Background.Declining family size is one factor that has been proposed to contribute to increasing asthma and hay fever prevalence, but its relative importance has not been quantified.Objective.Our purpose was to determine the change in asthma and hay fever prevalence that would be expected from the reduction in family size that has occurred in England/Wales and New Zealand over recent decades.Methods.The relative change in family size between 1961 and 1991 in England/Wales and New Zealand was determined from census data for these years.Summary weighted odds ratios were calculated for the associations among birth order, family size, and asthma and hay fever prevalence.The expected increase in the prevalence of asthma and hay fever between 1961 and 1991 resulting from changes in family size was then calculated.Results.The expected relative increase in the prevalence of asthma between 1961 and 1991 as a result of the smaller family size was 1% and 5% for England/ Wales and New Zealand, respectively; smaller family size would be expected to increase the prevalence of hay fever prevalence in England/Wales by 4%.Conclusions.Changes in family size over the last 30 years do not appear to explain much of the reported increase in asthma or hay fever prevalence.The contribution that other risk factors have made to these increases could be assessed with use of a similar approach.(
Irradiation decreases collagen type II synthesis and increases nitric oxide production and cell death in articular chondrocytes
Authors: J Ailland
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> When synovitis is proved, intra-articularly injected β emitting radionuclides like yttrium-90 (<sup>90</sup>Y) are used to treat the inflamed synovium. <b>Objective:</b> To study the viability, matrix production, and NO production during or after <sup>90</sup>Y treatment of chondrocytes. <b>Methods:</b> Monolayer, alginate, and explant cultures of primary bovine articular chondrocytes as well as synoviocytes were incubated with 0–3 MBq <sup>90</sup>Y/ml medium for four days from culture day 3 onwards. Cell viability was demonstrated by light and electron microscopy or by trypan blue or ethidium bromide/fluorescein diacetate staining, membrane integrity by measurement of lactate dehydrogenase (LDH) activity in the culture supernatants. Biosynthetic activity was demonstrated by incorporation of [<sup>3</sup>H]proline and immunocytochemical staining of collagen type II. NO production was measured with the Griess reagent. <b>Results:</b> In chondrocyte and synoviocyte monolayer cultures radiation caused a dose dependent increase in cell death and membrane destruction within four days. In alginate and explant cultures, where proliferation is low, no significantly increased LDH activity was seen, and cell viability was ∼100% for up to 14 days after irradiation. Collagen type II expression (alginate) and biosynthetic activity (alginate and explants) were decreased dose dependently while there was an increase in NO production. Light and electron microscopy data showed that five weeks after irradiation all cells in alginate and most cells in explants subjected to 3 MBq <sup>90</sup>Y/ml were dead, whereas after lower amounts of irradiation several morphologically intact cells were found. <b>Conclusions:</b> β Irradiation may influence the long term maintenance of cartilage tissue or the aetiology of degenerative joint diseases.
Studies on the pathogenesis of acute inflammation
Authors: Sterling K. Ainsworth, Fred Allison
Journal: Journal of Clinical Investigation (1970)

The inflammatory reaction induced in ear chambers of rabbits by heat injury was studied in nondiabetic animals made hyperglycemic with continuous infusions of glucose. Hypertonic solutions of glucose administered intravenously to rabbits induced the following triad: hyperglycemia, hyperosmolality, and metabolic lactic acidosis. It was found that relatively short periods of this metabolic abnormality were associated with a significant reduction in the intensity of the inflammatory reaction. There was no evidence microscopically of circulatory impairment within ear chambers; and since neither arterial hypotension nor oxygen deficit was recorded during experiments, it appeared most likely that decreased leucocytic margination per se best explained the inhibited exudative response. Hyperglycemia seemed the dominant factor responsible for this anti-inflammatory effect. It was found subsequently that hyperglycemia and hyperosmolality without metabolic acidosis impaired cellular exudation just as well.
The Mechanism by Which Epinastine Stops an Adenosine Analog from Contracting BDE Rat Airways
Authors: CHRISTOPHER J. MEADE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Epinastine is an antihistamine and antiallergic drug. The object of this work was to use a rat model of noncholinergic bronchospasm to identify novel nonantihistamine mechanisms that might contribute to the efficacy of this drug in asthma. Oral epinastine blocked bronchospasm (increase in RL) in BDE rats induced by the adenosine A3 receptor agonist N6-2-(4-aminophenyl)ethyladenosine with an ED50 of only 0.47 mg/kg. An intravenous dose of 10 microg/kg epinastine was also effective. In vitro, epinastine bound 5-HT2a, 5-HT7, and 5-HT3 receptors (Ki values, respectively, 21, 33, and 159 nM). In the in vivo rat model, 5-HT2a antagonist ketanserin, 5-HT7 agonist 5-carboxamidotryptamine, and (to a limited extent) 5-HT3 antagonist ondansetron could all, like epinastine, block bronchospasm, but the "classic" antihistamine chlorpheniramine was ineffective. Epinastine could not block bronchospasm in the presence of 1 mg/kg NK2 receptor antagonist L 659877 or 20 microg/kg potassium channel blocker iberiotoxin, suggesting the epinastine was acting on a neurokinin- and potassium channel-mediated mechanism. Epinastine has other modes of action apart from its antihistamine activity that may be relevant to its use in asthma.
Glyceryl Trinitrate Patches as an Alternative to Isosorbide Dinitrate Spray in the Treatment of Chronic Painful Diabetic Neuropathy
Authors: Gerry Rayman, Neil R. Baker, Singhan T.M. Krishnan
Journal: Diabetes Care (2003)

