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Sample records for growth inhibitors substances

  1. A Review of Plant Growth Substances

    Directory of Open Access Journals (Sweden)

    D.A. Agboola

    2014-10-01

    Full Text Available Plant growth substances are compounds, either natural or synthetic that modifies or controls through physiological action, the growth and maturation of plants. If the compound is produced within the plant, it is called a plant hormone or phytohormone. In general, it is accepted that there are five major classes of plant hormones. They are Auxins (IAA, Cytokinins, Gibberellins, Ethylene and Abscisic Acid. However, there are still many plant growth substances that cannot be grouped under these classes, though they also perform similar functions, inhibiting or promoting plant growth. These substances include Brassinosteroids (Brassins, Salicylic Acid, Jasmonic Acid, Fusicoccin, Batasins, Strigolactones, Growth stimulants (e.g. Hymexazol and Pyripropanol, Defoliants (e.g. Calcium Cyanamide, Dimethipin. Researchers are still working on the biosynthetic pathways of some of these substances. Plant growth substances are very useful in agriculture in both low and high concentrations. They affect seed growth, time of flowering, the sex of flowers, senescence of leaves and fruits, leaf formation, stem growth, fruit development and ripening, plant longevity, and even plant death. Some synthetic regulators are also used as herbicides and pesticides. Therefore, attention should be paid to the production and synthesis of these substances so that they affect plants in a way that would favour yield.

  2. DMPD: Endogenous anti-inflammatory substances, inter-alpha-inhibitor and bikunin. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17132099 Endogenous anti-inflammatory substances, inter-alpha-inhibitor and bikunin.... Kobayashi H. Biol Chem. 2006 Dec;387(12):1545-9. (.png) (.svg) (.html) (.csml) Show Endogenous anti-inflam...matory substances, inter-alpha-inhibitor and bikunin. PubmedID 17132099 Title Endogenous anti-inflammatory s

  3. Aromatase inhibitor (anastrozole) affects growth of endometrioma cells in culture.

    Science.gov (United States)

    Badawy, Shawky Z A; Brown, Shereene; Kaufman, Lydia; Wojtowycz, Martha A

    2015-05-01

    To study the effects of aromatase inhibitor (anastrozole) on the growth and estradiol secretion of endometrioma cells in culture. Endometrioma cells are grown in vitro until maximum growth before used in this study. This was done in the research laboratory for tissue culture, in an academic hospital. Testosterone at a concentration of 10 μg/mL was added as a substrate for the intracellular aromatase. In addition, aromatase inhibitor was added at a concentration of 200 and 300 μg/mL. The effect on cell growth and estradiol secretion is evaluated using Student's t-test. The use of testosterone increased estradiol secretion by endometrioma cells in culture. The use of aromatase inhibitor significantly inhibited the growth of endometrioma cells, and estradiol secretion. Aromatase inhibitor (anastrozole) may be an effective treatment for endometriosis due to inhibition of cellular aromatase. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Algal growth inhibition test results of 425 organic chemical substances

    DEFF Research Database (Denmark)

    Kusk, Kresten Ole; Christensen, Anne Munch; Nyholm, Niels

    2018-01-01

    The toxicity towards the algal species Pseudokirchneriella subcapitata of 425 organic chemical substances was tested in a growth inhibition test. Precautions were taken to prevent loss of the compounds from the water phase and the test system (closed test system, low biomass, shorter test duration......, silanized glass) and to keep pH constant by applying a higher alkalinity. Chemical phase distribution was modelled taking ionization, volatilisation, and adsorption to glass and biomass into consideration. If the modelled water concentration was below 90% of the nominal concentration the calculated EC...... values were corrected accordingly. The model helped to identify substances, where the calculated water concentration was too uncertain. Substances covering a wide range of physical-chemical properties and different modes of action were tested. Median effect concentrations (EC50) lower than 1000 mg/L were...

  5. Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Rudolf K F Beran

    Full Text Available During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA and heat-shock protein 90 (HSP90 which have each been reported to inhibit replication of hepatitis C virus (HCV. By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino-17-demethoxygeldanamycin (17-AAG to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA, exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

  6. Hepatocyte growth factor inhibitor-2 prevents shedding of matritpase

    DEFF Research Database (Denmark)

    Larsen, Brian R; Steffensen, Simon D; Nielsen, Nis V L

    2013-01-01

    Hepatocyte growth factor activator inhibitor-2 (HAI-2) is an inhibitor of many proteases in vitro, including the membrane-bound serine protease, matriptase. Studies of knock-out mice have shown that HAI-2 is essential for placental development only in mice expressing matriptase, suggesting that HAI......-2 is important for regulation of matriptase. Previous studies have shown that recombinant expression of matriptase was unsuccessful unless co-expressed with another HAI, HAI-1. In the present study we show that when human matriptase is recombinantly expressed alone in the canine cell line MDCK......, then human matriptase mRNA can be detected and the human matriptase ectodomain is shed to the media, suggesting that matriptase expressed alone is rapidly transported through the secretory pathway and shed. Whereas matriptase expressed together with HAI-1 or HAI-2 accumulates on the plasma membrane where...

  7. Mullerian Inhibiting Substance (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2004-01-01

    Mullerian Inhibiting Substance (MIS), a member of the TGFB family regulates growth, differentiation, and apoptosis in many cell types In the male embryo, MIS causes regression of the Mullerian duct...

  8. Use of cluster rhenium substances with alkyl ligands for inhibition of the Guerin carcinoma Growth

    Directory of Open Access Journals (Sweden)

    O. S. Voronkova

    2007-04-01

    Full Text Available Quantity and quality of erythrocytes, blood haemoglobin concentration, glucose levels in the erythrocytes and plasma, content of TBA-active products in blood plasma of rats were studied during development of the Guerin carcinoma, introduction of cis-platinum and cluster rhenium substances with organic ligands. It was shown that rhenium substances had essential antioxidant effects and changed the dynamic of tumour growth. The conclusion on perspectiveness of further investigations of rhenium substances with cluster fragment and organic ligands in experiments in vivo with changed redox-status of an organism was drawn.

  9. The use of Citrus tissue culture for mutation breeding. Effects of plant growth substances and gamma irradiation on embryogenesis

    International Nuclear Information System (INIS)

    Kochba, J.; Spiegel-Roy, P.

    1976-01-01

    An embryogenic callus subcultured from unfertilized ovules of the 'Shamouti' orange (Citrus sinensis) was established and is used for mutation-breeding. The callus is habituated and lines of differing embryogenic potential were established. The effect of growth substances and of gamma-irradiation on embryogenesis were studied. Auxins and cytokinins inhibited embryogenesis while inhibitors of auxin synthesis and a cytokinin antagonist significantly stimulate embryogenesis in an embryogenic line. A non-embryogenic callus line did not respond to these treatments. Stimulation of embryogenesis was observed when callus but not when the medium was irradiated. Age of callus prior to subculture and irradiation intensities modify irradiation induced embryogenesis by changing optimal dose range and radiosensitivity of the callus. Addition of IAA to unirradiated medium resulted in increased embryogenesis and greatly stimulated plantlet development in certain combinations of irradiation dose and IAA concentration. (author)

  10. Effect of ketoconazole in combination with other inhibitors of sterol synthesis on fungal growth.

    OpenAIRE

    Sud, I J; Feingold, D S

    1985-01-01

    The effect of combination of ketoconazole with other sterol synthesis inhibitors on fungal growth was tested against a variety of fungi selected for resistance to ketoconazole. All of the sterol inhibitors, at concentrations lower than their MICs, caused an increase greater than fourfold in the ketoconazole susceptibility of some fungi. Some of the sterol synthesis inhibitors showed this effect with ketoconazole at levels that may be achieved clinically.

  11. HELICOBACTER PYLORI GROWTH INHIBITION BY SUBSTANCE PRODUCED PSEUDOMONAS BY AEROGINOSA: IN VTRO STUDY

    Directory of Open Access Journals (Sweden)

    A FAZELI

    2003-03-01

    Full Text Available Resistance of H.pylori against metronidazole is increasingly appeared in reports of investigators of gastric infections. So that, seeking to find more effective anti-helicobacter drugs is a necessity. In this study, inhibitory effect of the P. aeroginosa-produced substance on H. pylori growth was determined using two methods, Cross-streak and Well-diffusion Only two out of 37 P. aeroginosa isalates were able to inhibit H. pylori growth which one of them was chosen for further investigation. Its antibacterial activity was tested on 31 isolates of H. pylori consisting 27 metrondazole-sensitive and 4 metronidazole-resistant isolates. The inhibitory substance was enable to kill both metrondazole-sensitive and resistant isolates of H. pylori. The substance could also inhibit the of several other bacteria including E.coli, Salmonella sp., Klebsiella sp., S. aureus and a gram positive bacilli. While the inhibitory effect of the substance had no change at 40c for 30 days, its effect substantially reduced by treating at 600c for 15 minutes. Treatment of substance at 600c (30 min. 80?c and 100?c (15 & 30min, and freezing (-20?c and melting (37?c inactivated its inhibitory effect completely. Treatment with trips in also could inactivate it. Thus P. aeroginosa-produced substance, probably is a protein and may be classified in bacteriocin group.

  12. Response of pine hypocotyl sections to growth regulators and related substances

    Directory of Open Access Journals (Sweden)

    J. Zakrzewski

    2015-01-01

    Full Text Available Growth response of Pinus silvestris hypocotyl sections to some synthetic growth regulators and related substances was studied. Elongation of hypocotyl sections was stimulated by naphtaleneacetic acid, indole-3-acetic acid, in-dole-3-propionic acid, indole-3-butyric acid, 2,4-dichlorophenoxyacetic acid, indoleaoetic amide, indoleacetic nitrile and coumarin. Indole-3-acetic acid and naphtaleneacetic acid extended period of growth up to 16 and 24 hours, respectively. Growth was inhibited by kinetin, trans-cinnamic acid and 2,3,5-tri-iodobenzoic acid. No effect of gibberellic acid, tryptophan and biotin was observed.

  13. Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors

    International Nuclear Information System (INIS)

    Amin, Oreekha; Beauchamp, Marie-Claude; Nader, Paul Abou; Laskov, Ido; Iqbal, Sanaa; Philip, Charles-André; Yasmeen, Amber; Gotlieb, Walter H.

    2015-01-01

    Impairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer. Tumors with BRCA1 mutations show increased expression of the Insulin-like growth factor type 1 receptor (IGF-1R). We previously have shown that inhibition of IGF-1R results in growth inhibition and apoptosis of ovarian tumor cells. In the current study, we aimed to investigate the correlation between HR and sensitivity to IGF-1R inhibition. Further, we hypothesized that IGF-1R inhibition might sensitize HR proficient cancers to Poly ADP ribose polymerase (PARP) inhibitors. Using ovarian and breast cancer cellular models with known BRCA1 status, we evaluated their HR functionality by RAD51 foci formation assay. The 50 % lethal concentration (LC50) of Insulin-like growth factor type 1 receptor kinase inhibitor (IGF-1Rki) in these cells was assessed, and western immunoblotting was performed to determine the expression of proteins involved in the IGF-1R pathway. Moreover, IGF-1R inhibitors were added on HR proficient cell lines to assess mRNA and protein expression of RAD51 by qPCR and western blot. Also, we explored the interaction between RAD51 and Insulin receptor substance 1 (IRS-1) by immunoprecipitation. Next, combination effect of IGF-1R and PARP inhibitors was evaluated by clonogenic assay. Cells with mutated/methylated BRCA1 showed an impaired HR function, and had an overactivation of the IGF-1R pathway. These cells were more sensitive to IGF-1R inhibition compared to HR proficient cells. In addition, the IGF-IR inhibitor reduced RAD51 expression at mRNA and protein levels in HR proficient cells, and sensitized these cells to PARP inhibitor. Targeting IGF-1R might lead to improved personalized therapeutic approaches in cancer patients with HR deficiency. Targeting both PARP and IGF-1R might increase the clinical efficacy in HR deficient patients and increase the population of patients who may benefit from PARP inhibitors

  14. 15. international conference on plant growth substances: Program -- Abstracts

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-12-31

    Since the 14th Conference in Amsterdam in 1991, progress in plant hormone research and developmental plant biology has been truly astonishing. The five ``classical`` plant hormones, auxin, gibberellin, cytokinin, ethylene, and abscisic acid, have been joined by a number of new signal molecules, e.g., systemin, jasmonic acid, salicylic acid, whose biosynthesis and functions are being understood in ever greater detail. Molecular genetics has opened new vistas in an understanding of transduction pathways that regulate developmental processes in response to hormonal and environmental signals. The program of the 15th Conference includes accounts of this progress and brings together scientists whose work focuses on physiological, biochemical, and chemical aspects of plant growth regulation. This volume contains the abstracts of papers presented at this conference.

  15. The effect of humic substances on germination and early growth of Lamb's Quarters (Chenopodium album agg.)

    Czech Academy of Sciences Publication Activity Database

    Šerá, Božena; Novák, František

    2011-01-01

    Roč. 66, č. 3 (2011), s. 470-476 ISSN 0006-3088 Institutional research plan: CEZ:AV0Z60870520; CEZ:AV0Z60660521 Keywords : Chenopodium album * growth stimulation * humic substance * lignite * seed germination Subject RIV: EH - Ecology, Behaviour Impact factor: 0.557, year: 2011

  16. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  17. Latent growth trajectories of substance use among pregnant and parenting adolescents.

    Science.gov (United States)

    Spears, Gwendolyn V; Stein, Judith A; Koniak-Griffin, Deborah

    2010-06-01

    We examine changes among adolescent girls in substance use during pregnancy and the postpartum period. Three separate latent growth curve analyses assessed the impact of psychosocial, behavioral, and sociodemographic factors on resumption of or change in use of cigarettes, alcohol, and marijuana. The Vulnerable Populations Model for Research and Clinical Practice (Flaskerud & Winslow, 1998) provided the theoretical foundation for this study. This is a secondary analysis of data from a sample of 305 ethnic minority females (245 Latina, 60 African American), aged 13-18 years, who were pregnant at baseline and were participating in an HIV prevention study conducted in inner-city alternative schools in Los Angeles County. Data collected at 4 time points captured changes in substance use from pregnancy through the postpartum period. Baseline predictors included ethnicity/race, partner substance use, childhood abuse history, religiosity, acculturation, depressive symptoms, length of gestation at baseline, and previous substance use. Common predictors of greater resumption and/or greater level of use included greater history of use before pregnancy, partner substance use, childhood abuse, and a longer time since childbirth. African Americans were more likely to be smoking at baseline when they were still pregnant and to use marijuana postpartum; Latinas were more likely to use alcohol over the course of pregnancy and postpartum. Other variables exerted an influence on specific substances. For instance, religiosity impacted cigarette and alcohol use. Findings may assist prenatal care providers to identify and counsel pregnant adolescents at risk for perinatal substance use and to prevent resumption or initiation of substance use after childbirth. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

  18. Mixture and single-substance toxicity of selective serotonin reuptake inhibitors toward algae and crustaceans

    DEFF Research Database (Denmark)

    Christensen, Anne Munch; Faaborg-Andersen, S.; Ingerslev, Flemming

    2007-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressant medications. primarily in the treatment of clinical depression. They are among the pharmaceuticals most often Prescribed in the industrialized countries. Selective serotonin reuptake inhibitors are compounds with an identi......Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressant medications. primarily in the treatment of clinical depression. They are among the pharmaceuticals most often Prescribed in the industrialized countries. Selective serotonin reuptake inhibitors are compounds...... with an identical mechanism of action in mammals (inhibit reuptake of serotonin), and they have been found in different aqeous as well as biological samples collected in the environment. In the present study, we tested the toxicities of five SSRIs (citalopram, fluoxetine, fluoxamine, paroxetine, and sertraline.......027 to 1.6 mg/L, and in daphnids, test EC50s ranged from 0.92 to 20 mg/L, with sertraline being one of the most toxic compounds. The test design and statistical analysis of results from mixture tests were based on isobole analysis. It was demonstrated that the mixture toxicity of the SSRIs in the two...

  19. Potentially hazardous substances in surface waters. II. Cholinesterase inhibitors in Dutch surface waters

    NARCIS (Netherlands)

    Greve, P.A.; Freudenthal, J.; Wit, S.L.

    1972-01-01

    Several analytical methods were employed to determine the concentrations of cholinesterase inhibitors in several Dutch surface waters. An Auto-Analyzer method was used for screening purposes; thin-layer chromatography and gas-liquid chromatography-mass spectrometry were used for identification and

  20. Parent Prevention Communication Profiles and Adolescent Substance Use: A Latent Profile Analysis and Growth Curve Model

    Science.gov (United States)

    Choi, Hye Jeong; Miller-Day, Michelle; Shin, YoungJu; Hecht, Michael L.; Pettigrew, Jonathan; Krieger, Janice L.; Lee, JeongKyu; Graham, John W.

    2017-01-01

    This current study identifies distinct parent prevention communication profiles and examines whether youth with different parental communication profiles have varying substance use trajectories over time. Eleven schools in two rural school districts in the Midwestern United States were selected, and 784 students were surveyed at three time points from the beginning of 7th grade to the end of 8th grade. A series of latent profile analyses were performed to identify discrete profiles/subgroups of substance-specific prevention communication (SSPC). The results revealed a 4-profile model of SSPC: Active-Open, Passive-Open, Active-Silent, and Passive-Silent. A growth curve model revealed different rates of lifetime substance use depending on the youth’s SSPC profile. These findings have implications for parenting interventions and tailoring messages for parents to fit specific SSPC profiles. PMID:29056872

  1. Effect of fermentation inhibitors in the presence and absence of activated charcoal on the growth of Saccharomyces cerevisiae.

    Science.gov (United States)

    Kim, Sung-Koo; Park, Don-Hee; Song, Se Hee; Wee, Young-Jung; Jeong, Gwi-Taek

    2013-06-01

    The acidic hydrolysis of biomass generates numerous inhibitors of fermentation, which adversely affect cell growth and metabolism. The goal of the present study was to determine the effects of fermentation inhibitors on growth and glucose consumption by Saccharomyces cerevisiae. We also conducted in situ adsorption during cell cultivation in synthetic broth containing fermentation inhibitors. In order to evaluate the effect of in situ adsorption on cell growth, five inhibitors, namely 5-hydroxymethylfurfural, levulinic acid, furfural, formic acid, and acetic acid, were introduced into synthetic broth. The existence of fermentation inhibitors during cell culture adversely affects cell growth and sugar consumption. Furfural, formic acid, and acetic acid were the most potent inhibitors in our culture system. The in situ adsorption of inhibitors by the addition of activated charcoal to the synthetic broth increased cell growth and sugar consumption. Our results indicate that detoxification of fermentation media by in situ adsorption may be useful for enhancing biofuel production.

  2. Soilless plant growth media influence the efficacy of phytohormones and phytohormone inhibitors.

    Science.gov (United States)

    Best, Norman B; Hartwig, Thomas; Budka, Joshua S; Bishop, Brandon J; Brown, Elliot; Potluri, Devi P V; Cooper, Bruce R; Premachandra, Gnanasiri S; Johnston, Cliff T; Schulz, Burkhard

    2014-01-01

    Plant growth regulators, such as hormones and their respective biosynthesis inhibitors, are effective tools to elucidate the physiological function of phytohormones in plants. A problem of chemical treatments, however, is the potential for interaction of the active compound with the growth media substrate. We studied the interaction and efficacy of propiconazole, a potent and specific inhibitor of brassinosteroid biosynthesis, with common soilless greenhouse growth media for rice, sorghum, and maize. Many of the tested growth media interacted with propiconazole reducing its efficacy up to a hundred fold. To determine the molecular interaction of inhibitors with media substrates, Fourier Transform Infrared Spectroscopy and sorption isotherm analysis was applied. While mica clay substrates absorbed up to 1.3 mg of propiconazole per g substrate, calcined clays bound up to 12 mg of propiconazole per g substrate. The efficacy of the gibberellic acid biosynthesis inhibitor, uniconazole, and the most active brassinosteroid, brassinolide, was impacted similarly by the respective substrates. Conversely, gibberellic acid showed no distinct growth response in different media. Our results suggest that the reduction in efficacy of propiconazole, uniconazole, and brassinolide in bioassays when grown in calcined clay is caused by hydrophobic interactions between the plant growth regulators and the growth media. This was further confirmed by experiments using methanol-water solvent mixes with higher hydrophobicity values, which reduce the interaction of propiconazole and calcined clay.

  3. Short Stature in Chronic Kidney Disease Treated with Growth Hormone and an Aromatase Inhibitor

    OpenAIRE

    Mendley, Susan R.; Spyropoulos, Fotios; Counts, Debra R.

    2015-01-01

    We describe an alternative strategy for management of severe growth failure in a 14-year-old child who presented with advanced chronic kidney disease close to puberty. The patient was initially treated with growth hormone for a year until kidney transplantation, followed immediately by a year-long course of an aromatase inhibitor, anastrozole, to prevent epiphyseal fusion and prolong the period of linear growth. Outcome was excellent, with successful transplant and anticipated complete correc...

  4. [The significance of vaginal fluid substances as growth media in genital mycosis].

    Science.gov (United States)

    Neumann, G; Gartzke, J; Böhme, H; Spitzbart, H

    1984-01-01

    By means of thin layer chromatography amino acids, lipids and phospholipids were detected in the vaginal fluids of pregnant and nonpregnant women with and without vaginal yeast colonization. Though pregnancy and/or yeast colonization do not seem to alter qualitatively the spectrum of amino acids and lipids of the vaginal fluid, an influence is supposed of these substances - like that of glucose - on growth and metabolism of the yeasts and on the clinical manifestation of vaginal candidosis.

  5. EFFECT OF HUMIC SUBSTANCES AND PROBIOTICS ON GROWTH PERFORMANCE AND MEAT QUALITY OF RABBITS

    Directory of Open Access Journals (Sweden)

    Vladimír Parkányi

    2012-04-01

    Full Text Available Normal 0 21 false false false MicrosoftInternetExplorer4  The aim of this work was determined effect of supplemental humic substances and probiotics on growth performance and meat quality of rabbits.  The growth performances were observed on two hundred and twelve growing rabbits assigned randomly by weight to two treatments. The treatments included: 1 Control group: in this group were rabbits fed with basal diet during all experiment (35th – 77th day, 2 experimental group: the animals were fed with basal diet+3kg/t humic substances – Humac Nature during whole experiment.  In this group was during fattening period (35th – 49th and 63rd – 70th days of age added to feed the probiotic preparation – Propoul (Lactobacillus fermentum CCM 7158 1x108 CFU 2 g per ten pieces. Body weight and feed intake were measured weekly in order to determine the average daily gain, average daily feed intake and gain/feed. The characteristics of meat quality were determined on twelve rabbit males at the age of 77 days, when the rabbits achieved average slaughter weight 2500g. Results of the whole experimental period showed that addition humic substances and probiotic preparation to the diet had positive effect (not significantly on intensity of growth live weight in the last phase of fattening period. The results of this study suggest that humic substances with probiotics might be utilized as a feed additive in the rabbit diet. It could not significantly improve growth performance and meat quality of rabbits.doi:10.5219/192 

  6. THE EFFECT OF FORMULATION HUMIC SUBSTANCE AND Trichoderma sp TO INCREASE PRODUCTION AND GROWTH OF CORN (Zea Mays,L

    Directory of Open Access Journals (Sweden)

    Ruly Eko Kusuma Kurniawan

    2017-06-01

    Full Text Available Research to determine of formulation humic subtance and Trichoderma sp to increase the production and growth of corn (zea mays,L. This research was conducted by extracting humic substance with fractionation organic matter method from cattle manure organic material. Trichoderma sp grow on corn medium and harvested after reaching a density of 1015 cfu. Created this compound formulation with mixing humic substance and Trichoderma sp. Indicator plant with F1 sweet corn Jago varieties. Aplication used humic substance in range 8%, 16%, and 32% on the recommended use NPK fertilizer for corn, as well as control without humic substance. The result showed application use 8% humic substance most good for plant growth and harvest. Additionally, nutrient uptake NPK fertilizer efficiency is increased and more effective than control and use of the formulation 16% and 32% humic substance.

  7. Suppression of elongation and growth of tomato seedlings by auxin biosynthesis inhibitors and modeling of the growth and environmental response.

    Science.gov (United States)

    Higashide, Tadahisa; Narukawa, Megumi; Shimada, Yukihisa; Soeno, Kazuo

    2014-04-02

    To develop a growth inhibitor, the effects of auxin inhibitors were investigated. Application of 30 μM L-α-aminooxy-β-phenylpropionic acid (AOPP) or (S)-methyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanoate (KOK1101), decreased the endogenous IAA levels in tomato seedlings at 8 days after sowing. Then, 10-1200 μM AOPP or KOK1101 were sprayed on the leaves and stem of 2-3 leaf stage tomato plants grown under a range of environmental conditions. We predicted plant growth and environmental response using a model based on the observed suppression of leaf enlargement. Spraying AOPP or KOK1101 decreased stem length and leaf area. Concentration-dependent inhibitions and dose response curves were observed. Although the effects of the inhibitors on dry weight varied according to the environmental conditions, the net assimilation rate was not influenced by the inhibitors. Accordingly, the observed decrease in dry weight caused by the inhibitors may result from decreased leaf area. Validation of the model based on observed data independent of the dataset showed good correlations between the observed and predicted values of dry weight and leaf area index.

  8. Pattern of growth and 14C-assimilates distributions in relation to photosynthesis in radish plants treated with growth substances

    Directory of Open Access Journals (Sweden)

    Z. Starck

    2015-01-01

    Full Text Available In a series of radish plants, with very thin hypocotyl and with a normal storage organ, the rates of photosynthesis, photorespiration and dark respiration did not differ. Therefore, the conclusion may be advanced, that translocation to the swollen hypocotyl is not determinated by the photosynthetic productivity, but rather the by storage capacity. To check it this is connected with an unbalanced hormonal content, plants were treated with lanoline paste, with IAA, GA3, zeatin and all three in mixture or with injections of GA3-water solution into the swollen hypocotyl. In young radish plants, with high rate of growth of aerial parts, treatment with the above mentioned substances stimulated 14CO2-assimilation and increased retention of assimilates in 14C-donors, probably owing to retardation of their senescence. It increased the competition for photosynthates between shoot and storage organ. In older plants, in the stage of accumulation of nutrients in the swollen hypocotyl, IAA +GA3+zeatin did not affect 14CO2-assimilation, but in plants treated with growth regulators separately, assimilation decreased; IAA and GA3 stimulated transport and accumulation of labelled substances in the swollen hypocotyl. On the basis of experimental data the conclusion may be advanced that responsiveness of the particular organs and processes to growth regulators depends on the stage of plant development. Phytohormone did not changed quantitatively the pattern of 14C-assimilates distribution. They stimulated processes with preference for particular stages of development.

  9. Comparison of Effect of Brassinosteroid and Gibberellin Biosynthesis Inhibitors on Growth of Rice Seedlings

    Directory of Open Access Journals (Sweden)

    Tadashi Matusmoto

    2016-01-01

    Full Text Available Brassinosteroid (BR and gibberellin (GA are two predominant plant hormones that regulate plant cell elongation. Mutants disrupt the biosynthesis of these hormones and display different degrees of dwarf phenotypes in rice. Although the role of each plant hormone in promoting the longitudinal growth of plants has been extensively studied using genetic methods, their relationship is still poorly understood. In this study, we used two specific inhibitors targeting BR and GA biosynthesis to investigate the roles of BR and GA in growth of rice seedlings. Yucaizol, a specific inhibitor of BR biosynthesis, and Trinexapac-ethyl, a commercially available inhibitor of GA biosynthesis, were used. The effect of Yucaizol on rice seedlings indicated that Yucaizol significantly retarded stem elongation. The IC50 value was found to be approximately 0.8 μmol/L. Yucaizol also induced small leaf angle phenocopy in rice seedlings, similarly to BR-deficient rice, while Trinexapac-ethyl did not. When Yucaizol combined with Trinexapac-ethyl was applied to the rice plants, the mixture of these two inhibitors retarded stem elongation of rice at lower doses. Our results suggest that the use of a BR biosynthesis inhibitor combined with a GA biosynthesis inhibitor may be useful in the development of new technologies for controlling rice plant height.

  10. Plant growth inhibitors isolated from sugarcane (Saccharum officinarum) straw.

    Science.gov (United States)

    Sampietro, Diego Alejandro; Vattuone, Marta Amelia; Isla, María Ines

    2006-07-01

    Several compounds related with plant defense and pharmacological activities have been isolated from sugarcane. Straw phytotoxins and their possible mechanisms of growth inhibition are largely unknown. A bioassay-guided fractionation of the phytotoxic constituents leachated from a sugarcane straw led to the isolation of trans-ferulic (trans-FA), cis-ferulic (cis-FA), vanillic (VA) and syringic (SA) acids. The straw leachates and their identified constituents significantly inhibited root growth of lettuce and four weeds. VA was more phytotoxic to root elongation than FA and SA. The identified phenolic compounds significantly increased leakage of root cell constituents, inhibited dehydrogenase activity and reduced chlorophyll content in lettuce. VA and FA inhibited mitotic index while SA increased cell division. Additive (VA-FA and FA-SA) and synergistic (VA-SA) interactions on root growth were observed at the response level of EC(25). Although the isolated compounds differed in their relative phytotoxic activities, the observed physiological responses suggest that they have a common mode of action. HPLC analysis indicated that sugarcane straw can potentially release 1.43 (ratio 2:1, trans:cis), 1.14 and 0.14mmolkg(-1) (straw dry weight) of FA, VA and SA, respectively. As phenolic acids are often found spatially concentrated in the top soil layers under plant straws, further studies are needed to establish the impact of these compounds in natural settings.

  11. Identification of a macromolecular crystal growth inhibitor in human urine as osteopontin

    DEFF Research Database (Denmark)

    Sørensen, Steen; Justesen, S J; Johnsen, A H

    1995-01-01

    , an unidentified protein rich in uronic acid, and uropontin have all been described as possessing such activity. We have recently isolated an unknown inhibitor of calcium oxalate crystal growth that co-eluted with trypsin inhibitor in several separation steps, which suggested its identity. The aim of the present......Macromolecules occurring in human urine inhibit the growth and/or aggregation of calcium oxalate crystals and may prevent the formation of kidney stones. Attention has focused particularly on proteins, as these seem to be most responsible for the inhibitory activity; three proteins, nephrocalcin...... study was to outline a simple procedure for isolating and identifying this inhibitor. Purification was done as follows: precipitation of the major proteins (albumin and uromucoid) with trichloroacetic acid, followed by anion exchange chromatography, hydroxyapatite chromatography, anion exchange...

  12. Effect of lignocellulose-derived inhibitors on growth and hydrogen production by Thermoanaerobacterium thermosaccharolyticum W16

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Guang-Li; Ren, Nan-Qi; Wang, Ai-Jie; Guo, Wan-Qian; Xu, Ji-Fei; Liu, Bing-Feng [State Key Lab of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090 (China)

    2010-12-15

    In the process of producing H{sub 2} from lignocellulosic materials, inhibitory compounds could be potentially formed during pre-treatment. This work experimentally investigated the effect of lignocellulose-derived inhibitors on growth and hydrogen production by Thermoanaerobacterium thermosaccharolyticum W16. Representative compounds presented in corn stover acid hydrolysate were added in various concentrations, individually or in various combinations and subsequently inhibitions on growth and H{sub 2} production were quantified. Acetate sodium was not inhibitory to T. thermosaccharolyticum W16, rather than it was stimulatory to the growth and H{sub 2} production. Alternatively, furfural, hydroxymethylfurfural (HMF), vanillin and syringaldehyde were potent inhibitors of growth and hydrogen production even though these compounds showed inhibitory effect depending on their concentrations. Synergistic inhibitory effects were exhibited in the introduction of combinations of inhibitors to the medium and in hydrolysate with concentrated inhibitors. Fermentation results from hydrolysates revealed that to increase the efficiency of this bioprocess from corn stover hydrolysate, the inhibitory compounds concentration must be reduced to the levels present in the raw hydrolysate. (author)

  13. Root growth of tomato seedlings intensified by humic substances from peat bogs

    Directory of Open Access Journals (Sweden)

    Alexandre Christofaro Silva

    2011-10-01

    Full Text Available Peats are an important reserve of humified carbon in terrestrial ecosystems. The interest in the use of humic substances as plant growth promoters is continuously increasing. The objective of this study was to evaluate the bioactivity of alkaline soluble humic substances (HS, humic (HA and fulvic acids (FA isolated from peats with different decomposition stages of organic matter (sapric, fibric and hemic in the Serra do Espinhaço Meridional, state of Minas Gerais. Dose-response curves were established for the number of lateral roots growing from the main plant axis of tomato seedlings. The bioactivity of HA was greatest (highest response in lateral roots at lowest concentration while FA did not intensify root growth. Both HS and HA stimulated root hair formation. At low concentrations, HS and HA induced root hair formation near the root cap, a typical hormonal imbalance effect in plants. Transgenic tomato with reporter gene DR5::GUS allowed the observation that the auxin-related signalling pathway was involved in root growth promotion by HA.

  14. Growth of bean and tomato plants as affected by root absorbed growth substances and atmospheric carbon dioxide

    Energy Technology Data Exchange (ETDEWEB)

    Tognoni, F; Halevy, A H; Wittwer, S H

    1967-01-01

    Bean and tomato plants were grown in solution culture root media containing pre-determined concentrations of gibberellin A/sub 3/ (GA), 1-naphthalene-acetic acid (NAA), N/sup 6/-benzyladenine (BA), (2-chloroethyl)trimethylammonium chloride (CCC), and at atmospheric levels of 300 and 1000 ppm of CO/sub 2/. Net assimilation rates (NAR), relative growth rates (RGR), leaf area ratios (LAR), root to top dry weight ratios (R/T) and changes in dry weight, size, and form of each organ were recorded. Gibberellin had no effect on RGR of either plant species but increased the NAR of tomatoes at 1000 ppm CO/sub 2/. Total dry weight was only slightly affected by GA but root growth and R/T were markedly depressed. CCC had no effect on NAR, but decreased RGR and LAR. Root growth of beans and R/T in both plants were promoted by CCC. NAR and RGR were strongly inhibited by BA and NAA. Inhibition of stem and leaf growth by CCC and NAA was greater than that for roots; thus, R/T ratios were increased. Root branching was promoted by NAA. High (1000 ppm), compared to the low (300 ppm), atmospheric levels of CO/sub 2/ generally promoted root growth and produced an increase in the R/T, both in the absence and presence of chemical treatment. The multiplicity of effects of the root-absorbed chemical growth substances and CO/sub 2/ on growth and photosynthesis is discussed.

  15. INVITED REVIEW: Inhibitors of myostatin as methods of enhancing muscle growth and development.

    Science.gov (United States)

    Chen, P R; Lee, K

    2016-08-01

    With the increasing demand for affordable, high-quality meat, livestock and poultry producers must continually find ways to maximize muscle growth in their animals without compromising palatability of the meat products. Muscle mass relies on myoblast proliferation during prenatal or prehatch stages and fiber hypertrophy through protein synthesis and nuclei donation by satellite cells after birth or hatch. Therefore, understanding the cellular and molecular mechanisms of myogenesis and muscle development is of great interest. Myostatin is a well-known negative regulator of muscle growth and development that inhibits proliferation and differentiation in myogenic cells as well as protein synthesis in existing muscle fibers. In this review, various inhibitors of myostatin activity or signaling are examined that may be used in animal agriculture for enhancing muscle growth. Myostatin inhibitors are relevant as potential therapies for muscle-wasting diseases and muscle weakness in humans and animals. Currently, there are no commercial myostatin inhibitors for agriculture or biomedical purposes because the safest and most effective option has yet to be identified. Further investigation of myostatin inhibitors and administration strategies may revolutionize animal production and the medical field.

  16. Short Stature in Chronic Kidney Disease Treated with Growth Hormone and an Aromatase Inhibitor

    Directory of Open Access Journals (Sweden)

    Susan R. Mendley

    2015-01-01

    Full Text Available We describe an alternative strategy for management of severe growth failure in a 14-year-old child who presented with advanced chronic kidney disease close to puberty. The patient was initially treated with growth hormone for a year until kidney transplantation, followed immediately by a year-long course of an aromatase inhibitor, anastrozole, to prevent epiphyseal fusion and prolong the period of linear growth. Outcome was excellent, with successful transplant and anticipated complete correction of height deficit. This strategy may be appropriate for children with chronic kidney disease and short stature who are in puberty.

  17. Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation.

    Science.gov (United States)

    Ikedo, Taichi; Minami, Manabu; Kataoka, Hiroharu; Hayashi, Kosuke; Nagata, Manabu; Fujikawa, Risako; Higuchi, Sei; Yasui, Mika; Aoki, Tomohiro; Fukuda, Miyuki; Yokode, Masayuki; Miyamoto, Susumu

    2017-06-19

    Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  18. Breast Cancer Prevention by Hormonally Induced Mammary Gland Differentiation: The Role of a Novel Mammary Growth Inhibitor and Differentiation Factor MRG

    National Research Council Canada - National Science Library

    Shi, Y

    2000-01-01

    We have previously identified and characterized a novel tumor growth inhibitor and a fatty acid binding protein in human mammary gland and named it as Mammary derived growth inhibitor Related Gene MRG...

  19. Omega-3 Fatty Acids and a Novel Mammary Derived Growth Inhibitor Fatty Acid Binding Protein MRG in Suppression of Mammary Tumor

    National Research Council Canada - National Science Library

    Liu, Yiliang

    2001-01-01

    We have previously identified and characterized a novel tumor growth inhibitor and a fatty acid binding protein in human mammary gland and named it as Mammary derived growth inhibitor Related Gene MRG...

  20. An isolate of Haemophilus haemolyticus produces a bacteriocin-like substance that inhibits the growth of nontypeable Haemophilus influenzae.

    Science.gov (United States)

    Latham, Roger D; Gell, David A; Fairbairn, Rory L; Lyons, A Bruce; Shukla, Shakti D; Cho, Kum Yin; Jones, David A; Harkness, Nick M; Tristram, Stephen G

    2017-04-01

    Nontypeable Haemophilus influenzae (NTHi) frequently colonises the upper respiratory tract and is an important cause of respiratory infections. Resistance to antibiotics is an emerging trend in NTHi and alternative prevention or treatment strategies are required. Haemophilus haemolyticus is a common commensal occupying the same niche as NTHi and, if able to produce substances that inhibit NTHi growth, may have a role as a probiotic. In this study, ammonium sulphate extracts from broth culture of 100 H. haemolyticus isolates were tested for the presence of substances inhibitory to NTHi using a well diffusion assay. One isolate produced a substance that consistently inhibited the growth of NTHi. The substance was inactivated by protease enzymes and had a molecular size of ca. 30 kDa as determined by size exclusion chromatography. When the substance was tested against bacteria from eight Gram-negative and three Gram-positive genera, only Haemophilus spp. were inhibited. Quantitative PCR testing showed the substance to be different to 'haemocin', the previously described bacteriocin of H. influenzae type b. These molecular characteristics, together with narrow-spectrum activity, suggest the substance may be a novel bacteriocin, and there is potential for this H. haemolyticus isolate to function as a probiotic for reduction of colonisation and subsequent infection with NTHi. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  1. Comparison of Effect of Brassinosteroid and Gibberellin Biosynthesis Inhibitors on Growth of Rice Seedlings

    OpenAIRE

    Matusmoto, Tadashi; Yamada, Kazuhiro; Yoshizawa, Yuko; Oh, Keimei

    2016-01-01

    Brassinosteroid (BR) and gibberellin (GA) are two predominant plant hormones that regulate plant cell elongation. Mutants disrupt the biosynthesis of these hormones and display different degrees of dwarf phenotypes in rice. Although the role of each plant hormone in promoting the longitudinal growth of plants has been extensively studied using genetic methods, their relationship is still poorly understood. In this study, we used two specific inhibitors targeting BR and GA biosynthesis to inve...

  2. Apyrase inhibitors enhance the ability of diverse fungicides to inhibit the growth of different plant-pathogenic fungi.

    Science.gov (United States)

    Kumar Tripathy, Manas; Weeraratne, Gayani; Clark, Greg; Roux, Stanley J

    2017-09-01

    A previous study has demonstrated that the treatment of Arabidopsis plants with chemical inhibitors of apyrase enzymes increases their sensitivity to herbicides. In this study, we found that the addition of the same or related apyrase inhibitors could potentiate the ability of different fungicides to inhibit the growth of five different pathogenic fungi in plate growth assays. The growth of all five fungi was partially inhibited by three commonly used fungicides: copper octanoate, myclobutanil and propiconazole. However, when these fungicides were individually tested in combination with any one of four different apyrase inhibitors (AI.1, AI.10, AI.13 or AI.15), their potency to inhibit the growth of five fungal pathogens was increased significantly relative to their application alone. The apyrase inhibitors were most effective in potentiating the ability of copper octanoate to inhibit fungal growth, and least effective in combination with propiconazole. Among the five pathogens assayed, that most sensitive to the fungicide-potentiating effects of the inhibitors was Sclerotinia sclerotiorum. Overall, among the 60 treatment combinations tested (five pathogens, four apyrase inhibitors, three fungicides), the addition of apyrase inhibitors increased significantly the sensitivity of fungi to the fungicide treatments in 53 of the combinations. Consistent with their predicted mode of action, inhibitors AI.1, AI.10 and AI.13 each increased the level of propiconazole retained in one of the fungi, suggesting that they could partially block the ability of efflux transporters to remove propiconazole from these fungi. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  3. Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors.

    Science.gov (United States)

    Bizarro, Ana; Sousa, Diana; Lima, Raquel T; Musso, Loana; Cincinelli, Raffaella; Zuco, Vantina; De Cesare, Michelandrea; Dallavalle, Sabrina; Vasconcelos, M Helena

    2018-02-13

    Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3- d ]isoxazole-4,9-diones as inhibitors of HSP90. In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds ( 5 and 8 ) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as "clients" of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition.

  4. KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces intrauterine growth restriction in mice.

    Science.gov (United States)

    Abe, Naomichi; Nakahara, Tsutomu; Morita, Akane; Wada, Yoshiko; Mori, Asami; Sakamoto, Kenji; Nagamitsu, Tohru; Ishii, Kunio

    2013-08-01

    We previously reported that treatment with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, during mid-pregnancy caused intrauterine growth restriction resulting from impairment of blood vessel growth in the labyrinthine zone of the placenta and fetal organs. However, the relative sensitivities of blood vessels in the placenta and fetal organs to vascular endothelial growth factor (VEGF) inhibitors have not been determined. In this study, we aimed to examine the effects of KRN633 on the vasculatures of organs in mother mice and their newborn pups by immunohistochemical analysis. Pregnant mice were treated daily with KRN633 (5 mg/kg) either from embryonic day 13.5 (E13.5) to E17.5 or from E13.5 to the day of delivery. The weights of the pups of KRN633-treated mice were lower than those of the pups of vehicle-treated mothers. However, no significant difference in body weight was observed between the vehicle- and KRN633-treated mice. The vascular development in the organs (the pancreas, kidney, and intestine) and intestinal lymphatic formation of the pups of KRN633-treated mothers was markedly impaired. In contrast, the KRN633 treatment showed no significant effect on the vascular beds in the organs, including the labyrinthine zone of the placenta, of the mother mice. These results suggest that blood vessels in fetal organs are likely to be more sensitive to reduced VEGF signaling than those in the mother. A partial loss of VEGF function during pregnancy could suppress vascular growth in the fetus without affecting the vasculature in the mother mouse, thereby increasing the risk of intrauterine growth restriction. © 2013 Wiley Periodicals, Inc.

  5. Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

    Directory of Open Access Journals (Sweden)

    Weidemann AK

    2013-09-01

    Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

  6. EFFECT OF USING NUTRITION MINERALS AND GROWTH SUBSTANCE ON PHYSICAL PROPERTIES OF ORANGE FRUITS

    Directory of Open Access Journals (Sweden)

    Tarek FOUDA

    2014-12-01

    Full Text Available This work was carried to investigate the characterization of orange fruits under using applications of nutrition minerals and one application of growth substance on physical properties of orange fruits at private farm in wadi el-netron, ELbehari governorate, Egypt during winter 2011to predict maturity stage of orange fruits . The physical properties including aspect ratio(AR, Area of flat surface(Af, Area of transverse surface (At, Arithmetic diameter (Da, Density (ρ, Geometric diameter (Dg, surface area (Sa, sphericity, Volume (V and weight and the results revealed that, the high increasing percentage of orange fruits were considered as follows 9.24, 17.08, 22.65, 9.70, 27.16, 9.70, 20.45, 6.38, 24.07 and 28.84 %

  7. Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis.

    Science.gov (United States)

    Weidemann, Anja K; Crawshaw, Ania A; Byrne, Emily; Young, Helen S

    2013-09-26

    Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF)-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation) and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased cardiovascular risk.

  8. Effects of six substances on the growth and freeze-drying of Lactobacillus delbrueckii subsp. bulgaricus.

    Science.gov (United States)

    Chen, He; Huang, Jie; Shi, Xiaoyu; Li, Yichao; Liu, Yu

    2017-01-01

    The efficacy of Lactobacillus delbrueckii subsp. bulgaricus as starter cultures for the dairy industry depends largely on the number of viable and active cells. Freeze-drying is the most convenient and successful method to preserve the bacterial cells. However, not all strains survived during freeze-drying. The effects of six substances including NaCl, sorbitol, mannitol, mannose, sodium glutamate, betaine added to the MRS medium on the growth and freeze-drying survival rate and viable counts of Lb. delbrueckii subsp. bulgaricus were studied through a single-factor test and Plackett-Burman design. Subsequently, the optimum freeze-drying conditions of Lb. delbrueckii subsp. bulgaricus were determined. Lb. delbrueckii subsp. bulgaricus survival rates were up to the maximum of 42.7%, 45.4%, 23.6%, while the concentrations of NaCl, sorbitol, sodium glutamate were 0.6%, 0.15%, 0.09%, respectively. In the optimum concentration, the viable counts in broth is 6.1, 6.9, 5.13 (×108 CFU/mL), respectively; the viable counts in freeze-drying power are 3.09, 5.2, 2.7 (×1010 CFU/g), respectively. Three antifreeze factors including NaCl, sorbitol, sodium glutamate have a positive effect on the growth and freeze-drying of Lb. delbrueckii subsp. bulgaricus. The results are beneficial for developing Lb. delbrueckii subsp. bulgaricus.

  9. Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice

    Science.gov (United States)

    Xiang, Wei; Ke, Zhiyuan; Zhang, Yong; Ho-Yuet Cheng, Grace; Irwan, Ishak Darryl; Sulochana, K N; Potturi, Padma; Wang, Zhengyuan; Yang, He; Wang, Jingyu; Zhuo, Lang; Kini, R Manjunatha; Ge, Ruowen

    2011-01-01

    Abstract Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain–hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ5 integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmen-tal vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis. PMID:19874420

  10. Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice.

    Science.gov (United States)

    Xiang, Wei; Ke, Zhiyuan; Zhang, Yong; Cheng, Grace Ho-Yuet; Irwan, Ishak Darryl; Sulochana, K N; Potturi, Padma; Wang, Zhengyuan; Yang, He; Wang, Jingyu; Zhuo, Lang; Kini, R Manjunatha; Ge, Ruowen

    2011-02-01

    Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain-hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ(5) integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmental vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  11. Trajectories of adolescent substance use development and the influence of healthy leisure: A growth mixture modeling approach.

    Science.gov (United States)

    Weybright, Elizabeth H; Caldwell, Linda L; Ram, Nilam; Smith, Edward A; Wegner, Lisa

    2016-06-01

    Considerable heterogeneity exists in adolescent substance use development. To most effectively prevent use, distinct trajectories of use must be identified as well as differential associations with predictors of use, such as leisure experience. The current study used a person-centered approach to identify distinct substance use trajectories and how leisure is associated with trajectory classes. Data came from a larger efficacy trial of 2.249 South African high school students who reported substance use at any time across 8 waves. Growth mixture modeling was used to identify developmental trajectories of substance use and the influence of healthy leisure. Results identified three increasing and one stable substance use trajectory and subjective healthy leisure served to protect against use. This study is the first of its kind to focus on a sample of South African adolescents and serves to develop a richer understanding of substance use development and the role of healthy leisure. Copyright © 2016 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  12. Therapies based on inhibitors of the epidermal growth factor receptor: enclosing the future

    International Nuclear Information System (INIS)

    Diaz, Arlhee; Lage, Agustin

    2007-01-01

    The Epidermal Growth Factor Receptor (EGFR) is considered an important target for rational drug design due to its key role in numerous tumors. Potential contribution of EGFR-related signaling pathways to promote tumorigenic processes, including cell proliferation, angiogenesis, and resistance to apoptosis has been well established. Two classes of anti-EGFR agents in late-stage clinical testing include monoclonal antibodies against extracellular EGFR domain (Cetuximab, Nimotuzumab) and small molecules tyrosine kinase inhibitors, which inhibit the receptor enzyme activity (Gefitinib, Erlotinib). A considerable body of evidence has emerged since its introduction in the treatment of cancer patients. However, important questions such as reliable surrogate markers to predict response to the treatment, or optimal sequence and combination of these agents with conventional therapies remain to be addressed. Identify and validate predictive factors to select patients likely to respond to EGFR inhibitors, such as mutations that confer resistance versus those associated with sensitivity is required. A better understanding of molecular mechanisms associated with antitumor activity will useful to predict the interaction of these agents with other therapies in order to avoid antagonisms or overlapping effects resulting in no adding effects. Finally, the benefits derived from EGFR inhibitors as first-line therapy in selected populations, and the optimal doses and ways to delivery to the tumor site resulting in optimal target modulation should be established by the ongoing investigation. (Author)

  13. A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance.

    Science.gov (United States)

    Lee, Hee Seung; Park, Soo Been; Kim, Sun A; Kwon, Sool Ki; Cha, Hyunju; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Song, Si Young

    2017-01-30

    Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future.

  14. Sodium chloride as a reference substance for the three growth endpoints used in the Lemna minor L. (1753 test

    Directory of Open Access Journals (Sweden)

    Aline Andrade Godoy

    2017-01-01

    Full Text Available Lemna sp. growth inhibition test standardized protocols suggest the use of compounds such as 3,5-dichlorophenol as reference substances for checking the test organism’s sensitivity routinely. However, this and other recommended chemicals present risks to human health and to the environment. Sodium chloride (NaCl appears as a less toxic alternative reference substance which has been successfully used in routine ecotoxicological tests. However, the evaluation of this compound in multiple growth endpoints used in the L. minor test, which is required for recommending it as a reference substance for this test organism, has not yet been reported. In the present study, NaCl was tested with L. minor for the growth endpoints frond number, total frond area and fresh weight. Results showed acceptable sensitivity and reproducibility (coefficient of variance < 15.0% for all three of the measured endpoints. Statistically significant differences were observed between the EC50 values calculated based on the three endpoints (p < 0.05. Total frond area was the most sensitive one, with average EC50 value of 2742.80 ± 245.7 mg L-1. It was anticipated that NaCl can be a suitable alternative reference substance and that total frond area should be the endpoint of choice for sensitivity toxicity tests using NaCl.

  15. Growth inhibitor of E. coli K-12 in a sample of 39KCl

    International Nuclear Information System (INIS)

    Luckey, T.D.

    1984-01-01

    Growth rates and total population of E. coli were reduced fourfold when natural KCl (/sup N/KCl) in the medium was replaced by 39 KCl from a particular source. A prolonged lag period was noted in cultures containing either /sup N/KCl or 39 KCl when inoculated with bacteria adapted to 39 KCl. These changes were not due to endogenous radiation because these differences were not observed when (a) the KCl concentrations were reduced from 50 to 5 mM and (b) the 39 KCl from the prime source was replaced with 39 KCl from a second source; also the addition of 40 KCl to 39 KCl did not improve growth. These results suggest that the 39 KCl from the primary source contained an unidentified inhibitor that is not readily detected by physical and chemical analyses. 8 references, 3 figures, 2 tables

  16. Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo

    International Nuclear Information System (INIS)

    Klenke, Frank M; Abdollahi, Amir; Bertl, Elisabeth; Gebhard, Martha-Maria; Ewerbeck, Volker; Huber, Peter E; Sckell, Axel

    2007-01-01

    As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo. In 10 male severe combined immunodeficient (SCID) mice, pieces of SW1353 chondrosarcomas were implanted into a cranial window preparation where the calvaria serves as the site for the orthotopic implantation of bone tumors. From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control). Angiogenesis, microcirculation, and growth of SW 1353 tumors were analyzed by means of intravital microscopy. SU6668 induced a growth arrest of chondrosarcomas within 7 days after the initiation of the treatment. Compared to Controls, SU6668 decreased functional vessel density and tumor size, respectively, by 37% and 53% on day 28 after tumor implantation. The time course of the experiments demonstrated that the impact on angiogenesis preceded the anti-tumor effect. Histological and immunohistochemical results confirmed the intravital microscopy findings. SU6668 is a potent inhibitor of chondrosarcoma tumor growth in vivo. This effect appears to be induced by the antiangiogenic effects of SU6668, which are mediated by the inhibition of the key angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta

  17. Novel LIMK2 Inhibitor Blocks Panc-1 Tumor Growth in a mouse xenograft model.

    Science.gov (United States)

    Rak, Roni; Haklai, Roni; Elad-Tzfadia, Galit; Wolfson, Haim J; Carmeli, Shmuel; Kloog, Yoel

    2014-01-01

    LIM kinases (LIMKs) are important cell cytoskeleton regulators that play a prominent role in cancer manifestation and neuronal diseases. The LIMK family consists of two homologues, LIMK1 and LIMK2, which differ from one another in expression profile, intercellular localization, and function. The main substrate of LIMK is cofilin, a member of the actin-depolymerizing factor (ADF) protein family. When phosphorylated by LIMK, cofilin is inactive. LIMKs play a contributory role in several neurodevelopmental disorders and in cancer growth and metastasis. We recently reported the development and validation of a novel LIMK inhibitor, referred to here as T56-LIMKi, using a combination of computational methods and classical biochemistry techniques. Here we report that T56-LIMKi inhibits LIMK2 with high specificity, and shows little or no cross-reactivity with LIMK1. We found that T56-LIMKi decreases phosphorylated cofilin (p-cofilin) levels and thus inhibits growth of several cancerous cell lines, including those of pancreatic cancer, glioma and schwannoma. Because the most promising in-vitro effect of T56-LIMKi was observed in the pancreatic cancer cell line Panc-1, we tested the inhibitor on a nude mouse Panc-1 xenograft model. T56-LIMKi reduced tumor size and p-cofilin levels in the Panc-1 tumors, leading us to propose T56-LIMKi as a candidate drug for cancer therapy.

  18. Estimating the effect of urease inhibitor on rice yield based on NDVI at key growth stages

    Directory of Open Access Journals (Sweden)

    Kailou LIU,Yazhen LI,Huiwen HU

    2014-06-01

    Full Text Available The effect of the urease inhibitor, N-(n-butyl thiophosphoric triamide (NBPT at a range of application rates on rice production was examined in a field experiment at Jinxian County, Jiangxi Province, China. The normalized difference vegetation index (NDVI was measured at key growth stages in both early and late rice. The results showed that the grain yield increased significantly when urea was applied with NBPT, with the highest yield observed at 1.00% NBPT (wt/wt. NDVI differed with the growth stage of rice; it remained steady from the heading to the filling stage. Rice yield could be predicted from the NDVI taken at key rice growing stages, with R2 ranging from 0.34 to 0.69 in early rice and 0.49 to 0.70 in late rice. The validation test showed that RMSE (t·hm-2 values were 0.77 and 0.87 in early and late rice, respectively. Therefore, it was feasible to estimate rice yield for different amounts of urease inhibitor using NDVI.

  19. The potential roles of hepatocyte growth factor (HGF-MET pathway inhibitors in cancer treatment

    Directory of Open Access Journals (Sweden)

    Parikh RA

    2014-06-01

    Full Text Available Rahul A Parikh,1 Peng Wang,2 Jan H Beumer,3 Edward Chu,1 Leonard J Appleman11Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; 2Division of Medical Oncology, University of Kentucky College of Medicine, Markey Cancer Center, Lexington, KY, USA; 3University of Pittsburgh School of Pharmacy, Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USAAbstract: MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF receptor, a member of the receptor tyrosine kinase (RTK family. HGF, also known as scatter factor (SF, is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis, mobility (motogenesis, and differentiation (morphogenesis; it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.Keywords: MET inhibitor, HGF inhibitor, cancer

  20. Novel Midkine Inhibitor iMDK Inhibits Tumor Growth and Angiogenesis in Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Masui, Masanori; Okui, Tatsuo; Shimo, Tsuyoshi; Takabatake, Kiyofumi; Fukazawa, Takuya; Matsumoto, Kenichi; Kurio, Naito; Ibaragi, Soichiro; Naomoto, Yoshio; Nagatsuka, Hitoshi; Sasaki, Akira

    2016-06-01

    Midkine is a heparin-binding growth factor highly expressed in various human malignant tumors. However, its role in the growth of oral squamous cell carcinoma is not well understood. In this study, we analyzed the antitumor effect of a novel midkine inhibitor (iMDK) against oral squamous cell carcinoma. Administration of iMDK induced a robust antitumor response and suppressed cluster of differentiation 31 (CD31) expression in oral squamous cell carcinoma HSC-2 cells and SAS cells xenograft models. iMDK inhibited the proliferation of these cells dose-dependently, as well as the expression of midkine and phospho-extracellular signal-regulated kinase in HSC-2 and SAS cells. Moreover, iMDK significantly inhibited vascular endothelial growth factor and induced tube growth of human umbilical vein endothelial cells in a dose-dependent fashion. These findings suggest that midkine is critically involved in oral squamous cell carcinoma and iMDK can be effectively used for the treatment of oral squamous cell carcinoma. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  1. A Benzimidazole Proton Pump Inhibitor Increases Growth and Tolerance to Salt Stress in Tomato

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    Michael J. Van Oosten

    2017-07-01

    Full Text Available Pre-treatment of tomato plants with micromolar concentrations of omeprazole (OP, a benzimidazole proton pump inhibitor in mammalian systems, improves plant growth in terms of fresh weight of shoot and roots by 49 and 55% and dry weight by 54 and 105% under salt stress conditions (200 mM NaCl, respectively. Assessment of gas exchange, ion distribution, and gene expression profile in different organs strongly indicates that OP interferes with key components of the stress adaptation machinery, including hormonal control of root development (improving length and branching, protection of the photosynthetic system (improving quantum yield of photosystem II and regulation of ion homeostasis (improving the K+:Na+ ratio in leaves and roots. To our knowledge OP is one of the few known molecules that at micromolar concentrations manifests a dual function as growth enhancer and salt stress protectant. Therefore, OP can be used as new inducer of stress tolerance to better understand molecular and physiological stress adaptation paths in plants and to design new products to improve crop performance under suboptimal growth conditions.Highlight: Omeprazole enhances growth of tomato and increases tolerance to salinity stress through alterations of gene expression and ion uptake and transport.

  2. Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth.

    Science.gov (United States)

    Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M; Yang, Jun; Starbuck, Michael W; Ravoori, Murali K; Kundra, Vikas; Vazquez, Elba; Navone, Nora M

    2012-03-01

    Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth

  3. A Novel Ras Inhibitor (MDC-1016 Reduces Human Pancreatic Tumor Growth in Mice

    Directory of Open Access Journals (Sweden)

    Gerardo G Mackenzie

    2013-10-01

    Full Text Available Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its persistent resistance to chemotherapy. The currently limited treatment options for pancreatic cancer underscore the need for more efficient agents. Because activating Kras mutations initiate and maintain pancreatic cancer, inhibition of this pathway should have a major therapeutic impact. We synthesized phospho-farnesylthiosalicylic acid (PFTS; MDC-1016 and evaluated its efficacy, safety, and metabolism in preclinical models of pancreatic cancer. PFTS inhibited the growth of human pancreatic cancer cells in culture in a concentration- and time-dependent manner. In an MIA PaCa-2 xenograft mouse model, PFTS at a dose of 50 and 100 mg/kg significantly reduced tumor growth by 62% and 65% (P < .05 vs vehicle control. Furthermore, PFTS prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. PFTS appeared to be safe, with the animals showing no signs of toxicity during treatment. Following oral administration, PFTS was rapidly absorbed, metabolized to FTS and FTS glucuronide, and distributed through the blood to body organs. Mechanistically, PFTS inhibited Ras-GTP, the active form of Ras, both in vitro and in vivo, leading to the inhibition of downstream effector pathways c-RAF/mitogen-activated protein-extracellular signal-regulated kinase (ERK kinase (MEK/ERK1/2 kinase and phosphatidylinositol 3-kinase/AKT. In addition, PFTS proved to be a strong combination partner with phospho-valproic acid, a novel signal transducer and activator of transcription 3 (STAT3 inhibitor, displaying synergy in the inhibition of pancreatic cancer growth. In conclusion, PFTS, a direct Ras inhibitor, is an efficacious agent for the treatment of pancreatic cancer in preclinical models, deserving further evaluation.

  4. Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.

    Science.gov (United States)

    Yamanegi, Koji; Kawabe, Mutsuki; Futani, Hiroyuki; Nishiura, Hiroshi; Yamada, Naoko; Kato-Kogoe, Nahoko; Kishimoto, Hiromitsu; Yoshiya, Shinichi; Nakasho, Keiji

    2015-05-01

    The level of vascular endothelial growth inhibitor (VEGI) has been reported to be negatively associated with neovascularization in malignant tumors. The soluble form of VEGI is a potent anti-angiogenic factor due to its effects in inhibiting endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis that can be subsequently blocked by decoy receptor 3 (DcR3). We investigated the effects of sodium valproate (VPA) and trichostatin A (TSA), histone deacetylase inhibitors, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Consequently, treatment with VPA and TSA increased the VEGI and DR3 expression levels without inducing DcR3 production in the OS cell lines. In contrast, the effect on the HMVE cells was limited, with no evidence of growth inhibition or an increase in the DR3 and DcR3 expression. However, VPA-induced soluble VEGI in the OS cell culture medium markedly inhibited the vascular tube formation of HMVE cells, while VEGI overexpression resulted in enhanced OS cell death. Taken together, the HDAC inhibitor has anti-angiogenesis and antitumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. This study indicates that the HDAC inhibitor may be exploited as a therapeutic strategy modulating the soluble VEGI/DR3 pathway in osteosarcoma patients.

  5. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    Science.gov (United States)

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types.

  6. Weed Suppressing Potential and Isolation of Potent Plant Growth Inhibitors from Castanea crenata Sieb. et Zucc

    Directory of Open Access Journals (Sweden)

    Phung Thi Tuyen

    2018-02-01

    Full Text Available This study isolated, determined, and quantified plant growth inhibitors in Japanese chestnut (Castanea crenata Sieb. et Zucc, a deciduous species native to Japan and Korea. In laboratory assays, C. crenata leaves showed strong inhibition on germination and seedling growth of Echinochloa crus-galli (barnyardgrass, Lactuca sativa (lettuce, and Raphanus sativus (radish. Laboratory and greenhouse trials showed that leaves of C. crenata appeared as a promising material to manage weeds, especially the dicot weeds. By GC-MS and HPLC analyses, gallic, protocatechuic, p-hydroxybenzoic, caffeic, ferulic, ellagic, and cinnamic acids were identified and quantified, of which ellagic acid was present in the highest quantity (2.36 mg/g dried leaves. By column chromatography and spectral data (1H- and 13C-NMR, IR, and LC-MS analysis, a compound identified as 2α,3β,7β,23-tetrahydroxyurs-12-ene-28-oic acid (1 was purified from the methanolic leaf extract of C. crenata (0.93 mg/g dried leaves. This constituent showed potent inhibition on growth of E. crus-galli, a problematic weed in agricultural practice. The inhibition of the compound 1 (IC50 = 2.62 and 0.41 mM was >5 fold greater than that of p-hydroxybenzoic acid (IC50 = 15.33 and 2.11 mM on shoot and root growth of E. crus-galli, respectively. Results suggest that the isolated the compound 1 has potential to develop natural herbicides to manage E. crus-galli. This study is the first to isolate and identify 2α,3β,7β,23-tetrahydroxyurs-12-ene-28-oic acid in a plant and report its plant growth inhibitory potential.

  7. Inhibitors of the epidermal growth factor receptor in apple juice extract.

    Science.gov (United States)

    Kern, Melanie; Tjaden, Zeina; Ngiewih, Yufanyi; Puppel, Nicole; Will, Frank; Dietrich, Helmut; Pahlke, Gudrun; Marko, Doris

    2005-04-01

    The polyphenol-rich extract of a consumer-relevant apple juice blend was found to potently inhibit the growth of the human colon cancer cell line HT29 in vitro. The epidermal growth factor receptor (EGFR) and its subsequent signaling cascade play an important role in the regulation of cell proliferation in HT29 cells. The protein tyrosine kinase activity of an EGFR preparation was effectively inhibited by the polyphenol-rich apple juice extract. Treatment of intact cells with this extract resulted in the suppression of the subsequent mitogen-activated protein kinase cascade. Amongst the so far identified apple juice constituents, the proanthocyanidins B1 and B2 as well as quercetin-3-glc (isoquercitrin) and quercetin-3-gal (hyperoside) were found to possess substantial EGFR-inhibitory properties. However, as to be expected from the final concentration of these potential EGFR inhibitors in the original polyphenol-rich extract, a synthetic mixture of the apple juice constituents identified and available so far, including both proanthocyanidins and the quercetin glycosides, showed only marginal inhibitory effects on the EGFR. These results permit the assumption that yet unknown constituents contribute substantially to the potent EGFR-inhibitory properties of polyphenol-rich apple juice extract. In summary, the polyphenol composition of apple juice possesses promising growth-inhibitory properties, affecting proliferation-associated signaling cascades in colon tumor cells.

  8. Characterization of the sulfate uptake and assimilation pathway from Xanthomonas citri - targets for bacterial growth inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Tambascia, C.; Balan, A. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil)

    2012-07-01

    Full text: Microorganisms require sulfur for growth and obtain it either for inorganic sulfate or organosulfur compounds. ATP-Binding Cassete (SulT family) or major facilitator superfamily-type (SulP) transporters are responsible for the sulfate transport into the cell. In Xanthomonas citri, the phytopathogenic bacterium that causes the canker citrus disease, there are no reports related to the importance of these transporters during in vitro or in vivo infection. We identified in X. citri genome all the genes that belong to the well-characterized cys regulon from Escherichia coli and Salmonella typhimurium, which includes three ABC transporters and all the enzymes necessary for sulfate oxide reduction to sulfide and cysteine. Once these genes have been shown to be extremely important for bacteria growth and development in different environments, we chose the sbpcysWUA and cysDNCHIJG operons, which encodes the ABC inorganic sulfate ABC transporter and all the enzymes necessary for conversion of sulfate in cysteine, respectively. As a step for crystallization trials and resolution of their tridimensional structures, the referred genes were amplified and cloned into the cloning vector pGEM T-easy. In addition, using bioinformatics tools and molecular modeling we characterized all the protein functions as well as built tridimensional models of their structure for determination of the active sites. The importance of each protein is discussed aiming the discovery of a good target for development of inhibitors that could block the bacterium growth. (author)

  9. Characterization of the sulfate uptake and assimilation pathway from Xanthomonas citri - targets for bacterial growth inhibitors

    International Nuclear Information System (INIS)

    Tambascia, C.; Balan, A.

    2012-01-01

    Full text: Microorganisms require sulfur for growth and obtain it either for inorganic sulfate or organosulfur compounds. ATP-Binding Cassete (SulT family) or major facilitator superfamily-type (SulP) transporters are responsible for the sulfate transport into the cell. In Xanthomonas citri, the phytopathogenic bacterium that causes the canker citrus disease, there are no reports related to the importance of these transporters during in vitro or in vivo infection. We identified in X. citri genome all the genes that belong to the well-characterized cys regulon from Escherichia coli and Salmonella typhimurium, which includes three ABC transporters and all the enzymes necessary for sulfate oxide reduction to sulfide and cysteine. Once these genes have been shown to be extremely important for bacteria growth and development in different environments, we chose the sbpcysWUA and cysDNCHIJG operons, which encodes the ABC inorganic sulfate ABC transporter and all the enzymes necessary for conversion of sulfate in cysteine, respectively. As a step for crystallization trials and resolution of their tridimensional structures, the referred genes were amplified and cloned into the cloning vector pGEM T-easy. In addition, using bioinformatics tools and molecular modeling we characterized all the protein functions as well as built tridimensional models of their structure for determination of the active sites. The importance of each protein is discussed aiming the discovery of a good target for development of inhibitors that could block the bacterium growth. (author)

  10. Inhibition of growth hormone and prolactin secretion by a serine proteinase inhibitor

    International Nuclear Information System (INIS)

    Rappay, G.; Nagy, I.; Makara, G.B.; Horvath, G.; Karteszi, M.; Bacsy, E.; Stark, E.

    1984-01-01

    The action of the tripeptide aldehyde t-butyloxycarbonyl-DPhe-Pro-Arg-H (boc-fPR-H), belonging to a family of serine proteinase inhibitors, on the release of immunoreactive prolactin (iPRL) and growth hormone (iGH) has been studied. In rat anterior pituitary cell cultures and pituitary quarters 1 mM boc-fPR-H inhibited basal iPRL and iGH release. Thyroliberin-induced iPRL release by cultured cells was also markedly inhibited with a concomitant accumulation of intracellular iPRL. During the short- and long-term exposure of cells to boc-fPR-H there were no changes in total cell protein contents and in activities of some lysosomal marker enzymes. The marked inhibition of basal as well as stimulated hormone release in the presence of the enzyme inhibitor might suggest that at least a portion of the hormones is released via a proteolytic enzyme-dependent process

  11. A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth

    Science.gov (United States)

    Barbosa, Armenio Jorge; Di Virgilio, Valeria; Fittipaldi, Raffaella; Fabini, Edoardo; Bertucci, Carlo; Varchi, Greta; Moyer, Mary Pat; Caretti, Giuseppina; Del Rio, Alberto; Simone, Cristiano

    2016-01-01

    SMYD3 is a histone lysine methyltransferase that plays an important role in transcriptional activation as a member of an RNA polymerase complex, and its oncogenic role has been described in different cancer types. We studied the expression and activity of SMYD3 in a preclinical model of colorectal cancer (CRC) and found that it is strongly upregulated throughout tumorigenesis both at the mRNA and protein level. Our results also showed that RNAi-mediated SMYD3 ablation impairs CRC cell proliferation indicating that SMYD3 is required for proper cancer cell growth. These data, together with the importance of lysine methyltransferases as a target for drug discovery, prompted us to carry out a virtual screening to identify new SMYD3 inhibitors by testing several candidate small molecules. Here we report that one of these compounds (BCI-121) induces a significant reduction in SMYD3 activity both in vitro and in CRC cells, as suggested by the analysis of global H3K4me2/3 and H4K5me levels. Of note, the extent of cell growth inhibition by BCI-121 was similar to that observed upon SMYD3 genetic ablation. Most of the results described above were obtained in CRC; however, when we extended our observations to tumor cell lines of different origin, we found that SMYD3 inhibitors are also effective in other cancer types, such as lung, pancreatic, prostate, and ovarian. These results represent the proof of principle that SMYD3 is a druggable target and suggest that new compounds capable of inhibiting its activity may prove useful as novel therapeutic agents in cancer treatment. PMID:25728514

  12. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.

    Science.gov (United States)

    Cheng, Xiao Jiao; Lin, Jia Cheng; Ding, Yan Fei; Zhu, Liming; Ye, Jing; Tu, Shui Ping

    2016-02-09

    Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.

  13. Covalent cross-linking of insulin-like growth factor-1 to a specific inhibitor from human serum

    International Nuclear Information System (INIS)

    Ooi, G.T.; Herington, A.C.

    1986-01-01

    Previous studies have shown that a specific inhibitor of insulin-like growth factor (IGF) action in vitro can be isolated from normal human serum and subsequently partially purified on an IGF-affinity column. The ability of the inhibitor to bind the IGFs has now been confirmed directly using covalent cross-linking techniques. When 125 I-IGF-1 was cross-linked to inhibitor using disuccinimidyl suberate, five specifically labelled bands were seen on SDS-PAGE and autoradiography. Two bands (MW 21.5 K and 25.5 K) were intensely labelled, while the remaining three (MW 37 K, 34 K and 18 K) appeared as minor bands only. Inhibitor bioactivity, following further analysis by hydrophobic interaction chromatography or Con A-Sepharose affinity chromatography, was always associated with the presence of the 21.5 K and/or 25.5 K bands

  14. Modulators of inhibitor of growth (ING) family expression in development and disease.

    Science.gov (United States)

    Maher, Stacey K; Helbing, Caren C

    2009-05-01

    The inhibitor of growth (ING) gene family proteins regulate many critical cellular processes such as cell proliferation and growth, apoptosis, DNA repair, senescence, angiogenesis, and drug resistance. Their transcripts and proteins are differentially expressed in health and disease and there is evidence for developmental regulation. The vast majority of studies have characterized ING levels in the context of cancer. However, relatively little attention has been paid to the expression of ING family members in other contexts. This review summarizes the findings from human and animal model systems that provide insight into the factors influencing the expression of these important proteins. We examine the influence of cell cycle and aging as well as genotoxic stress on ING expression levels and evaluate several emerging areas of inquiry demonstrating that ING gene activity may be modulated by factors such as the p53 tumor suppressor, DNA methylation, and ING proteins themselves with external factors such as hormones, reactive oxygen species, TGFbeta signalling, and other proteins of pathological significance also influencing ING levels. We then briefly discuss the influence of post-translational modification and changes in subcellular localization as it pertains to modulation of ING expression. Understanding how ING expression is modulated represents a vital aspect of effective drug targeting strategies.

  15. Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Zhao Y

    2015-08-01

    Full Text Available Yuanyuan Zhao,1,* Jing Zhang,2,* Ying Tian,1,* Cong Xue,1 Zhihuang Hu,1 Li Zhang1,3 1Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, 2Department of Medical Oncology, the First Affiliated Hospital of Guang Zhou Traditional Chinese Medicine University, 3National Anti-Cancer Drug Research Centre, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this work Purpose: We explored the effect of hepatocyte growth factor (HGF/Met signaling pathway on nasopharyngeal carcinoma (NPC cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI to block HGF-induced biological signaling.Experimental design: Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.Results: Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 µmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus

  16. Screening a library of household substances for inhibitors of phosphatases: An introduction to high-throughput screening.

    Science.gov (United States)

    Taylor, Ann T S

    2005-01-01

    Library screening methods are commonly used in industry and research. This article describes an experiment that screens a library of household substances for properties that would make a good "drug," including enzyme inhibition, neutral pH, and nondenaturing to proteins, using wheat germ acid phosphatase as the target protein. An adaptation of the experiment appropriate for lower level biochemistry or outreach is also described. This work was supported by Wabash College through the Haines Fund for the Study of Biochemistry and the National Science Foundation through Grant DUE 0126242. Copyright © 2005 International Union of Biochemistry and Molecular Biology, Inc.

  17. Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo

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    Petru Edgar

    2010-03-01

    Full Text Available Abstract Background Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21WAF1 and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo. Results Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 μM already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 μM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3 as well as class II (HDAC7 were preferentially affected by this treatment. Vorinostat significantly increased p21WAF1 expression and apoptosis. Nude mice injected with 5 × 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice. Conclusions Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.

  18. Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

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    Gadgeel, Shirish M; Wozniak, Antoinette

    2013-07-01

    Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Inhibitors of pan PI3K signaling synergize with BRAF or MEK inhibitors to prevent BRAF-mutant melanoma cell growth

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    Melanie eSweetlove

    2015-06-01

    Full Text Available BRAF and MEK inhibitors have improved outcomes for patients with BRAF-mutant melanoma, but their efficacy is limited by both intrinsic and acquired resistance. Activation of the PI3K pathway can mediate resistance to these agents, providing a strong rationale for combination therapy in melanoma. Here, a panel of 9 low passage human metastatic melanoma cell lines with BRAF mutations were tested in cell proliferation and protein expression assays for sensitivity to inhibitors of MEK (selumetinib and BRAF (vemurafenib as single agents and in combination with inhibitors of pan-PI3K (ZSTK474, pan-PI3K/mTOR (BEZ235, individual PI3K isoforms (p110α, A66; p110β, TGX-221; p110γ, AS-252424; p110δ, idelalisib, or mTORC1/2 (KU-0063794. Selumetinib and vemurafenib potently inhibited cell proliferation in all cell lines, especially in those that expressed low levels of pAKT. ZSTK474 and BEZ235 also inhibited cell proliferation in all cell lines and enhanced the antitumor activity of selumetinib and vemurafenib in the majority of lines by either interacting synergistically or additively to increase potency or by inducing cytotoxicity by significantly increasing the magnitude of cell growth inhibition. Furthermore, ZSTK474 or BEZ235 combined with selumetinib to produce robust inhibition of pERK, pAKT and pS6 expression and synergistic inhibition of NZM20 tumor growth. The inhibitors of individual PI3K isoforms or mTORC1/2 were less effective at inhibiting cell proliferation either as single agents or in combination with selumetinib or vemurafenib, although KU-0063794 synergistically interacted with vemurafenib and increased the magnitude of cell growth inhibition with selumetinib or vemurafenib in certain cell lines. Overall, these results suggest that the sensitivity of BRAF-mutant melanoma cells to BRAF or MEK inhibitors is at least partly mediated by activation of the PI3K pathway and can be enhanced by combined inhibition of the BRAF/MEK and PI3K

  20. Improving Lowland Rice (O. sativa L. cv. MR219 Plant Growth Variables, Nutrients Uptake, and Nutrients Recovery Using Crude Humic Substances

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    Perumal Palanivell

    2015-01-01

    Full Text Available High cation exchange capacity and organic matter content of crude humic substances from compost could be exploited to reduce ammonia loss from urea and to as well improve rice growth and soil chemical properties for efficient nutrients utilization in lowland rice cultivation. Close-dynamic air flow system was used to determine the effects of crude humic substances on ammonia volatilization. A pot experiment was conducted to determine the effects of crude humic substances on rice plant growth, nutrients uptake, nutrients recovery, and soil chemical properties using an acid soil mixed with three rates of crude humic substances (20, 40, and 60 g pot−1. Standard procedures were used to evaluate rice plant dry matter production, nutrients uptake, nutrients recovery, and soil chemical properties. Application of crude humic substances increased ammonia volatilization. However, the lowest rate of crude humic substances (20 g pot−1 significantly improved total dry matter, nutrients uptake, nutrients recovery, and soil nutrients availability compared with crude humic substances (40 and 60 g pot−1 and the normal fertilization. Apart from improving growth of rice plants, crude humic substances can be used to ameliorate acid soils in rice cultivation. The findings of this study are being validated in our ongoing field trials.

  1. Improving Lowland Rice (O. sativa L. cv. MR219) Plant Growth Variables, Nutrients Uptake, and Nutrients Recovery Using Crude Humic Substances.

    Science.gov (United States)

    Palanivell, Perumal; Ahmed, Osumanu Haruna; Ab Majid, Nik Muhamad; Jalloh, Mohamadu Boyie; Susilawati, Kasim

    2015-01-01

    High cation exchange capacity and organic matter content of crude humic substances from compost could be exploited to reduce ammonia loss from urea and to as well improve rice growth and soil chemical properties for efficient nutrients utilization in lowland rice cultivation. Close-dynamic air flow system was used to determine the effects of crude humic substances on ammonia volatilization. A pot experiment was conducted to determine the effects of crude humic substances on rice plant growth, nutrients uptake, nutrients recovery, and soil chemical properties using an acid soil mixed with three rates of crude humic substances (20, 40, and 60 g pot(-1)). Standard procedures were used to evaluate rice plant dry matter production, nutrients uptake, nutrients recovery, and soil chemical properties. Application of crude humic substances increased ammonia volatilization. However, the lowest rate of crude humic substances (20 g pot(-1)) significantly improved total dry matter, nutrients uptake, nutrients recovery, and soil nutrients availability compared with crude humic substances (40 and 60 g pot(-1)) and the normal fertilization. Apart from improving growth of rice plants, crude humic substances can be used to ameliorate acid soils in rice cultivation. The findings of this study are being validated in our ongoing field trials.

  2. The Small Molecule DAM Inhibitor, Pyrimidinedione, Disrupts Streptococcus pneumoniae Biofilm Growth In Vitro.

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    Mukesh Kumar Yadav

    Full Text Available Streptococcus pneumoniae persist in the human nasopharynx within organized biofilms. However, expansion to other tissues may cause severe infections such as pneumonia, otitis media, bacteremia, and meningitis, especially in children and the elderly. Bacteria within biofilms possess increased tolerance to antibiotics and are able to resist host defense systems. Bacteria within biofilms exhibit different physiology, metabolism, and gene expression profiles than planktonic cells. These differences underscore the need to identify alternative therapeutic targets and novel antimicrobial compounds that are effective against pneumococcal biofilms. In bacteria, DNA adenine methyltransferase (Dam alters pathogenic gene expression and catalyzes the methylation of adenine in the DNA duplex and of macromolecules during the activated methyl cycle (AMC. In pneumococci, AMC is involved in the biosynthesis of quorum sensing molecules that regulate competence and biofilm formation. In this study, we examine the effect of a small molecule Dam inhibitor, pyrimidinedione, on Streptococcus pneumoniae biofilm formation and evaluate the changes in global gene expression within biofilms via microarray analysis. The effects of pyrimidinedione on in vitro biofilms were studied using a static microtiter plate assay, and the architecture of the biofilms was viewed using confocal and scanning electron microscopy. The cytotoxicity of pyrimidinedione was tested on a human middle ear epithelium cell line by CCK-8. In situ oligonucleotide microarray was used to compare the global gene expression of Streptococcus pneumoniae D39 within biofilms grown in the presence and absence of pyrimidinedione. Real-time RT-PCR was used to study gene expression. Pyrimidinedione inhibits pneumococcal biofilm growth in vitro in a concentration-dependent manner, but it does not inhibit planktonic cell growth. Confocal microscopy analysis revealed the absence of organized biofilms, where cell

  3. Growth of Cucurbita maxima L. plants in the presence of the cycloartenol synthase inhibitor U18666A.

    Science.gov (United States)

    Fenner, G P; Raphiou, I

    1995-03-01

    Squash, like other Cucurbitaceae, have unique sterol profiles that offer an excellent opportunity to examine the relationship between sterol biosynthesis and plant growth. To determine the effect of sterol biosynthesis inhibition on squash growth, Cucurbita maxima seedlings with and without cotyledons were subjected to increasing concentrations of the cycloarternol synthase (EC 5.4.99.8) inhibitor 3 beta-(2-diethylaminoethoxy)androstenone (U18666A). Inhibition of shoot growth was concentration-dependent (from 0, 2, 5, 10, and 20 microM); plants with intact cotyledons grew to 26.4, 23.7, 21.6, 20.0, and 15.6 cm, respectively, at the above inhibitor concentrations, compared to 25.5, 19.4, 17.0, 12.0, and 11 cm for plants with severed cotyledons. In plants with severed cotyledons, 10 and 20 microM U18666A caused rapid necrosis of the first two, newly emerged, primary leaves, and halted new leaf formation. Secondary root formation was initially affected at all inhibitor concentrations regardless of whether cotyledons were present or not. Vegetative tissue showed a decrease in the accumulation of the major squash sterol, 7,22-stigmastadienol, accompanied by increased accumulation of minor sterol components. Sterol profiles in cotyledons were unaltered. The data show that sterols are crucial for maintaining plant growth and viability, but do not address the cotyledonary effect on growth with respect to sterol biosynthesis.