In the October 2002 issue of Diabetes Care , we reported (1) the benefit of isosorbide dinitrate (ISDN) in the treatment of painful diabetic neuropathy. This stance was based on the speculation that the impaired nitric oxide (NO) generation might play a role in the pathogenesis of neuropathic pain through defects in local vasodilatation. This was a double-blind, randomized, placebo-controlled, two-period, crossover design study of 22 diabetic patients. The ISDN spray reduced overall neuropathic pain ( P = 0.02) and burning sensation ( P = 0.006). Fifty percent of the patients reported improvement in their quality of life and wanted to continue the ISDN spray. Since then, this publication has received considerable interest, with numerous inquiries from clinicians and …
Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs
Authors: Akio Hirata, Tetsuo Minamino, Hiroshi Asanuma, Masashi Fujita, Masakatsu Wakeno, Masafumi Myoishi, Osamu Tsukamoto, Ken-ichiro Okada, Hidekazu Koyama, Kazuo Komamura, Seiji Takashima, Yoshiro Shinozaki, Hidezo Mori, Masamichi Shiraga, Masafumi Kitakaze, Masatsugu Hori
Journal: Journal of the American College of Cardiology (2006)
Comparison of One-, Two-, and Three-Dimensional Measurements of Childhood Brain Tumors
Authors: K E Warren, N Patronas, A A Aikin, P S Albert, F M Balis
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: End points for assessing drug activity in brain tumors are determined by measuring the change in tumor size by magnetic resonance imaging (MRI) relative to a pretreatment or best-response scan. Traditionally, two-dimensional (2D) tumor measurements have been used, but one-dimensional (1D) measurements have recently been proposed as an alternative. Because software to estimate three-dimensional (3D) tumor volume from digitized MRI images is available, we compared all three methods of tumor measurement for childhood brain tumors and clinical outcome. Methods: Tumor size from 130 MRI scans from 32 patients (32 baseline and 98 follow-up scans, for a total of 130 scans; median, three scans per patient; range, two to 18 scans) was measured by each method. Tumor-response category (partial response, minor response, stable disease, or progressive disease) was determined from the percentage change in tumor size between the baseline or best-response scan and follow-up scans. Time to clinical progression was independently determined by chart review. All statistical tests were two-sided. Results: Concordances between 1D and 2D, 1D and 3D, and 2D and 3D were 83% (95% confidence interval [CI] = 67% to 99%), 61% (95% CI = 47% to 75%), and 66% (95% CI = 52% to 80%), respectively, on follow-up scans. Concordances for 1D and 3D and for 2D and 3D were statistically significantly lower than the concordance for 1D and 2D (P<.001 and P = .003, respectively). Concordance among 1D, 2D, and 3D methods in detecting partial response was high; there was less concordance in classifying tumors in the minor response and progressive-disease categories. Median times to progression measured by the 1D, 2D, and 3D methods were 154, 105, and 112 days, respectively, compared with 114 days based on neurologic symptoms and signs (P = .09 for overall comparison). Conclusions: Detection of partial responses was not influenced by the measurement method, but estimating time to disease progression may be method dependent for childhood brain tumors.
Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&amp;MPNr-EuroNet (COST action BM0902) study
Authors: J V Jovanovic, A Ivey, A M Vannucchi, E Lippert, E Oppliger Leibundgut, B Cassinat, N Pallisgaard, N Maroc, S Hermouet, G Nickless, P Guglielmelli, B A van der Reijden, J H Jansen, T Alpermann, S Schnittger, A Bench, K Tobal, B Wilkins, K Cuthill, D McLornan, K Yeoman, S Akiki, J Bryon, S Jeffries, A Jones, M J Percy, S Schwemmers, A Gruender, T W Kelley, S Reading, A Pancrazzi, M F McMullin, H L Pahl, N C P Cross, C N Harrison, J T Prchal, C Chomienne, J J Kiladjian, T Barbui, D Grimwade
Journal: Leukemia (2013)