  4. INHIBITION OF THE GROWTH OF TOLERANT YEAST Saccharomyces cerevisiae STRAIN I136 BY A MIXTURE OF SYNTHETIC INHIBITORS

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    Eny Ida Riyanti

    2017-09-01

    Full Text Available Biomass from lignocellulosic wastes is a potential source for biobased products.  However, one of the constraints in utilization of biomass hydrolysate is the presence of inhibitors. Therefore, the use of inhibitor-tolerant microorganisms in the fermentation is required. The study aimed to investigate the effect of a mixture of inhibitors on the growth of Saccharomyces cerevisiae strain I136 grown in medium containing synthetic inhibitors (acetic acid, formic acid, furfural, 5-hydroxymethyl furfural/5-HMF, and levulinic acid in four different concentrations with a mixture of carbon sources, glucose  (50 g.l-1 and xylose (50 g.l-1 at 30oC. The parameters related to growth and fermentation products were observed. Results showed that the strain was able to grow in media containing natural inhibitors (BSL medium with µmax of 0.020/h. Higher level of synthetic inhibitors prolonged the lag phase, decreased the cell biomass and ethanol production, and specific growth rate. The strain could detoxify furfural and 5-HMF and produced the highest ethanol (Y(p/s of 0.32 g.g-1 when grown in BSL. Glucose was utilized as its level decreased in a result of increase in cell biomass, in contrast to xylose which was not consumed. The highest cell biomass was produced in YNB with Y (x/s value of 0.25 g.g-1. The strain produced acetic acid as a dominant side product and could convert furfural into a less toxic compound, hydroxyl furfural. This robust tolerant strain provides basic information on resistance mechanism and would be useful for bio-based cell factory using lignocellulosic materials. 

  5. Concurrent Autophagy Inhibition Overcomes the Resistance of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Human Bladder Cancer Cells.

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    Kang, Minyong; Lee, Kyoung-Hwa; Lee, Hye Sun; Jeong, Chang Wook; Kwak, Cheol; Kim, Hyeon Hoe; Ku, Ja Hyeon

    2017-02-04

    Despite the potential therapeutic efficacy of epithelial growth factor receptor (EGFR) inhibitors in the treatment of advanced stage bladder cancer, there currently is no clear evidence to support this hypothesis. In this study, we investigate whether the concurrent treatment of autophagy-blocking agents with EGFR inhibitors exerts synergistic anti-cancer effects in T24 and J82 human bladder cancer cells. Lapatinib and gefitinib were used as EGFR inhibitors, and bafilomycin A1 (BFA1), chloroquine (CQ) and 3-methyladenine (3-MA) were used as the pharmacologic inhibitors of autophagy activities. To assess the proliferative and self-renewal capabilities, the Cell Counting Kit-8 (CCK-8) assay and a clonogenic assay were performed, respectively. To examine apoptotic cell death, flow cytometry using annexin-V/propidium iodide (PI) was used. To measure the autophagy activities, the expression levels of LC3I and II was determined by Western blot analysis. To validate the synergistic effects of autophagy inhibition with EGFR inhibitors, we specifically blocked key autophagy regulatory gene ATG12 by transfection of small interference RNA and examined the phenotypic changes. Of note, lapatinib and gefitinib triggered autophagy activities in T24 and J82 human bladder cancer cells, as indicated by upregulation of LC3II. More importantly, inhibiting autophagy activities with pharmacologic inhibitors (BFA1, CQ or 3-MA) remarkably reduced the cell viabilities and clonal proliferation of T24 and J82 cells, compared to those treated with either of the agents alone. We also obtained similar results of the enhanced anti-cancer effects of EGFR inhibitors by suppressing the expression of ATG12. Notably, the apoptotic assay showed that synergistic anti-cancer effects were induced via the increase of apoptotic cell death. In summary, concomitant inhibition of autophagy activities potentiated the anti-cancer effects of EGFR inhibitors in human bladder cancer cells, indicating a novel

  6. Concurrent Autophagy Inhibition Overcomes the Resistance of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Human Bladder Cancer Cells

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    Minyong Kang

    2017-02-01

    Full Text Available Despite the potential therapeutic efficacy of epithelial growth factor receptor (EGFR inhibitors in the treatment of advanced stage bladder cancer, there currently is no clear evidence to support this hypothesis. In this study, we investigate whether the concurrent treatment of autophagy-blocking agents with EGFR inhibitors exerts synergistic anti-cancer effects in T24 and J82 human bladder cancer cells. Lapatinib and gefitinib were used as EGFR inhibitors, and bafilomycin A1 (BFA1, chloroquine (CQ and 3-methyladenine (3-MA were used as the pharmacologic inhibitors of autophagy activities. To assess the proliferative and self-renewal capabilities, the Cell Counting Kit-8 (CCK-8 assay and a clonogenic assay were performed, respectively. To examine apoptotic cell death, flow cytometry using annexin-V/propidium iodide (PI was used. To measure the autophagy activities, the expression levels of LC3I and II was determined by Western blot analysis. To validate the synergistic effects of autophagy inhibition with EGFR inhibitors, we specifically blocked key autophagy regulatory gene ATG12 by transfection of small interference RNA and examined the phenotypic changes. Of note, lapatinib and gefitinib triggered autophagy activities in T24 and J82 human bladder cancer cells, as indicated by upregulation of LC3II. More importantly, inhibiting autophagy activities with pharmacologic inhibitors (BFA1, CQ or 3-MA remarkably reduced the cell viabilities and clonal proliferation of T24 and J82 cells, compared to those treated with either of the agents alone. We also obtained similar results of the enhanced anti-cancer effects of EGFR inhibitors by suppressing the expression of ATG12. Notably, the apoptotic assay showed that synergistic anti-cancer effects were induced via the increase of apoptotic cell death. In summary, concomitant inhibition of autophagy activities potentiated the anti-cancer effects of EGFR inhibitors in human bladder cancer cells, indicating

  7. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models

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    Bladt, Friedhelm, E-mail: Friedhelm.Bladt@merckgroup.com; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree [EMD Serono, and Merck Serono Research and Development, Merck KGaA, Darmstadt 64293 (Germany)

    2014-08-19

    The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling.

  8. Targeting Fibroblast Growth Factor 23 Signaling with Antibodies and Inhibitors, Is There a Rationale?

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    Seiji Fukumoto

    2018-02-01

    Full Text Available Fibroblast growth factor 23 (FGF23 is a phosphotropic hormone mainly produced by bone. FGF23 reduces serum phosphate by suppressing intestinal phosphate absorption through reducing 1,25-dihydroxyvitamin D and proximal tubular phosphate reabsorption. Excessive actions of FG23 result in several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemic rickets (XLH and tumor-induced osteomalacia. While neutral phosphate and active vitamin D are standard therapies for child patients with XLH, these medications have several limitations both in their effects and adverse events. Several approaches that inhibit FGF23 actions including anti-FGF23 antibodies and inhibitors of FGF signaling have been shown to improve phenotypes of model mice for FG23-related hypophosphatemic diseases. In addition, clinical trials indicated that a humanized anti-FGF23 antibody increased serum phosphate and improved quality of life in patients with XLH. Furthermore, circulatory FGF23 is high in patients with chronic kidney disease (CKD. Many epidemiological studies indicated the association between high FGF23 levels and various adverse events especially in patients with CKD. However, it is not known whether the inhibition of FGF23 activities in patients with CKD is beneficial for these patients. In this review, recent findings concerning the modulation of FGF23 activities are discussed.

  9. Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors.

    Science.gov (United States)

    Shao, Yi; Zhong, Dian-Sheng

    2018-04-01

    Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8-16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.

  10. Insulin-like growth factor receptor inhibitors: baby or the bathwater?

    Science.gov (United States)

    Yee, Douglas

    2012-07-03

    The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response, larger randomized phase III trials have not shown clear clinical benefit of targeting this pathway in combination with conventional strategies. These disappointing results have resulted in the discontinuation of several anti-IGF1R programs. However, the conduct of these trials has brought to the forefront several important factors that need to be considered in the conduct of future clinical trials. The need to develop biomarkers, a clearer understanding of insulin receptor function, and defining rational combination regimens all require further consideration. In this commentary, the current state of IGF1R inhibitors in cancer therapy is reviewed.

  11. Release of UV-absorbing substances from maize coleoptiles during auxin-, fusicoccin- and acid-mediated elongation growth

    International Nuclear Information System (INIS)

    Miyamoto, K.; Schopfer, P.

    1997-01-01

    Isolated cell walls from maize coleoptiles prepared under conditions that preserve the ability for enzymatic hemicellulose autolysis release UV-absorbing substances into the incubation medium in a time-dependent reaction with an optimal rate at pH 6–7. The reaction can be inhibited by low temperature and protein-denaturing treatments, indicating an enzymatic process. Spectroscopic and chromatographic analyses showed that the liberated substances represent a complex mixture of free and bound (alkali-hydrolyzable) phenolic compounds with similar absorption spectra restricted to the range below 300 nm and thus excluding hydroxycinnamic acids from cell-wall esters. A spectroscopically and chromatographically similar mixture of soluble UV-absorbing substances is released if living (abraded) maize coleoptiles or coleoptile segments are incubated in water or buffer, suggesting that insoluble phenolic materials in the cell wall are metabolized also in vivo. This reaction can be promoted by anaerobic conditions and application of fusicoccin whereas auxin had a slightly inhibitory effect. No clear relationship to elongation growth could be demonstrated. We conclude from these results that polymeric phenolic constituents of the cell wall are subject to enzymatic degradation in muro similar to polysaccharide autolysis and that this process is under metabolic control

  12. Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1 in Colorectal Cancer Cells

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    Cyril Sobolewski

    2015-08-01

    Full Text Available The RNA-binding protein tristetraprolin (TTP promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE. In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC inhibitors (Trichostatin A, SAHA and sodium butyrate promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells and cervix carcinoma cells (HeLa. We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1. Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer.

  13. Synergism between demethylation inhibitor fungicides or gibberellin inhibitor plant growth regulators and bifenthrin in a pyrethroid-resistant population of Listronotus maculicollis (Coleoptera: Curculionidae).

    Science.gov (United States)

    Ramoutar, D; Cowles, R S; Requintina, E; Alm, S R

    2010-10-01

    In 2007-2008, the "annual bluegrass weevil," Listronotus maculicollis Kirby (Coleoptera: Curculionidae), a serious pest of Poa annua L. (Poales: Poaceae) on U.S. golf courses, was shown to be resistant to two pyrethroids, bifenthrin and lambda-cyhalothrin. In 2008, we showed that bifenthrin resistance was principally mediated by oxidase detoxification (cytochrome P450 [P450]). P450s can be inhibited by demethylation inhibitor fungicides and gibberellin inhibitor plant growth regulators, both of which are commonly used on golf courses. We tested these compounds for synergistic activity with bifenthin against a pyrethroid-resistant population of L. maculicollis. The LD50 value for bifenthrin was significantly reduced from 87 ng per insect (without synergists) to 9.6-40 ng per insect after exposure to the fungicides fenarimol, fenpropimorph, prochloraz, propiconazole, and pyrifenox and the plant growth regulators flurprimidol, paclobutrazol, and trinexapac-ethyl. Simulated field exposure with formulated products registered for use on turf revealed enhanced mortality when adult weevils were exposed to bifenthrin (25% mortality, presented alone) combined with field dosages of propiconizole, fenarimol, flurprimidol, or trinexapac-ethyl (range, 49-70% mortality).

  14. Dextrins from Maize Starch as Substances Activating the Growth of Bacteroidetes and Actinobacteria Simultaneously Inhibiting the Growth of Firmicutes, Responsible for the Occurrence of Obesity.

    Science.gov (United States)

    Barczynska, Renata; Kapusniak, Janusz; Litwin, Mieczyslaw; Slizewska, Katarzyna; Szalecki, Mieczyslaw

    2016-06-01

    Unarguably, diet has a significant impact on human intestinal microbiota. The role of prebiotics as substances supporting the maintenance of appropriate body weight and reducing the demand for energy via stimulation of the growth of beneficial microbiota of the gut and formation products such as short-chain fatty acids, is more and more often highlighted. The objective of this study was to evaluate whether dextrins from maize starch resistant to enzymatic digestion stimulate the growth of Bacteroidetes and Actinobacteria strains representing a majority of the population of colon microbiota in lean individuals and limit the growth of Firmicutes bacterial strains representing a majority of the population of colon microbiota in obese individuals. The study was conducted with the use of in vitro method, using isolates from faeces of children characterized by normal weight, overweight and obesity. It was demonstrated that dextrins from maize starch equally efficient stimulate the growth of the isolates derived from normal-weight, overweight and obese children, and therefore may be added to foods as a beneficial component stimulating growth of strains belonging to Actinobacteria and Bacteroidetes for both overweight, obese and normal-weight children.

  15. DMH1, a small molecule inhibitor of BMP type i receptors, suppresses growth and invasion of lung cancer.

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    Jijun Hao

    Full Text Available The bone morphogenetic protein (BMP signaling cascade is aberrantly activated in human non-small cell lung cancer (NSCLC but not in normal lung epithelial cells, suggesting that blocking BMP signaling may be an effective therapeutic approach for lung cancer. Previous studies demonstrated that some BMP antagonists, which bind to extracellular BMP ligands and prevent their association with BMP receptors, dramatically reduced lung tumor growth. However, clinical application of protein-based BMP antagonists is limited by short half-lives, poor intra-tumor delivery as well as resistance caused by potential gain-of-function mutations in the downstream of the BMP pathway. Small molecule BMP inhibitors which target the intracellular BMP cascades would be ideal for anticancer drug development. In a zebrafish embryo-based structure and activity study, we previously identified a group of highly selective small molecule inhibitors specifically antagonizing the intracellular kinase domain of BMP type I receptors. In the present study, we demonstrated that DMH1, one of such inhibitors, potently reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in NSCLC cells by blocking BMP signaling, as indicated by suppression of Smad 1/5/8 phosphorylation and gene expression of Id1, Id2 and Id3. Additionally, DMH1 treatment significantly reduced the tumor growth in human lung cancer xenograft model. In conclusion, our study indicates that small molecule inhibitors of BMP type I receptors may offer a promising novel strategy for lung cancer treatment.

  16. Potential role for epidermal growth factor receptor inhibitors in combined-modality therapy for non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Kim, Dong Wook; Choy, Hak

    2004-01-01

    There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology/oncology. The epidermal growth factor receptor (EGFR) has been a molecular target of significant interest and investigation, and preclinical and clinical studies support a role for targeted therapy in a variety of cancers, including non-small-cell lung cancer (NSCLC) via compounds that specifically inhibit EGFR. ZD1839, IMC-C225, and OSI-774 are the most clinically developed of these compounds. Interestingly, preclinical studies have demonstrated that EGFR inhibitors may have radiation-sensitizing properties, as well as increased cytotoxic activity in combination with chemotherapeutic agents, suggesting a potential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy of Stage III NSCLC. Therefore, clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of EGFR inhibitors to the standard combined-modality regimen (chemotherapy/radiation therapy ± surgery) for Stage III NSCLC. This article reviews preclinical and clinical data supporting the role for EGFR inhibitors alone or in combination with chemotherapy/radiation therapy for locally advanced NSCLC. Also, it will provide an overview of ongoing and proposed clinical studies investigating the potential role for EGFR inhibitors in Stage III NSCLC

  17. 5-(2-Aminopropyl)indole (5-IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO).

    Science.gov (United States)

    Herraiz, Tomás; Brandt, Simon D

    2014-01-01

    5-(2-Aminopropyl)indole (5-IT) is a psychoactive compound that has recently been associated with several fatal and non-fatal intoxications in a number of European countries. There are indications that acute effects may include symptoms of monoaminergic (e.g. serotonin) toxicity and one mechanism involved in the increase of serotonin levels includes the inhibition of monoamine oxidase. This study investigated the effect of 5-IT on human MAO-A and -B isozymes using kynuramine as the substrate. Substrate conversion to 4-hydroxyquinoline was monitored by high-performance liquid chromatography coupled to diode array detection. This method was employed to determine the extent of MAO inhibition (IC50 and Ki ) and it was found that 5-IT was a selective, competitive and reversible inhibitor of MAO-A. 5-IT revealed a relatively potent ability to inhibit MAO-A (IC50  =1.6 μM and Ki  =0.25 μM) while MAO-B inhibition was not observed (0-500 μM 5-IT). Under identical experimental conditions, other established inhibitors of MAO-A and antidepressants provided the following IC50 values: clorgyline 16 nM, harmaline 20 nM, toloxatone 6.7 μM and moclobemide >500 μM. These data indicated that 5-IT was less potent than clorgyline and harmaline but more potent than toloxatone and moclobemide under the in-vitro conditions studied. The inhibition of MAO-A suggests that 5-IT by itself or in combination with other substances may be able to potentiate serotonergic/monoaminergic effects and further studies are needed to clarify its relevance to the adverse effects reported for 5-IT. Copyright © 2013 John Wiley & Sons, Ltd.

  18. Different aspects of S-carvone, a natural potato sprout growth inhibitor

    NARCIS (Netherlands)

    Oosterhaven, J.

    1995-01-01

    After harvest, potato tubers are usually stored at a temperature of 6-8°C in combination with the application of a synthetic sprout inhibitor. Frequently used sprout inhibitors are isopropyl N-phenyl-carbamate (propham or IPC), isopropyl N-(3-chlorophenyl)carbamate (chlorpropham or CIPC) or

  19. Changes in endogenous growth inhibitors in onion bulbs (Allium cepa L. cv. Sochaczewska during storage

    Directory of Open Access Journals (Sweden)

    Elżbieta Kielak

    2013-12-01

    Full Text Available Changes in inhibitor activity in the onion bulbs (Allium cepa L. cv. Sochaczewska during storage were investigated. Onions were dried under an umbrella roof until October 15th or November 15th and thereafter stored in a cold-room at 0-1°C until May 15th. The activity of inhibitors fluctuated markedly during the storage period. At least two peaks and two decreases of inhibitor activity were observed. The weather conditions seemed to strongly influence the level and the date of appearance of inhibitors in onions. Higher inhibitor activity is usually connected with better storage and less sprouting of onions during storage. Prolonged drying under an umbrella roof enhanced onion quality after storage only in these cases when it actually improved the drying of onions.

  20. MK-2206, an AKT Inhibitor, Promotes Caspase-Independent Cell Death and Inhibits Leiomyoma Growth

    Science.gov (United States)

    Sefton, Elizabeth C.; Qiang, Wenan; Serna, Vanida; Kurita, Takeshi; Wei, Jian-Jun; Chakravarti, Debabrata

    2013-01-01

    Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs. PMID:24002033

  1. AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E

    2016-02-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60-70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52-70%) and 21% (95% CI, 12-34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1-4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy.

  2. Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2006-01-01

    MIS is a member of the TGF family. The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth than either agent alone...

  3. Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations

    Directory of Open Access Journals (Sweden)

    Ludovica Ciuffreda

    2009-08-01

    Full Text Available The Raf/MEK/ERK pathway is an importantmediator of tumor cell proliferation and angiogenesis. Here, weinvestigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC50 in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G1-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27KIP1 and apoptosis (Bcl-2 and survivin regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma.

  4. Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor.

    Science.gov (United States)

    Chirivi, R G; Garofalo, A; Crimmin, M J; Bawden, L J; Stoppacciaro, A; Brown, P D; Giavazzi, R

    1994-08-01

    The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.

  5. Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis

    International Nuclear Information System (INIS)

    Younis, Sidra; Javed, Qamar; Blumenberg, Miroslav

    2015-01-01

    EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways. Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors. The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis. This metaanalysis suggests that ‘combination therapies’ can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding

  6. Measuring and modeling the hygroscopic growth of two humic substances in mixed aerosol particles of atmospheric relevance

    Directory of Open Access Journals (Sweden)

    I. R. Zamora

    2013-09-01

    Full Text Available The hygroscopic growth of atmospheric particles affects atmospheric chemistry and Earth's climate. Water-soluble organic carbon (WSOC constitutes a significant fraction of the dry submicron mass of atmospheric aerosols, thus affecting their water uptake properties. Although the WSOC fraction is comprised of many compounds, a set of model substances can be used to describe its behavior. For this study, mixtures of Nordic aquatic fulvic acid reference (NAFA and Fluka humic acid (HA, with various combinations of inorganic salts (sodium chloride and ammonium sulfate and other representative organic compounds (levoglucosan and succinic acid, were studied. We measured the equilibrium water vapor pressure over bulk solutions of these mixtures as a function of temperature and solute concentration. New water activity (aw parameterizations and hygroscopic growth curves at 25 °C were calculated from these data for particles of equivalent composition. We examined the effect of temperature on the water activity and found a maximum variation of 9% in the 0–30 °C range, and 2% in the 20–30 °C range. Five two-component mixtures were studied to understand the effect of adding a humic substance (HS, such as NAFA and HA, to an inorganic salt or a saccharide. The deliquescence point at 25 °C for HS-inorganic mixtures did not change significantly from that of the pure inorganic species. However, the hygroscopic growth of HA / inorganic mixtures was lower than that exhibited by the pure salt, in proportion to the added mass of HA. The addition of NAFA to a highly soluble solute (ammonium sulfate, sodium chloride or levoglucosan in water had the same effect as the addition of HA to the inorganic species for most of the water activity range studied. Yet, the water uptake of these NAFA mixtures transitioned to match the growth of the pure salt or saccharide at high aw values. The remaining four mixtures were based on chemical composition data for different

  7. Restoration of Transforming Growth Factor Beta Signaling by Histone Deacetylase Inhibitors in Human Prostate Carcinoma

    National Research Council Canada - National Science Library

    Qian, Zheng D

    2006-01-01

    The goal of the current grant is to investigate the potential antitumor activity of histone deacetylase inhibitor MS-275 along with the activation of TGFb signaling pathway with the restoration of TGFb receptor II...

  8. Restoration of Transforming Growth Factor Beta Signaling by Histone Deacetylase Inhibitors in Human Prostate Carcinoma

    National Research Council Canada - National Science Library

    Qian, Zheng D

    2005-01-01

    The goal of the current grant is to investigate the potential antitumor activity of histone deacetylase inhibitor MS-275 a with the activation of TGFb signaling pathway with the restoration of TGFbeta receptor II...

  9. Inhibition of the growth of Alexandrium tamarense by algicidal substances in Chinese fir (Cunninghamia lanceolata).

    Science.gov (United States)

    Yang, Wei-Dong; Liu, Jie-Sheng; Li, Hong-Ye; Zhang, Xin-Lian; Qi, Yu-Zao

    2009-10-01

    The wood sawdust from Chinese fir (Cunninghamia lanceolata) exhibited stronger inhibition on the growth of Alexandrium tamarense than those from alder (Alnus cremastogyne), pine (Pinus massoniana), birch (Betula alnoides) and sapele (Entandrophragma cylindricum). The water extract, acetone-water extract and essential oil from fir sawdust were all shown to inhibit the growth of A. tamarense. The inhibition of fir essential oil was the strongest among all the above wood sources while the half effective concentration was only 0.65 mg/L. These results suggested that the fir essential oil may play an important role in the algicidal effect of Chinese fir.

  10. Adhesion, Growth, and Maturation of Vascular Smooth Muscle Cells on Low-Density Polyethylene Grafted with Bioactive Substances

    Directory of Open Access Journals (Sweden)

    Martin Parizek

    2013-01-01

    Full Text Available The attractiveness of synthetic polymers for cell colonization can be affected by physical, chemical, and biological modification of the polymer surface. In this study, low-density polyethylene (LDPE was treated by an Ar+ plasma discharge and then grafted with biologically active substances, namely, glycine (Gly, polyethylene glycol (PEG, bovine serum albumin (BSA, colloidal carbon particles (C, or BSA+C. All modifications increased the oxygen content, the wettability, and the surface free energy of the materials compared to the pristine LDPE, but these changes were most pronounced in LDPE with Gly or PEG, where all the three values were higher than in the only plasma-treated samples. When seeded with vascular smooth muscle cells (VSMCs, the Gly- or PEG-grafted samples increased mainly the spreading and concentration of focal adhesion proteins talin and vinculin in these cells. LDPE grafted with BSA or BSA+C showed a similar oxygen content and similar wettability, as the samples only treated with plasma, but the nano- and submicron-scale irregularities on their surface were more pronounced and of a different shape. These samples promoted predominantly the growth, the formation of a confluent layer, and phenotypic maturation of VSMC, demonstrated by higher concentrations of contractile proteins alpha-actin and SM1 and SM2 myosins. Thus, the behavior of VSMC on LDPE can be regulated by the type of bioactive substances that are grafted.

  11. A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance

    OpenAIRE

    Lee, Hee Seung; Park, Soo Been; Kim, Sun A; Kwon, Sool Ki; Cha, Hyunju; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Song, Si Young

    2017-01-01

    Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resis...

  12. Method for Bacterial Growth and Ammonia Production and Effect of Inhibitory Substances in Disposable Absorbent Hygiene Products.

    Science.gov (United States)

    Forsgren-Brusk, Ulla; Yhlen, Birgitta; Blomqvist, Marie; Larsson, Peter

    The purpose of this study was to evaluate a pragmatic laboratory method to provide a technique for developing incontinence products better able to reduce malodor when used in the clinical setting. Bacterial growth and bacterially formed ammonia in disposable absorbent incontinence products was measured by adding synthetic urine inoculated with bacteria to test samples cut from the crotch area of the product. The inhibitory effect's of low pH (4.5 and 4.9) and 3 antimicrobial substances-chlorhexidine, polyhexamethylene biguanide (PHMB), and thymol-at 2 concentrations each, were studied. From the initial inocula of 3.3 log colony-forming units per milliliter (cfu/mL) at baseline, the bacterial growth of the references increased to 5.0 to 6.0 log cfu/mL at 6 hours for Escherichia coli, Proteus mirabilis, and Enterococcus faecalis. At 12 hours there was a further increase to 7.0 to 8.9 log cfu/mL. Adjusting the pH of the superabsorbent in the incontinence product from 6.0 to pH 4.5 and pH 4.9 significantly (P disposable absorbent products to inhibit bacterial growth and ammonia production. This technique, we describe, provides a pragmatic method for assessing the odor-inhibiting capacity of specific incontinence products.

  13. In vitro effects of substance P analogue [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P on human tumour and normal cell growth.

    OpenAIRE

    Everard, M. J.; Macaulay, V. M.; Miller, J. L.; Smith, I. E.

    1992-01-01

    Analogues of the neurotransmitter substance P (SP) can interact with neuropeptide receptors, and are reported to inhibit growth of small cell lung cancer cell lines (SCLC CLs). We found [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P (D-Phe5SP) significantly inhibited DNA synthesis by 10/10 human tumour CLs; six SCLC, one N-SCLC (squamous), two ovarian and one squamous cervical carcinoma, with inhibition to 50% control levels (IC50) of 20-50 microM. There was dose dependent inhibition of colony...

  14. Effect of simulated microgravity on growth and production of exopolymeric substances of Micrococcus luteus space and earth isolates.

    Science.gov (United States)

    Mauclaire, Laurie; Egli, Marcel

    2010-08-01

    Microorganisms tend to form biofilms on surfaces, thereby causing deterioration of the underlaying material. In addition, biofilm is a potential health risk to humans. Therefore, microorganism growth is not only an issue on Earth but also in manned space habitats like the International Space Station (ISS). The aim of the study was to identify physiological processes relevant for Micrococcus luteus attachment under microgravity conditions. The results demonstrate that simulated microgravity influences physiological processes which trigger bacterial attachment and biofilm formation. The ISS strains produced larger amounts of exopolymeric substances (EPS) compared with a reference strain from Earth. In contrast, M. luteus strains were growing faster, and Earth as well as ISS isolates produced a higher yield of biomass under microgravity conditions than under normal gravity. Furthermore, microgravity caused a reduction of the colloidal EPS production of ISS isolates in comparison with normal gravity, which probably influences biofilm thickness and stability as well.

  15. Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion.

    Directory of Open Access Journals (Sweden)

    Mattias Kalén

    Full Text Available The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs--originally developed for Alzheimer's disease--are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A--a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX, a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.

  16. Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

    International Nuclear Information System (INIS)

    Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

    2005-01-01

    Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E 2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G 0 /G 1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E 2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and

  17. Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth.

    Science.gov (United States)

    Koo, Junghui; Yue, Ping; Gal, Anthony A; Khuri, Fadlo R; Sun, Shi-Yong

    2014-05-01

    mTOR kinase inhibitors that target both mTORC1 and mTORC2 are being evaluated in cancer clinical trials. Here, we report that glycogen synthase kinase-3 (GSK3) is a critical determinant for the therapeutic response to this class of experimental drugs. Pharmacologic inhibition of GSK3 antagonized their suppressive effects on the growth of cancer cells similarly to genetic attenuation of GSK3. Conversely, expression of a constitutively activated form of GSK3β sensitized cancer cells to mTOR inhibition. Consistent with these findings, higher basal levels of GSK3 activity in a panel of human lung cancer cell lines correlated with more efficacious responses. Mechanistic investigations showed that mTOR kinase inhibitors reduced cyclin D1 levels in a GSK3β-dependent manner, independent of their effects on suppressing mTORC1 signaling and cap binding. Notably, selective inhibition of mTORC2 triggered proteasome-mediated cyclin D1 degradation, suggesting that mTORC2 blockade is responsible for GSK3-dependent reduction of cyclin D1. Silencing expression of the ubiquitin E3 ligase FBX4 rescued this reduction, implicating FBX4 in mediating this effect of mTOR inhibition. Together, our findings define a novel mechanism by which mTORC2 promotes cell growth, with potential implications for understanding the clinical action of mTOR kinase inhibitors. ©2014 AACR.

  18. Widespread Dependence of Backup NHEJ on Growth State: Ramifications for the Use of DNA-PK Inhibitors

    International Nuclear Information System (INIS)

    Singh, Satyendra K.; Wu Wenqi; Zhang Lihua; Klammer, Holger; Wang Minli; Iliakis, George

    2011-01-01

    Purpose: The backup pathway of nonhomologous end joining (B-NHEJ) enables cells to process DNA double-strand breaks (DSBs) when the DNA-PK-dependent pathway of NHEJ (D-NHEJ) is compromised. Our previous results show marked reduction in the activity of B-NHEJ when LIG4 -/- mouse embryo fibroblasts (MEFs) cease to grow and enter a plateau phase. The dependence of B-NHEJ on growth state is substantially stronger than that of D-NHEJ and points to regulatory mechanisms or processing determinants that require elucidation. Because the different D-NHEJ mutants show phenotypes distinct in their details, it is necessary to characterize the dependence of their DSB repair capacity on growth state and to explore species-specific responses. Methods and Materials: DSB repair was measured in cells of different genetic background from various species using pulsed-field gel electrophoresis, or the formation of γ-H2AX foci, at different stages of growth. Results: Using pulsed-field gel electrophoresis, we report a marked reduction of B-NHEJ during the plateau phase of growth in KU and XRCC4, mouse or Chinese hamster, mutants. Notably, this reduction is only marginal in DNA-PKcs-deficient cells. However, reduced B-NHEJ is also observed in repair proficient, plateau-phase cells after treatment with DNA-PK inhibitors. The reduction of B-NHEJ activity in the plateau phase of growth does not derive from the reduced expression of participating proteins, is detectable by γ-H2AX foci analysis, and leads to enhanced cell killing. Conclusions: These results further document the marked dependence on growth state of an essential DSB repair pathway and show the general nature of the effect. Molecular characterization of the mechanism underlying this response will help to optimize the administration of DNA repair inhibitors as adjuvants in radiation therapy.

  19. Crystal growth of pure substances: Phase-field simulations in comparison with analytical and experimental results

    Science.gov (United States)

    Nestler, B.; Danilov, D.; Galenko, P.

    2005-07-01

    A phase-field model for non-isothermal solidification in multicomponent systems [SIAM J. Appl. Math. 64 (3) (2004) 775-799] consistent with the formalism of classic irreversible thermodynamics is used for numerical simulations of crystal growth in a pure material. The relation of this approach to the phase-field model by Bragard et al. [Interface Science 10 (2-3) (2002) 121-136] is discussed. 2D and 3D simulations of dendritic structures are compared with the analytical predictions of the Brener theory [Journal of Crystal Growth 99 (1990) 165-170] and with recent experimental measurements of solidification in pure nickel [Proceedings of the TMS Annual Meeting, March 14-18, 2004, pp. 277-288; European Physical Journal B, submitted for publication]. 3D morphology transitions are obtained for variations in surface energy and kinetic anisotropies at different undercoolings. In computations, we investigate the convergence behaviour of a standard phase-field model and of its thin interface extension at different undercoolings and at different ratios between the diffuse interface thickness and the atomistic capillary length. The influence of the grid anisotropy is accurately analyzed for a finite difference method and for an adaptive finite element method in comparison.

  20. The Heparanase Inhibitor PG545 Attenuates Colon Cancer Initiation and Growth, Associating with Increased p21 Expression

    Directory of Open Access Journals (Sweden)

    Preeti Singh

    2017-03-01

    Full Text Available Heparanase activity is highly implicated in cellular invasion and tumor metastasis, a consequence of cleavage of heparan sulfate and remodeling of the extracellular matrix underlying epithelial and endothelial cells. Heparanase expression is rare in normal epithelia, but is often induced in tumors, associated with increased tumor metastasis and poor prognosis. In addition, heparanase induction promotes tumor growth, but the molecular mechanism that underlines tumor expansion by heparanase is still incompletely understood. Here, we provide evidence that heparanase down regulates the expression of p21 (WAF1/CIP1, a cyclin-dependent kinase inhibitor that attenuates the cell cycle. Notably, a reciprocal effect was noted for PG545, a potent heparanase inhibitor. This compound efficiently reduced cell proliferation, colony formation, and tumor xenograft growth, associating with a marked increase in p21 expression. Utilizing the APC Min+/− mouse model, we show that heparanase expression and activity are increased in small bowel polyps, whereas polyp initiation and growth were significantly inhibited by PG545, again accompanied by a prominent induction of p21 levels. Down-regulation of p21 expression adds a novel feature for the emerging pro-tumorigenic properties of heparanase, while the potent p21 induction and anti-tumor effect of PG545 lends optimism that it would prove an efficacious therapeutic in colon carcinoma patients.

  1. Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

    International Nuclear Information System (INIS)

    Pappano, William N; Sheppard, George S; Donawho, Cherrie; Buchanan, Fritz G; Davidsen, Steven K; Bell, Randy L; Wang, Jieyi; Jung, Paul M; Meulbroek, Jonathan A; Wang, Yi-Chun; Hubbard, Robert D; Zhang, Qian; Grudzien, Meagan M; Soni, Niru B; Johnson, Eric F

    2009-01-01

    The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation

  2. Effect of soil contamination with oil substances on the growth of selected plants

    International Nuclear Information System (INIS)

    Sara, V.; Kult, L.; Vavra, J.

    1993-12-01

    The growth of barley, maize, wheat and alfalfa was studied in dependence on the level of soil pollution with crude oil. Attention was also paid to the effect of such contamination on the vanadium and nickel contents of the above-ground parts of the plants. Experiments revealed that, with the exception of alfalfa, the vanadium content of plants which had been grown in the contaminated soil was about one-half with respect to the values observed in plants grown in uncontaminated soil, and the nickel content was also lower than in control plants. Introduced into the soil by injection in concentrations of 180 to 500 ppm, crude oil was found to induce local damage in the plants, resulting in a smaller size of the plants and a delayed or missing earing phase, with repercussions on the grain size and quantity. (J.B.). 2 tabs., 6 figs

  3. Growth inhibition of Listeria spp. on Camembert cheese by bacteria producing inhibitory substances.

    Science.gov (United States)

    Sulzer, G; Busse, M

    1991-12-01

    Bacterial strains exhibiting antimicrobial activity towards other bacteria are quite common in nature. During the past few years several genera have been shown to exert inhibitory action against Listeria. spp. In the present work strains of Enterococcus, Lactobacillus and Lactococcus were tested for their influence on the development of Listeria spp. on Camembert cheese. Partial or complete inhibition of growth of Listeria spp. was observed using various inhibitory bacteria. Complete inhibition occurred when the inhibitory strain was used as a starter culture and there was a low level of contamination with Listeria spp. during the first stage of ripening. Very little inhibition occurred if the inhibitory strain was added together with the starter culture.

  4. The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

    International Nuclear Information System (INIS)

    Klenke, Frank Michael; Gebhard, Martha-Maria; Ewerbeck, Volker; Abdollahi, Amir; Huber, Peter E; Sckell, Axel

    2006-01-01

    The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases

  5. Comparison of ALS functionality and plant growth in ALS-inhibitor susceptible and resistant Myosoton aquaticum L.

    Science.gov (United States)

    Liu, Weitang; Bai, Shuang; Jia, Sisi; Guo, Wenlei; Zhang, Lele; Li, Wei; Wang, Jinxin

    2017-10-01

    Herbicide target-site resistance mutations may cause pleiotropic effects on plant ecology and physiology. The effect of several known (Pro197Ser, Pro197Leu Pro197Ala, and Pro197Glu) target-site resistance mutations of the ALS gene on both ALS functionality and plant vegetative growth of weed Myosoton aquaticum L. (water chickweed) have been investigated here. The enzyme kinetics of ALS from four purified water chickweed populations that each homozygous for the specific target-site resistance-endowing mutations were characterized and the effect of these mutations on plant growth was assessed via relative growth rate (RGR) analysis. Plants homozygous for Pro197Ser and Pro197Leu exhibited higher extractable ALS activity than susceptible (S) plants, while all ALS mutations with no negative change in ALS kinetics. The Pro197Leu mutation increased ALS sensitivity to isoleucine and valine, and Pro197Glu mutation slightly increased ALS sensitivity to isoleucine. RGR results indicated that none of these ALS resistance mutations impose negative pleiotropic effects on relative growth rate. However, resistant (R) seeds had a lowed germination rate than S seeds. This study provides baseline information on ALS functionality and plant growth characteristics associated with ALS inhibitor resistance-endowing mutations in water chickweed. Copyright © 2017. Published by Elsevier Inc.

  6. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice

    DEFF Research Database (Denmark)

    Kamoun, Walid S; Ley, Carsten D; Farrar, Christian T

    2009-01-01

    anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. METHODS: We treated...... mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis...... by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation -- as measured by MRI and by dry/wet weight measurement of water content -- but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage...

  7. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Liang Y

    2016-05-01

    growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells. Our findings suggest that cholesterol biosynthesis inhibitors such as RO, when used in combination with commonly used chemotherapeutic drugs or ERβ specific ligands, could represent a novel therapeutic approach to prevent the growth of prostate cancer tumors. Keywords: prostate cancer, cholesterol biosynthesis inhibitor, cell viability, xenograft, castration resistant

  8. Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats.

    Science.gov (United States)

    Nakano, Ayuki; Nakahara, Tsutomu; Mori, Asami; Ushikubo, Hiroko; Sakamoto, Kenji; Ishii, Kunio

    2016-02-01

    Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8. The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN633. However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRN633-treated rats, compared to vehicle (0.5% methylcellulose)-treated animals. Similar observations were made with axitinib-treated rats. Expressions of VEGF and VEGFR-2 were enhanced on P14 in KRN633-treated rat retinas. The second round of KRN633 treatment on P11 and P12 completely blocked abnormal retinal vascular growth on P14, but thereafter induced ROP-like abnormal retinal blood vessels by P21. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner. Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. SNX-25a, a novel Hsp90 inhibitor, inhibited human cancer growth more potently than 17-AAG.

    Science.gov (United States)

    Wang, Shaoxiang; Wang, Xiao; Du, Zhan; Liu, Yuting; Huang, Dane; Zheng, Kai; Liu, Kaisheng; Zhang, Yi; Zhong, Xueyun; Wang, Yifei

    2014-07-18

    17-Allylamino-17-demethoxygeldanamycin (17-AAG), a typical Hsp90 inhibitor derived from geldanamycin (GA), has entered Phase III clinical trials for cancer therapy. However, it has several significant limitations such as poor solubility, limited bioavailability and unacceptable hepatotoxicity. In this study, the anticancer activity and mechanism of SNX-25a, a novel Hsp90 inhibitor, was investigated comparing with that of 17-AAG. We showed that SNX-25a triggered growth inhibition more sensitively than 17-AAG against many human cancer cells, including K562, SW-620, A375, Hep-2, MCF-7, HepG2, HeLa, and A549 cell lines, especially at low concentrations (AAG, SNX-25a was more potent in arresting the cell cycle at G2 phase, and displayed more potent effects on human cancer cell apoptosis and Hsp90 client proteins. It also exhibited a stronger binding affinity to Hsp90 than 17-AAG using molecular docking. Considering the superiority effects on Hsp90 affinity, cell growth, cell cycle, apoptosis, and Hsp90 client proteins, SNX-25a is supposed as a potential anticancer agent that needs to be explored in detail. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib.

    Science.gov (United States)

    Wiedmann, Marcus; Feisthammel, Jürgen; Blüthner, Thilo; Tannapfel, Andrea; Kamenz, Thomas; Kluge, Annett; Mössner, Joachim; Caca, Karel

    2006-08-01

    cell lines. Gefitinib, erlotinib and NVP-AEE788 caused a significant growth inhibition in vitro; however, there was a significant difference in efficacy (NVP-AEE788>erlotinib>gefitinib). After 14 days of in-vivo treatment, using the chimeric mouse model, tumors had a significantly reduced volume and mass after NVP-AEE788, but not after erlotinib treatment, as compared with placebo. Reduction of proliferation (signalling via the mitogen-activated protein kinase pathway), induction of apoptosis and inhibition of angiogenesis were the main mechanisms of drug action. No significant reduction of anti-apoptotic AKT phosphorylation, however, occurred, which may be a possible counter mechanism of the tumor. Epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 expression was detectable in biliary tract cancer, and receptor inhibition exerts marked effects on tumor growth in vitro and in vivo, which was strongest for the dual EGFR/ErbB-2 inhibitor NVP-AEE788. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.

  11. Effects of heavy metals on Cyanothece sp. CCY 0110 growth, extracellular polymeric substances (EPS) production, ultrastructure and protein profiles.

    Science.gov (United States)

    Mota, Rita; Pereira, Sara B; Meazzini, Marianna; Fernandes, Rui; Santos, Arlete; Evans, Caroline A; De Philippis, Roberto; Wright, Phillip C; Tamagnini, Paula

    2015-04-29

    The effects of several heavy metals on the growth/survival, EPS production, ultrastructure and protein profiles of the highly efficient extracellular polymeric substances (EPS)-producer cyanobacterium Cyanothece sp. CCY 0110 were evaluated. Our results clearly show that each heavy metal affects the cells in a particular manner, triggering distinctive responses. Concerning chronic exposure, cells were more affected by Cu(2+) followed by Pb(2+), Cd(2+), and Li(+). The presence of metal leads to remarkable ultrastructural changes, mainly at the thylakoid level. The comparison of the proteomes (iTRAQ) allowed to follow the stress responses and to distinguish specific effects related to the time of exposure and/or the concentration of an essential (Cu(2+)) and a non-essential (Cd(2+)) metal. The majority of the proteins identified and with fold changes were associated with photosynthesis, CO2 fixation and carbohydrate metabolism, translation, and nitrogen and amino acid metabolism. Moreover, our results indicate that during chronic exposure to sub-lethal concentrations of Cu(2+), the cells tune down their metabolic rate to invest energy in the activation of detoxification mechanisms, which eventually result in a remarkable recovery. In contrast, the toxic effects of Cd(2+) are cumulative. Unexpectedly, the amount of released polysaccharides (RPS) was not enhanced by the presence of heavy metals. This work shows the holistic effects of different heavy metals on the cells of the highly efficient EPS-producer the cyanobacterium Cyanothece sp. CCY 0110. The growth/survival, EPS production, ultrastructure, protein profiles and stress response were evaluated. The knowledge generated by this study will contribute to the implementation of heavy-metal removal systems based on cyanobacteria EPS or their isolated polymers. Copyright © 2015. Published by Elsevier B.V.

  12. Review of the use of Ceramium tenuicorne growth inhibition test for testing toxicity of substances, effluents, products sediment and soil

    Science.gov (United States)

    Eklund, Britta

    2017-08-01

    A growth inhibition test has been developed based on two clones of the red macroalga Ceramium tenuicorne, one originating from 7 PSU and the other from 20 PSU. The species can be adapted to different salinities and the test can be carried out between 4 and 32 PSU. This test became an ISO standard in 2010 (ISO 107 10) for testing of chemicals and water effluents. In this study new and published data has been compiled on toxicity of single substances, waste waters from pulp mills, leachates from antifouling paints, harbour sediments and soil used for maintenance of leisure boats. The results show that the alga is sensitive to both metals and organic compounds and to biocides used in antifouling paints. By testing leachates from antifouling paints these could be ranked according to their toxicity. Similarly, the toxicity of waste waters from pulp mills was determined and the efficiency of secondary treatment evaluated. Further, the test method proved useful to test the toxicity in sediment samples. Sediments from small town harbours and ship lanes were shown to be harmful and compounds originating from antifouling paints were responsible for a large part of the inhibiting effect. The alga proved to be sensitive to contaminants leaking from boat yard soil. The growth inhibition test is a robust test that has high repeatability and reproducibility and easily can be applied on water, soil and sediment samples without being too costly. The species is found worl-wide in temperate waters, which makes the results relevant for large areas. In the Baltic Sea C. tenuicorne is the most common red alga species and is thus particularly relevant for this area. The overall results show that contaminants from boat activities and the use of antifouling paints in particular pose a threat to the environment.

  13. PEROXOTITANATE- AND MONOSODIUM METAL-TITANATE COMPOUNDS AS INHIBITORS OF BACTERIAL GROWTH

    Energy Technology Data Exchange (ETDEWEB)

    Hobbs, D.

    2011-01-19

    Sodium titanates are ion-exchange materials that effectively bind a variety of metal ions over a wide pH range. Sodium titanates alone have no known adverse biological effects but metal-exchanged titanates (or metal titanates) can deliver metal ions to mammalian cells to alter cell processes in vitro. In this work, we test a hypothesis that metal-titanate compounds inhibit bacterial growth; demonstration of this principle is one prerequisite to developing metal-based, titanate-delivered antibacterial agents. Focusing initially on oral diseases, we exposed five species of oral bacteria to titanates for 24 h, with or without loading of Au(III), Pd(II), Pt(II), and Pt(IV), and measuring bacterial growth in planktonic assays through increases in optical density. In each experiment, bacterial growth was compared with control cultures of titanates or bacteria alone. We observed no suppression of bacterial growth by the sodium titanates alone, but significant (p < 0.05, two-sided t-tests) suppression was observed with metal-titanate compounds, particularly Au(III)-titanates, but with other metal titanates as well. Growth inhibition ranged from 15 to 100% depending on the metal ion and bacterial species involved. Furthermore, in specific cases, the titanates inhibited bacterial growth 5- to 375-fold versus metal ions alone, suggesting that titanates enhanced metal-bacteria interactions. This work supports further development of metal titanates as a novel class of antibacterials.

  14. Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells.

    Science.gov (United States)

    Kato, Taigo; Inoue, Hiroyuki; Imoto, Seiya; Tamada, Yoshinori; Miyamoto, Takashi; Matsuo, Yo; Nakamura, Yusuke; Park, Jae-Hyun

    2016-04-05

    T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.

  15. Phosphite fertilisers as inhibitors of Hymenoscyphus fraxineus (anamorph Chalara fraxinea growth in tests in vitro

    Directory of Open Access Journals (Sweden)

    Tkaczyk Miłosz

    2017-03-01

    Full Text Available This study is designed to test the potential for reducing the growth of the mycelium of the fungus Hymenoscyphus fraxineus (anamorph Chalara fraxinea by using phosphite preparations at various concentrations in vitro. The study shows that adding pure phosphite to potato dextrose agar media inhibits the development of the fungus, but if the preparation is applied in the form of ammonium phosphite (Actifos, the growth of fungus will be accelerated. Probably the addition of nitrogen contained in the product Actifos has positive effect on the mycelial growth, but pure phosphite restricts its development. These studies are preliminary and only show the potential use of phosphite to reduce the development of H. fraxineus; however, to completely confirm its operation, further research is needed in this area.

  16. The synthetic inhibitor of Fibroblast Growth Factor Receptor PD166866 controls negatively the growth of tumor cells in culture

    Directory of Open Access Journals (Sweden)

    Castelli Mauro

    2009-12-01

    Full Text Available Abstract Background Many experimental data evidence that over-expression of various growth factors cause disorders in cell proliferation. The role of the Fibroblast Growth Factors (FGF in growth control is indisputable: in particular, FGF1 and its tyrosine kinase receptor (FGFR1 act through a very complex network of mechanisms and pathways. In this work we have evaluated the antiproliferative activity effect of PD166866, a synthetic molecule inhibiting the tyrosin kinase action of FGFR1. Methods Cells were routinely grown in Dulbecco Modified Eagle's medium supplemented with newborn serum and a penicillin-streptomycin mixture. Cell viability was evaluated by Mosmann assay and by trypan blue staining. DNA damage was assessed by in situ fluorescent staining with Terminal Deoxynucleotidyl Transferase dUTP nick end labeling (TUNEL assay. Assessment of oxidative stress at membrane level was measured by quantitative analysis of the intra-cellular formation of malonyl-dialdheyde (MDA deriving from the decomposition of poly-unsaturated fatty acids. The expression of Poly-ADP-Ribose-Polymerase (PARP, consequent to DNA fragmentation, was evidenced by immuno-histochemistry utilizing an antibody directed against an N-terminal fragment of the enzyme. Results The bioactivity of the drug was investigated on Hela cells. Cytoxicity was assessed by the Mosmann assay and by vital staining with trypan blue. The target of the molecule is most likely the cell membrane as shown by the significant increase of the intracellular concentration of malonyl-dihaldheyde. The increase of this compound, as a consequence of the treatment with PD166866, is suggestive of membrane lipoperoxidation. The TUNEL assay gave a qualitative, though clear, indication of DNA damage. Furthermore we demonstrate intracellular accumulation of poly-ADP-ribose polymerase I. This enzyme is a sensor of nicks on the DNA strands and this supports the idea that treatment with the drug induces cell

  17. Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth.

    Science.gov (United States)

    Chua, Ming Jang; Arnold, Megan S J; Xu, Weijun; Lancelot, Julien; Lamotte, Suzanne; Späth, Gerald F; Prina, Eric; Pierce, Raymond J; Fairlie, David P; Skinner-Adams, Tina S; Andrews, Katherine T

    2017-04-01

    Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC 50 9-370 nM), with belinostat, panobinostat and vorinostat having 8-45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC 50  > 20 μM) or S. mansoni schistosomula (IC 50  > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC 50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4-7 and 4-10 after infection (P < 0.05), respectively. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

    Directory of Open Access Journals (Sweden)

    Ming Jang Chua

    2017-04-01

    Full Text Available Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9–370 nM, with belinostat, panobinostat and vorinostat having 8–45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF or human embryonic kidney (HEK 293 cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM or S. mansoni schistosomula (IC50 > 10 μM, however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM. Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days, with a significant reduction in parasitemia observed on days 4–7 and 4–10 after infection (P < 0.05, respectively.

  19. In silico-based identification of human α-enolase inhibitors to block cancer cell growth metabolically

    Science.gov (United States)

    Lung, Jrhau; Chen, Kuan-Liang; Hung, Chien-Hui; Chen, Chih-Cheng; Hung, Ming-Szu; Lin, Yu-Ching; Wu, Ching-Yuan; Lee, Kuan-Der; Shih, Neng-Yao; Tsai, Ying Huang

    2017-01-01

    Unlimited growth of cancer cells requires an extensive nutrient supply. To meet this demand, cancer cells drastically upregulate glucose uptake and metabolism compared to normal cells. This difference has made the blocking of glycolysis a fascinating strategy to treat this malignant disease. α-enolase is not only one of the most upregulated glycolytic enzymes in cancer cells, but also associates with many cellular processes or conditions important to cancer cell survival, such as cell migration, invasion, and hypoxia. Targeting α-enolase could simultaneously disturb cancer cells in multiple ways and, therefore, is a good target for anticancer drug development. In the current study, more than 22 million chemical structures meeting the criteria of Lipinski’s rule of five from the ZINC database were docked to α-enolase by virtual screening. Twenty-four chemical structures with docking scores better than that of the enolase substrate, 2-phosphoglycerate, were further screened by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties prediction. Four of them were classified as non-mutagenic, non-carcinogenic, and capable of oral administration where they showed steady interactions to α-enolase that were comparable, even superior, to the currently available inhibitors in molecular dynamics (MD) simulation. These compounds may be considered promising leads for further development of the α-enolase inhibitors and could help fight cancer metabolically. PMID:29180852

  20. Compost and Crude Humic Substances Produced from Selected Wastes and Their Effects on Zea mays L. Nutrient Uptake and Growth

    Science.gov (United States)

    Palanivell, Perumal; Susilawati, Kasim; Ahmed, Osumanu Haruna; Majid, Nik Muhamad

    2013-01-01

    Production of agriculture and timber commodities leads generation of enormous quantity of wastes. Improper disposal of these agroindustrial wastes pollutes the environment. This problem could be reduced by adding value to them. Therefore, a study was carried out to analyse and compare the nutrients content of RS, RH, SD, and EFB of composts and crude humic substances; furthermore, their effect on growth, dry matter production, and nutrient uptake for Zea mays L., and selected soil chemical properties were evaluated. Standard procedures were used to analyze humic acids (HA), crude fulvic acids (CFA), crude humin (CH), soil, dry matter production and nutrient uptake. Sawdust and RS compost matured at 42 and 47 days, respectively, while RH and EFB composts were less matured at 49th day of composting. Rice straw compost had higher ash, N, P, CEC, HA, K, and Fe contents with lower organic matter, total organic carbon, and C/N and C/P ratios. The HA of sawdust compost showed higher carbon, carboxylic, K, and Ca contents compared to those of RS, RH, and EFB. Crude FA of RS compost showed highest pH, total K, Ca, Mg, and Na contents. Crude humin from RS compost had higher contents of ash, N, P, and CEC. Rice straw was superior in compost, CFA, and CH, while sawdust compost was superior in HA. Application of sawdust compost significantly increased maize plants' diameter, height, dry matter production, N, P, and cations uptake. It also reduced N, P, and K based chemical fertilizer use by 90%. Application of CH and the composts evaluated in this study could be used as an alternative for chemical fertilizers in maize cultivation. PMID:24319353

  1. Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-β superfamily inhibitors.

    Science.gov (United States)

    Mies, Anna; Platzbecker, Uwe

    2017-07-01

    Patients with lower-risk myelodysplastic syndromes (MDS) are mainly affected by chronic anemia and fatigue. Treatment strategies aim to improve anemia and quality of life, as well as iron overload due to red blood cell transfusion support. To promote proliferation and differentiation of erythropoiesis, erythropoiesis-stimulating agents (ESAs) such as erythropoietin (EPO) and mimetics are applied as first-line therapy in a large fraction of lower-risk MDS patients. In general, ESAs yield favorable responses in about half of the patients, although responses are often short-lived. In fact, many ESA-refractory patients harbor defects in late-stage erythropoiesis downstream of EPO action. Novel transforming growth factor (TGF)-β superfamily inhibitors sotatercept and luspatercept represent a promising approach to alleviate anemia by stimulating erythroid differentiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer

    International Nuclear Information System (INIS)

    Dovzhanskiy, Dmitriy I; Arnold, Stefanie M; Hackert, Thilo; Oehme, Ina; Witt, Olaf; Felix, Klaus; Giese, Nathalia; Werner, Jens

    2012-01-01

    Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited. Histone deacetylase inhibitors are a new and promising drug family with strong anticancer activity. The aim of this study was to examine the efficacy of in vitro and in vivo treatment with the novel pan-HDAC inhibitor belinostat on the growth of human PDAC cells. The proliferation of tumour cell lines (T3M4, AsPC-1 and Panc-1) was determined using an MTT assay. Apoptosis was analysed using flow cytometry. Furthermore, p21 Cip1/Waf1 and acetylated histone H4 (acH4) expression were confirmed by immunoblot analysis. The in vivo effect of belinostat was studied in a chimeric mouse model. Antitumoural activity was assessed by immunohistochemistry for Ki-67. Treatment with belinostat resulted in significant in vitro and in vivo growth inhibition of PDAC cells. This was associated with a dose-dependent induction of tumour cell apoptosis. The apoptotic effect of gemcitabine was further enhanced by belinostat. Moreover, treatment with belinostat increased expression of the cell cycle regulator p21 Cip1/Waf1 in Panc-1, and of acH4 in all cell lines tested. The reductions in xenograft tumour volumes were associated with inhibition of cell proliferation. Experimental treatment of human PDAC cells with belinostat is effective in vitro and in vivo and may enhance the efficacy of gemcitabine. A consecutive study of belinostat in pancreatic cancer patients alone, and in combination with gemcitabine, could further clarify these effects in the clinical setting

  3. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

    Directory of Open Access Journals (Sweden)

    Zhang H

    2016-11-01

    Full Text Available Haijun Zhang Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Republic of China Abstract: Lung cancer, ~80%–85% of which is non-small-cell lung cancer (NSCLC, is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR gene (EGFRm+, such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs. Keywords: lung cancer, epidermal growth factor receptor, tyrosine kinase inhibitors, T790M mutation

  4. Significance of Interleukin-6 Signaling in the Resistance of Pharyngeal Cancer to Irradiation and the Epidermal Growth Factor Receptor Inhibitor

    International Nuclear Information System (INIS)

    Chen, C.-C.; Chen, W.-C.; Lu, C.-H.; Wang, W.-H.; Lin, P.-Y.; Lee, K.-D.; Chen, M.-F.

    2010-01-01

    Purpose: Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful. Targeting epithelial growth factor receptor (EGFR) could be a potential treatment strategy providing additional benefits, but only a subset of these tumors gives a clinically significant response to EGFR inhibitors. The aim has been to identify the role of interleukin-6 (IL-6) signaling and its predictive power in the treatment response of pharyngeal cancer. Methods and Materials: Human pharyngeal cancer cell lines, including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu-C225-R, were selected. Changes in tumor growth, response to treatment, and responsible signaling pathway were investigated in vitro. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining, and correlations were made between levels of IL-6, IL-6 receptor (IL-6R), p-AKT, and p-STAT3 expression and the clinical outcome of patients. Results: In vitro, either extrinsic IL-6 stimulation of cancer cells or intrinsically activated IL-6 signaling detected in FADu-C225-R cells results in resistance to irradiation and EGFR inhibitor. Blocking IL-6 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments. The responsible mechanisms included decreased p-STAT3, less nuclear translocation of EGFR, and subsequently attenuated epithelial-mesenchymal transition. Regarding clinical data, staining of p-STAT3 and IL-6 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients. Conclusions: IL-6 and p-STAT3 may be significant predictors of pharyngeal carcinoma, and regulating IL-6 signaling can be considered a promising therapeutic approach.

  5. A RhoGDP dissociation inhibitor spatially regulates growth in root hair cells

    Czech Academy of Sciences Publication Activity Database

    Carol, R.J.; Takeda, S.; Linstead, P.; Durrant, M.C.; Toupalová, Hana; Derbyshire, P.; Drea, S.; Žárský, Viktor; Dolan, L.

    2005-01-01

    Roč. 438, č. 7070 (2005), s. 1013-1016 ISSN 0028-0836 R&D Projects: GA ČR GA204/02/1461 Institutional research plan: CEZ:AV0Z50380511 Keywords : NADPH OXIDASE * MEDICAGO-TRUNCATULA * TIP GROWTH Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 29.273, year: 2005

  6. An application of analyzing the trajectories of two disorders: A parallel piecewise growth model of substance use and attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Mamey, Mary Rose; Barbosa-Leiker, Celestina; McPherson, Sterling; Burns, G Leonard; Parks, Craig; Roll, John

    2015-12-01

    Researchers often want to examine 2 comorbid conditions simultaneously. One strategy to do so is through the use of parallel latent growth curve modeling (LGCM). This statistical technique allows for the simultaneous evaluation of 2 disorders to determine the explanations and predictors of change over time. Additionally, a piecewise model can help identify whether there are more than 2 growth processes within each disorder (e.g., during a clinical trial). A parallel piecewise LGCM was applied to self-reported attention-deficit/hyperactivity disorder (ADHD) and self-reported substance use symptoms in 303 adolescents enrolled in cognitive-behavioral therapy treatment for a substance use disorder and receiving either oral-methylphenidate or placebo for ADHD across 16 weeks. Assessing these 2 disorders concurrently allowed us to determine whether elevated levels of 1 disorder predicted elevated levels or increased risk of the other disorder. First, a piecewise growth model measured ADHD and substance use separately. Next, a parallel piecewise LGCM was used to estimate the regressions across disorders to determine whether higher scores at baseline of the disorders (i.e., ADHD or substance use disorder) predicted rates of change in the related disorder. Finally, treatment was added to the model to predict change. While the analyses revealed no significant relationships across disorders, this study explains and applies a parallel piecewise growth model to examine the developmental processes of comorbid conditions over the course of a clinical trial. Strengths of piecewise and parallel LGCMs for other addictions researchers interested in examining dual processes over time are discussed. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

  7. Registered report: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors2

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: Edward Greenfield, Erin Griner, The Reproducibility Project: Cancer Biology† ### Abstract The [Reproducibility Project: Cancer Biology](https://osf.io/e81xl/wiki/home/) seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered Report describes the proposed replication plan of key experiments from “Widespread potential for growth-factor-d...

  8. The Effect of Robusta Coffe Extract (Coffea Robusta) as Inhibitors of Growth Staphylococcus Aureus

    OpenAIRE

    Mumun Nurmilawati, Muhammad Ainul Yaqin

    2015-01-01

    Chlorogenic and caffeine acid, which is a non-volatile organic acids in coffee, which can prevent the growth of some gram-positive and gram-negative bacteria including Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Pseudomonas fluorescens, Staphylococcus aureus, Bacillus cereus, Lactobacillus bulgaricus, Streptococcus lactis and Streptococcus faecalis.Subject used in this study was Staphylococcus aureus were divided into 5 groups, where each group consisting of 8 repetitions. The...

  9. Insulin-like Growth Factor Receptor Inhibitors: Baby or the Bathwater?

    OpenAIRE

    Yee, Douglas

    2012-01-01

    The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response...

  10. Validation of FRET Assay for the Screening of Growth Inhibitors of Escherichia coli Reveals Elongasome Assembly Dynamics

    Science.gov (United States)

    van der Ploeg, René; Goudelis, Spyridon Theodoros; den Blaauwen, Tanneke

    2015-01-01

    The increase in antibiotic resistant bacteria demands the development of new antibiotics against preferably new targets. The common approach is to test compounds for their ability to kill bacteria or to design molecules that inhibit essential protein activities in vitro. In the first case, the mode of action of the drug is unknown and in the second case, it is not known whether the compound will pass the impermeable barrier of the bacterial envelope. We developed an assay that detects the target of a compound, as well as its ability to pass the membrane(s) simultaneously. The Escherichia coli cytoskeletal protein MreB recruits protein complexes (elongasomes) that are essential for cell envelope growth. An in cell Förster Resonance Energy Transfer (FRET) assay was developed to detect the interaction between MreB molecules and between MreB and the elongasome proteins RodZ, RodA and PBP2. Inhibition of the polymerization of MreB by S-(3,4-dichlorobenzyl) isothiourea (A22) or of the activity of PBP2 by mecilinam resulted in loss or reduction of all measured interactions. This suggests that the interactions between the elongasome proteins are governed by a combination of weak affinities and substrate availability. This validated in cell FRET assay can be used to screen for cell envelope growth inhibitors. PMID:26263980

  11. Validation of FRET Assay for the Screening of Growth Inhibitors of Escherichia coli Reveals Elongasome Assembly Dynamics

    Directory of Open Access Journals (Sweden)

    René van der Ploeg

    2015-07-01

    Full Text Available The increase in antibiotic resistant bacteria demands the development of new antibiotics against preferably new targets. The common approach is to test compounds for their ability to kill bacteria or to design molecules that inhibit essential protein activities in vitro. In the first case, the mode of action of the drug is unknown and in the second case, it is not known whether the compound will pass the impermeable barrier of the bacterial envelope. We developed an assay that detects the target of a compound, as well as its ability to pass the membrane(s simultaneously. The Escherichia coli cytoskeletal protein MreB recruits protein complexes (elongasomes that are essential for cell envelope growth. An in cell Förster Resonance Energy Transfer (FRET assay was developed to detect the interaction between MreB molecules and between MreB and the elongasome proteins RodZ, RodA and PBP2. Inhibition of the polymerization of MreB by S-(3,4-dichlorobenzyl isothiourea (A22 or of the activity of PBP2 by mecilinam resulted in loss or reduction of all measured interactions. This suggests that the interactions between the elongasome proteins are governed by a combination of weak affinities and substrate availability. This validated in cell FRET assay can be used to screen for cell envelope growth inhibitors.

  12. Mechanisms Down-Regulating Sprouty1, a Growth Inhibitor in Prostate Cancer

    Science.gov (United States)

    2008-10-01

    fibroblast growth factor signaling is down-regulated in prostate cancer. Kwabi-Addo B (2004) Orlando, FL (Oral; mini symposium). • AACR/NCI/EORTC...contains a classic signal peptide PP FRS2 Sos Grb2 Cbl Ras FGFR1-DN MEK ERK STAT3 STAT3 Sprouty PLC - Extracellular stimulus Nucleus P Raf PI3K Receptor... thesis system for reverse transcription-PCR and according to the manufactur- er’s protocol. Real-time PCR was carried out in a Bio-Rad iCycler real

  13. The Histone Deacetylase Inhibitor, Vorinostat, Reduces Tumor Growth at the Metastatic Bone Site and Associated Osteolysis, but Promotes Normal Bone Loss

    OpenAIRE

    Pratap, Jitesh; Akech, Jacqueline; Wixted, John J.; Szabo, Gabriela; Hussain, Sadiq; McGee-Lawrence, Meghan E.; Li, Xiaodong; Bedard, Krystin; Dhillon, Robinder J.; van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.; Westendorf, Jennifer J.; Lian, Jane B.

    2010-01-01

    Vorinostat, an oral histone deacetylase inhibitor with anti-tumor activity, is in clinical trials for hematological and solid tumors that metastasize and compromise bone structure. Consequently, there is a requirement to establish the effects of vorinostat on tumor growth within bone. Breast (MDA-231) and prostate (PC3) cancer cells were injected into tibias of SCID/NCr mice and the effects of vorinostat on tumor growth and osteolytic disease were assessed by radiography, μCT, histological an...

  14. The intestinotrophic peptide, GLP-2, counteracts the gastrointestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, erlotinib, and cisplatin

    DEFF Research Database (Denmark)

    Rasmussen, Andreas Rosén; Viby, Niels-Erik; Hare, Kristine Juul

    2010-01-01

    Erlotinib, an epidermal-growth-factor receptor inhibitor, belongs to a new generation of targeted cancer therapeutics. Gastrointestinal side-effects are common and have been markedly aggravated when erlotinib is combined with cytostatics. We examined the effects of erlotinib alone and combined wi...

  15. Dead Pericarps of Dry Fruits Function as Long-Term Storage for Active Hydrolytic Enzymes and Other Substances That Affect Germination and Microbial Growth

    Directory of Open Access Journals (Sweden)

    James Godwin

    2017-12-01

    Full Text Available It is commonly assumed that dead pericarps of dry indehiscent fruits have evolved to provide an additional physical layer for embryo protection and as a means for long distance dispersal. The pericarps of dry fruits undergo programmed cell death (PCD during maturation whereby most macromolecules such DNA, RNA, and proteins are thought to be degraded and their constituents remobilized to filial tissues such as embryo and endosperm. We wanted to test the hypothesis that the dead pericarp represents an elaborated layer that is capable of storing active proteins and other substances for increasing survival rate of germinating seeds. Using in gel assays we found that dead pericarps of both dehiscent and indehiscent dry fruits of various plant species including Arabidopsis thaliana and Sinapis alba release upon hydration multiple active hydrolytic enzymes that can persist in an active form for decades, including nucleases, proteases, and chitinases. Proteomic analysis of indehiscent pericarp of S. alba revealed multiple proteins released upon hydration, among them proteases and chitinases, as well as proteins involved in reactive oxygen species (ROS detoxification and cell wall modification. Pericarps appear to function also as a nutritional element-rich storage for nitrate, potassium, phosphorus, sulfur, and others. Sinapis alba dehiscent and indehiscent pericarps possess germination inhibitory substances as well as substances that promote microbial growth. Collectively, our study explored previously unknown features of the dead pericarp acting also as a reservoir of biological active proteins, and other substances capable of “engineering” the microenvironment for the benefit of the embryo.

  16. Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors.

    Science.gov (United States)

    Taniguchi, Hirokazu; Takeuchi, Shinji; Fukuda, Koji; Nakagawa, Takayuki; Arai, Sachiko; Nanjo, Shigeki; Yamada, Tadaaki; Yamaguchi, Hiroyuki; Mukae, Hiroshi; Yano, Seiji

    2017-01-01

    Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  17. Influence of Plant Growth Regulators and Humic Substance on the Phytoremediation of Nickel in a Ni-Polluted Soil

    Directory of Open Access Journals (Sweden)

    Mahshid Shafigh

    2017-06-01

    Full Text Available Introduction: Plants can uptake, bioaccumulate and immobilize different metals in their tissues. Phytoremediation technique has been used to remove hazardous substances including heavy metals from the environment. Assisted phytoremediation is usually the process of applying a chemical additive to heavy metal contaminated soils to enhance the metal uptake by plants. The main objective of present study was to investigate the effectiveness of plant growth regulators (PGRs and a humic substance (HS on Ni phytoremediation by maize in a Ni-pollutrd calcareous soil. Materials and Methods: The experiment designed as a 5×3 factorial trial arranged in a completely randomized design with three replicates. Three kilograms of soil was placed in plastic pots and pots were watered with distilled water to field capacity and maintained at this moisture level throughout the experiment by watering the pots to a constant weight. The soils were polluted with 250 mg Ni Kg-1 as Ni-nitrate Ni (NO32. Six maize (Zea mays L. seeds were planted 2 cm deep in soil and thinned to three uniform stands 1 week after emergence. Treatments consisted of three levels of soil application of commercially humic substance, HS, (0, 3, and 6 mg kg as Humax 95-WSG containing about 80% humic acid, and about 15% fulvic acid and five levels of PGRs (0 or 10 µM GA3, IAA, BAP and SA. The HS was applied as split doses in three times at 15 day intervals along with irrigation water. The seedlings were exposed to aqueous solutions of HS 16 days after sowing for the first time. Prepared solutions of PGRs were sprayed three times at 15 day intervals from emergence. Seven weeks after planting, shoots were harvested and roots were separated from soil carefully, both parts were rinsed with distilled water and dried at 65°C for 72 h, weighed, ground, and dry meshed at 550°C. Root and shoot dry matter and Ni concentration and uptake and phytoremediation criteria were considered as plant responses

  18. Intron retention regulates the expression of pectin methyl esterase inhibitor (Pmei) genes during wheat growth and development.

    Science.gov (United States)

    Rocchi, V; Janni, M; Bellincampi, D; Giardina, T; D'Ovidio, R

    2012-03-01

    Pectin is an important component of the plant cell wall and its remodelling occurs during normal plant growth or following stress responses. Pectin is secreted into the cell wall in a highly methyl-esterified form and subsequently de-methyl-esterified by pectin methyl esterase (PME), whose activity is controlled by the pectin methyl esterase inhibitor protein (PMEI). Cereal cell wall contains a low amount of pectin; nonetheless the level and pattern of pectin methyl esterification play a primary role during development or pathogen infection. Since few data are available on the role of PMEI in plant development and defence of cereal species, we isolated and characterised three Pmei genes (Tdpmei2.1, Tdpmei2.2 and Tdpmei3) and their encoded products in wheat. Sequence comparisons showed a low level of intra- and inter-specific sequence conservation of PMEIs. Tdpmei2.1 and Tdpmei2.2 share 94% identity at protein level, but only 20% identity with the product of Tdpmei3. All three Tdpmei genes code for functional inhibitors of plant PMEs and do not inhibit microbial PMEs or a plant invertase. RT-PCR analyses demonstrated, for the first time to our knowledge, that Pmei genes are regulated by intron retention. Processed and unprocessed transcripts of Tdpmei2.1 and Tdpmei2.2 accumulated in several organs, but anthers contained only mature transcripts. Tdpmei3 lacks introns and its transcript accumulated mainly in stem internodes. These findings suggest that products encoded by these Tdpmei genes control organ- or tissue-specific activity of specific PME isoforms in wheat. © 2011 German Botanical Society and The Royal Botanical Society of the Netherlands.

  19. Clinical development of galunisertib (LY2157299 monohydrate, a small molecule inhibitor of transforming growth factor-beta signaling pathway

    Directory of Open Access Journals (Sweden)

    Herbertz S

    2015-08-01

    Full Text Available Stephan Herbertz,1 J Scott Sawyer,2 Anja J Stauber,2 Ivelina Gueorguieva,3 Kyla E Driscoll,4 Shawn T Estrem,2 Ann L Cleverly,3 Durisala Desaiah,2 Susan C Guba,2 Karim A Benhadji,2 Christopher A Slapak,2 Michael M Lahn21Lilly Deutschland GmbH, Bad Homburg, Germany; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK; 4Lilly Research Laboratories, Eli Lilly and Company, New York, NY, USA Abstract: Transforming growth factor-beta (TGF-β signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab

  20. Dialkoxyquinazolines: Screening Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

    Energy Technology Data Exchange (ETDEWEB)

    VanBrocklin, Henry F.; Lim, John K.; Coffing, Stephanie L.; Hom,Darren L.; Negash, Kitaw; Ono, Michele Y.; Hanrahan, Stephen M.; Taylor,Scott E.; Vanderpoel, Jennifer L.; Slavik, Sarah M.; Morris, Andrew B.; Riese II, David J.

    2005-09-01

    The epidermal growth factor receptor (EGFR), a long-standingdrug development target, is also a desirable target for imaging. Sixteendialkoxyquinazoline analogs, suitable for labeling with positron-emittingisotopes, have been synthesized and evaluated in a battery of in vitroassays to ascertain their chemical and biological properties. Thesecharacteristics provided the basis for the adoption of a selection schemato identify lead molecules for labeling and in vivo evaluation. A newEGFR tyrosine kinase radiometric binding assay revealed that all of thecompounds possessed suitable affinity (IC50 = 0.4 - 51 nM) for the EGFRtyrosine kinase. All of the analogs inhibited ligand-induced EGFRtyrosine phosphorylation (IC50 = 0.8 - 20 nM). The HPLC-estimatedoctanol/water partition coefficients ranged from 2.0-5.5. Four compounds,4-(2'-fluoroanilino)- and 4-(3'-fluoroanilino)-6,7-diethoxyquinazoline aswell as 4-(3'-chloroanilino)- and4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the bestcombination of characteristics that warrant radioisotope labeling andfurther evaluation in tumor-bearing mice.

  1. Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors.

    Science.gov (United States)

    Cui, Jing; Peng, Xia; Gao, Dingding; Dai, Yang; Ai, Jing; Li, Yingxia

    2017-08-15

    Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy because of its critical role in promoting cancer formation and progression. In a continuing effort to improve the cellular activity of hit compound 7r bearing an indazole scaffold, which was previously discovered by our group, several compounds harnessing fluorine substituents were designed, synthesized and biological evaluated. Besides, the region extended out to the ATP binding pocket toward solvent was also explored. Among them, compound 2a containing 2,6-difluoro-3-methoxyphenyl residue exhibited the most potent activities (FGFR1: less than 4.1nM, FGFR2: 2.0±0.8nM). More importantly, compound 2a showed an improved antiproliferative effect against KG1 cell lines and SNU16 cell lines with IC 50 values of 25.3±4.6nM and 77.4±6.2nM respectively. Copyright © 2017. Published by Elsevier Ltd.

  2. Dialkoxyquinazolines: Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

    International Nuclear Information System (INIS)

    VanBrocklin, Henry F.; Lim, John K.; Coffing, Stephanie L.; Hom, Darren L.; Negash, Kitaw; Ono, Michele Y.; Hanrahan, Stephen M.; Taylor, Scott E.; Vanderpoel, Jennifer L.; Slavik, Sarah M.; Morris, Andrew B.; Riese II, David J.

    2005-01-01

    The epidermal growth factor receptor (EGFR), a long-standing drug development target, is also a desirable target for imaging. Sixteen dialkoxyquinazoline analogs, suitable for labeling with positron-emitting isotopes, have been synthesized and evaluated in a battery of in vitro assays to ascertain their chemical and biological properties. These characteristics provided the basis for the adoption of a selection schema to identify lead molecules for labeling and in vivo evaluation. A newEGFR tyrosine kinase radiometric binding assay revealed that all of the compounds possessed suitable affinity (IC50 = 0.4 - 51 nM) for the EGFR tyrosine kinase. All of the analogs inhibited ligand-induced EGFR tyrosine phosphorylation (IC50 = 0.8 - 20 nM). The HPLC-estimated octanol/water partition coefficients ranged from 2.0-5.5. Four compounds,4-(2'-fluoroanilino)- and 4-(3'-fluoroanilino)-6,7-diethoxyquinazoline as well as 4-(3'-chloroanilino)- and4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the best combination of characteristics that warrant radioisotope labeling and further evaluation in tumor-bearing mice

  3. Personalized Radiation Oncology: Epidermal Growth Factor Receptor and Other Receptor Tyrosine Kinase Inhibitors.

    Science.gov (United States)

    Higgins, Geoff S; Krause, Mechthild; McKenna, W Gillies; Baumann, Michael

    Molecular biomarkers are currently evaluated in preclinical and clinical studies in order to establish predictors for treatment decisions in radiation oncology. The receptor tyrosine kinases (RTK) are described in the following text. Among them, the most data are available for the epidermal growth factor receptor (EGFR) that plays a major role for prognosis of patients after radiotherapy, but seems also to be involved in mechanisms of radioresistance, specifically in repopulation of tumour cells between radiotherapy fractions. Monoclonal antibodies against the EGFR improve locoregional tumour control and survival when applied during radiotherapy, however, the effects are heterogeneous and biomarkers for patient selection are warranted. Also other RTK´s such as c-Met and IGF-1R seem to play important roles in tumour radioresistance. Beside the potential to select patients for molecular targeting approaches combined with radiotherapy, studies are also needed to evluate radiotherapy adaptation approaches for selected patients, i.e. adaptation of radiation dose, or, more sophisticated, of target volumes.

  4. Pantothenamides are potent, on-target inhibitors of Plasmodium falciparum growth when serum pantetheinase is inactivated.

    Directory of Open Access Journals (Sweden)

    Christina Spry

    Full Text Available Growth of the virulent human malaria parasite Plasmodium falciparum is dependent on an extracellular supply of pantothenate (vitamin B(5 and is susceptible to inhibition by pantothenate analogues that hinder pantothenate utilization. In this study, on the hunt for pantothenate analogues with increased potency relative to those reported previously, we screened a series of pantothenamides (amide analogues of pantothenate against P. falciparum and show for the first time that analogues of this type possess antiplasmodial activity. Although the active pantothenamides in this series exhibit only modest potency under standard in vitro culture conditions, we show that the potency of pantothenamides is selectively enhanced when the parasite culture medium is pre-incubated at 37°C for a prolonged period. We present evidence that this finding is linked to the presence in Albumax II (a serum-substitute routinely used for in vitro cultivation of P. falciparum of pantetheinase activity: the activity of an enzyme that hydrolyzes the pantothenate metabolite pantetheine, for which pantothenamides also serve as substrates. Pantetheinase activity, and thereby pantothenamide degradation, is reduced following incubation of Albumax II-containing culture medium for a prolonged period at 37°C, revealing the true, sub-micromolar potency of pantothenamides. Importantly we show that the potent antiplasmodial effect of pantothenamides is attenuated with pantothenate, consistent with the compounds inhibiting parasite proliferation specifically by inhibiting pantothenate and/or CoA utilization. Additionally, we show that the pantothenamides interact with P. falciparum pantothenate kinase, the first enzyme involved in converting pantothenate to coenzyme A. This is the first demonstration of on-target antiplasmodial pantothenate analogues with sub-micromolar potency, and highlights the potential of pantetheinase-resistant pantothenamides as antimalarial agents.

  5. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth.

    Science.gov (United States)

    Bowden, Gregory D; Land, Kirkwood M; O'Connor, Roberta M; Fritz, Heather M

    2018-04-01

    The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60-70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036-0.12; 95% CI] or 21.9 ng/ml [12.1-40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection. Copyright © 2018. Published by Elsevier Ltd.

  6. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth

    Directory of Open Access Journals (Sweden)

    Gregory D. Bowden

    2018-04-01

    Full Text Available The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM, a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60–70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83% have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18 of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036–0.12; 95% CI] or 21.9 ng/ml [12.1–40.3; 95% CI]. These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection. Keywords: Drug repurposing, High-throughput screen, Sarcocystis neurona, Equine protozoal myeloencephalitis

  7. The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation.

    Science.gov (United States)

    Larkin, Emily; Hager, Christopher; Chandra, Jyotsna; Mukherjee, Pranab K; Retuerto, Mauricio; Salem, Iman; Long, Lisa; Isham, Nancy; Kovanda, Laura; Borroto-Esoda, Katyna; Wring, Steve; Angulo, David; Ghannoum, Mahmoud

    2017-05-01

    Candida auris , a new multidrug-resistant Candida spp. which is associated with invasive infection and high rates of mortality, has recently emerged. Here, we determined the virulence factors (germination, adherence, biofilm formation, phospholipase and proteinase production) of 16 C. auris isolates and their susceptibilities to 11 drugs belonging to different antifungal classes, including a novel orally bioavailable 1,3-β-d-glucan synthesis inhibitor (SCY-078). We also examined the effect of SCY-078 on the growth, ultrastructure, and biofilm-forming abilities of C. auris Our data showed that while the tested strains did not germinate, they did produce phospholipase and proteinase in a strain-dependent manner and had a significantly reduced ability to adhere and form biofilms compared to that of Candida albicans ( P = 0.01). C. auris isolates demonstrated reduced susceptibility to fluconazole and amphotericin B, while, in general, they were susceptible to the remaining drugs tested. SCY-078 had an MIC 90 of 1 mg/liter against C. auris and caused complete inhibition of the growth of C. auris and C. albicans Scanning electron microscopy analysis showed that SCY-078 interrupted C. auris cell division, with the organism forming abnormal fused fungal cells. Additionally, SCY-078 possessed potent antibiofilm activity, wherein treated biofilms demonstrated significantly reduced metabolic activity and a significantly reduced thickness compared to the untreated control ( P < 0.05 for both comparisons). Our study shows that C. auris expresses several virulence determinants (albeit to a lesser extent than C. albicans ) and is resistant to fluconazole and amphotericin B. SCY-078, the new orally bioavailable antifungal, had potent antifungal/antibiofilm activity against C. auris , indicating that further evaluation of this antifungal is warranted. Copyright © 2017 Larkin et al.

  8. Increased Bowel Toxicity in Patients Treated With a Vascular Endothelial Growth Factor Inhibitor (VEGFI) After Stereotactic Body Radiation Therapy (SBRT)

    Energy Technology Data Exchange (ETDEWEB)

    Barney, Brandon M., E-mail: barney.brandon@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Markovic, Svetomir N. [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Laack, Nadia N.; Miller, Robert C.; Sarkaria, Jann N. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Macdonald, O. Kenneth [Therapeutic Radiologists Incorporated, Kansas City, Kansas (United States); Bauer, Heather J.; Olivier, Kenneth R. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2013-09-01

    Purpose: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. Methods and Materials: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. Results: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log–rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). Conclusions: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future.

  9. Use of Aromatase Inhibitors in Large Cell Calcifying Sertoli Cell Tumors: Effects on Gynecomastia, Growth Velocity, and Bone Age

    Science.gov (United States)

    Crocker, Melissa K.; Gourgari, Evgenia; Stratakis, Constantine A.

    2014-01-01

    Context: Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. Objective: To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. Design: Case series of a very rare tumor and chart review of cases treated at other institutions. Setting: Tertiary care and referral center. Patients: Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. Interventions: Patients were treated for a total of 6–60 months on AIT. Main Outcome Measures: Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. Results: Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. Conclusions: Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy. PMID:25226294

  10. The heat shock protein 90 inhibitor 17-AAG suppresses growth and induces apoptosis in human cholangiocarcinoma cells.