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21 500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6–85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.
Phase II trial of a complex polyriboinosinic-polyribocytidylic acid with poly-L-lysine and carboxymethyl cellulose in the treatment of children with acute leukemia and neuroblastoma: a report from the Children's Cancer Study Group.
Authors: Beatrice C. Lampkin, Arthur S. Levine, Hilton Levy, William Krivit, Denman Hammond
Journal: Cancer Research (1985)

Therapeutic efficacy and toxicity were evaluated in 28 children with acute lymphoblastic leukemia, in ten with acute nonlymphoblastic leukemia (ANLL), and in 13 with metastatic neuroblastoma. All were refractory to standard chemotherapeutic agents and 25 were refractory to an investigational drug. The initial dose was 12 mg/m2/day and was based on an established maximal dose tolerated in adults. This dose was found to be intolerable in 5 of 5 children with leukemia. Similarly an initial dose of 9 mg/m2/day was intolerable in 4 of 5 patients with leukemia. The starting dose in the next 28 children with leukemia or neuroblastoma was 3 mg/m2. This drug was gradually increased to the highest tolerated dose by 3-mg/m2 increments. Fifteen children with acute lymphoblastic leukemia, 3 children with ANLL, and 2 children with neuroblastoma received the drug daily. Seven patients with ANLL and 7 patients with neuroblastoma received the drug biweekly. Seventeen patients with acute lymphoblastic leukemia, 6 patients with ANLL, and 5 patients with neuroblastoma had an adequate trial of the drug. An adequate trial was defined as a minimum of 5 weeks of therapy unless progressive disease developed. Side effects of the drug were striking and included fever, hypotension, myalgia, bone pain, arthralgia, arthritis, abdominal pain, liver toxicity, thrombocytopenia, and neurotoxicity. No complete remission occurred although interferon levels above 100 units/ml were induced in nearly 50% of the patients.
The <i>DOT1L</i> rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males
Authors: Evangelos Evangelou, Ana M Valdes, Martha C Castano-Betancourt, M Doherty, Sally Doherty, Tonu Esko, Thorvaldur Ingvarsson, John P A Ioannidis, Margreet Kloppenburg, Andres Metspalu, Evangelia E Ntzani, Kalliope Panoutsopoulou, P Eline Slagboom, Lorraine Southam, Tim D Spector, Unnur Styrkarsdottir, Kari Stefanson, André G Uitterlinden, Margaret Wheeler, Eleftheria Zeggini, Ingrid Meulenbelt, Joyce B van Meurs
Journal: Annals of the Rheumatic Diseases (2013)

Osteoarthritis (OA) of the hip is a major cause of pain, disability and use of healthcare resources.1 Although OA is multifactorial, it is known to have significant genetic contribution and a number of studies have attempted to dissect such contribution (see2 for review).

The DOT1L gene encodes the DOT1-like histone H3 methyltransferaseis, a potentially dedicated enzyme for Wnt target gene activation in leukaemia recently shown to be associated with endochondral bone formation.3

A polymorphism (rs12982744) in DOT1L has been found to be strongly associated with minimum joint space width (minJSW) at the hip. This exact same single nucleotide polymorphism (SNP) was previously identified to be associated with increased height.4 ,5 The C allele associated with lower minJSW and lower height was associated with hip OA, although this association did not reach genome-wide significance (GWS) (OR 1.14, CI 1.06 to 1.22; p=1.5  ×  10−4).3

The GWS level of p<5×10−8 is the threshold at which genetic associations are considered credible.6 The aim of our study was to prove that common genetic variation in the DOT1L gene is important …