    Science.gov (United States)

    Zhang, Jianjun; Zheng, Zhichao; Zhao, Yan; Zhang, Tao; Gu, Xiaohu; Yang, Wei

    2013-11-01

    The aim of this study was to investigate the effects of 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a heat shock protein 90 (HSP90) inhibitor, on the proliferation, cell cycle, and apoptosis of human cholangiocarcinoma (CCA) cells. Cell proliferation and cell cycle distribution were measured by the MTT assay and flow cytometry analysis, respectively. Induction of apoptosis was determined by flow cytometry and Hoechst staining. The expressions of cleaved poly ADP-ribose polymerase (PARP), Bcl-2, Survivin, and Cyclin B1 were detected by Western blot analysis. The activity of caspase-3 was also examined. We found that 17-AAG inhibited cell growth and induced G2/M cell cycle arrest and apoptosis in CCA cells together with the down-regulation of Bcl-2, Survivin and Cyclin B1, and the up-regulation of cleaved PARP. Moreover, increased caspase-3 activity was also observed in CCA cells treated with 17-AAG. In conclusion, our data suggest that the inhibition of HSP90 function by 17-AAG may provide a promising therapeutic strategy for the treatment of human CCA.

  11. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.

    Science.gov (United States)

    Liu, Bing; Huang, XinPing; Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

    2016-09-06

    Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.

  12. Aurora kinase inhibitors attached to iron oxide nanoparticles enhances inhibition of the growth of liver cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xiquan [Southeast University, State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering (China); Xie, Li [Southeast University, Zhongda Hospital, School of Medicine (China); Zheng, Ming; Yao, Juan [Jiangsu Chai Tai Tianqing Pharmaceutical Co. Ltd. (China); Song, Lina [Southeast University, State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering (China); Chang, Weiwei [Jiangsu Chai Tai Tianqing Pharmaceutical Co. Ltd. (China); Zhang, Yu; Ji, Min, E-mail: minji888@hotmail.com; Gu, Ning, E-mail: guning@seu.edu.cn [Southeast University, State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering (China); Zhan, Xi, E-mail: zhan01@gmail.com [University of Maryland School of Medicine, The Center of Vascular and Inflammatory Diseases, The Department of Pathology (United States)

    2015-06-15

    We have developed a novel Aurora kinase inhibitor (AKI) AM-005, an analogue of pan-AKI AT-9283. To improve the intracellular efficacy of AM-005 and AT-9283, we utilized magnetite nanoparticles (NPs) to deliver AM-005 and AT-9283 into human SMMC-7721 and HepG2 liver cancer cells. The drug-loaded NPs were prepared through quasi-emulsion solvent diffusion of magnetite NPs with AM-005 or AT-9283. The encapsulated drugs were readily released from NPs, preferentially at low pHs. Upon exposure, cancer cells effectively internalized drug-loaded NPs into lysosome-like vesicles, which triggered a series of cellular changes, including the formation of enlarged cytoplasm, the significant increase of membrane permeability, and the generation of reactive oxygen species (ROS). The increased ROS synthesis sustained over 72 h, whereas that in the cells treated with free-form drugs declined rapidly after 48 h. However, chemical sequestration of the iron core of NPs had a minor influence on the generation of intracellular ROS. On the other hand, uncoupling of AM-005 uptake with NP internalization into cells failed to induce ROS synthesis. Overall, our approach achieved two-fold increase in suppressing the viability of tumor cells in vitro and the growth of tumors in vivo. We conclude that magnetite NPs can be used as pH responsive nanocarriers that are able to improve the efficacy of AKIs.

  13. Growth and development of Colorado potato beetle larvae, Leptinotarsa decemlineata, on potato plants expressing the oryzacystatin II proteinase inhibitor.

    Science.gov (United States)

    Cingel, Aleksandar; Savić, Jelena; Vinterhalter, Branka; Vinterhalter, Dragan; Kostić, Miroslav; Jovanović, Darka Šešlija; Smigocki, Ann; Ninković, Slavica

    2015-08-01

    Plant proteinase inhibitors (PIs) are attractive tools for crop improvement and their heterologous expression can enhance insect resistance in transgenic plants. PI oryzacystatin II (OCII), isolated from rice, showed potential in controlling pests that utilize cysteine proteinases for protein digestion. To evaluate the applicability of the OCII gene in enhancing plant defence, OCII-transformed potatoes were bioassayed for resistance to Colorado potato beetle (Leptinotarsa decemlineata Say). Feeding on transformed leaves of potato cultivars Desiree and Jelica significantly affected larval growth and development, but did not change mortality rates. During the L2 and L3 developmental stages larvae consumed the OCII-transformed foliage faster as compared to the nontransformed control. Also these larvae reached the prepupal stage (end of L4 stage) 2 days earlier than those fed on control leaves. However, the total amounts of consumed OCII-transformed leaves were up to 23% lower than of control, and the maximal weights of prepupal larvae were reduced by up to 18% as compared to larvae fed on nontransformed leaves. The reduction in insect fitness reported in this study in combination with other control measures, could lead to improved CPB resistance management in potato.

  14. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Hua Xie

    Full Text Available Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h and sustained (≥24 h inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells.

  15. Development of potential selective and reversible pyrazoline based MAO-B inhibitors as MAO-B PET tracer precursors and reference substances for the early detection of Alzheimer's disease.

    Science.gov (United States)

    Neudorfer, Catharina; Shanab, Karem; Jurik, Andreas; Schreiber, Veronika; Neudorfer, Carolina; Vraka, Chrysoula; Schirmer, Eva; Holzer, Wolfgang; Ecker, Gerhard; Mitterhauser, Markus; Wadsak, Wolfgang; Spreitzer, Helmut

    2014-09-15

    Since high MAO-B levels are present in early stages of AD, the MAO-B system can be designated as an appropriate and prospective tracer target of molecular imaging biomarkers for the detection of early AD. According to the preceding investigations of Mishra et al. the aim of this work was the development of a compound library of selective and reversible MAO-B inhibitors by performing bioisosteric modifications of the core structure of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazoles. In conclusion, 13 new pyrazoline based derivatives have been prepared, which will serve as precursor substances for future radiolabeling as well as reference compounds for the investigation of increased MAO-B levels in AD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Abscinazole-F1, a conformationally restricted analogue of the plant growth retardant uniconazole and an inhibitor of ABA 8'-hydroxylase CYP707A with no growth-retardant effect.

    Science.gov (United States)

    Todoroki, Yasushi; Kobayashi, Kyotaro; Shirakura, Minaho; Aoyama, Hikaru; Takatori, Kokichi; Nimitkeatkai, Hataitip; Jin, Mei-Hong; Hiramatsu, Saori; Ueno, Kotomi; Kondo, Satoru; Mizutani, Masaharu; Hirai, Nobuhiro

    2009-09-15

    To develop a specific inhibitor of abscisic acid (ABA) 8'-hydroxylase, a key enzyme in the catabolism of ABA, a plant hormone involved in stress tolerance, seed dormancy, and other various physiological events, we designed and synthesized conformationally restricted analogues of uniconazole (UNI), a well-known plant growth retardant, which inhibits a biosynthetic enzyme (ent-kaurene oxidase) of gibberellin as well as ABA 8'-hydroxylase. Although most of these analogues were less effective than UNI in inhibition of ABA 8'-hydroxylase and rice seedling growth, we found that a lactol-bridged analogue with an imidazole is a potent inhibitor of ABA 8'-hydroxylase but not of plant growth. This compound, abscinazole-F1, induced drought tolerance in apple seedlings upon spray treatment with a 10 microM solution.

  17. Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors.

    Science.gov (United States)

    Akula, Sravani; Kamasani, Swapna; Sivan, Sree Kanth; Manga, Vijjulatha; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

    2018-05-01

    A significant proportion of patients with lung cancer carry mutations in the EGFR kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain has been shown to cause enhanced efficacy of inhibitor treatment in patients with NSCLC. Several less frequent (uncommon) mutations in the EGFR kinase domain with potential implications in treatment response have also been reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity or resistance. A large-scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed, and drug sensitivity profiles for each mutant toward seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity toward each drug as compared with that of adenosine triphosphate was calculated for each mutant. The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental, and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity toward first- and next-generation kinase inhibitors. The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  18. Mass production of 'Swan's Golden', Cupressus sempervirens by tissue culture and its radiation breeding. 2. Study on growth regulating substance to stimulate the elongation of shoot apex

    International Nuclear Information System (INIS)

    Suda, Hirokatsu

    1997-01-01

    Some species of 'Swan's Golden' have been propagated by means of grafting because propagation by cutting is difficult. However, not a few species of the plant are easily lodged, resulting that spreading of 'Swan's Golden' is difficult. Here, an investigation was made on growth regulating substances added into the basal medium in respects of their kinds and concentrations and also the kind of medium for successive culture. As the basal medium, SH medium supplemented with 4 g/l of gel-light and 3 g/l of carbon-powder was used. The optimum medium for the initiation of culture was the basal medium added with zeatin (Ze) and gibberellin (GA) and it was also suitable for successive culture after the 14 day. The medium added with Ze and benzyladenine (BA) or Ze alone was found to be most suitable for the culture after the 28 day. The concentration was optimum at 1 - 2.5 mg/l for either of these growth regulating substances. (M.N.)

  19. L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro.

    Science.gov (United States)

    Huang, Hongbiao; Liu, Ningning; Guo, Haiping; Liao, Siyan; Li, Xiaofen; Yang, Changshan; Liu, Shouting; Song, Wenbin; Liu, Chunjiao; Guan, Lixia; Li, Bing; Xu, Li; Zhang, Change; Wang, Xuejun; Dou, Q Ping; Liu, Jinbao

    2012-01-01

    L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21(cip1) gene, mRNA and protein in cancer cells but not p27(kip1); (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21(cip1) gene but not p27(kip1) detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance.

  20. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta.

    Directory of Open Access Journals (Sweden)

    Helena Kaihola

    Full Text Available Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12 and compared them with placenta from depressed (n = 12 and healthy mothers (n = 12. Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the

  1. Cutaneous side-effects in patients on long-term treatment with epidermal growth factor receptor inhibitors.

    Science.gov (United States)

    Osio, A; Mateus, C; Soria, J-C; Massard, C; Malka, D; Boige, V; Besse, B; Robert, C

    2009-09-01

    Acute and subacute cutaneous side-effects of epidermal growth factor receptor inhibitors (EGFRIs) are very frequent and well known. Much less is known about the chronic cutaneous effects of these drugs and about their potential psychosocial impact on patients. We performed a retrospective study of patients treated with EGFRIs for more than 6 months. All patients had a detailed dermatological examination. The primary cancer, associated chemotherapies, skin treatment, evolution of skin symptoms and their impact on quality of life (QoL) as evaluated by the Dermatology Life Quality Index (DLQI) were noted. Seven men and nine women were identified. The mean length of EGFRI treatment was 10 months (range 6-27). At the time of examination, all patients (100%) had cutaneous side-effects. Grade I or II folliculitis was found in 37.5% of the patients. Additional skin manifestations were xerosis (100%), mucositis (69%), hair abnormalities (87.5%), eyelash trichomegaly (62.5%), facial hypertrichosis (56%), painful paronychia (56%) and onycholysis (44%). Dose reduction or EGFRI discontinuation for skin toxicity were needed in six patients (37.5%). DLQI evaluation showed a moderate to strong impact on QoL in four patients (25%). Cutaneous side-effects are found in 100% of patients treated with EGFRIs for more than 6 months and have a significant effect on patients' QoL. The clinical spectrum of skin manifestation varies over time. As the use of EGFRIs rapidly increases, it is critical for us to improve our knowledge in the understanding and managment of these skin manifestations.

  2. Interplay between intergrin-linked kinase and ribonuclease inhibitor affects growth and metastasis of bladder cancer through signaling ILK pathways.

    Science.gov (United States)

    Zhuang, Xiang; Lv, Mengxin; Zhong, Zhenyu; Zhang, Luyu; Jiang, Rong; Chen, Junxia

    2016-08-30

    Integrin-linked kinase (ILK) is a multifunctional adaptor protein which is involved with protein signalling within cells to modulate malignant (cancer) cell movement, cell cycle, metastasis and epithelial-mesenchymal transition (EMT). Our previous experiment demonstrated that ILK siRNA inhibited the growth and induced apoptosis of bladder cancer cells as well as increased the expression of Ribonuclease inhibitor (RI), an important cytoplasmic protein with many functions. We also reported that RI overexpression inhibited ILK and phosphorylation of AKT and GSK3β. ILK and RI gene both locate on chromosome 11p15 and the two genes are always at the adjacent position of same chromosome during evolution, which suggest that ILK and RI could have some relationship. However, underlying interacting mechanisms remain unclear between them. Here, we postulate that RI might regulate ILK signaling pathway via interacting with ILK. Co-immunoprecipitation, GST pull-down and co-localization under laser confocal microscope assay were used to determine the interaction between ILK and RI exogenously and endogenously. Furthermore, we further verified that there is a direct binding between the two proteins by fluorescence resonance energy transfer (FRET) in cells. Next, The effects of interplay between ILK and RI on the key target protein expressions of PI3K/AKT/mTOR signaling pathway were determined by western blot, immunohistochemistry and immunofluorescence assay in vivo and in vitro. Finally, the interaction was assessed using nude mice xenograft model. We first found that ILK could combine with RI both in vivo and in vitro by GST pull-down, co-immunoprecipitation (Co-IP) and FRET. The protein levels of ILK and RI revealed a significant inverse correlation in vivo and in vitro. Subsequently, The results showed that up-regulating ILK could increase cell proliferation, change cell morphology and regulate cell cycle. We also demonstrated that the overexpression of ILK remarkably

  3. Effects of some inhibitors on the growth and lipid accumulation of oleaginous yeast Rhodosporidium toruloides and preparation of biodiesel by enzymatic transesterification of the lipid.

    Science.gov (United States)

    Zhao, Xuebing; Peng, Feng; Du, Wei; Liu, Canming; Liu, Dehua

    2012-08-01

    Microbial lipid produced using yeast fermentation with inexpensive carbon sources such as lignocellulosic hydrolyzate can be an alternative feedstock for biodiesel production. Several inhibitors that can be generated during acid hydrolysis of lignocellulose were added solely or together into the culture medium to study their individual inhibitory actions and their synergistic effects on the growth and lipid accumulation of oleaginous yeast Rhodosporidium toruloides. When the inhibitors were present in isolation in the medium, to obtain a high cell biomass accumulation, the concentrations of formic acid, acetic acid, furfural and vanillin should be lower than 2, 5, 0.5 and 1.5 g/L, respectively. However, the synergistic effects of these compounds could dramatically decrease the minimum critical inhibitory concentrations leading to significant growth and lipid production inhibitions. Unlike the above-cited inhibitors, sodium lignosulphonate had no negative influence on biomass accumulation when its concentration was in the range of 0.5-2.0 g/L; in effect, it was found to facilitate cell growth and sugar-to-lipid conversion. The fatty acid compositional profile of the yeast lipid was in the compositional range of various plant oils and animal tallow. Finally, the crude yeast lipid from bagasse hydrolyzate could be well converted into fatty acid methyl ester (FAME, biodiesel) by enzymatic transesterification in a tert-butanol system with biodiesel yield of 67.2% and lipid-to-biodiesel conversion of 88.4%.

  4. Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts.

    Science.gov (United States)

    Mellinghoff, Ingo K; Tran, Chris; Sawyers, Charles L

    2002-09-15

    Experiments with human prostate cancer cell lines have shown that forced overexpression of the ErbB2-receptor tyrosine kinase (RTK) promotes androgen-independent growth and increases androgen receptor-transcriptional activity in a ligand-independent fashion. To investigate the relationship between ErbB-RTK signaling and androgen in genetically unmanipulated human prostate cancer, we performed biochemical and biological studies with the dual ErbB1/ErbB2 RTK inhibitor PKI-166 using human prostate cancer xenograft models with isogenic sublines reflecting the transition from androgen-dependent to androgen-independent growth. In the presence of low androgen concentrations, PKI-166 showed profound growth-inhibitory effects on tumor growth, which could be partially reversed by androgen add-back. At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI-166 to retard tumor growth. The level of extracellular signal-regulated kinase activation correlated with the response to PKI-166 treatment, whereas the expression levels of ErbB1 and ErbB2 did not. These results suggest that ErbB1/ErbB2 RTKs play an important role in the biology of androgen-independent prostate cancer and provide a rationale for clinical evaluation of inhibitors targeted to this pathway.

  5. Mangiferin, a novel nuclear factor kappa B-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model

    Energy Technology Data Exchange (ETDEWEB)

    Takeda, Tomoya; Tsubaki, Masanobu; Sakamoto, Kotaro; Ichimura, Eri; Enomoto, Aya; Suzuki, Yuri [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-, Osaka (Japan); Itoh, Tatsuki [Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Nara (Japan); Imano, Motohiro [Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka (Japan); Tanabe, Genzoh; Muraoka, Osamu [Laboratory of Pharmaceutical Organic Chemistry, School of Pharmacy, Kinki University, Kowakae, Higashi-, Osaka (Japan); Matsuda, Hideaki [Department of Natural Drugs Resources, Kinki University School of Pharmacy, Kowakae, Higashi-, Osaka (Japan); Satou, Takao [Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka (Japan); Nishida, Shozo, E-mail: nishida@phar.kindai.ac.jp [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-, Osaka (Japan)

    2016-09-01

    Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma. - Highlights: • Mangiferin prolongs survival in mice by inhibiting metastasis and tumor growth • Mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation • Mangiferin regulates the expression of MMPs, VLAs, and apoptosis regulatory proteins.

  6. SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Yang, Li; Weng, Wei; Sun, Zhi-Xin; Fu, Xian-Jie; Ma, Jun; Zhuang, Wen-Fang

    2015-01-01

    Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, and concomitantly increased level of sphingosine-1-phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short-chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI-II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent. - Highlights: • SKI-II inhibits proliferation and survival of primary and transformed AML cells. • SKI-II induces apoptotic death of AML cells, but is safe to normal PBMCs. • SKI-II is more efficient than two known SphK1 inhibitors in inhibiting AML cells. • SKI-II inhibits SphK1 activity, while increasing ceramide production in AML cells. • SKI-II dose-dependently inhibits U937 xenograft growth in SCID mice

  7. SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Li; Weng, Wei; Sun, Zhi-Xin; Fu, Xian-Jie; Ma, Jun, E-mail: majuntongrensh1@126.com; Zhuang, Wen-Fang, E-mail: wenfangzhuangmd@163.com

    2015-05-15

    Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, and concomitantly increased level of sphingosine-1-phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short-chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI-II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent. - Highlights: • SKI-II inhibits proliferation and survival of primary and transformed AML cells. • SKI-II induces apoptotic death of AML cells, but is safe to normal PBMCs. • SKI-II is more efficient than two known SphK1 inhibitors in inhibiting AML cells. • SKI-II inhibits SphK1 activity, while increasing ceramide production in AML cells. • SKI-II dose-dependently inhibits U937 xenograft growth in SCID mice.

  8. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta

    NARCIS (Netherlands)

    Kaihola, Helena; Olivier, Jocelien; Poromaa, Inger Sundström; Åkerud, Helena

    2015-01-01

    Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a

  9. A Systematic Review and Meta-Analysis on the Safety of Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Retinopathy of Prematurity

    Science.gov (United States)

    Pertl, Laura; Steinwender, Gernot; Mayer, Christoph; Hausberger, Silke; Pöschl, Eva-Maria; Wackernagel, Werner; Wedrich, Andreas; El-Shabrawi, Yosuf; Haas, Anton

    2015-01-01

    Introduction Laser photocoagulation is the current gold standard treatment for proliferative retinopathy of prematurity (ROP). However, it permanently reduces the visual field and might induce myopia. Vascular endothelial growth factor (VEGF) inhibitors for the treatment of ROP may enable continuing vascularization of the retina, potentially allowing the preservation of the visual field. However, for their use in infants concern remains. This meta-analysis explores the safety of VEGF inhibitors. Methods The Ovid Interface was used to perform a systematic review of the literature in the databases PubMed, EMBASE and the Cochrane Library. Results This meta-analysis included 24 original reports (including 1.457 eyes) on VEGF inhibitor treatment for ROP. The trials were solely observational except for one randomized and two case-control studies. We estimated a 6-month risk of retreatment per eye of 2.8%, and a 6-month risk of ocular complication without the need of retreatment of 1.6% per eye. Systemic complications were only reported as isolated incidents. Discussion VEGF inhibitors seem to be associated with low recurrence rates and ocular complication rates. They may have the benefit of potentially allowing the preservation of visual field and lower rates of myopia. Due to the lack of data, the risk of systemic side effects cannot be assessed. PMID:26083024

  10. Transforming growth factor β1, matrix metalloproteinase-2 and its tissue inhibitor in patients with pseudoexfoliation glaucoma/syndrome

    Directory of Open Access Journals (Sweden)

    Đorđević-Jocić Jasmina

    2012-01-01

    Full Text Available Background/Aim. Transforming growth factor-b1 (TGF-b1, oxidative stress and imbalance between matrix metalloproteinases (MMPs and their tissue inhibitors (TIMPs may play an important role in pathogenesis of pseudoexfoliation syndrome/glaucoma (PEX Sy/Gl. The aim of the study was to measure concentrations of TGF- b1, MMP-2, TIMP-2 in the aqueous humor in the examined group, as well as to compare the biochemical findings with the following clinical parameters: degree of chamber angle pigmantation, presence of pseudoexfoliation and the value of intraocular pressure (IOP. Methods. Aqueous samples from 30 patients with cataract, 30 patients with PEX Sy, 36 patients with PEX Gl, and 42 patients with primary open-angle glaucoma (POAG were collected during phacoemulsification cataract surgery. TGF b1, MMP-2, TIMP-2 Fluotokine Multi Analyze Profiling kits and Luminex technology were used to simultaneously measure TGF b1, MMP-2 and TIMP-2. Results. TGF- β1, MMP-2, TIMP-2 were detected in human aqueous from all the groups with the highest level in the group with PEX Gl. Statistically, a significant correlation between the levels of TGF b1, MMP-2, TIMP-2 in the aqueous humor of the patients with PEX Gl and the IOP value was confirmed (p < 0.05. In this group, the positive correlations between the TGF b1 concentration in the aqueous humor and the presence of pseudoexfoliation (p < 0.01, on the one hand, and between the TIMP-2 level and the presence of pseudoexfoliation (p < 0.05, on the other, were reported. A statistically significant positive correlation of TGF-b1 and MMP-2, and the degree of chamber angle pigmentation in the PEX Gl group was confirmed (p < 0.05. In the POAG group, TIMP-2 values were in a negative correlation with the degree of pigmentation (p < 0.05, and the IOP value (p < 0.05. Conclusion. TGF b1 and MMP-2 affect the degree of chamber angle pigmentation and the degree of pseudoexfoliation in patients with pseudoexfoliative glaucoma.

  11. Use of a small molecule cell cycle inhibitor to control cell growth and improve specific productivity and product quality of recombinant proteins in CHO cell cultures.

    Science.gov (United States)

    Du, Zhimei; Treiber, David; McCarter, John D; Fomina-Yadlin, Dina; Saleem, Ramsey A; McCoy, Rebecca E; Zhang, Yuling; Tharmalingam, Tharmala; Leith, Matthew; Follstad, Brian D; Dell, Brad; Grisim, Brent; Zupke, Craig; Heath, Carole; Morris, Arvia E; Reddy, Pranhitha

    2015-01-01

    The continued need to improve therapeutic recombinant protein productivity has led to ongoing assessment of appropriate strategies in the biopharmaceutical industry to establish robust processes with optimized critical variables, that is, viable cell density (VCD) and specific productivity (product per cell, qP). Even though high VCD is a positive factor for titer, uncontrolled proliferation beyond a certain cell mass is also undesirable. To enable efficient process development to achieve consistent and predictable growth arrest while maintaining VCD, as well as improving qP, without negative impacts on product quality from clone to clone, we identified an approach that directly targets the cell cycle G1-checkpoint by selectively inhibiting the function of cyclin dependent kinases (CDK) 4/6 with a small molecule compound. Results from studies on multiple recombinant Chinese hamster ovary (CHO) cell lines demonstrate that the selective inhibitor can mediate a complete and sustained G0/G1 arrest without impacting G2/M phase. Cell proliferation is consistently and rapidly controlled in all recombinant cell lines at one concentration of this inhibitor throughout the production processes with specific productivities increased up to 110 pg/cell/day. Additionally, the product quality attributes of the mAb, with regard to high molecular weight (HMW) and glycan profile, are not negatively impacted. In fact, high mannose is decreased after treatment, which is in contrast to other established growth control methods such as reducing culture temperature. Microarray analysis showed major differences in expression of regulatory genes of the glycosylation and cell cycle signaling pathways between these different growth control methods. Overall, our observations showed that cell cycle arrest by directly targeting CDK4/6 using selective inhibitor compound can be utilized consistently and rapidly to optimize process parameters, such as cell growth, qP, and glycosylation profile in

  12. Supercritical CO2 impregnation of PLA/PCL films with natural substances for bacterial growth control in food packaging.

    Science.gov (United States)

    Milovanovic, Stoja; Hollermann, Gesa; Errenst, Cornelia; Pajnik, Jelena; Frerich, Sulamith; Kroll, Stephen; Rezwan, Kurosch; Ivanovic, Jasna

    2018-05-01

    Biodegradable polymers with antibacterial properties are highly desirable materials for active food packaging applications. Thymol, a dietary monoterpene phenol with a strong antibacterial activity is abundant in plants belonging to the genus Thymus. This study presents two approaches for supercritical CO 2 impregnation of poly(lactic acid)(PLA)/poly(ε-caprolactone)(PCL) blended films to induce antibacterial properties of the material: (i) a batch impregnation process for loading pure thymol, and (ii) an integrated supercritical extraction-impregnation process for isolation of thyme extract and its incorporation into the films, operated in both batch or semi-continuous modes with supercritical solution circulation. The PCL content in films, impregnation time and CO 2 flow regime were varied to maximize loading of the films with thymol or thyme extract with preserving films' structure and thermal stability. Representative film samples impregnated with thymol and thyme extract were tested against Gram (-) (Escherichia coli) and Gram(+) (Bacillus subtilis) model strains, by measuring their metabolic activity and re-cultivation after exposure to the films. The film containing thymol (35.8 wt%) showed a strong antibacterial activity leading to a total reduction of bacterial cell viability. Proposed processes enable fast, controlled and organic solvent-free fabrication of the PLA/PCL films containing natural antibacterial substances at moderately low temperature, with a compact structure and a good thermal stability, for potential use as active food packaging materials. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Substance use - prescription drugs

    Science.gov (United States)

    Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance ...

  14. Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures

    Science.gov (United States)

    Subbiah, Vivek; Naing, Aung; Brown, Robert E.; Chen, Helen; Doyle, Laurence; LoRusso, Patricia; Benjamin, Robert; Anderson, Pete; Kurzrock, Razelle

    2011-01-01

    Background Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy. Methodology/Principal Findings This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well. Conclusion/Significance Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures. PMID

  15. Plasmodium falciparum transfected with ultra bright NanoLuc luciferase offers high sensitivity detection for the screening of growth and cellular trafficking inhibitors.

    Directory of Open Access Journals (Sweden)

    Mauro F Azevedo

    Full Text Available Drug discovery is a key part of malaria control and eradication strategies, and could benefit from sensitive and affordable assays to quantify parasite growth and to help identify the targets of potential anti-malarial compounds. Bioluminescence, achieved through expression of exogenous luciferases, is a powerful tool that has been applied in studies of several aspects of parasite biology and high throughput growth assays. We have expressed the new reporter NanoLuc (Nluc luciferase in Plasmodium falciparum and showed it is at least 100 times brighter than the commonly used firefly luciferase. Nluc brightness was explored as a means to achieve a growth assay with higher sensitivity and lower cost. In addition we attempted to develop other screening assays that may help interrogate libraries of inhibitory compounds for their mechanism of action. To this end parasites were engineered to express Nluc in the cytoplasm, the parasitophorous vacuole that surrounds the intraerythrocytic parasite or exported to the red blood cell cytosol. As proof-of-concept, these parasites were used to develop functional screening assays for quantifying the effects of Brefeldin A, an inhibitor of protein secretion, and Furosemide, an inhibitor of new permeation pathways used by parasites to acquire plasma nutrients.

  16. The inhibitor of growth protein 5 (ING5 depends on INCA1 as a co-factor for its antiproliferative effects.

    Directory of Open Access Journals (Sweden)

    Feng Zhang

    Full Text Available The proteins of the Inhibitor of Growth (ING family are involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. For ING5, its actual role in growth suppression and the necessary partners are not known. In a yeast-two-hybrid approach with human bone marrow derived cDNA, we identified ING5 as well as several other proteins as interaction partners of Inhibitor of cyclin A1 (INCA1 that we previously characterized as a novel interaction partner of cyclin A1/CDK2. ING5 expression in leukemic AML blasts was severely reduced compared to normal bone marrow. In line, ING5 inhibited bone marrow colony formation upon retroviral transduction. However, Inca1(-/- bone marrow colony formation was not suppressed by ING5. In murine embryonic fibroblast (MEF cells from Inca1(+/+ and Inca1(-/- mice, overexpression of ING5 suppressed cell proliferation only in the presence of INCA1, while ING5 had no effect in Inca1(-/- MEFs. ING5 overexpression induced a delay in S-phase progression, which required INCA1. Finally, ING5 overexpression enhanced Fas-induced apoptosis in Inca1(+/+ MEFs, while Inca1(-/- MEFs were protected from Fas antibody-induced apoptosis. Taken together, these results indicate that ING5 is a growth suppressor with suppressed expression in AML whose functions depend on its interaction with INCA1.

  17. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model.

    Science.gov (United States)

    Kurundkar, Deepali; Srivastava, Ritesh K; Chaudhary, Sandeep C; Ballestas, Mary E; Kopelovich, Levy; Elmets, Craig A; Athar, Mohammad

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin

    International Nuclear Information System (INIS)

    Wang, Quan; Wei, Feng; Lv, Guoyue; Li, Chunsheng; Liu, Tongjun; Hadjipanayis, Costas G; Zhang, Guikai; Hao, Chunhai; Bellail, Anita C

    2013-01-01

    There is growing evidence indicating the insulin-like growth factor 1 receptor (IGF-1R) plays a critical role in the progression of human colorectal carcinomas. IGF-1R is an attractive drug target for the treatment of colon cancer. Picropodophyllin (PPP), of the cyclolignan family, has recently been identified as an IGF-1R inhibitor. The aim of this study is to determine the therapeutic response and mechanism after colorectal carcinoma treatment with PPP. Seven colorectal carcinoma cell lines were treated with PPP. Following treatment, cells were analyzed for growth by a cell viability assay, sub-G1 apoptosis by flow cytometry, caspase cleavage and activation of AKT and extracellular signal-regulated kinase (ERK) by western blot analysis. To examine the in vivo therapeutic efficacy of PPP, mice implanted with human colorectal carcinoma xenografts underwent PPP treatment. PPP treatment blocked the phosphorylation of IGF-1R, AKT and ERK and inhibited the growth of TP53 wild-type but not mutated colorectal carcinoma cell lines. The treatment of PPP also induced apoptosis in TP53 wild-type cells as evident by the presence of sub-G1 cells and the cleavage of caspase-9, caspase-3, DNA fragmentation factor-45 (DFF45), poly (ADP-ribose) polymerase (PARP), and X-linked inhibitor of apoptosis protein (XIAP). The loss of BAD phosphorylation in the PPP-treated TP53 wild type cells further suggested that the treatment induced apoptosis through the BAD-mediated mitochondrial pathway. In contrast, PPP treatment failed to induce the phosphorylation of AKT and ERK and caspase cleavage in TP53 mutated colorectal carcinoma cell lines. Finally, PPP treatment suppressed the growth of xenografts derived from TP53 wild type but not mutated colorectal carcinoma cells. We report the association of TP53 mutations with the resistance of treatment of colorectal carcinoma cells in culture and in a xenograft mouse model with the IGF-1R inhibitor PPP. TP53 mutations often occur in colorectal

  19. Human aqueous humor levels of transforming growth factor-β2: Association with matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases

    OpenAIRE

    Jia, Yan; Yue, Yu; Hu, Dan-Ning; Chen, Ji-Li; Zhou, Ji-Bo

    2017-01-01

    The present study aims to investigate the association of transforming growth factor-β2 (TGF-β2) and matrix metalloproteinases (MMPs), MMP-2 and MMP-3, and tissue inhibitors of matrix metalloproteinases (TIMPs), TIMP-1, TIMP-2 and TIMP-3 in the aqueous humor of patients with high myopia or cataracts. The levels of TGF-β2 and MMPs/TIMPs were measured with the Luminex xMAP Technology using commercially available Milliplex xMAP kits. The association between TGF-β2 and MMPs/TIMPs levels was analyz...

  20. Bacterial contaminants from frozen puff pastry production process and their growth inhibition by antimicrobial substances from lactic acid bacteria.

    Science.gov (United States)

    Rumjuankiat, Kittaporn; Keawsompong, Suttipun; Nitisinprasert, Sunee

    2017-05-01

    Seventy-five bacterial contaminants which still persisted to cleaning system from three puff pastry production lines (dough forming, layer and filling forming, and shock freezing) were identified using 16S rDNA as seven genera of Bacillus , Corynebacterium , Dermacoccus , Enterobacter , Klebsiella, Pseudomonas , and Staphylococcus with detection frequencies of 24.00, 2.66, 1.33, 37.33, 1.33, 2.66, and 30.66, respectively. Seventeen species were discovered while only 11 species Bacillus cereus, B. subtilis, B. pumilus, Corynebacterium striatum , Dermacoccus barathri , Enterobacter asburiae, Staphylococcus kloosii, S. haemolyticus, S. hominis, S. warneri , and S. aureus were detected at the end of production. Based on their abundance, the highest abundance of E. asburiae could be used as a biomarker for product quality. While a low abundance of the mesophile pathogen C. striatum , which causes respiratory and nervous infection and appeared only at the shock freezing step was firstly reported for its detection in bakery product. Six antimicrobial substances (AMSs) from lactic acid bacteria, FF1-4, FF1-7, PFUR-242, PFUR-255, PP-174, and nisin A were tested for their inhibition activities against the contaminants. The three most effective were FF1-7, PP-174, and nisin A exhibiting wide inhibition spectra of 88.00%, 85.33%, and 86.66%, respectively. The potential of a disinfectant solution containing 800 AU/ml of PP-174 and nisin A against the most resistant strains of Enterobacter , Staphylococcus , Bacillus and Klebsiella was determined on artificially contaminated conveyor belt coupons at 0, 4, 8, 12, and 16 hr. The survival levels of the test strains were below 1 log CFU/coupon at 0 hr. The results suggested that a combined solution of PP-174 and nisin A may be beneficial as a sanitizer to inhibit bacterial contaminants in the frozen puff pastry industry.

  1. R-268712, an orally active transforming growth factor-β type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model.

    Science.gov (United States)

    Terashima, Hideki; Kato, Mikio; Ebisawa, Masayuki; Kobayashi, Hideki; Suzuki, Kanae; Nezu, Yoshikazu; Sada, Toshio

    2014-07-05

    R-268712 is a novel and specific inhibitor of activin receptor-like kinase 5 (ALK5), a transforming growth factor β (TGF-β) type I receptor. Evaluation of in vitro inhibition indicated that R-268712 is a potent and selective inhibitor of ALK5 with an IC50 of 2.5nM, an approximately 5000-fold more selectivity for ALK5 than p38 mitogen-activated protein kinase (MAPK). Oral administration of R-268712 at doses of 1, 3 and 10mg/kg also inhibited the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model. Additionally, we evaluated the efficacy of R-268712 in a heminephrectomized anti-Thy1 glomerulonephritis model at doses of 0.3 and 1mg/kg. R-268712 reduced proteinuria and glomerulosclerosis significantly with improvement of renal function. Collectively, these results suggested that R-268712 and other ALK5 inhibitors could suppress glomerulonephritis as well as glomerulosclerosis by an inhibitory mechanism that involves suppression of TGF-β signaling. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Constitutive over-expression of rice chymotrypsin protease inhibitor gene OCPI2 results in enhanced growth, salinity and osmotic stress tolerance of the transgenic Arabidopsis plants.

    Science.gov (United States)

    Tiwari, Lalit Dev; Mittal, Dheeraj; Chandra Mishra, Ratnesh; Grover, Anil

    2015-07-01

    Protease inhibitors are involved primarily in defense against pathogens. In recent years, these proteins have also been widely implicated in response of plants to diverse abiotic stresses. Rice chymotrypsin protease inhibitor gene OCPI2 is highly induced under salt and osmotic stresses. The construct containing the complete coding sequence of OCPI2 cloned downstream to CaMV35S promoter was transformed in Arabidopsis and single copy, homozygous transgenic lines were produced. The transgenic plants exhibited significantly enhanced tolerance to NaCl, PEG and mannitol stress as compared to wild type plants. Importantly, the vegetative and reproductive growth of transgenic plants under unstressed, control conditions was also enhanced: transgenic plants were more vigorous than wild type, resulting into higher yield in terms of silique number. The RWC values and membrane stability index of transgenic in comparison to wild type plants was higher. Higher proline content was observed in the AtOCPI2 lines, which was associated with higher transcript expression of pyrroline-5-carboxylate synthase and lowered levels of proline dehydrogenase genes. The chymotrypsin protease activities were lower in the transgenic as against wild type plants, under both unstressed, control as well as stressed conditions. It thus appears that rice chymotrypsin protease inhibitor gene OCPI2 is a useful candidate gene for genetic improvement of plants against salt and osmotic stress. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  3. Programmed Application of Transforming Growth Factor β3 and Rac1 Inhibitor NSC23766 Committed Hyaline Cartilage Differentiation of Adipose-Derived Stem Cells for Osteochondral Defect Repair.

    Science.gov (United States)

    Zhu, Shouan; Chen, Pengfei; Wu, Yan; Xiong, Si; Sun, Heng; Xia, Qingqing; Shi, Libing; Liu, Huanhuan; Ouyang, Hong Wei

    2014-10-01

    Hyaline cartilage differentiation is always the challenge with application of stem cells for joint repair. Transforming growth factors (TGFs) and bone morphogenetic proteins can initiate cartilage differentiation but often lead to hypertrophy and calcification, related to abnormal Rac1 activity. In this study, we developed a strategy of programmed application of TGFβ3 and Rac1 inhibitor NSC23766 to commit the hyaline cartilage differentiation of adipose-derived stem cells (ADSCs) for joint cartilage repair. ADSCs were isolated and cultured in a micromass and pellet culture model to evaluate chondrogenic and hypertrophic differentiation. The function of Rac1 was investigated with constitutively active Rac1 mutant and dominant negative Rac1 mutant. The efficacy of ADSCs with programmed application of TGFβ3 and Rac1 inhibitor for cartilage repair was studied in a rat model of osteochondral defects. The results showed that TGFβ3 promoted ADSCs chondro-lineage differentiation and that NSC23766 prevented ADSC-derived chondrocytes from hypertrophy in vitro. The combination of ADSCs, TGFβ3, and NSC23766 promoted quality osteochondral defect repair in rats with much less chondrocytes hypertrophy and significantly higher International Cartilage Repair Society macroscopic and microscopic scores. The findings have illustrated that programmed application of TGFβ3 and Rac1 inhibitor NSC23766 can commit ADSCs to chondro-lineage differentiation and improve the efficacy of ADSCs for cartilage defect repair. These findings suggest a promising stem cell-based strategy for articular cartilage repair. ©AlphaMed Press.

  4. Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells.

    Science.gov (United States)

    Nakata, Daisuke; Koyama, Ryokichi; Nakayama, Kazuhide; Kitazawa, Satoshi; Watanabe, Tatsuya; Hara, Takahito

    2017-06-01

    Recent evidence suggests that androgen receptor (AR) splice variants, including AR-V7, play a pivotal role in resistance to androgen blockade in prostate cancer treatment. The development of new therapeutic agents that can suppress the transcriptional activities of AR splice variants has been anticipated as the next generation treatment of castration-resistant prostate cancer. High-throughput screening of AR-V7 signaling inhibitors was performed using an AR-V7 reporter system. The effects of a glycogen synthase kinase-3 (GSK3) inhibitor, LY-2090314, on endogenous AR-V7 signaling were evaluated in an AR-V7-positive cell line, JDCaP-hr, by quantitative reverse transcription polymerase chain reaction. The relationship between AR-V7 signaling and β-catenin signaling was assessed using RNA interference. The effect of LY-2090314 on cell growth in various prostate cancer cell lines was also evaluated. We identified GSK3 inhibitors as transcriptional suppressors of AR-V7 using a high-throughput screen with an AR-V7 reporter system. LY-2090314 suppressed the reporter activity and endogenous AR-V7 activity in JDCaP-hr cells. Because silencing of β-catenin partly rescued the suppression, it was evident that the suppression was mediated, at least partially, via the activation of β-catenin signaling. AR-V7 signaling and β-catenin signaling reciprocally regulate each other in JDCaP-hr cells, and therefore, GSK3 inhibition can repress AR-V7 transcriptional activity by accumulating intracellular β-catenin. Notably, LY-2090314 selectively inhibited the growth of AR-V7-positive prostate cancer cells in vitro. Our findings demonstrate the potential of GSK3 inhibitors in treating advanced prostate cancer driven by AR splice variants. In vivo evaluation of AR splice variant-positive prostate cancer models will help illustrate the overall significance of GSK3 inhibitors in treating prostate cancer. © 2017 Wiley Periodicals, Inc.

  5. Evaluating the effectiveness of the SMART contract-signing strategy in reducing the growth of Swedish Adolescents’ substance use and problem behaviors

    Directory of Open Access Journals (Sweden)

    Cristian Bortes

    2016-06-01

    Full Text Available Abstract Background In 2013, around 40 % of the schools in Sweden had structured programs to prevent tobacco and alcohol debut in compulsory school. There has unfortunately been a lack of scientific evidence to support most of the prevention methods focusing on primary prevention in schools in Sweden. The aim and purpose of the present study is to evaluate the effectiveness of the Non-Governmental Organization SMART contract-signing strategy in reducing the growth of youth substance use and other problem behaviors amongst Swedish adolescents. Methods Students from five schools in a medium-sized Swedish municipality were surveyed in three waves from 7th to 9th grade of compulsory school. We used General Linear Model (GLM repeated-measures ANOVA to test if the outcome measures smoking, use of snus and alcohol, drunkenness, delinquency, and bullying significantly changed different amounts over time in groups that had participated in the SMART program for long time, a short time, sporadically- or not at all. Groups were compared on demographic background variables, and outcome measures were assessed on all measurement occasions by a one-way ANOVA. The magnitude of group differences at the end of the study was estimated according to Cohen’s d. Results Number of years with a contract has an effect on the levels of self-reported youth problems in 9th grade. We found small to medium-sized differences in measured outcomes between students who participated in the program for the longest period of time, 5 years, and who participated for the shortest time, 0–2 years. Conclusion Findings suggests that the SMART program has preventive effects on adolescent substance use.

  6. Dacomitinib, an irreversible Pan-ErbB inhibitor significantly abrogates growth in head and neck cancer models that exhibit low response to cetuximab.

    Directory of Open Access Journals (Sweden)

    Ferdows Ather

    Full Text Available Aberrant epidermal growth factor (EGF signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC, and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804, a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR, HER-2 and HER-4 tyrosine kinases, to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity.

  7. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 2114, Bethesda, MD 20892 (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  8. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    International Nuclear Information System (INIS)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C.; Ballestas, Mary E.; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  9. The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

    International Nuclear Information System (INIS)

    Kerl, Kornelius; Eveslage, Maria; Jung, Manfred; Meisterernst, Michael; Frühwald, Michael; Ries, David; Unland, Rebecca; Borchert, Christiane; Moreno, Natalia; Hasselblatt, Martin; Jürgens, Heribert; Kool, Marcel; Görlich, Dennis

    2013-01-01

    Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors

  10. Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials.

    Science.gov (United States)

    Rodon, Jordi; DeSantos, Victoria; Ferry, Robert Jean; Kurzrock, Razelle

    2008-09-01

    The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone-IGF-IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment.

  11. Transforming growth factor β-activated kinase 1 inhibitor suppresses the proliferation in triple-negative breast cancer through TGF-β/TGFR pathway.

    Science.gov (United States)

    Zhang, Liangyu; Fu, Zelong; Li, Xia; Tang, Haitao; Luo, Jiesi; Zhang, Dehui; Zhuang, Yongzhi; Han, Zhiyang; Yin, Mingzhu

    2017-09-01

    Breast cancer is one of the most invasive cancer types in female population. The functional activity of Transforming growth factor β-activated kinase 1 (TAK1) in breast cancer progression increasingly attracts attention as it provides a potential target for antibreast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells. We found that the TAK1 is robustly activated within cancer cell population of clinic-derived TNBC samples and the human breast cancer cell lines in culture. Furthermore, we determined the effect of 5Z-7-oxozeaenol (5Z-O), a TAK1-specific small molecule inhibitor, on proliferation of human TNBC cell line. 5Z-O treatment significantly suppressed the proliferation of human TNBC cells. Collectively, these demonstrate the role of TAK1 in human breast cancer and the antiproliferate effect of TAK1 inhibitor. Our study sets the stage for further research on TAK1 as a promising target for development of anti-TNBC drugs and therapeutic strategies. © 2017 John Wiley & Sons A/S.

  12. Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms.

    Science.gov (United States)

    Wagner, Jessica; Kline, C Leah; Zhou, Lanlan; Khazak, Vladimir; El-Deiry, Wafik S

    2018-01-22

    Small molecule ONC201 is an investigational anti-tumor agent that upregulates intra-tumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 therapy in advanced cancer patients has been completed and the drug has progressed into Phase II trials in several cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease has a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. We investigated the potential combination of VEGF inhibitors such as bevacizumab and its murine-counterpart; along with other anti-angiogenic agents and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) models. We utilized non-invasive imaging and immunohistochemistry to determine potential mechanisms of action. Our results demonstrate significant tumor regression or complete tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. Our results indicate that ONC201 and anti-angiogenic agents act through distinct mechanisms while increasing tumor cell death and inhibiting proliferation. With the use of both a murine VEGF inhibitor in syngeneic models, and bevacizumab in human cell line-derived xenografts, we demonstrate that ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising approach for further testing in the clinic for the treatment of CRC.

  13. The expression of cyclin-dependent kinase inhibitors p15, p16, p21, and p27 during ovarian follicle growth initiation in the mouse

    Directory of Open Access Journals (Sweden)

    Bayrak Aykut

    2003-05-01

    Full Text Available Abstract Background Cyclins regulate the cell cycle in association with cyclin dependent kinases (CDKs. CDKs are under inhibitory control of cyclin dependent kinase inhibitors (CDKIs. Method In this study we tested the expression of CDKIs p15, p16, p21 and p27 by immunohistochemistry to determine the role of CDKIs in the initiation of primordial follicle growth. Ovaries were collected from 60-day-old cycling B6D2F1/J mice (n = 16. Results Expression of p15, p16, p21 and p27 did not vary in granulosa and theca cells by the follicle stage. However, p16 staining was stronger (++ in the oocytes of all primordial, and 57.4 ± 3.1% of primary follicles compared to the remaining primary and more advanced follicles (+. Interestingly, primary follicles with weaker (+ oocyte staining for p16 had significantly larger mean follicle diameter compared to the primary and primordial follicles with stronger (++ oocyte staining (55.6 ± 2.1 vs. 32.0 ± 1.0 and 26.5 ± 0.7 μm, respectively, p Conclusions These preliminary findings suggest that the initiation of oocyte growth, which seems to lead follicle growth, is associated with diminished p16 expression in the mouse ovary. Further studies are needed to investigate the factors that regulate the expression of p16 in the oocyte, which might also govern the initiation of primordial follicle growth.

  14. Inhibition of adipose triglyceride lipase (ATGL) by the putative tumor suppressor G0S2 or a small molecule inhibitor attenuates the growth of cancer cells.

    Science.gov (United States)

    Zagani, Rachid; El-Assaad, Wissal; Gamache, Isabelle; Teodoro, Jose G

    2015-09-29

    The G0/G1 switch gene 2 (G0S2) is methylated and silenced in a wide range of human cancers. The protein encoded by G0S2 is an endogenous inhibitor of lipid catabolism that directly binds adipose triglyceride lipase (ATGL). ATGL is the rate-limiting step in triglyceride metabolism. Although the G0S2 gene is silenced in cancer, the impact of ATGL in the growth and survival of cancer cells has never been addressed. Here we show that ectopic expression of G0S2 in non-small cell lung carcinomas (NSCL) inhibits triglyceride catabolism and results in lower cell growth. Similarly, knockdown of ATGL increased triglyceride levels, attenuated cell growth and promoted apoptosis. Conversely, knockdown of endogenous G0S2 enhanced the growth and invasiveness of cancer cells. G0S2 is strongly induced in acute promyelocytic leukemia (APL) cells in response to all trans retinoic acid (ATRA) and we show that inhibition of ATGL in these cells by G0S2 is required for efficacy of ATRA treatment. Our data uncover a novel tumor suppressor mechanism by which G0S2 directly inhibits activity of a key intracellular lipase. Our results suggest that elevated ATGL activity may be a general property of many cancer types and potentially represents a novel target for chemotherapy.

  15. Negative Effect of Proton-pump Inhibitors (PPIs) on Helicobacter pylori Growth, Morphology, and Urease Test and Recovery after PPI Removal--An In vitro Study.

    Science.gov (United States)

    Saniee, Parastoo; Shahreza, Somayeh; Siavoshi, Farideh

    2016-04-01

    Proton-pump inhibitor (PPI) consumption does lead to false-negative results of Helicobacter pylori diagnostic tests such as biopsy culture and rapid urease test (RUT). Helicobacter pylori isolates from 112 dyspeptic patients with (56.5%) or without (43.5%) PPI consumption were recruited for examining the negative effects of omeprazole (OMP), lansoprazole (LPZ), and pantoprazole (PAN) on H. pylori viability, morphology, and urease, in vitro. The effect of a sublethal concentration of OMP on bacterial features and their recovery after removal of OMP was also assessed. Of 112 culture-positive gastric biopsies, 87.5% were RUT positive and 12.5% RUT negative. There was a significant correlation between negative RUT results and PPI consumption (p urease of 90.3% of isolates between 0 and 40 minutes and 54.4% between 20 and 40 minutes, respectively. PAN did not inhibit H. pylori growth and urease. Three 3-day (9 days) consecutive subcultures of H. pylori on brucella blood agar (BBA) supplemented with OMP resulted in reduced bacterial viability (1+), compared with control (4+), change of spiral morphology to coccoid, and reduction in pink color intensity in urea agar. Bacterial growth (1+), morphology, and urease test did not improve after the first 3-day and second 3-day (6 days) subcultures on BBA. However, relative recovery occurred after the third 3-day (9 days) subculture and complete recovery was observed after the fourth 3-day (12 days) subculture, as confluent growth (4+), 100% spiral cells, and strong urease test. Proton-pump Inhibitors exert transient negative effects on H. pylori viability, morphology, and urease test. Accordingly, cessation of PPI consumption at least 12 days before endoscopy could help avoiding false-negative results of H. pylori diagnostic tests. © 2015 John Wiley & Sons Ltd.

  16. Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models.

    Science.gov (United States)

    Koonce, Nathan A; Griffin, Robert J; Dings, Ruud P M

    2017-12-09

    Galectin-1 is a hypoxia-regulated protein and a prognostic marker in head and neck squamous cell carcinomas (HNSCC). Here we assessed the ability of non-peptidic galectin-1 inhibitor OTX008 to improve tumor oxygenation levels via tumor vessel normalization as well as tumor growth inhibition in two human HNSCC tumor models, the human laryngeal squamous carcinoma SQ20B and the human epithelial type 2 HEp-2. Tumor-bearing mice were treated with OTX008, Anginex, or Avastin and oxygen levels were determined by fiber-optics and molecular marker pimonidazole binding. Immuno-fluorescence was used to determine vessel normalization status. Continued OTX008 treatment caused a transient reoxygenation in SQ20B tumors peaking on day 14, while a steady increase in tumor oxygenation was observed over 21 days in the HEp-2 model. A >50% decrease in immunohistochemical staining for tumor hypoxia verified the oxygenation data measured using a partial pressure of oxygen (pO₂) probe. Additionally, OTX008 induced tumor vessel normalization as tumor pericyte coverage increased by approximately 40% without inducing any toxicity. Moreover, OTX008 inhibited tumor growth as effectively as Anginex and Avastin, except in the HEp-2 model where Avastin was found to suspend tumor growth. Galectin-1 inhibitor OTX008 transiently increased overall tumor oxygenation via vessel normalization to various degrees in both HNSCC models. These findings suggest that targeting galectin-1-e.g., by OTX008-may be an effective approach to treat cancer patients as stand-alone therapy or in combination with other standards of care.

  17. The papain inhibitor (SPI) of Streptomyces mobaraensis inhibits bacterial cysteine proteases and is an antagonist of bacterial growth

    NARCIS (Netherlands)

    S. Zindel (Stephan); W.E. Kaman (Wendy); S. Fröls (Sabrina); F. Pfeifer (Felicitas); A. Peters (Annette); J.P. Hays (John); H.-L. Fuchsbauer (Hans-Lothar)

    2013-01-01

    textabstractA novel papain inhibitory protein (SPI) from Streptomyces mobaraensis was studied to measure its inhibitory effect on bacterial cysteine protease activity (Staphylococcus aureus SspB) and culture supernatants (Porphyromonas gingivalis, Bacillus anthracis). Further, growth of Bacillus

  18. Development of Nano-Liposomal Formulations of Epidermal Growth Factor Receptor Inhibitors and their Pharmacological Interactions on Drug-Sensitive and Drug-Resistant Cancer Cell Lines

    Science.gov (United States)

    Trummer, Brian J.

    A rapidly expanding understanding of molecular derangements in cancer cell function has led to the development of selective, targeted chemotherapeutic agents. Growth factor signal transduction networks are frequently activated in an aberrant fashion, particularly through the activity of receptor tyrosine kinases (RTK). This has spurred an intensive effort to develop receptor tyrosine kinase inhibitors (RTKI) that are targeted to specific receptors, or receptor subfamilies. Chapter 1 reviews the pharmacology, preclinical, and clinical aspects of RTKIs that target the epidermal growth factor receptor (EGFR). EGFR inhibitors demonstrate significant success at inhibiting phosphorylation-based signaling pathways that promote cancer cell proliferation. Additionally RTKIs have physicochemical and structural characteristics that enable them to function as inhibitors of multi-drug resistance transport proteins. Thus EGFR inhibitors and other RTKIs have both on-target and off-target activities that could be beneficial in cancer therapy. However, these agents exert a number of side effects, some of which arise from their hydrophobic nature and large in vivo volume of distribution. Side effects of the EGFR inhibitor gefitinib include skin rash, severe myelotoxicity when combined with certain chemotherapeutic agents, and impairment of the blood brain barrier to xenobiotics. Weighing the preclinical and clinical observations with the EGFR inhibitors, we developed the primary overall hypothesis of this research: that drug-carrier formulations of RTKIs such as the EGFR inhibitors could be developed based on nanoparticulate liposomal carriers. Theoretically, this carrier strategy would ameliorate toxicity and improve the biodistribution and tumor selectivity of these agents. We hypothesized specifically that liposomal formulations could shift the biodistribution of EGFR inhibitors such as gefitinib away from skin, bone marrow, and the blood brain barrier, and toward solid tumors

  19. Production of xylitol by a Coniochaeta ligniaria strain tolerant of inhibitors and defective in growth on xylose.

    Science.gov (United States)

    Nichols, Nancy N; Saha, Badal C

    2016-05-01

    In conversion of biomass to fuels or chemicals, inhibitory compounds arising from physical-chemical pretreatment of the feedstock can interfere with fermentation of the sugars to product. Fungal strain Coniochaeta ligniaria NRRL30616 metabolizes the furan aldehydes furfural and 5-hydroxymethylfurfural, as well as a number of aromatic and aliphatic acids and aldehydes. Use of NRRL30616 to condition biomass sugars by metabolizing the inhibitors improves their fermentability. Wild-type C. ligniaria has the ability to grow on xylose as sole source of carbon and energy, with no accumulation of xylitol. Mutants of C. ligniaria unable to grow on xylose were constructed. Xylose reductase and xylitol dehydrogenase activities were reduced by approximately two thirds in mutant C8100. The mutant retained ability to metabolize inhibitors in biomass hydrolysates. Although C. ligniaria C8100 did not grow on xylose, the strain converted a portion of xylose to xylitol, producing 0.59 g xylitol/g xylose in rich medium and 0.48 g xylitol/g xylose in corn stover dilute acid hydrolysate. 2016 American Institute of Chemical Engineers Biotechnol. Prog., 2016 © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:606-612, 2016. © 2016 American Institute of Chemical Engineers.

  20. SUMO expression shortens the lag phase of Saccharomyces cerevisiae yeast growth caused by complex interactive effects of major mixed fermentation inhibitors found in hot-compressed water-treated lignocellulosic hydrolysate.

    Science.gov (United States)

    Jayakody, Lahiru N; Kadowaki, Masafumi; Tsuge, Keisuke; Horie, Kenta; Suzuki, Akihiro; Hayashi, Nobuyuki; Kitagaki, Hiroshi

    2015-01-01

    The complex inhibitory effects of inhibitors present in lignocellulose hydrolysate suppress the ethanol fermentation of Saccharomyces cerevisiae. Although the interactive inhibitory effects play important roles in the actual hydrolysate, few studies have investigated glycolaldehyde, the key inhibitor of hot-compressed water-treated lignocellulose hydrolysate. Given this challenge, we investigated the interactive effects of mixed fermentation inhibitors, including glycolaldehyde. First, we confirmed that glycolaldehyde was the most potent inhibitor in the hydrolysate and exerted interactive inhibitory effects in combination with major inhibitors. Next, through genome-wide analysis and megavariate data modeling, we identified SUMOylation as a novel potential mechanism to overcome the combinational inhibitory effects of fermentation inhibitors. Indeed, overall SUMOylation was increased and Pgk1, which produces an ATP molecule in glycolysis by substrate-level phosphorylation, was SUMOylated and degraded in response to glycolaldehyde. Augmenting the SUMO-dependent ubiquitin system in the ADH1-expressing strain significantly shortened the lag phase of growth, released cells from G2/M arrest, and improved energy status and glucose uptake in the inhibitor-containing medium. In summary, our study was the first to establish SUMOylation as a novel platform for regulating the lag phase caused by complex fermentation inhibitors.

  1. MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.

    Science.gov (United States)

    Togashi, Yosuke; Mizuuchi, Hiroshi; Tomida, Shuta; Terashima, Masato; Hayashi, Hidetoshi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-12-01

    MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3% of all lung adenocarcinomas. Patients with lung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported. The CRISPR/Cas9 system is a recently developed genome-engineering tool that can easily and rapidly cause small insertions or deletions. We created an in vitro model for MET exon 14 deletion using the CRISPR/Cas9 system and the HEK293 cell line. The phenotype, which included MET inhibitor sensitivity, was then investigated in vitro. Additionally, MET splice site mutations were analyzed in several cancers included in The Cancer Genome Atlas (TCGA) dataset. An HEK293 cell line with a MET exon 14 deletion was easily and rapidly created; this cell line had a higher MET protein expression level, enhanced MET phosphorylation, and prolonged MET activation. In addition, a direct comparison of phenotypes using this system demonstrated enhanced cellular growth, colony formation, and MET inhibitor sensitivity. In the TCGA dataset, lung adenocarcinomas had the highest incidence of MET exon 14 deletions, while other cancers rarely carried such mutations. Approximately 10% of the lung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion. These findings suggested that this system may be useful for experiments requiring the creation of specific mutations, and the present experimental findings encourage the development of MET-targeted therapy against lung cancer carrying the MET exon 14 deletion. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Effect of trypsin inhibitor activity in soya bean on growth performance, protein digestibility and incidence of sub-clinical necrotic enteritis in broiler chicken flocks.

    Science.gov (United States)

    Palliyeguru, M W C D; Rose, S P; Mackenzie, A M

    2011-06-01

    1. The effect of three different levels of dietary trypsin inhibitor activity (achieved by varying the amount of non-toasted full fat soya bean in replacement for toasted full fat soya bean) on the incidence of spontaneously-occurring sub-clinical necrotic enteritis (NE) in broiler chickens was compared. A fourth dietary treatment compared the effect of a diet that used potato protein concentrate as the major protein source. The determined trypsin inhibitor activity increased with the increasing content of non-toasted soya bean: 1·90, 6·21, 8·46 and 3·72 mg/g for the three soya bean diets (0, 100 and 200 g of non-toasted soya bean/kg) and the potato protein diet respectively. 2. Although increasing amounts of the non-toasted full-fat soya bean increased the feed intakes of the birds, there was a marked reduction in protein digestibility, weight gain and feed conversion efficiency. 3. There was a linear increase in sub-clinical NE lesions in the duodenum, jejunum, mid small intestine and ileum with increasing non-toasted soya bean. Caecal Clostridium perfringens counts increased with the increasing dietary content of non-toasted soya bean. Serum α-toxin antibodies were higher in the birds fed the 200 g non-toasted soya bean/kg diet compared with the other diets. 4. The results demonstrated that variation in the amount of non-toasted dietary soya bean not only affects growth performance of broilers but also affects the incidence of sub-clinical necrotic enteritis in the flock. Ensuring the lowest possible trypsin-inhibitor activity in soya bean samples is a valuable tool to improve the health and welfare of birds and in reducing the financial losses from this disease.

  3. Smad signaling pathway is a pivotal component of tissue inhibitor of metalloproteinases-3 regulation by transforming growth factor beta in human chondrocytes.

    Science.gov (United States)

    Qureshi, Hamid Yaqoob; Ricci, Gemma; Zafarullah, Muhammad

    2008-09-01

    Transforming growth factor beta (TGF-beta1) promotes cartilage matrix synthesis and induces tissue inhibitor of metalloproteinases-3 (TIMP-3), which inhibits matrix metalloproteinases, aggrecanases and TNF-alpha-converting enzyme implicated in articular cartilage degradation and joint inflammation. TGF-beta1 activates Akt, ERK and Smad2 pathways in chondrocytes. Here we investigated previously unexplored roles of specific Smads in TGF-beta1 induction of TIMP-3 gene by pharmacological and genetic knockdown approaches. TGF-beta1-induced Smad2 phosphorylation and TIMP-3 protein expression could be inhibited by the Smad2/3 phosphorylation inhibitors, PD169316 and SB203580 and by Smad2-specific siRNA. Specific inhibitor of Smad3 (SIS3) and Smad3 siRNA abolished TGF-beta induction of TIMP-3. Smad2/3 siRNAs also down regulated TIMP-3 promoter-driven luciferase activities, suggesting transcriptional regulation. SiRNA-driven co-Smad4 knockdown abrogated TIMP-3 augmentation by TGF-beta. TIMP-3 promoter deletion analysis revealed that -828 deletion retains the original promoter activity while -333 and -167 deletions display somewhat reduced activity suggesting that most of the TGF-beta-responsive, cis-acting elements are found in the -333 fragment. Chromatin Immunoprecipitation (ChIP) analysis confirmed binding of Smad2 and Smad4 with the -940 and -333 promoter sequences. These results suggest that receptor-activated Smad2 and Smad3 and co-Smad4 critically mediate TGF-beta-stimulated TIMP-3 expression in human chondrocytes and TIMP-3 gene is a target of Smad signaling pathway.

  4. Bioactive substances

    Digital Repository Service at National Institute of Oceanography (India)

    Wahidullah, S.

    Chemistry related to certain bioactive molecules, from Indian Ocean Region, developed into drugs or which served as models for the synthesis of more effective bioactive substances or in use in fundamental studies of physiological and biochemical...

  5. MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level.

    Science.gov (United States)

    Han, Yong Hwan; Park, Woo Hyun

    2010-07-01

    Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In the present study, we evaluated the effects of MG132 on the growth of A549 lung cancer cells in relation to cell growth, ROS and glutathione (GSH) levels. Treatment with MG132 inhibited the growth of A549 cells with an IC(50) of approximately 20 microM at 24 hours. DNA flow cytometric analysis indicated that 0.5 approximately 30 microM MG132 induced a G1 phase arrest of the cell cycle in A549 cells. Treatment with 10 or 30 microM MG132 also induced apoptosis, as evidenced by sub-G1 cells and annexin V staining cells. This was accompanied by the loss of mitochondrial membrane potential (MMP; Delta psi m). The intracellular ROS levels including O(2) (*-) were strongly increased in 10 or 30 microM MG132-treated A549 cells but were down-regulated in 0.1, 0.5 or 1 microM MG132-treated cells. Furthermore, 10 or 30 microM MG132 increased mitochondrial O(2) (*- ) level but 0.1, 0.5 or 1 microM MG132 decreased that. In addition, 10 or 30 microM MG132 induced GSH depletion in A549 cells. In conclusion, MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels. Our present data provide important information on the anti-growth mechanisms of MG132 in A549 lung cancer cells in relation to ROS and GSH.

  6. Effects of nitrogen fertilization and nitrification inhibitor product on vegetative growth, production and oil quality in ‘Arbequina’ hedgerow and ‘Picual’ vase-trained orchards

    International Nuclear Information System (INIS)

    Centeno, A.; García, J.M.; Gómez-del-Campo, M.

    2017-01-01

    Two experiments were carried out in olive orchards in the center of Spain over a three-year period. In this cold and dry area, growers traditionally apply large amounts of N with no experimental knowledge. An ‘Arbequina’ hedgerow and ‘Picual’ vase orchards were fertilized with two N-doses applied to the soil in spring with or without the nitrification inhibitor (DMPP). Vegetative growth, fruit and oil characteristics were evaluated. These variables were affected by the N-treatment during the 3rd year. The lowest N-application increased vegetative growth, while when N-leaf composition was higher than 2%, fruit dry weight, oil content and oil phenol content were reduced. ‘Picual’ did not respond to N-applications. The effect of DMPP on growth or production was not consistent and a lower phenolic content was obtained for ‘Arbequina’. Our results demonstrated that in this dry land, N-fertilization is not always necessary and oil quality can be negatively affected with high doses. [es

  7. Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity.

    Science.gov (United States)

    Xu, Yun-Yun; Li, Si-Ning; Yu, Gao-Jian; Hu, Qing-Hua; Li, Huan-Qiu

    2013-10-01

    Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11μM for Hep G2, IC50=0.82μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Psychotoxic Substances

    Science.gov (United States)

    1964-11-16

    halluci- nations , disturbances of body perception, depersonalization symptoms, and a "psychotic" status. Also with the derivatives, the individual...the substance had also local anesthetic properties. After clinical testing, ibogaine was then used as stimulans for neurasthenics and convalescents1 1 3...con- siderably disturbed by this group of substances. The optic halluci- nations consist to a small extent in scenic proceedings of actions, more

  9. Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.

    Science.gov (United States)

    Mori, Yoshikazu; Hirokawa, Takatsugu; Aoki, Katsuyuki; Satomi, Hisanori; Takeda, Shuichi; Aburada, Masaki; Miyamoto, Ken-ichi

    2008-05-01

    We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFbeta R-ligand interactions, is urgently needed. Here we present models of the PDGFbeta R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by alpha-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFbeta R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.

  10. N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells.

    Science.gov (United States)

    Medina-Enríquez, Miriam Marlene; Alcántara-Farfán, Verónica; Aguilar-Faisal, Leopoldo; Trujillo-Ferrara, José Guadalupe; Rodríguez-Páez, Lorena; Vargas-Ramírez, Alba Laura

    2015-06-01

    Many cancer cells have high expression of ornithine decarboxylase (ODC) and there is a concerted effort to seek new inhibitors of this enzyme. The aim of the study was to initially characterize the inhibition properties, then to evaluate the cytotoxicity/antiproliferative cell based activity of N-ω-chloroacetyl-l-ornithine (NCAO) on three human cancer cell lines. Results showed NCAO to be a reversible competitive ODC inhibitor (Ki = 59 µM) with cytotoxic and antiproliferative effects, which were concentration- and time-dependent. The EC50,72h of NCAO was 15.8, 17.5 and 10.1 µM for HeLa, MCF-7 and HepG2 cells, respectively. NCAO at 500 µM completely inhibited growth of all cancer cells at 48 h treatment, with almost no effect on normal cells. Putrescine reversed NCAO effects on MCF-7 and HeLa cells, indicating that this antiproliferative activity is due to ODC inhibition.

  11. Evaluation of radiolabeled ML04, a putative irreversible inhibitor of epidermal growth factor receptor, as a bioprobe for PET imaging of EGFR-overexpressing tumors

    International Nuclear Information System (INIS)

    Abourbeh, Galith; Dissoki, Samar; Jacobson, Orit; Litchi, Amir; Daniel, Revital Ben; Laki, Desirediu; Levitzki, Alexander; Mishani, Eyal

    2007-01-01

    Overexpression of epidermal growth factor receptor (EGFR) has been implicated in tumor development and malignancy. Evaluating the degree of EGFR expression in tumors could aid in identifying patients for EGFR-targeted therapies and in monitoring treatment. Nevertheless, no currently available assay can reliably quantify receptor content in tumors. Radiolabeled inhibitors of EGFR-TK could be developed as bioprobes for positron emission tomography imaging. Such imaging agents would not only provide a noninvasive quantitative measurement of EGFR content in tumors but also serve as radionuclide carriers for targeted radiotherapy. The potency, reversibility, selectivity and specific binding characteristics of ML04, an alleged irreversible inhibitor of EGFR, were established in vitro. The distribution of the F-18-labeled compound and the extent of EGFR-specific tumor uptake were evaluated in tumor-bearing mice. ML04 demonstrated potent, irreversible and selective inhibition of EGFR, combined with specific binding to the receptor in intact cells. In vivo distribution of the radiolabeled compound revealed tumor/blood and tumor/muscle activity uptake ratios of about 7 and 5, respectively, 3 h following administration of a radiotracer. Nevertheless, only minor EGFR-specific uptake of the compound was detected in these studies, using either EGFR-negative tumors or blocking studies as controls. To improve the in vivo performance of ML04, administration via prolonged intravenous infusion is proposed. Detailed pharmacokinetic characterization of this bioprobe could assist in the development of a kinetic model that would afford accurate measurement of EGFR content in tumors

  12. Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells.

    Science.gov (United States)

    Fuse, Marisa A; Plati, Stephani Klingeman; Burns, Sarah S; Dinh, Christine T; Bracho, Olena; Yan, Denise; Mittal, Rahul; Shen, Rulong; Soulakova, Julia N; Copik, Alicja J; Liu, Xue Zhong; Telischi, Fred F; Chang, Long-Sheng; Franco, Maria Clara; Fernandez-Valle, Cristina

    2017-11-01

    Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G 1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387-98. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. Hand-foot skin reaction with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis.

    Science.gov (United States)

    Li, Jing; Gu, Jian

    2017-11-01

    A meta-analysis was conducted to systematically review the risk of hand-foot skin reaction (HFSR) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with cancer. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with VEGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till May 2017. Twenty-one RCTs and 9552 patients were included. The current analysis suggested that the use of VEGFR-TKIs increased the risk of all-grade HFSR (7.04;95%CI, 5.33-9.30;pcancer type, whereas the RR of high-grade HFSR did not. The risk of all-grade and high-grade HFSR did not affect by drug types, treatment line, median age and treatment duration. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model.

    Science.gov (United States)

    Lu, Jiaxiong; Guan, Shan; Zhao, Yanling; Yu, Yang; Woodfield, Sarah E; Zhang, Huiyuan; Yang, Kristine L; Bieerkehazhi, Shayahati; Qi, Lin; Li, Xiaonan; Gu, Jerry; Xu, Xin; Jin, Jingling; Muscal, Jodi A; Yang, Tianshu; Xu, Guo-Tong; Yang, Jianhua

    2017-08-01

    Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. A Phase II Safety and Efficacy Study of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Patients With Metastatic Urothelial Cancer

    Science.gov (United States)

    Pili, Roberto; Qin, Rui; Flynn, P.J.; Picus, Joel; Millward, Michael; Ho, Wing Ming; Pitot, Henry; Tan, Winston; Miles, Kiersten M.; Erlichman, Charles; Vaishampayan, Ulka

    2013-01-01

    Vascular endothelial growth factor (VEGF) is expressed in human bladder tumors. A phase II study was conducted to assess the VEGF inhibitor pazopanib in patients with metastatic, urothelial carcinoma. Nineteen patients with one prior systemic therapy were enrolled. No objective responses were observed and median progression-free survival was 1.9 months. The role of anti-VEGF therapies in urothelial carcinoma remains to be determined. Background Vascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. Methods Patients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. Results Nineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. Conclusions Pazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. PMID:23891158

  16. The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qiang; Song, Xin-mao; Ji, Yang-yang; Jiang, Hui; Xu, Lin-gen, E-mail: drlingenxu@126.com

    2013-11-01

    Highlights: •AZD8055 induces significant cytotoxic effects in cultured HNSCC cells. •AZD8055 blocks mTORC1 and mTORC2 activation in cultured HNSCC cells. •JNK activation is required for AZD8055-induced HNSCC cell death. •AZD8055 inhibits Hep-2 cell growth in vivo, and was more efficient than rapamycin. -- Abstract: The serine/threonine kinase mammalian target of rapamycin (mTOR) promotes cell survival and proliferation, and is constitutively activated in head and neck squamous cell carcinoma (HNSCC). Thus mTOR is an important target for drug development in this disease. Here we tested the anti-tumor ability of AZD8055, the novel mTOR inhibitor, in HNSCC cells. AZD8055 induced dramatic cell death of HNSCC lines (Hep-2 and SCC-9) through autophagy. AZD8055 blocked both mTOR complex (mTORC) 1 and mTORC2 activation without affecting Erk in cultured HNSCC cells. Meanwhile, AZD8055 induced significant c-Jun N-terminal kinase (JNK) activation, which was also required for cancer cell death. JNK inhibition by its inhibitors (SP 600125 and JNK-IN-8), or by RNA interference (RNAi) alleviated AZD8055-induced cell death. Finally, AZD8055 markedly increased the survival of Hep-2 transplanted mice through a significant reduction of tumor growth, without apparent toxicity, and its anti-tumor ability was more potent than rapamycin. Meanwhile, AZD8055 administration activated JNK while blocking mTORC1/2 in Hep-2 tumor engrafts. Our current results strongly suggest that AZD8055 may be further investigated for HNSCC treatment in clinical trials.

  17. Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice

    DEFF Research Database (Denmark)

    Winding, Bent; NicAmhlaoibh, Róisín; Misander, Henriette

    2002-01-01

    Breast cancer frequently leads to incurable bone metastasis. Essential requirements for the development of bone metastasis are cell-cell and cell-matrix interactions, release of bioactive growth factors and cytokines, and removal of large amounts of bone matrix. Matrix metalloproteinases (MMPs...

  18. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling

    DEFF Research Database (Denmark)

    Adams, T E; Hansen, J A; Starr, R

    1998-01-01

    Four members (SOCS-1, SOCS-2, SOCS-3, and CIS) of a family of cytokine-inducible, negative regulators of cytokine receptor signaling have recently been identified. To address whether any of these genes are induced in response to growth hormone (GH), serum-starved 3T3-F442A fibroblasts were incuba...

  19. Olive phenolics as c-Met inhibitors: (--Oleocanthal attenuates cell proliferation, invasiveness, and tumor growth in breast cancer models.

    Directory of Open Access Journals (Sweden)

    Mohamed R Akl

    Full Text Available Dysregulation of the Hepatocyte growth factor (HGF/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT, angiogenesis, invasion, and metastasis. (--Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (--oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (--oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (--oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (--oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (--oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (--oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.

  20. Galunisertib (LY2157299), a transforming growth factor-β receptor I kinase inhibitor, attenuates acute pancreatitis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Liu, X. [Department of General Surgery, the Affiliated Hospital of Qingdao University, Qingdao (China); Department of General Surgery, People' s Hospital of Chengyang, Qingdao (China); Yu, M. [Department of Clinical Laboratory, the Women and Children' s Hospital of Qingdao, Qingdao (China); Chen, Y. [Department of Traditional Chinese Medicine, the Affiliated Hospital of Qingdao University, Qingdao (China); Zhang, J. [Department of General Surgery, the Affiliated Hospital of Qingdao University, Qingdao (China)

    2016-08-08

    Galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-β receptor I (TGF-βRI), is the only known TGF-β pathway inhibitor. In the present study, we investigated the effect of galunisertib on taurocholate (TAC)-induced acute pancreatitis (AP) in rats, and the role of TGF-β and NF-κB signaling pathways. AP was induced by infusion of TAC into the pancreatic duct of Sprague-Dawley male rats (n=30). The rats (220±50 g) were administered galunisertib intragastrically [75 mg·kg{sup -1}·day{sup -1} for 2 days (0 and 24 h)]. Serum IL-1β, IL-6, TNF-α, amylase (AMY), lipase (LIP), and myeloperoxidase (MPO) levels were measured by ELISA. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA); NF-κBp65 and TGF-β1 proteins, as well as TGF-βRI and p-Smad2/3 proteins, were detected by western blot assay. Cell apoptosis was detected by TUNEL assay. H&E staining was used to evaluate the histopathological alterations of the pancreas. Galunisertib treatment attenuated the severity of AP and decreased the pancreatic histological score. In addition, number of apoptotic cells were significantly increased in the galunisertib-treated group (16.38±2.26) than in the AP group (8.14±1.27) and sham-operated group (1.82±0.73; P<0.05 and P<0.01, respectively). Galunisertib decreased the expression levels of TGF-βRI and p-Smad2/3 and inhibited NF-κB activation and p65 translocation compared with the sham-operated group. Furthermore, serum IL-1β, IL-6, TNF-α, AMY and LIP levels and tissue MPO activity were significantly decreased in the galunisertib-treated group. Our data demonstrate that galunisertib attenuates the severity of TAC-induced experimental AP in rats by inducing apoptosis in the pancreas, inhibiting the activation of TGF-β signals and NF-κB as well as the secretion of pro-inflammatory cytokines.

  1. Growth in Spending on and Use of Services for Mental and Substance Use Disorders After the Great Recession Among Individuals With Private Insurance.

    Science.gov (United States)

    Mark, Tami L; Hodgkin, Dominic; Levit, Katharine R; Thomas, Cindy Parks

    2016-05-01

    Recessions are associated with increased prevalence of mental and substance use disorders, but their effect on use of behavioral health services is less clear. This study examined changes in spending per enrollee for behavioral health services compared with general medical services among individuals with private insurance following the Great Recession that began in 2007. The National Survey on Drug Use and Health was used to examine the prevalence of behavioral health conditions among persons with private insurance from 2004 to 2013. Truven Health MarketScan Commercial Claims and Encounters data (2004-2012) were used to calculate use of and spending on treatment of behavioral and general medical conditions before and after the recession among individuals with employer-sponsored private health insurance. There was a statistically significant increase in serious psychological distress and episodes of major depression between 2007 and 2010. Between 2004-2009 and 2009-2012, the growth in average annual spending per individual slowed for general medical care (from 6.6% to 3.7%) but accelerated for behavioral health care (from 4.8% to 6.6%). From 2009 to 2012, the percentage of individuals receiving inpatient treatment, outpatient treatment, and prescription drugs for behavioral conditions increased, whereas use of these services for general medical care decreased or remained flat. Out-of-pocket costs increased more slowly for behavioral conditions than for other medical conditions. The recession was associated with increased need for and use of behavioral health services among individuals with private insurance. The Mental Health Parity and Addiction Equity Act may have also played a role in facilitating increasing use of behavioral health services after 2008.

  2. Inhibition effect of proteasome inhibitor MG132 combined with X-ray irradiation on cell growth, metastasis and cycle distribution of human lung adenocarcinoma cells

    International Nuclear Information System (INIS)

    Liu Jing; Tang Yiting; Zhou Jundong; Zhang Shuyu; Cao Han; Wu Jinchang; Luo Judong; Chen Guanglie; Cao Jianping

    2014-01-01

    Objective: To study the effects of proteasome inhibitor MG132 on the growth, metastasis, and cell cycle distribution of human lung adenocarcinoma cells A549 irradiated by X-rays. Methods: After treatment of MG132 and irradiation,cell proliferation was detected by MTT assay. Survival was measured by clonogenic assay. Cell migration ability was detected by the Scratch migration assay. Cell invasion ability was detected by transwell migration assay. Cell cycle distribution were analyzed by flow cytometry assay. Protein expression was detected by Western blot assay. Results: MG132 alone inhibited cell growth in a dose-and time-dependent manner. MG132 in combination with radiation significantly suppressed the growth, migration and invasion of A549 cells compared to the control (F =554.78, 954.64, P<0.01). MG132 enhanced radiation-induced G 1 -arrest (t =4.44, 12.41, 3.52, 6.72, P<0.05). The G 1 cell cycle distribution rate of MG132 plus RT group was increased to (71.05 ± 4.17)%. The expressions of MMP-2, MMP-9 and Cyclin D1 were significantly suppressed by MG132 in combination with radiation, while the expression of P53 was up-regulated. Conclusions: MG132 inhibits cell growth, migration and invasion ability, and induces G 1 cell cycle arrest of A549 cells treated with MG132 in combination with radiation, in which the down-regulation of MMPs and Cyclin D1 and up-regulation of P53 may be involved. (authors)

  3. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma

    International Nuclear Information System (INIS)

    Baumann, Philipp; Mandl-Weber, Sonja; Oduncu, Fuat; Schmidmaier, Ralf

    2009-01-01

    NVP-BEZ235 is a new inhibitor of phosphoinositol-3-kinase (PI3 kinase) and mammalian target of rapamycin (mTOR) whose efficacy in advanced solid tumours is currently being evaluated in a phase I/II clinical trial. Here we show that NVP-BEZ235 inhibits growth in common myeloma cell lines as well as primary myeloma cells at nanomolar concentrations in a time and dose dependent fashion. Further experiments revealed induction of apoptosis in three of four cell lines. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the BrdU assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, pRb and cdc25a. NVP-BEZ235 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1. Furthermore we show that the stimulatory effect of CD40-ligand (CD40L), insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6) and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BEZ235. In addition, synergism studies revealed synergistic and additive activity of NVP-BEZ235 together with melphalan, doxorubicin and bortezomib. Taken together, inhibition of PI3 kinase/mTOR by NVP-BEZ235 is highly effective and NVP-BEZ235 represents a potential new candidate for targeted therapy in multiple myeloma

  4. Drug Holiday in Metastatic Renal-Cell Carcinoma Patients Treated With Vascular Endothelial Growth Factor Receptor Inhibitors.

    Science.gov (United States)

    Mittal, Kriti; Derosa, Lisa; Albiges, Laurence; Wood, Laura; Elson, Paul; Gilligan, Timothy; Garcia, Jorge; Dreicer, Robert; Escudier, Bernard; Rini, Brian

    2018-01-04

    Tyrosine kinase inhibitor (TKI) therapy in metastatic renal-cell carcinoma (mRCC) is noncurative and may be associated with significant toxicities. Some patients may receive treatment breaks as a result of TKI-related adverse effects or planned drug holidays. In this retrospective study, mRCC patients who underwent drug holidays during TKI therapy at 2 different institutions were analyzed. A drug holiday was defined as a period of drug cessation for ≥ 3 months for reasons other than progressive disease. Of the 112 patients, the median duration of the first drug holiday for the overall cohort was 16.8 months (95% confidence interval, 12.5-26.4), and 40 patients (36%) remain on the first drug holiday. Overall, patients received a median of 2 lines of treatment. Complete response before the initial drug holiday (n = 14) was associated with a longer surveillance period (P = .0004). The observed median survival of this cohort was 71.7 months (range, 1.3 to 93+ months). Some selected mRCC patients with a favorable response to TKIs may be eligible for drug holidays. The cohort evaluated in this retrospective study represents a highly selected group of patients with indolent disease biology. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Growth

    Science.gov (United States)

    John R. Jones; George A. Schier

    1985-01-01

    This chapter considers aspen growth as a process, and discusses some characteristics of the growth and development of trees and stands. For the most part, factors affecting growth are discussed elsewhere, particularly in the GENETICS AND VARIATION chapter and in chapters in PART 11. ECOLOGY. Aspen growth as it relates to wood production is examined in the WOOD RESOURCE...

  6. Combination treatment with ionising radiation and gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor (EGFR) inhibitor, significantly inhibits bladder cancer cell growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Colquhoun, AJ; Mchugh, LA; Tulchinsky, E.; Kriajevska, M.; Mellon, JK

    2007-01-01

    External beam radiotherapy (EBRT) is the principal bladder-preserving monotherapy for muscle-invasive bladder cancer. Seventy percent of muscle-invasive bladder cancers express epidermal growth factor receptor (EGFR), which is associated with poor prognosis. Ionising radiation (IR) stimulates EGFR causing activation of cytoprotective signalling cascades and thus may be an underlying cause of radioresistance in bladder tumours. We assessed the ability of IR to activate EGFR in bladder cancer cells and the effect of the anti-EGFR therapy, gefitinib on potential radiation-induced activation. Subsequently we assessed the effect of IR on signalling pathways downstream of EGFR. Finally we assessed the activity of gefitinib as a monotherapy, and in combination with IR, using clonogenic assay in vitro, and a murine model in vivo. IR activated EGFR and gefitinib partially inhibited this activation. Radiation-induced activation of EGFR activated the MAPK and Akt pathways. Gefitinib partially inhibited activation of the MAPK pathway but not the Akt pathway. Treatment with combined gefitinib and IR significantly inhibited bladder cancer cell colony formation more than treatment with gefitinib alone (p=0.001-0.03). J82 xenograft tumours treated with combined gefitinib and IR showed significantly greater growth inhibition than tumours treated with IR alone (p=0.04). Combining gefitinib and IR results in significantly greater inhibition of invasive bladder cancer cell colony formation in vitro and significantly greater tumour growth inhibition in vivo. Given the high frequency of EGFR expression by bladder tumours and the low toxicity of gefitinib there is justification to translate this work into a clinical trial. (author)

  7. Flipped script for gefitinib: A reapproved tyrosine kinase inhibitor for first-line treatment of epidermal growth factor receptor mutation positive metastatic nonsmall cell lung cancer.

    Science.gov (United States)

    Bogdanowicz, Brian S; Hoch, Matthew A; Hartranft, Megan E

    2017-04-01

    Purpose The approval history, pharmacology, pharmacokinetics, clinical trials, efficacy, dosing recommendations, drug interactions, safety, place in therapy, and economic considerations of gefitinib are reviewed. Summary Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer death. Platinum-based chemotherapy and tyrosine kinase inhibitors, such as erlotinib and afatinib, are recommended therapies for nonsmall cell lung cancer. The European Medicines Association based their approval of gefitinib on the randomized, multicenter Iressa Pan-Asia Study (IPASS, NCT00322452) and a single-arm study showing effectiveness in Caucasians (IFUM, NCT01203917). Both studies were recently referenced by the United States Food & Drug Administration to reapprove gefitinib for the first-line treatment of advanced nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 substitution. Diarrhea, acneiform rash, and interstitial lung disease are known side effects of gefitinib. Conclusion Use of gefitinib for the first-line therapy of metastatic nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions (residues 747-750) or exon 21 substitution mutation (L858R) is well-documented and supported.

  8. Effects of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in EGFR-mutated non-small cell lung cancer.

    Science.gov (United States)

    Yang, Guangdie; Yao, Yinan; Zhou, Jianya; Zhao, Qiong

    2012-06-01

    Epidermal growth factor receptor (EGFR) is one of the most promising targets for non-small cell lung cancer (NSCLC). Our study demonstrated the antitumor effects of icotinib hydrochloride, a highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in two EGFR-mutated lung cancer cell lines compared to A549, a cell line without EGFR mutations. We incubated PC-9 and HCC827 human lung cancer cell lines both with (E746-A750) mutations with various concentrations of icotinib and gefitinib for 48 h. Cell proliferation and migration were determined using a real-time cell invasion and migration assay and cytotoxicity assay. Apoptosis was assessed by measuring Annexin V staining using flow cytometry. The antitumor effects of icotinib compared to gefitinib were similar and were most effective in reducing the proliferation of EGFR-mutated cells compared to non-mutated controls. Our results suggest the possibility of icotinib as a new therapeutic agent of EGFR-mutated cancer cells, which has the potential to be used in the first-line treatment of EGFR-mutated NSCLC.

  9. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer.

    Science.gov (United States)

    Matulonis, Ursula A; Berlin, Suzanne; Ivy, Percy; Tyburski, Karin; Krasner, Carolyn; Zarwan, Corrine; Berkenblit, Anna; Campos, Susana; Horowitz, Neil; Cannistra, Stephen A; Lee, Hang; Lee, Julie; Roche, Maria; Hill, Margaret; Whalen, Christin; Sullivan, Laura; Tran, Chau; Humphreys, Benjamin D; Penson, Richard T

    2009-11-20

    Angiogenesis is important for epithelial ovarian cancer (EOC) growth, and blocking angiogenesis can lead to EOC regression. Cediranib is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) -1, VEGFR-2, VEGFR-3, and c-kit. We conducted a phase II study of cediranib for recurrent EOC or peritoneal or fallopian tube cancer; cediranib was administered as a daily oral dose, and the original dose was 45 mg daily. Because of toxicities observed in the first 11 patients, the dose was lowered to 30 mg. Eligibility included 16 weeks, or CA-125 nonprogression > 16 weeks), which was the primary end point, was 30%; eight patients (17%; 95% CI, 7.6% to 30.8%) had a PR, six patients (13%; 95% CI, 4.8% to 25.7%) had SD, and there were no CRs. Eleven patients (23%) were removed from study because of toxicities before two cycles. Grade 3 toxicities (> 20% of patients) included hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism occurred in 43% of patients. Grade 4 toxicities included CNS hemorrhage (n = 1), hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No bowel perforations or fistulas occurred. Median PFS was 5.2 months, and median OS has not been reached; median follow-up time is 10.7 months. Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs.

  10. Treatment of erythrocytes with the 2-cys peroxiredoxin inhibitor, Conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine.

    Directory of Open Access Journals (Sweden)

    Mariana Brizuela

    Full Text Available The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2, which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl-1,4-dioxide-quinoxaline; BBMQ, has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ, an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria.

  11. Effect of radiotherapy in combination with liposomal MTP-PE or inhibitors of metabolism of eicosanoids on the growth of experimental fibrosarcoma

    International Nuclear Information System (INIS)

    Fedorocko, P.; Sedlakova, Z.; Mackova, N.; Sabol, M.; Eliasova, V.; Kocikova, A.; Matula, P.

    1998-01-01

    The immunophenotypization, tumorigenicity and immunogenicity of the tumor were characterized. The tumorigenic dose of the fibrosarcoma G5:1:13 for mice C3H/DiSn when administered s.c. is 1x10 5 per mouse. With this dose, tumors with an average volume of 64 mm 3 on day 6 developed; 98-100% mice died on day 120. The phenotype of the fibrosarcoma, which is immunogenic, is MHC-I + , HNC-II - , B7 - , B7.2 - . After administration of irradiated tumor cells (2 doses, s.c., 1x10 6 per mouse), a tumor developed in none of the animals to which the non-irradiated tumor cells had been administered. The effect of the individual factors was examined. Gamma radiation affected survival of the mice as follows: 2x8 Gy (60%), 4x6 Gy (80%), 5x5 Gy (80%), 3x7 Gy (80%), in positive correlation with the tumor size. The growth was affected similarly by MTP-PE (40%), diclofenac (40%), ibuprofen (40%) and flurbiprofen (30%). When diclofenac was combined with MTP-PE, a surprising strengthening of the tumor growth was observed. This finding is very important in view of the clinical use of MTP-PE and inhibitors of arachidonic acid metabolism in the treatment of tumorous diseases

  12. Is Transforming Growth Factor-β Signaling Activated in Human Hypertrophied Prostate Treated by 5-Alpha Reductase Inhibitor?

    Directory of Open Access Journals (Sweden)

    Hye Kyung Kim

    2013-01-01

    Full Text Available Background and Aim. It is well known that androgen deprivation relates to penile fibrosis, so we hypothesize that long-term treatment with 5-alphareductase inhibitors (5ARIs may increase the risk of fibrosis of prostate. Patients and Methods. Thirty-two BPH patients who underwent transurethral resection of the prostate were enrolled. The patients were divided into two groups: group one, 16 patients underwent TURP who had been treated with tamsulosin for 2 years; group two, 16 patients underwent TURP who had been treated with combination of tamsulosin and dutasteride for at least 1 year. We evaluated the expressions of nNOS, iNOS, eNOS, TGF-β1, TGF-β2, phosphorylated-Smad2/3 (p-Smad2/3, E-cadherin, N-cadherin, and α-smooth muscle actin in the resected prostate tissues by western blotting, and the TGF-β concentration was determined by ELISA kit. Results. The expressions of 3 isoforms of NOS were significantly increased in group 2 except of eNOS in lateral prostate, and the expressions of TGF-β1, TGF-β2, and p-Smad2/3 increased about 2-fold compared with group 1. In group 2, the E-cadherin expression decreased while N-cadherin expression increased significantly. Conclusions. The overexpression of nNOS may contribute to prostate smooth muscle relaxation; however, long-time treatment with 5 ARI increases the risk of fibrosis of prostate.

  13. A small molecule inhibitor of ETV1, YK-4-279, prevents prostate cancer growth and metastasis in a mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Said Rahim

    Full Text Available The erythroblastosis virus E26 transforming sequences (ETS family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.We recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S-YK-4-279 is the active enantiomer in prostate cancer cells.Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential

  14. GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth In Vitro and In Vivo

    DEFF Research Database (Denmark)

    Raab, Marc S.; Breitkreutz, Iris; Anderhub, Simon

    2012-01-01

    In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells......) for proliferation and survival were in the range of 1 to 5 μmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro...

  15. A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

    Directory of Open Access Journals (Sweden)

    Partha S Bhattacharjee

    2011-01-01

    Full Text Available Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp derived from the receptor binding region of human apolipoprotein E (apoE inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

  16. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice

    Science.gov (United States)

    Gerasimova, Maria; Rose, Michael A.; Masuda, Takahiro; Satriano, Joseph; Mayoux, Eric; Koepsell, Hermann; Thomson, Scott C.; Rieg, Timo

    2013-01-01

    Our previous work has shown that gene knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300 mg/dl) and prevented glomerular hyperfiltration but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300 mg/kg of diet for 15 wk; corresponding to 60–80 mg·kg−1·day−1) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita diabetes, empagliflozin, and Akita + empagliflozin similarly increased renal membrane SGLT2 expression (by 38–56%) and reduced the expression of SGLT1 (by 33–37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/SGLT1 protein expression are expected to enhance the BG-lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187–237 vs. 517–535 mg/dl in vehicle group; 100–140 mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306 μl/min) and completely prevented the diabetes-induced increase in glomerular filtration rate (GFR) (255 vs. 397 μl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG. PMID:24226524

  17. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models

    Science.gov (United States)

    Piao, Yuji; Park, Soon Young; Henry, Verlene; Smith, Bryan D.; Tiao, Ningyi; Flynn, Daniel L.

    2016-01-01

    Background Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy. Methods We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone. Results In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone. Conclusions Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma. PMID:26965451

  18. Shared Substance

    DEFF Research Database (Denmark)

    Gjerlufsen, Tony; Klokmose, Clemens Nylandsted; Eagan, James

    2011-01-01

    This paper presents a novel middleware for developing flexible interactive multi-surface applications. Using a scenario-based approach, we identify the requirements for this type of applications. We then introduce Substance, a data- oriented framework that decouples functionality from data, and S...

  19. A trypsin inhibitor from Tecoma stans leaves inhibits growth and promotes ATP depletion and lipid peroxidation in Candida albicans and Candida krusei

    Directory of Open Access Journals (Sweden)

    Leydianne Leite de Siqueira Patriota

    2016-04-01

    Full Text Available Tecoma stans (yellow elder has shown medicinal properties and antimicrobial activity. Previous reports on antifungal activity of T. stans preparations and presence of trypsin inhibitor activity from T. stans leaves stimulated the investigation reported here. In this work, we proceeded to the purification and characterization of a trypsin inhibitor (TesTI, which was investigated for anti-Candida activity. Finally, in order to determine the potential of TesTI as a new natural chemotherapeutic product, its cytotoxicity to human peripheral blood mononuclear cells (PBMCs was evaluated. TesTI was isolated from saline extract by ammonium sulphate fractionation followed by ion exchange and gel filtration chromatographies. Antifungal activity was evaluated by determining the minimal inhibitory (MIC and fungicide (MFC concentrations using fungal cultures containing only yeast form or both yeast and hyphal forms. Candida cells treated with TesTI were evaluated for intracellular ATP levels and lipid peroxidation. Cytotoxicity of TesTI to PBMCs was evaluated by MTT assay. TesTI (39.8 kDa, pI 3.41, Ki 43 nM inhibited similarly the growth of both C. albicans and C. krusei culture types at MIC of 100 µg/mL. The MFCs were 200 µg/mL for C. albicans and C. krusei. Time-response curves revealed that TesTI (at MIC was more effective at inhibiting the replication of C. albicans cells. At MIC, TesTI promoted reduction of ATP levels and lipid peroxidation in the Candida cells, being not cytotoxic to PBMCs. In conclusion, TesTI is an antifungal agent against C. albicans and C. krusei, without toxicity to human cells.

  20. Use of multitarget tyrosine kinase inhibitors to attenuate platelet-derived growth factor signalling in lung disease

    Directory of Open Access Journals (Sweden)

    Rana Kanaan

    2017-10-01

    Full Text Available Platelet-derived growth factors (PDGFs and their receptors (PDGFRs play a fundamental role in the embryonic development of the lung. Aberrant PDGF signalling has been documented convincingly in a large variety of pulmonary diseases, including idiopathic pulmonary arterial hypertension, lung cancer and lung fibrosis. Targeting PDGF signalling has been proven to be effective in these diseases. In clinical practice, the most effective way to block PDGF signalling is to inhibit the activity of the intracellular PDGFR kinases. Although the mechanism of action of such drugs is not specific for PDGF signalling, the medications have a broad therapeutic index that allows clinical use. The safety profile and therapeutic opportunities of these and future medications that target PDGFs and PDGFRs are reviewed.

  1. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines

    International Nuclear Information System (INIS)

    Mokhtari, Reza Bayat; Kumar, Sushil; Islam, Syed S; Yazdanpanah, Mehrdad; Adeli, Khosrow; Cutz, Ernest; Yeger, Herman

    2013-01-01

    Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. In vitro studies were used for the dose–response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0–80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids

  2. Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab

    Directory of Open Access Journals (Sweden)

    Chen Gang

    2012-03-01

    Full Text Available Abstract Background The epidermal growth factor receptor (EGFR is a validated therapeutic target in non-small cell lung cancer (NSCLC. However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations confer resistance to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs or a monoclonal antibody cetuximab. Methods NSCLC cells (cell lines HCC827, H292, H358, H1650, and H1975 were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity, and apoptotic morphology were monitored by spectrophotometry, fluorimetry, and fluorescence microscopy. The combined effect of EGFR siRNA and different drugs was evaluated using a combination index. Results EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied, albeit with a different magnitude. The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs. The effects of siRNA probably correlate with the overall oncogenic significance of the receptor, which is only partly inhibited by the TKIs. The cells which showed weak response to TKIs, such as the H1975 cell line containing the T790M resistance mutation, were found to be responsive to siRNA knockdown of EGFR, as were cell lines with downstream TKI resistance mutations. The cell line HCC827, harboring an exon 19 deletion mutation, was more than 10-fold

  3. PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells

    International Nuclear Information System (INIS)

    Crosswell, Hal E; Dasgupta, Anindya; Alvarado, Carlos S; Watt, Tanya; Christensen, James G; De, Pradip; Durden, Donald L; Findley, Harry W

    2009-01-01

    c-Met is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been demonstrated in different tumors and linked to aggressive and metastatic tumor phenotypes. In vitro and in vivo studies have demonstrated inhibition of c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752. This study investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and tumor tissue from patients with NBL, as well as the effects of PHA665752 on growth and motility of NBL cell lines. The effect of the tumor suppressor protein PTEN on migration and proliferation of tumor cells treated with PHA665752 was also evaluated. Expression of c-Met and HGF in NBL cell lines SH-EP and SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in NBL cell proliferation and migration was evaluated in c-Met-positive cells and c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were used to measure migration and proliferation/cell-survival of tumor cells, respectively. The PPAR-γ agonist rosiglitazone was used to assess the effect of PTEN on PHA665752-induced inhibition of NBL cell proliferation/cell-survival and migration High c-Met expression was detected in SH-EP cells and primary tumors from patients with advanced-stage disease. C-Met/HGF signaling induced both migration and proliferation of SH-EP cells. Migration and proliferation/cell-survival were inhibited by PHA665752 in a dose-dependent manner. We also found that induced overexpression of PTEN following treatment with rosiglitazone significantly enhanced the inhibitory effect of PHA665752 on NBL-cell migration and proliferation. c-Met is highly expressed in most tumors from

  4. Genetic blockade of insulin-like growth factor-1 receptor via recombinant adenovirus in lung cancer can be enhanced by the histone deacetylase inhibitor, vorinostat.

    Science.gov (United States)

    Park, Mi-Young; Kim, Dal Rae; Eo, Eun Young; Lim, Hyo Jeong; Park, Jong Sun; Cho, Young-Jae; Yoon, Ho-Il; Lee, Jae Ho; Lee, Choon-Taek

    2013-01-01

    Many approaches have been suggested as anti-tumor therapy for targeting insulin-like growth factor 1 receptor (IGF-1R), such as monoclonal antibodies and tyrosine kinase inhibitor. We introduced recombinant adenoviruses expressing antisense, dominant negative or short hairpin RNA to IGF-1R. Moreover, we demonstrated that histone deacetylase inhibitor (vorinostat) can increase the transduction efficiency of adenoviruses by increasing CAR-induced transduction and by enhancing the transcription of the adenoviral transgene. In the present study, we showed that the combination of ad-sh (short hairpin) IGF-1R with vorinostat leads to a synergistic enhancement of IGF-1R blockade. We measured the change in IGF-1R upon cotreatment with vorinostat and ad-shIGF-1R. Changes in transduction efficiency of ad-shIGF-1R were measured by fluorescent microscopy. Changes in apoptotic proportion and cell survival after the cotreatment were measured by the sub-G1 assay and cell counts. The effect of nuclear factor (NF)-κB activation was also measured by NF-κB p65 activation enzyme-linked immunosorbent assay. Drug interactions were analyzed upon cotreatment with ad-shIGF-1R, vorinostat and cisplatin. Combined treatment of ad-shIGF-1R and vorinostat synergistically suppressed the IGF-1R expression in lung cancer cell lines and also increased the transduction efficiency of ad-shIGF-1R. Ad-shIGF-1R and vorinostat cotreatment increased apoptotic cell death and synergistically suppressed cell growth compared to ad-shIGF-1R or vorinostat treatment alone. Vorinostat suppressed NF-κB activation, which was activated by ad-shIGF-1R. Moreover, triple combination of ad-shIGF-1R, vorinostat and cisplatin demonstrated synergistic cytotoxicity on lung cancer cells. Vorinostat enhanced the blocking capability of ad-shIGF-1R. The combined treatment of vorinostat and ad-sh-IGF-1R appears to have promising potential as a new therapeutic approach for lung cancer. Copyright © 2013 John Wiley & Sons, Ltd.

  5. A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.

    Science.gov (United States)

    Viloria, Katrina; Munasinghe, Amanda; Asher, Sharan; Bogyere, Roberto; Jones, Lucy; Hill, Natasha J

    2016-11-25

    SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.

  6. Deconstructing Quinoline-Class Antimalarials to Identify Fundamental Physicochemical Properties of Beta-Hematin Crystal Growth Inhibitors.

    Science.gov (United States)

    Olafson, Katy N; Nguyen, Tam Q; Vekilov, Peter G; Rimer, Jeffrey D

    2017-10-04

    A versatile approach to control crystallization involves the use of modifiers, which are additives that interact with crystal surfaces and alter their growth rates. Elucidating a modifier's binding specificity to anisotropic crystal surfaces is a ubiquitous challenge that is critical to their design. In this study, we select hematin, a byproduct of malaria parasites, as a model system to examine the complementarity of modifiers (i.e., antimalarial drugs) to β-hematin crystal surfaces. We divide two antimalarials, chloroquine and amodiaquine, into segments consisting of a quinoline base, common to both drugs, and side chains that differentiate their modes of action. Using a combination of scanning probe microscopy, bulk crystallization, and analytical techniques, we show that the base and side chain work synergistically to reduce the rate of hematin crystallization. In contrast to general observations that modifiers retain their function upon segmentation, we show that the constituents do not act as modifiers. A systematic study of quinoline isomers and analogues shows how subtle rearrangement and removal of functional moieties can create effective constituents from previously ineffective modifiers, along with tuning their inhibitory modes of action. These findings highlight the importance of specific functional moieties in drug compounds, leading to an improved understanding of modifier-crystal interactions that could prove to be applicable to the design of new antimalarials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Matrix protein of vesicular stomatitis virus: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation.

    Science.gov (United States)

    Zhou, Y; Wen, F; Zhang, P; Tang, R; Li, Q

    2013-03-01

    Malignant ascites is common in various types of cancers and is difficult to manage. Vascular endothelial growth factor (VEGF) has a pivotal role in malignant ascites. The matrix protein of vesicular stomatitis virus (VSVMP) has been shown to inhibit host gene expression and induce the apoptosis of cancer cells. The present study was designed to determine whether VSVMP suppresses the formation of ascites in ascites-producing peritoneal carcinomatosis. BALB/c female mice, 6-8 weeks old, bearing peritoneal tumors of H22 or MethA cells received an intraperitoneal administration of 50 μg VSVMP/250 μg liposome complexes, 50 μg empty plasmid/250 μg liposome complexes or 0.9% NaCl solution, respectively, every 2 days for 3 weeks. Administration of VSVMP resulted in a significant inhibition in ascites formation, improvement in health condition and prolonged survival of the treated mice. Decreased peritoneum osmolarity and reduced tumor vascularity coincided with dramatic reductions in the VEGF level in ascites fluid and plasma. Examination of floating tumor cells collected from the peritoneal wash revealed an apparently increased number of apoptotic cells and profound downregulation of VEGF mRNA in the VSVMP-treated mice. Our data indicate for the first time that in BALB/c mice bearing H22 or MethA cell peritoneal tumors, VSVMP may inhibit VEGF production and suppress angiogenesis, consequently abolishing ascites formation.

  8. HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice.

    Directory of Open Access Journals (Sweden)

    Thaiz Ferraz Borin

    Full Text Available A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors. HET0016 effects were analyzed on MDA-MB-231 derived breast cancer in mouse and in vitro cell line. MDA-MB-231 tumor cells were implanted in animals' right flank and randomly assigned to early (1 and 2, starting treatments on day 0, or delayed groups (3 and 4 on day 8 after implantation of tumor. Animals received HET0016 (10 mg/kg treatment via intraperitoneal injection for 5 days/week for either 3 or 4 weeks. Control group received vehicle treatment. Tumor sizes were measured on days 7, 14, 21, and 28 and the animals were euthanized on day 22 and 29. Proteins were extracted from the whole tumor and from cells treated with 10 µM HET0016 for 4 and 24 hrs. Protein array kits of 20 different cytokines/factors were used. ELISA was performed to observe the HIF-1α and MMP-2 protein expression. Other markers were confirmed by IHC. HET0016 significantly inhibited tumor growth in all treatment groups at all-time points compared to control (p<0.05. Tumor growth was completely inhibited on three of ten animals on early treatment group. Treatment groups showed significantly lower expression of pro-angiogenic factors compared to control at 21 days; however, there was no significant difference in HIF-1α expression after treatments. Similar results were found in vitro at 24 hrs of HET0016 treatment. After 28 days, significant increase of angiogenin, angiopoietin-1/2, EGF-R and IGF-1 pro-angiogenic factors were found (p<0.05 compared to control, as well as an higher intensity of all factors were found when compared to that of 21 day's data, suggesting a treatment resistance. HET0016 inhibited tumor growth by reducing expression of different set of pro-angiogenic factors; however, a resistance to treatment seemed to happen after 21 days.

  9. Circulating levels of interleukin-6, vascular endothelial growth factor, YKL-40, matrix metalloproteinase-3, and total aggrecan in spondyloarthritis patients during 3 years of treatment with TNFα inhibitors

    DEFF Research Database (Denmark)

    Pedersen, Susanne Juhl; Hetland, Merete Lund; Sørensen, Inge Juul

    2010-01-01

    The objectives of the study were to investigate short and long-term changes and relations to treatment response of plasma interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), YKL-40, matrix metalloproteinase-3 (MMP-3), and total aggrecan in patients with spondyloarthritis (SpA) treated...... with tumor necrosis factor-alpha (TNFα) inhibitors and to compare with levels in healthy subjects. Biomarkers were measured in an observational cohort of 49 SpA patients (ankylosing spondylitis, n=32, and psoriatic arthritis, n=17) initiating TNFα inhibitor therapy (infliximab, n=38; etanercept, n=8...

  10. Hair Growth Promoting and Anticancer Effects of p21-activated kinase 1 (PAK1 Inhibitors Isolated from Different Parts of Alpinia zerumbet

    Directory of Open Access Journals (Sweden)

    Nozomi Taira

    2017-01-01

    Full Text Available PAK1 (p21-activated kinase 1 is an emerging target for the treatment of hair loss (alopecia and cancer; therefore, the search for PAK1 blockers to treat these PAK1-dependent disorders has received much attention. In this study, we evaluated the anti-alopecia and anticancer effects of PAK1 inhibitors isolated from Alpinia zerumbet (alpinia in cell culture. The bioactive compounds isolated from alpinia were found to markedly promote hair cell growth. Kaempferol-3-O-β-d-glucuronide (KOG and labdadiene, two of the isolated compounds, increased the proliferation of human follicle dermal papilla cells by approximately 117%–180% and 132%–226%, respectively, at 10–100 μM. MTD (2,5-bis(1E,3E,5E-6-methoxyhexa-1,3,5-trien-1-yl-2,5-dihydrofuran and TMOQ ((E-2,2,3,3-tetramethyl-8-methylene-7-(oct-6-en-1-yloctahydro-1H-quinolizine showed growth-promoting activity around 164% and 139% at 10 μM, respectively. The hair cell proliferation induced by these compounds was significantly higher than that of minoxidil, a commercially available treatment for hair loss. Furthermore, the isolated compounds from alpinia exhibited anticancer activity against A549 lung cancer cells with IC50 in the range of 67–99 μM. Regarding the mechanism underlying their action, we hypothesized that the anti-alopecia and anticancer activities of these compounds could be attributed to the inhibition of the oncogenic/aging kinase PAK1.

  11. Icotinib, a potent and specific EGFR tyrosine kinase inhibitor, inhibits growth of squamous cell carcinoma cell line A431 through negatively regulating AKT signaling.

    Science.gov (United States)

    Gao, Zhenzhen; Chen, Wei; Zhang, Xiaohua; Cai, Peifen; Fang, Xianying; Xu, Qiang; Sun, Yang; Gu, Yanhong

    2013-06-01

    Icotinib is a potent and specific epidermal growth factor receptor tyrosine kinase inhibitor. In this study, we reported that icotinib had the antitumor activity on human squamous cell carcinoma cell line A431 in vitro. Meanwhile, adhesion to fibronectin and expression of integrin α3 and β1 were significantly reduced in a dose-dependent manner after the treatment of icotinib. Moreover, icotinib induced cell cycle arrested and affected expression of various cell cycle related proteins in squamous cancer cell line A431, whereas it did not cause apoptosis. Furthermore, icotinib remarkably down-regulated phosphorylation of protein kinase B (AKT) though blocking the interaction between 3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT in A431 cells. Taken together, it is shown that the small molecular compound, icotinib, has an anti-squamous cell carcinoma activity in vitro and its antitumor mechanism is associated with the blockage of the interaction between PDK1 and AKT. These results provide a novel strategy for anti-squamous cell carcinoma therapy. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  12. Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature.

    Science.gov (United States)

    Massey, Paul R; Okman, Jonathan S; Wilkerson, Julia; Cowen, Edward W

    2015-06-01

    Inhibition of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitors (TKIs) is associated with cutaneous adverse effects that increase patient morbidity. Our objective was to examine the skin toxicity profile of anti-VEGFR TKIs and determine the changing incidence in clinical trials. PubMed was queried for phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving ≥50 patients. Adverse events were abstracted, with results presented in both fixed and random effects models. Odds ratios (OR) and 95 % confidence intervals (CIs) were estimated for studies with at least two arms. Across 82 included studies, all grades rash (OR, 2.68; 95 % CI, 2.45-2.94), hand-foot skin reaction (HFSR) (OR, 2.70; 95 % CI, 2.43-3.00), and pruritus (OR, 1.25; 95 % CI, 1.12-1.39) were associated with anti-VEGFR TKIs. Vandetanib had the highest incidence of rash (41 %), while sorafenib was most commonly associated with HFSR (37 %) and pruritus (14 %). The incidence of HFSR from 2000 to 2013 showed an upward trend (r (2) = 0.042, p = 0.10) and in sunitinib therapy increased significantly (r (2) = 0.237, p = 0.04). The incidence of HFSR, rash, and pruritus varies considerably by drug. Our data suggest a continued need to address skin toxicities and improve reporting strategies.

  13. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

    Science.gov (United States)

    Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

    2012-12-01

    Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

  14. Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study

    International Nuclear Information System (INIS)

    Liu, SongRan; Qiu, Bo; Chen, LiKun; Wang, Fang; Liang, Ying; Cai, PeiQiang; Zhang, Li; Chen, ZhaoLin; Liu, ShiLiang; Liu, MengZhong; Liu, Hui

    2015-01-01

    Non-small cell lung cancer (NSCLC) with brain metastasis (BM) harboring an epidermal growth factor receptor (EGFR) mutation shows good response to tyrosine kinase inhibitors (TKIs). This study is to assess the appropriate timing of brain radiotherapy (RT) for asymptomatic BM in EGFR mutant NSCLC patients. There were 628 patients diagnosed with EGFR mutant NSCLC between October 2005 and December 2011. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT. With a median follow-up of 26 months, the 2-year OS was 40.6 %. Univariate analyses revealed that ECOG performance status (p = 0.006), other distant metastases (p = 0.002) and first line systemic treatment (p = 0.032) were significantly associated with overall survival (OS). Multivariate analyses revealed that other sites of distant metastases (p = 0.030) were prognostic factor. The timing of brain RT was not significantly related to OS (p = 0.246). The 2-year BM progression-free survival (PFS) was 26.9 %. Brain RT as first-line therapy failed to demonstrate a significant association with BM PFS (p = 0.643). First-line brain RT failed to improve long-term survival in TKI-naïve EGFR mutant NSCLC patients with asymptomatic BM. Prospective studies are needed to validate these clinical findings

  15. Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis.

    Science.gov (United States)

    Li, Jing; Gu, Jian

    2017-10-01

    The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p fatigue (1.97; 95% CI1.44-2.70; p fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

  16. Augmented growth inhibition of B16-BL6 melanoma by combined treatment with a selective matrix metalloproteinase inhibitor, MMI-166, and cytotoxic agents.

    Science.gov (United States)

    Hojo, Kanji; Maki, Hideo; Sawada, Takuko Yamada; Maekawa, Ryuji; Yoshioka, Takayuki

    2002-01-01

    MMI-166 is a selective matrix metalloproteinase (MMP) inhibitor. The purpose of this study was to evaluate the antitumor efficacy of the combined treatment of MMI-166 with paclitaxel or carboplatin. Mice bearing B16-BL6 melanoma were treated p.o. with MMI-166 from 1 day after tumor inoculation. The mice were administered i.v. with either paclitaxel or carboplatin at the maximum tolerated dose (MTD). MMI-166 monotherapy inhibited in vivo growth of the B16-BL6 tumor to an extent similar to that of paclitaxel or carboplatin monotherapy. When MMI-166 was combined with paclitaxel or carboplatin, the antitumor efficacy was significantly (p B16-BL6 tumor cells nor does it augment the cytotoxicity of paclitaxel or carboplatin. These results indicate that augmented antitumor activity of the combination treatment was not simply due to the augmentation of direct cytotoxic activity, but was rather an additive effect of the antitumor activities of different mechanisms. They suggest the effectiveness of a combination therapy of MMI-166 with paclitaxel or carboplatin in clinical therapy.

  17. A willingness-to-pay study of oral epidermal growth factor tyrosine kinase inhibitors in advanced non-small cell lung cancer.

    Science.gov (United States)

    Leighl, Natasha B; Tsao, W Stephen; Zawisza, Dianne L; Nematollahi, Mahsan; Shepherd, Frances A

    2006-01-01

    Oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are new agents in the treatment of advanced non-small cell lung cancer (NSCLC). Phase II studies demonstrate objective tumor responses and symptom improvement, combined with minimal toxicity and the convenience of an oral agent. We evaluated patient utility through willingness-to-pay (WTP) for these agents in the treatment of advanced NSCLC in Canada. Advanced NSCLC patients and healthy subjects participated in a structured interview and bidding exercise, reviewing current evidence supporting EGFR TKI therapy in advanced NSCLC and patient willingness-to-pay for treatment. Fifty-seven patients and 54 healthy subjects participated. The median amount both groups were willing to pay for a month of oral EGFR TKI therapy was $100 CAD (range $0-5000 per month). A minority of NSCLC patients received employment income, the majority relying on disability, pension income, and social assistance for financial support. Affordability of these agents was a key concern for both advanced NSCLC patients and healthy subjects. Univariate predictors of WTP included marital status, prior chemotherapy treatment, receiving pension income or financial social assistance. In multivariate analysis, only prior chemotherapy remained a significant predictor of WTP (p=0.049). Both advanced NSCLC patients and healthy subjects feel oral EGFR TKIs are worth paying for in the treatment of advanced NSCLC, but are willing to pay only a fraction of the market price. As many advanced NSCLC patients are financially disadvantaged, the potential for restricted access to newer therapies is of concern.

  18. Substance abuse and cancer.

    Science.gov (United States)

    Moussas, G I; Papadopoulou, A G

    2017-01-01

    Substance abuse is a health problem with serious psychological and psychiatric dimensions and multiple social and economic consequences. Cancer is a disease that threatens not only life and physical integrity but mental health as well. Oncology patients suffer from mental disorders in high rates, especially from depression and anxiety. The role of substance abuse in the pathogenesis of cancer is studied systematically, since there are research data supporting the mutagenic effects of certain substances. It has been supported that a possible dysregulation of the immune system is linked to the oncogenic processes induced by substances of abuse. Specifically, opioids are the first addictive substances that have been identified as oncogenic factors. However, conflicting results have been offered by experimental animal studies, which showed that opioids, such as morphine, depending on the dosage administered, may not only enhance the process of tumor growth, but also inhibit it. Additionally, research data indicate that the use of cannabis may be associated with cancer, either as an independent factor or in relation to other mutagenics, although it is not yet clear to which extent these effects may be connected to the disease, especially once the consumption of tobacco and alcohol by these patients are taken into account. However, it has been argued that certain cannabinoids may have biological -anticancer- activities which could be used therapeutically without being accompanied by the corresponding 9-tetrahydrocannabinol psychoactive effects. It is well known that alcohol is a risk factor for developing head and neck cancer, and epidemiological studies indicate that the higher the consumption of alcohol, the more mortality due to cancer increases. In addition, it is suggested that there is no safety level for alcohol consumption regarding the risk of developing cancer; that is even a minimum daily consumption is associated with the occurrence of certain types of cancer

  19. Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma

    Directory of Open Access Journals (Sweden)

    Shankar A

    2016-03-01

    Full Text Available Adarsh Shankar,1 Thaiz F Borin,2 Asm Iskander,1 Nadimpalli RS Varma,3 Bhagelu R Achyut,1 Meenu Jain,1 Tom Mikkelsen,4 Austin M Guo,5 Wilson B Chwang,3 James R Ewing,6 Hassan Bagher-Ebadian,6 Ali S Arbab11Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA; 2Laboratory of Molecular Investigation of Cancer (LIMC, Faculty of Medicine of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Brazil; 3Department of Radiology, Cellular and Molecular Imaging Laboratory, 4Department of Neurosurgery, Henry Ford Health System, Detroit, MI, 5Department of Pharmacology, New York Medical College, Valhalla, NY, 6Department of Neurology and Radiology, Henry Ford Health System, Detroit, MI, USA Background: Due to the hypervascular nature of glioblastoma (GBM, antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N'-(4-butyl-2 methylphenylformamidine (HET0016, which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE synthesis. The aims of the studies were to determine 1 whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2 whether the treatment schedule would have a crucial impact on controlling GBM.Methods: U251 human glioma cells (4×105 were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8–21 days treatment of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0–21 days treatment was to mimic cases following radiation therapy or surgery. There were four

  20. Plant HDAC inhibitor chrysin arrest cell growth and induce p21WAF1 by altering chromatin of STAT response element in A375 cells

    International Nuclear Information System (INIS)

    Pal-Bhadra, Manika; Bhadra, Utpal; Ramaiah, M Janaki; Reddy, T Lakshminarayan; Krishnan, Anita; Pushpavalli, SNCVL; Babu, K Suresh; Tiwari, Ashok K; Rao, J Madhusudana; Yadav, Jhillu S

    2012-01-01

    Chrysin and its analogues, belongs to flavonoid family and possess potential anti-tumour activity. The aim of this study is to determine the molecular mechanism by which chrysin controls cell growth and induce apoptosis in A375 cells. Effect of chrysin and its analogues on cell viability and cell cycle analysis was determined by MTT assay and flowcytometry. A series of Western blots was performed to determine the effect of chrysin on important cell cycle regulatory proteins (Cdk2, cyclin D1, p53, p21, p27). The fluorimetry and calorimetry based assays was conducted for characterization of chrysin as HDAC inhibitor. The changes in histone tail modification such as acetylation and methylation was studied after chrysin treatment was estimated by immuno-fluorescence and western blot analysis. The expression of Bcl-xL, survivin and caspase-3 was estimated in chrysin treated cells. The effect of chrysin on p21 promoter activity was studied by luciferase and ChIP assays. Chrysin cause G1 cell cycle arrest and found to inhibit HDAC-2 and HDAC-8. Chrysin treated cells have shown increase in the levels of H3acK14, H4acK12, H4acK16 and decrease in H3me2K9 methylation. The p21 induction by chrysin treatment was found to be independent of p53 status. The chromatin remodelling at p21 WAF1 promoter induces p21 activity, increased STAT-1 expression and epigenetic modifications that are responsible for ultimate cell cycle arrest and apoptosis. Chrysin shows in vitro anti-cancer activity that is correlated with induction of histone hyperacetylation and possible recruitment of STAT-1, 3, 5 proteins at STAT (−692 to −684) region of p21 promoter. Our results also support an unexpected action of chrysin on the chromatin organization of p21 WAF1 promoter through histone methylation and hyper-acetylation. It proposes previously unknown sequence specific chromatin modulations in the STAT responsive elements for regulating cell cycle progression negatively via the induction of the CDK

  1. Quantitative Tyrosine Phosphoproteomics of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-treated Lung Adenocarcinoma Cells Reveals Potential Novel Biomarkers of Therapeutic Response.

    Science.gov (United States)

    Zhang, Xu; Maity, Tapan; Kashyap, Manoj K; Bansal, Mukesh; Venugopalan, Abhilash; Singh, Sahib; Awasthi, Shivangi; Marimuthu, Arivusudar; Charles Jacob, Harrys Kishore; Belkina, Natalya; Pitts, Stephanie; Cultraro, Constance M; Gao, Shaojian; Kirkali, Guldal; Biswas, Romi; Chaerkady, Raghothama; Califano, Andrea; Pandey, Akhilesh; Guha, Udayan

    2017-05-01

    Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence 747 LREA 750 , are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations. However, 30-40% of patients with EGFR mutations exhibit primary resistance to these TKIs, underscoring the unmet need of identifying additional biomarkers of treatment response. Here, we sought to characterize the dynamics of tyrosine phosphorylation upon EGFR TKI treatment of mutant EGFR-driven human lung adenocarcinoma cell lines with varying sensitivity to EGFR TKIs, erlotinib and afatinib. We employed stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative mass spectrometry to identify and quantify tyrosine phosphorylated peptides. The proportion of tyrosine phosphorylated sites that had reduced phosphorylation upon erlotinib or afatinib treatment correlated with the degree of TKI-sensitivity. Afatinib, an irreversible EGFR TKI, more effectively inhibited tyrosine phosphorylation of a majority of the substrates. The phosphosites with phosphorylation SILAC ratios that correlated with the TKI-sensitivity of the cell lines include sites on kinases, such as EGFR-Y1197 and MAPK7-Y221, and adaptor proteins, such as SHC1-Y349/350, ERRFI1-Y394, GAB1-Y689, STAT5A-Y694, DLG3-Y705, and DAPP1-Y139, suggesting these are potential biomarkers of TKI sensitivity. DAPP1, is a novel target of mutant EGFR signaling and Y-139 is the major site of DAPP1 tyrosine phosphorylation. We also uncovered several off-target effects of these TKIs, such as MST1R-Y1238

  2. Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs

    OpenAIRE

    Puvanenthiran, Soozana; Essapen, Sharadah; Seddon, Alan M.; Modjtahedi, Helmout

    2016-01-01

    Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer s...

  3. Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.

    Science.gov (United States)

    Yamaguchi, Fumihiro; Fukuchi, Kunihiko; Yamazaki, Yohei; Takayasu, Hiromi; Tazawa, Sakiko; Tateno, Hidetsugu; Kato, Eisuke; Wakabayashi, Aya; Fujimori, Mami; Iwasaki, Takuya; Hayashi, Makoto; Tsuchiya, Yutaka; Yamashita, Jun; Takeda, Norikazu; Kokubu, Fumio

    2014-02-01

    The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.

  4. Correlation of degree of hypothyroidism with survival outcomes in patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors.

    Science.gov (United States)

    Bailey, Erin B; Tantravahi, Srinivas K; Poole, Austin; Agarwal, Archana M; Straubhar, Alli M; Batten, Julia A; Patel, Shiven B; Wells, Chesley E; Stenehjem, David D; Agarwal, Neeraj

    2015-06-01

    Hypothyroidism is a common adverse effect of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in patients with metastatic renal cell carcinoma (mRCC). Some studies have shown an association with improved survival. However, hypothyroidism severity has not been correlated with survival outcomes. We report the incidence and severity of VEGFR-TKI therapy-associated hypothyroidism in correlation with the survival outcomes of patients with mRCC. A retrospective analysis of patients with mRCC who received VEGFR-TKIs (2004 through 2013) was conducted from a single institutional database. Hypothyroidism, progression-free survival (PFS), and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazard models. Of 125 patients with mRCC, 65 were eligible. Their median age was 59 years (range, 45-79 years), and 46 (70.8%) were male. Hypothyroidism occurred in 25 patients (38.5%), of whom 13 had a peak thyroid-stimulating hormone (TSH) level > 10 mIU/L during treatment. The median OS was significantly longer in patients with a peak TSH > 10 mIU/L than in patients with a peak TSH of ≤ 10 mIU/L (not reached vs. 21.4 months, P = .005). On multivariate analysis, risk criteria, number of previous therapies, and severe hypothyroidism (TSH > 10 mIU/L) during VEGFR-TKI therapy remained significant for improvements in PFS and OS. The severity of VEGFR-TKI therapy-associated hypothyroidism (TSH > 10 mIU/L) was associated with improved survival outcomes in patients with mRCC and should not necessitate a dose reduction or therapy discontinuation. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Cost-Effectiveness Analysis of Different Sequences of the Use of Epidermal Growth Factor Receptor Inhibitors for Wild-Type KRAS Unresectable Metastatic Colorectal Cancer.

    Science.gov (United States)

    Riesco-Martínez, Maria Carmen; Berry, Scott R; Ko, Yoo-Joung; Mittmann, Nicole; Giotis, Angie; Lien, Kelly; Wong, William W L; Chan, Kelvin K W

    2016-06-01

    Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev), and epithelial growth factor receptor inhibitors (EGFRI). The most cost-effective regimen remains unclear. A Markov model was constructed to examine the costs and outcomes of three treatment strategies: strategy A (reference strategy): EGFRI monotherapy in third line ([3L]; ie, first-line [1L]: Bev + FOLFIRI [FP + I] or FOLFOX [FP + O]; second line [2L]: FOLFIRI/FOLFOX; 3L: EGFRI); strategy B: EGFRI and I in 3L (ie, 1L: Bev + FOLFIRI/FOLFOX; 2L: FOLFIRI/FOLFOX; 3L: EGFRI + I); and strategy C: EGFRI in 1L (ie, 1L: EGFRI + FOLFIRI/FOLFOX; 2L: Bev + FOLFIRI/FOLFOX; 3L: best supportive care). Efficacy data of the treatments were obtained from the literature. Health system resource use information was derived from chart review and the literature. Using Euro-QOL 5 Dimensions, utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature. The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars. All three strategies had similar efficacy, but strategy C was most expensive. The incremental cost-effectiveness ratios (ICERs) for strategies B and C compared with A were 119,623 and 3,176,591, respectively. The model was primarily driven by the acquisition cost of the drugs. Strategy B was most cost effective when the willingness-to-pay threshold was > $130,000 per quality-adjusted life-year. Sensitivity analysis showed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1L with hazard ratio pricing relative to Bev. Copyright © 2016 by American Society of Clinical Oncology.

  6. The impact of calcineurin inhibitors on neutrophil gelatinase-associated lipocalin and fibroblast growth factor 23 in long-term kidney transplant patients.

    Science.gov (United States)

    Bleskestad, Inger Hjørdis; Thorsen, Inga Strand; Jonsson, Grete; Skadberg, Øyvind; Gøransson, Lasse Gunnar

    2017-08-01

    Neutrophil gelatinase-associated lipocalin (NGAL), a protein with bacteriostatic functions rapidly excreted from stimulated or damaged epithelial cells, is elevated in acute and chronic kidney disease. A calcineurin dependent signaling pathway for fibroblast growth factor 23 (FGF23) has been revealed, but the effect of calcineurin inhibitors (CNIs) on the levels of NGAL and markers of mineral metabolism in long-term kidney transplant patients has not been explored. In a cross-sectional study, 39 patients who received a first kidney transplant more than 10 years ago were split into two groups based on whether (n=28) or not (n=11) they used CNIs. Only patients with well-functioning grafts defined as an estimated glomerular filtration rate ≥45 mL/min per 1.73 m 2 were included. The median levels of NGAL, intact parathyroid hormone (iPTH), and iFGF23 were significantly higher in CNI users vs CNI nonusers, 167.0 (134.0-235.0) ng/mL vs 105.0 (91.3-117.0) ng/mL, P<.001, 13.8 (10.0-17.3) pmol/L vs 8.4 (6.4-9.9) pmol/L, P=.003, and 81.6 (56.4-116.5) pg/mL vs 61.8 (43.3-72.1) pg/mL, P=.04 respectively. The median levels of iFGF23 were higher in CNI users compared to CNI nonusers giving support to the notion of a CNI induced FGF23 resistance in the parathyroid. The net result of CNIs side effects needs to be further explored. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in males, smokers, and non-adenocarcinoma lung cancer in patients with EGFR mutations.

    Science.gov (United States)

    Zeng, Zhu; Chen, Hua-Jun; Yan, Hong-Hong; Yang, Jin-Ji; Zhang, Xu-Chao; Wu, Yi-Long

    2013-09-27

    The demographical/clinical characteristics of being Asian, having an adenocarcinoma, being female, and being a "never-smoker" are regarded as favorable predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in non-small cell lung cancer (NSCLC) with unknown EGFR gene status. In this study, we examined the effects of the supposedly unfavorable clinical variables in EGFR-mutant patients. In total, 159 EGFR-mutant NSCLC patients' clinical features were correlated with progression-free survival (PFS), response rate (RR), and overall survival (OS). Multivariate analysis of clinical characteristics was performed using the Cox and logistic regression methods. There were 90 females (56.6%), 112 never-smokers (70.4%), and 153 patients with adenocarcinomas (96.2%). All patients were treated with EGFR-TKI, and 52.8% received TKI in a first-line setting. The median PFS of patients receiving first-line TKI was similar, regardless of gender (males vs females: 9.1 vs 9.7 months, p=0.793), smoking status (never-smokers vs smokers: 9.9 vs 9.1 months, p=0.570), or histology (adenocarcinoma vs non-adenocarcinoma: 9.7 vs 9.2 months, p=0.644). OS curves of first-line TKI-treated patients were also not associated with gender (p=0.722), smoking status (p=0.579), or histology (p=0.480). Similar results of PFS and OS were obtained for patients who received TKI beyond first-line. Multivariate analysis indicated that none of these clinical factors was an independent predictor of survival. The supposedly 'favorable' clinical factors of female gender, non-smoking status, and adenocarcinoma were not independent predictive factors for PFS or OS in this population of EGFR-mutant NSCLC patients.

  8. The Mechanism of Action of the Histone Deacetylase Inhibitor Vorinostat Involves Interaction with the Insulin-Like Growth Factor Signaling Pathway

    Science.gov (United States)

    Sarfstein, Rive; Bruchim, Ilan; Fishman, Ami; Werner, Haim

    2011-01-01

    A correlation between components of the insulin-like growth factor (IGF) system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR) signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa) and uterine serous papillary (Type II, USPC-2) endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat. PMID:21931726

  9. The mechanism of action of the histone deacetylase inhibitor vorinostat involves interaction with the insulin-like growth factor signaling pathway.

    Directory of Open Access Journals (Sweden)

    Rive Sarfstein

    Full Text Available A correlation between components of the insulin-like growth factor (IGF system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa and uterine serous papillary (Type II, USPC-2 endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat.

  10. Mass production of `Swan`s Golden`, Cupressus sempervirens by tissue culture and its radiation breeding. 2. Study on growth regulating substance to stimulate the elongation of shoot apex

    Energy Technology Data Exchange (ETDEWEB)

    Suda, Hirokatsu [Tokyo Metropolitan Isotope Research Center (Japan)

    1997-09-01

    Some species of `Swan`s Golden` have been propagated by means of grafting because propagation by cutting is difficult. However, not a few species of the plant are easily lodged, resulting that spreading of `Swan`s Golden` is difficult. Here, an investigation was made on growth regulating substances added into the basal medium in respects of their kinds and concentrations and also the kind of medium for successive culture. As the basal medium, SH medium supplemented with 4 g/l of gel-light and 3 g/l of carbon-powder was used. The optimum medium for the initiation of culture was the basal medium added with zeatin (Ze) and gibberellin (GA) and it was also suitable for successive culture after the 14 day. The medium added with Ze and benzyladenine (BA) or Ze alone was found to be most suitable for the culture after the 28 day. The concentration was optimum at 1 - 2.5 mg/l for either of these growth regulating substances. (M.N.)

  11. Substance Identification Information from EPA's Substance Registry

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Substance Registry Services (SRS) is the authoritative resource for basic information about substances of interest to the U.S. EPA and its state and tribal...

  12. Substance Use and the Treatment of Resistant Depression in Adolescents

    Science.gov (United States)

    Goldstein, Benjamin I.; Shamseddeen, Wael; Spirito, Anthony; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Asarnow, Joan Rosenbaum; Vitiello, Benedetto; Ryan, Neal; Birmaher, Boris; Mayes, Taryn; Onorato, Matthew; Zelazny, Jamie; Brent, David A.

    2009-01-01

    Objective: Despite the known association between substance use disorders and major depressive disorder (MDD) among adolescents, little is known regarding substance use among adolescents with MDD. Method: Youths with MDD who had not improved after an adequate selective serotonin reuptake inhibitor trial (N = 334) were enrolled in the Treatment of…

  13. Hydrolytic Amino Acids Employed as a Novel Organic Nitrogen Source for the Preparation of PGPF-Containing Bio-Organic Fertilizer for Plant Growth Promotion and Characterization of Substance Transformation during BOF Production

    Science.gov (United States)

    Feng, Chenglong; Ran, Wei; Yu, Guanghui; Zhang, Yingjun; Shen, Qirong

    2016-01-01

    Opportunity costs seriously limit the large-scale production of bio-organic fertilizers (BOFs) both in China and internationally. This study addresses the utilization of amino acids resulting from the acidic hydrolysis of pig corpses as organic nitrogen sources to increase the density of TrichodermaharzianumT-E5 (a typical plant growth-promoting fungi, PGPF). This results in a novel, economical, highly efficient and environmentally friendly BOF product. Fluorescence excitation-emission matrix (EEM) spectroscopy combined with fluorescence regional integration (FRI) was employed to monitor compost maturity levels, while pot experiments were utilized to test the effects of this novel BOF on plant growth. An optimization experiment, based on response surface methodologies (RSMs), showed that a maximum T-E5 population (3.72 × 108 ITS copies g−1) was obtained from a mixture of 65.17% cattle manure compost (W/W), 19.33% maggot manure (W/W), 15.50% (V/W)hydrolytic amino acid solution and 4.69% (V/W) inoculum at 28.7°C after a 14 day secondary solid fermentation. Spectroscopy analysis revealed that the compost transformation process involved the degradation of protein-like substances and the formation of fulvic-like and humic-like substances. FRI parameters (PI, n, PII, n, PIII, n and PV, n) were used to characterize the degree of compost maturity. The BOF resulted in significantly higher increased chlorophyll content, shoot length, and shoot and root dry weights of three vegetables (cucumber, tomato and pepper) by 9.9%~22.4%, 22.9%~58.5%, 31.0%~84.9%, and 24.2%~34.1%, respectively. In summary, this study presents an operational means of increasing PGPF T-E5 populations in BOF to promote plant growth with a concomitant reduction in production cost. In addition, a BOF compost maturity assessment using fluorescence EEM spectroscopy and FRI ensured its safe field application. PMID:26974549

  14. Metal corrosion inhibitors and ecology

    International Nuclear Information System (INIS)

    Krasts, H.; Svarce, J.; Berge, B.

    1999-01-01

    The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

  15. Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells in Phenotypic Screening: A Transforming Growth Factor-β Type 1 Receptor Kinase Inhibitor Induces Efficient Cardiac Differentiation.

    Science.gov (United States)

    Drowley, Lauren; Koonce, Chad; Peel, Samantha; Jonebring, Anna; Plowright, Alleyn T; Kattman, Steven J; Andersson, Henrik; Anson, Blake; Swanson, Bradley J; Wang, Qing-Dong; Brolen, Gabriella

    2016-02-01

    Several progenitor cell populations have been reported to exist in hearts that play a role in cardiac turnover and/or repair. Despite the presence of cardiac stem and progenitor cells within the myocardium, functional repair of the heart after injury is inadequate. Identification of the signaling pathways involved in the expansion and differentiation of cardiac progenitor cells (CPCs) will broaden insight into the fundamental mechanisms playing a role in cardiac homeostasis and disease and might provide strategies for in vivo regenerative therapies. To understand and exploit cardiac ontogeny for drug discovery efforts, we developed an in vitro human induced pluripotent stem cell-derived CPC model system using a highly enriched population of KDR(pos)/CKIT(neg)/NKX2.5(pos) CPCs. Using this model system, these CPCs were capable of generating highly enriched cultures of cardiomyocytes under directed differentiation conditions. In order to facilitate the identification of pathways and targets involved in proliferation and differentiation of resident CPCs, we developed phenotypic screening assays. Screening paradigms for therapeutic applications require a robust, scalable, and consistent methodology. In the present study, we have demonstrated the suitability of these cells for medium to high-throughput screens to assess both proliferation and multilineage differentiation. Using this CPC model system and a small directed compound set, we identified activin-like kinase 5 (transforming growth factor-β type 1 receptor kinase) inhibitors as novel and potent inducers of human CPC differentiation to cardiomyocytes. Significance: Cardiac disease is a leading cause of morbidity and mortality, with no treatment available that can result in functional repair. This study demonstrates how differentiation of induced pluripotent stem cells can be used to identify and isolate cell populations of interest that can translate to the adult human heart. Two separate examples of phenotypic

  16. Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma

    Science.gov (United States)

    Saji, Hisashi; Sakai, Hiroki; Kimura, Hiroyuki; Miyazawa, Tomoyuki; Marushima, Hideki; Nakamura, Haruhiko

    2017-01-01

    Objective We previously reported that the staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS) and postoperative recurrence survival (PRS) has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database. Patients and methods We retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014. Results EGFR mutants (M) were detected in 16/56 patients (29%). The patients with EGFR M had a better OS than those with EGFR wild-type (WT) status (5-year survival: 50.3% vs 43.1, P=0.133). There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656), and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033). The 3-year PRS rate for patients with M/pathologic stage (p-stage) I–II (87.5%) was better than that for patients with M/p-stage III (60.0%), WT/p-stage I–II (52.7%), and WT/p-stage III (43.8%). There was a significant difference between patients with M/p-stage I and WT/p-stage I–II or WT/p-stage III (P=0.021 and 0.030, respectively). During the study period, of the 16 patients with mutants, 12 patients (75%) received EGFR-tyrosine kinase inhibitor (TKI) therapy and among the 40 patients with WT, no patient received EGFR-TKI therapy. Multivariate survival analysis showed that patients with EGFR-TKI therapy had a statistically significant association with favorable PRS (hazard ratio 0.271; 95% confidence interval 0.074–1.000; P=0.050). Conclusion EGFR status and p-stage were found to be essential prognostic factors for

  17. Increased risk of severe infections in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Ma Q

    2015-08-01

    Full Text Available Qing Ma, Li-Yan Gu, Yao-Yao Ren, Li-Li Zeng, Ting Gong, Dian-Sheng Zhong Department of Oncology, The General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China Background: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs have been widely used in a variety of solid malignancies. Concerns have arisen regarding the risk of severe infections (≥grade 3 with use of these drugs, but the contribution of VEGFR-TKIs to infections is still unknown.Methods: The databases of PubMed and abstracts presented at oncology conferences’ proceedings were searched for relevant studies from January 2000 to December 2014. Summary incidences, Peto odds ratio (Peto OR, and 95% confidence intervals (CIs were calculated by using either random-effects or fixed-effects models according to the heterogeneity of included studies.Results: A total of 16,488 patients from 27 randomized controlled trials were included. The risk of developing severe (Peto OR 1.69, 95% CI: 1.45–1.96, P<0.001 and fatal infections (Peto OR 1.78, 95% CI: 1.13–2.81, P=0.013 was significantly increased in patients treated with VEGFR-TKIs when compared to controls. Exploratory subgroup analysis showed no effect of tumor types, phase of trials, or agent used on the Peto OR of severe infections. When stratified according to specific infectious events, the risks of high-grade febrile neutropenia, pneumonia, fever, and sepsis were increased compared with controls, with Peto ORs of 1.57 (95% CI: 1.30–1.88, P<0.001, 1.79 (95% CI: 1.29–2.49, P<0.001, 5.35 (95% CI: 1.47–19.51, P=0.011, and 3.68 (95% CI: 1.51–8.99, P=0.004, respectively. Additionally, VEGFR-TKIs significantly increased the risk of fatal sepsis (OR 3.66, 95% CI: 1.47–9.13, P=0.005 but not fatal pneumonia (OR 1.34, 95% CI: 0.80–2.25, P=0.26.Conclusion: The use of VEGFR-TKIs significantly increases the risk of developing severe and fatal infectious events in cancer

  18. Influence of Expression Plasmid of Connective Tissue Growth Factor and Tissue Inhibitor of Metalloproteinase-1 shRNA on Hepatic Precancerous Fibrosis in Rats.

    Science.gov (United States)

    Zhang, Qun; Shu, Fu-Li; Jiang, Yu-Feng; Huang, Xin-En

    2015-01-01

    In this study, influence caused by expression plasmids of connective tissue growth factor (CTGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) short hairpin RNA (shRNA) on mRNA expression of CTGF,TIMP-1,procol-α1 and PCIII in hepatic tissue with hepatic fibrosis, a precancerous condition, in rats is analyzed. To screen and construct shRNA expression plasimid which effectively interferes RNA targets of CTGF and TIMP-1 in rats. 50 cleaning Wistar male rats are allocated randomly at 5 different groups after precancerous fibrosis models and then injection of shRNA expression plasimids. Plasmid psiRNA-GFP-Com (CTGF and TIMP-1 included), psiRNA-GFP-CTGF, psiRNA-GFP-TIMP-1 and psiRNA- DUO-GFPzeo of blank plasmid are injected at group A, B, C and D, respectively, and as model control group that none plasimid is injected at group E. In 2 weeks after last injection, to hepatic tissue at different groups, protein expression of CTGF, TIMP-1, procol-α1and PC III is tested by immunohistochemical method and,mRNA expression of CTGF,TIMP-1,procol-α1 and PCIII is measured by real-time PCR. One-way ANOVA is used to comparison between-groups. Compared with model group, there is no obvious difference of mRNA expression among CTGF,TIMP-1,procol-α1,PC III and of protein expression among CTGF, TIMP-1, procol-α1, PC III in hepatic tissue at group injected with blank plasmid. Expression quantity of mRNA of CTGF, TIMP-1, procol-α1 and PCIII at group A, B and C decreases, protein expression of CTGF, TIMP-1, procol-α1, PC III in hepatic tissue is lower, where the inhibition of combination RNA interference group (group A) on procol-α1 mRNA transcription and procol-α1 protein expression is superior to that of single interference group (group B and C) (P<0.01 or P<0.05). RNA interference on CTGF and/or TIMP-1 is obviously a inhibiting factor for mRNA and protein expression of CTGF, TIMP-1, procol-α1 and PCIII. Combination RNA interference on genes of CTGF and TIMP-1 is superior

  19. Baseline and Trend of Lymphocyte-to-Monocyte Ratio as Prognostic Factors in Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer Patients Treated with First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

    Directory of Open Access Journals (Sweden)

    Yu-Mu Chen

    Full Text Available Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC receiving first-line epidermal growth factor receptor (EGFR-tyrosine kinase inhibitors (TKIs has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS and overall survival (OS in EGFR-mutant patients with NSCLC.Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR, determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR.The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001, whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001.A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs.

  20. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.

    Science.gov (United States)

    McNaughton, Melissa; Pitman, Melissa; Pitson, Stuart M; Pyne, Nigel J; Pyne, Susan

    2016-03-29

    Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.

  1. [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro.

    OpenAIRE

    Woll, P J; Rozengurt, E

    1988-01-01

    In the search for a more potent bombesin antagonist, we found [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P to be effective in mouse fibroblasts and to inhibit the growth of small cell lung cancer, a tumor that secretes bombesin-like peptides that may act as autocrine growth factors. In murine Swiss 3T3 cells, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P proved to be a bombesin antagonist as judged by the following criteria: (i) inhibition of DNA synthesis induced by gastrin-releasing peptide and ot...

  2. Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Saji H

    2017-08-01

    Full Text Available Hisashi Saji,1,2 Hiroki Sakai,1 Hiroyuki Kimura,1 Tomoyuki Miyazawa,1 Hideki Marushima,1 Haruhiko Nakamura1 1Department of Chest Surgery, St Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa, Japan; 2Department of Thoracic Surgery, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Objective: We previously reported that the staging system and epidermal growth factor receptor (EGFR mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS and postoperative recurrence survival (PRS has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database.Patients and methods: We retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014.Results: EGFR mutants (M were detected in 16/56 patients (29%. The patients with EGFR M had a better OS than those with EGFR wild-type (WT status (5-year survival: 50.3% vs 43.1, P=0.133. There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656, and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033. The 3-year PRS rate for patients with M/pathologic stage (p-stage I–II (87.5% was better than that for patients with M/p-stage III (60.0%, WT/p-stage I–II (52.7%, and WT/p-stage III (43.8%. There was a significant difference between patients with M/p-stage I and WT/p-stage I–II or WT/p-stage III (P=0.021 and 0.030, respectively. During the study period, of the 16 patients with mutants, 12 patients (75% received EGFR-tyrosine kinase inhibitor (TKI therapy and among the 40 patients with WT, no patient received

  3. The role of plant growth substances in the regulation of the cell cycle in antheridial filaments of Chara vulgaris L. I. Effect of gibberellic acid on some, processes in the course of the cell cycle

    Directory of Open Access Journals (Sweden)

    Mirosław Godlewski

    2015-01-01

    Full Text Available The effect of gibberellic acid (10-4 M on the incorporation of 8-14C adenine, 3H phenylalanine, the dimensions of mitotic cells and the durations of particular stages in the cell cycle were studied in synchronously dividing cells of the antheridial filaments in Chara vulgaris L. during succesive periods of growth and differentiation. GA3 strongly stimulates the uptake of both labeled precursors in the course of a whole interphase and in all generations of the antheridial filaments; approximatively in proportion to the intensity of the process in the control. The gibberellin causes a slight increment in cell dimensions and strongly reduces the cell cycle durations: the S, G2, and M to a similar degree. The earlier is the generation of the antheridial filament, the more pronounced is the influence of the plant growth substance. Since the gibberellin stimulated the course of all examined processes, the present study did not reveal any stage of interphase to be especially sensitive to GA3. The results suggest to interpret the effect of GA3 as an unspecific stimulator of metabolism in cells of the antheridial filaments of Chara vulgaris L.

  4. HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

    Science.gov (United States)

    Papp, Eszter; Mohammadi, Hakimeh; Loutfy, Mona R.; Yudin, Mark H.; Murphy, Kellie E.; Walmsley, Sharon L.; Shah, Rajiv; MacGillivray, Jay; Silverman, Michael; Serghides, Lena

    2015-01-01

    Background. Protease inhibitor (PI)–based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels. Methods. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women. Results. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile. Conclusions. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes. PMID:25030058

  5. HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction.

    Science.gov (United States)

    Papp, Eszter; Mohammadi, Hakimeh; Loutfy, Mona R; Yudin, Mark H; Murphy, Kellie E; Walmsley, Sharon L; Shah, Rajiv; MacGillivray, Jay; Silverman, Michael; Serghides, Lena

    2015-01-01

    Protease inhibitor (PI)-based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

  6. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  7. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  8. TSCA Chemical Substance Inventory

    Science.gov (United States)

    Section 8 (b) of the Toxic Substances Control Act (TSCA) requires EPA to compile, keep current, and publish a list of each chemical substance that is manufactured or processed in the United States for TSCA uses.

  9. Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor.

    Science.gov (United States)

    Ojeda, Norma B; Royals, Thomas P; Alexander, Barbara T

    2013-04-01

    This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg(-1)·min(-1)) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls (P back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced (P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats.

  10. The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action

    International Nuclear Information System (INIS)

    Hamtiaux, Laurie; Masquelier, Julien; Muccioli, Giulio G; Bouzin, Caroline; Feron, Olivier; Gallez, Bernard; Lambert, Didier M

    2012-01-01

    The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated. We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments. The N-arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol and N- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor. This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis

  11. The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action

    Directory of Open Access Journals (Sweden)

    Hamtiaux Laurie

    2012-03-01

    Full Text Available Abstract Background The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated. Methods We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments. Results The N-arachidonoylethanolamine (anandamide, AEA, 2-arachidonoylglycerol and N- palmitoylethanolamine (PEA reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor. Conclusions This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the

  12. Inhibitor production by normal rat tracheal epithelial cells influences the frequency of spontaneous and X-ray-induced enhanced growth variants

    International Nuclear Information System (INIS)

    Terzaghi-Howe, M.

    1989-01-01

    A cell culture model was used to assay for the induction of cell populations with enhanced growth capacity in culture in irradiated normal rat tracheal epithelial cells (NTEC). Some growth conditions appear to favor the proliferation of both normal and carcinogen-exposed populations, while others appear to select for populations previously exposed to carcinogen. In the present report we focus on what growth conditions are critical for controlling the emergence of spontaneous and X-ray induced proliferating epithelial foci (PEF) and what factor(s) directly influences the relative frequency of PEF in irradiated and control NTEC cultures. (author)

  13. Perfluoroalkyl Substances, Sex Hormones, and Insulin-like Growth Factor-1 at 6-9 Years of Age: A Cross-Sectional Analysis within the C8 Health Project.

    Science.gov (United States)

    Lopez-Espinosa, Maria-Jose; Mondal, Debapriya; Armstrong, Ben G; Eskenazi, Brenda; Fletcher, Tony

    2016-08-01

    Exposure to some perfluoroalkyl substances (PFAS), such as perfluorohexane sulfonate (PFHxS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA), may alter levels of sex hormones and insulin-like growth factor-1 (IGF-1) in animals. Human studies on this topic are scarce, and none have been conducted in young children. We investigated the relationship between levels of PFAS and estradiol, total testosterone, and IGF-1 in 2,292 children (6-9 years of age) from the C8 Health Project who lived near a chemical plant in the Mid-Ohio Valley (USA) with local contamination from PFOA. Serum samples were collected in 2005-2006 and analyzed for PFAS, sex hormones, and IGF-1. Results from regression models were expressed as the adjusted percentage difference (95% CI) per sex-specific interquartile range (IQR) increment of each PFAS serum concentration. Analyses by PFAS quartiles were also conducted. Median concentrations of PFHxS, PFOA, PFOS, and PFNA were 8, 35, 22, and 1.7 ng/mL in boys and 7, 30, 21, and 1.7 ng/mL in girls. In boys, PFOA concentrations were significantly associated with testosterone levels (-4.9%; 95% CI: -8.7, -0.8%); PFOS with estradiol (-4.0%; 95% CI: -7.7, -0.1%), testosterone (-5.8%; 95% CI: -9.4, -2.0%), and IGF-1 (-5.9%; 95% CI: -8.3, -3.3%); and PFNA with IGF-1 (-3.5%; 95% CI: -6.0, -1.0%). In girls, significant associations were found between PFOS and testosterone (-6.6%; 95% CI: -10.1, -2.8%) and IGF-1 (-5.6%; -8.2, -2.9%); and PFNA and IGF-1 (-3.8%; 95% CI: -6.4, -1.2%). In both sexes, the magnitudes of the associations decreased monotonically across quartiles for both testosterone and IGF-1 in relation to PFOS, and for IGF-1 and PFNA in girls. To our knowledge, this is the first study suggesting that PFAS are associated with lower levels of IGF-1 and sex hormones in young children. Lopez-Espinosa MJ, Mondal D, Armstrong BG, Eskenazi B, Fletcher T. 2016. Perfluoroalkyl substances, sex hormones, and

  14. Effects of the vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor SU5416 on in vitro cultures of Plasmodium falciparum

    DEFF Research Database (Denmark)

    Hempel, Casper; Hoyer, Nils; Staalsø, Trine

    2014-01-01

    BACKGROUND: Vascular endothelial growth factor (VEGF) is taken up by parasitized red blood cells during malaria and stimulates intra-erythrocytic growth of Plasmodium falciparum in vitro. The cause and consequence of this uptake is not understood. METHODS: Plasmodium falciparum was cultured......, SU5416, dose-dependently inhibited growth. None of the treatments reduced intracellular VEGF levels. Thus, the anti-parasitic effect of SU5416 seemed independent of VEGF uptake. SU5416 reduced phosphorylated tyrosine in parasitized red blood cells. Similarly, the broad-spectrum tyrosine kinase...... in vitro. Parasite growth and intracellular VEGF levels were assessed using flow cytometry. Intracellular VEGF was visualized by fluorescence immunocytochemistry. Phosphorylated tyrosine was measured by western blotting. In vivo assessment of intra-erythrocytic VEGF was performed in Plasmodium berghei ANKA...

  15. Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs.

    Science.gov (United States)

    Puvanenthiran, Soozana; Essapen, Sharadah; Seddon, Alan M; Modjtahedi, Helmout

    2016-11-01

    Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 µM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2

  16. Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.

    Science.gov (United States)

    Nan, Yang; Guo, Liyun; Song, Yunpeng; Wang, Le; Yu, Kai; Huang, Qiang; Zhong, Yue

    2017-08-01

    Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo. In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method. The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone. Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.

  17. Angiogenesis Inhibitors

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... as vascular endothelial growth factor (VEGF) , bind to receptors on the surface of normal endothelial cells. When ...

  18. Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Shaw, Duncan E; Baig, Ferheen; Bruce, Ian; Chamoin, Sylvie; Collingwood, Stephen P; Cross, Sarah; Dayal, Satish; Drückes, Peter; Furet, Pascal; Furminger, Vikki; Haggart, Deborah; Hussey, Martin; Konstantinova, Irena; Loren, Jon C; Molteni, Valentina; Roberts, Sonia; Reilly, John; Saunders, Alex M; Stringer, Rowan; Sviridenko, Lilya; Thomas, Matthew; Thomson, Christopher G; Tomlins, Christine; Wen, Ben; Yeh, Vince; Pearce, Andrew C

    2016-09-08

    A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.

  19. Nitrogen uptake and balance of the fertilizers urea, urea with urease inhibitor, and ammonium nitrate applied to spring wheat at stem elongation growth stage

    International Nuclear Information System (INIS)

    Matzel, W.; Lippold, H.; Heber, R.

    1979-01-01

    The use of urea containing 1% of diamido phosphoric acid phenyl ester, which is a urease inhibitor, for the top dressing of spring wheat on light soil allows the loss of nitrogen due to volatilization of ammonia from urea to be prevented. The urease inhibitor has no effect whatsoever upon the uptake of urea nitrogen by spring wheat. Even in those cases where the volatilization of ammonia is prevented, plants will take up 5 to 6% less nitrogen from urea than from ammonium nitrate. This is due primarily to the higher degree of immobilization of urea nitrogen in the soil. The volatilization of ammonia from urea applied to the surface of the soil was in the region of 25% when the soil surface was moist and 10% when the soil surface was dry, the percentages given above being related to the amount of fertilizer nitrogen applied to the soil. The plant uptake of fertilizer nitrogen applied as a second dose at stem elongation will be complete after two to three weeks or after six weeks under favourable or unfavourable conditions, respectively. Proceeding immediately after application of the fertilizer nitrogen are the processes resulting in both loss of nitrogen and its immobilization. The proportion of absorbed fertilizer nitrogen recovered in the grain will be the greater the later the nitrogen is incorporated into the plant. The use in pot experiments of labelled nitrogen fertilizers enables statistically significant differences in effects to be determined even in those cases in which the differences are only relatively small in degree. (author)

  20. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.

    Science.gov (United States)

    Yokota, Asumi; Kimura, Shinya; Masuda, Satohiro; Ashihara, Eishi; Kuroda, Junya; Sato, Kiyoshi; Kamitsuji, Yuri; Kawata, Eri; Deguchi, Yasuyuki; Urasaki, Yoshimasa; Terui, Yasuhito; Ruthardt, Martin; Ueda, Takanori; Hatake, Kiyohiko; Inui, Ken-ichi; Maekawa, Taira

    2007-01-01

    Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

  1. Isolation and identification of an allelopathic substance from Hibiscus sabdariffa.

    Science.gov (United States)

    Suwitchayanon, Prapaipit; Pukclai, Piyatida; Ohno, Osamu; Suenaga, Kiyotake; Kato-Noguchi, Hisashi

    2015-05-01

    In this study, an allelopathic substance was isolated from an aqueous methanol extract of Hibiscus sabdariffa L. by column chromatography and reverse phase HPLC. The chemical structure of the substance was determined by 1H NMR spectroscopy and mass spectrometry as trimethyl allo-hydroxycitrate. Trimethyl allo-hydroxycitrate inhibited the growth of cress hypocotyls and roots at concentrations greater than 10 mM. The concentrations required for 50% growth inhibition of the hypocotyls and roots of cress were 20.3 and 14.4 mM, respectively. The inhibitory activity of trimethyl allo-hydroxycitrate suggests that the substance may act as an allelopathic substance of H. sabdariffa.

  2. Korean ethnicity as compared with white ethnicity is an independent favorable prognostic factor for overall survival in non-small cell lung cancer before and after the oral epidermal growth factor receptor tyrosine kinase inhibitor era.

    Science.gov (United States)

    Ahn, Myung-Ju; Lee, Jeeyun; Park, Yun-Hee; Ahn, Jin-Seok; Ziogas, Argyrios; Zell, Jason A; Park, Keunchil; Ou, Sai-Hong Ignatius

    2010-08-01

    We have previously demonstrated, using a regional California Cancer Registry database, that Asian ethnicity is an independent favorable prognostic factor for overall survival (OS) in non-small cell lung cancer (NSCLC). Retrospective population-based analysis of Korean and US white patients with NSCLC with known smoking status from Samsung Cancer Center, Seoul, South Korea, and a Southern California Regional Cancer Registry between 1998 and 2005 with follow-up through February 2008 to allow for even case ascertainment periods before and after 2002, when epidermal growth factor receptor tyrosine kinase inhibitors were introduced in Korea and considered as the year of reference. A total of 4622 Korean and 8846 US white patients were analyzed. Median age of diagnosis was 63 years versus 71 years for Korean and white patients, respectively (P white patients were never-smokers. There was significant OS improvement in never-smokers when compared with ever-smokers among either Korean patients (p white (p white patients (p = 0.5641). Except for stage II patients (p = 0.0723), univariate analysis revealed Korean patients had improved OS compared with US white patients among stages I, III, and IV, respectively (all p white; hazard ratio (HR) = 0.869; p white ethnicity improved during 2002-2005 (HR = 0.795; p white ethnicity is an independent favorable prognostic factor for OS in NSCLC. In addition, greater survival benefit among Korean patients with NSCLC was noted in the postepidermal growth factor receptor tyrosine kinase inhibitor era (2002 and after) compared with US white ethnicity.

  3. Quantification of transforming growth factor-beta in biological material using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct

    NARCIS (Netherlands)

    VanWaarde, MAWH; VanAssen, AJ; Kampinga, HH; Konings, AWT; Vujaskovic, Z

    1997-01-01

    Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, can be quantified by a variety of bioassays or immunoassays. One of the disadvantages of these techniques is that they require sample purification to remove components that interfere with the TGF-beta signal. In the current

  4. NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells

    Czech Academy of Sciences Publication Activity Database

    Krejčí, Pavel; Murakami, S.; Procházková, J.; Trantírek, L.; Chlebová, K.; Ouyang, Z.; Aklian, A.; Smutný, J.; Bryja, Vítězslav; Kozubík, Alois; Wilcox, W.R.

    2010-01-01

    Roč. 285, č. 27 (2010), s. 20644-20653 ISSN 0021-9258 Grant - others:GA ČR(CZ) GA301/09/0587 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : NF449 * fibroblast growth factor receptor * antagonist Subject RIV: BO - Biophysics Impact factor: 5.328, year: 2010

  5. Increased activity of digoxin-like substance in low-renin hypertension in acromegaly

    Energy Technology Data Exchange (ETDEWEB)

    Soszynski, P.; Slowinska-Srzednicka, J.; Zgliczynski, S. (Medical Center for Postgraduate Education, Warsaw (Poland))

    1990-01-01

    Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels. In conclusion, an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly.

  6. Increased activity of digoxin-like substance in low-renin hypertension in acromegaly

    International Nuclear Information System (INIS)

    Soszynski, P.; Slowinska-Srzednicka, J.; Zgliczynski, S.

    1990-01-01

    Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels. In conclusion, an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly

  7. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

    Science.gov (United States)

    Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

  8. Attenuation of the DNA Damage Response by Transforming Growth Factor-Beta Inhibitors Enhances Radiation Sensitivity of Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo

    Energy Technology Data Exchange (ETDEWEB)

    Du, Shisuo; Bouquet, Sophie; Lo, Chen-Hao; Pellicciotta, Ilenia; Bolourchi, Shiva [Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States); Parry, Renate [Varian Medical Systems, Palo Alto, California (United States); Barcellos-Hoff, Mary Helen, E-mail: mhbarcellos-hoff@nyumc.org [Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States)

    2015-01-01

    Purpose: To determine whether transforming growth factor (TGF)-β inhibition increases the response to radiation therapy in human and mouse non–small-cell lung carcinoma (NSCLC) cells in vitro and in vivo. Methods and Materials: TGF-β–mediated growth response and pathway activation were examined in human NSCLC NCI-H1299, NCI-H292, and A549 cell lines and murine Lewis lung cancer (LLC) cells. Cells were treated in vitro with LY364947, a small-molecule inhibitor of the TGF-β type 1 receptor kinase, or with the pan-isoform TGF-β neutralizing monoclonal antibody 1D11 before radiation exposure. The DNA damage response was assessed by ataxia telangiectasia mutated (ATM) or Trp53 protein phosphorylation, γH2AX foci formation, or comet assay in irradiated cells. Radiation sensitivity was determined by clonogenic assay. Mice bearing syngeneic subcutaneous LLC tumors were treated with 5 fractions of 6 Gy and/or neutralizing or control antibody. Results: The NCI-H1299, A549, and LLC NSCLC cell lines pretreated with LY364947 before radiation exposure exhibited compromised DNA damage response, indicated by decreased ATM and p53 phosphorylation, reduced γH2AX foci, and increased radiosensitivity. The NCI-H292 cells were unresponsive. Transforming growth factor-β signaling inhibition in irradiated LLC cells resulted in unresolved DNA damage. Subcutaneous LLC tumors in mice treated with TGF-β neutralizing antibody exhibited fewer γH2AX foci after irradiation and significantly greater tumor growth delay in combination with fractionated radiation. Conclusions: Inhibition of TGF-β before radiation attenuated DNA damage recognition and increased radiosensitivity in most NSCLC cells in vitro and promoted radiation-induced tumor control in vivo. These data support the rationale for concurrent TGF-β inhibition and RT to provide therapeutic benefit in NSCLC.

  9. A Case Report of Ischemic Stroke in a Patient with Metastatic Gastric Cancer Secondary to Treatment with the Vascular Endothelial Growth Factor Receptor-2 Inhibitor Ramucirumab

    Directory of Open Access Journals (Sweden)

    Michael E. Christiansen

    2016-06-01

    Full Text Available Ramucirumab is an antiangiogenesis agent targeting the vascular endothelial growth factor receptor-2 (VEGFR-2, approved to treat advanced gastric and colon cancer. In clinical trials, it was shown to cause a small increase in arterial thromboembolism compared to placebo, including cerebral and myocardial ischemia, which was not statistically significant. Detailed case reports are lacking and we here present one of the first case reports of stroke secondary to ramucirumab-induced in situ thrombosis.

  10. Substance use - cocaine

    Science.gov (United States)

    Substance abuse - cocaine; Drug abuse - cocaine; Drug use - cocaine ... thinking clearly Mood and emotional problems, such as aggressive or violent behavior Restlessness and tremors Sleep problems ...

  11. Substance use - phencyclidine (PCP)

    Science.gov (United States)

    PCP; Substance abuse - phencyclidine; Drug abuse - phencyclidine; Drug use - phencyclidine ... a result, you may act strangely or become aggressive and violent. PCP's other harmful effects include: It ...

  12. Inibidores de síntese de giberelinas e crescimento de mudas de mangueira 'Tommy Atkins' Synthesis inhibitors of gibberellins and mango 'Tommy Atkins' seedlings growth

    Directory of Open Access Journals (Sweden)

    Maria Aparecida do Carmo Mouco

    2010-02-01

    Full Text Available A mangicultura no semiárido brasileiro destaca-se pelos altos rendimentos, pela qualidade do fruto produzido e pela possibilidade de produção durante todo o ano, devido a condições climáticas e tecnologias para o manejo do crescimento vegetativo e da floração, com uso da irrigação, podas e retardantes vegetais. O paclobutrazol aplicado ao solo é utilizado no manejo da produção da mangueira na maioria dos pomares. Entretanto, há a necessidade de identificar retardantes vegetais que possam ser aplicados via foliar, de forma a minimizar os resíduos no solo e evitar o uso de quantidades inadequadas ao longo dos anos. Assim, este trabalho teve como objetivo avaliar retardantes vegetais aplicados via foliar na inibição do crescimento vegetativo de mudas de mangueira 'Tommy Atkins'. Prohexadione-Ca, etil-trinexapac e cloreto de chlormequat, aplicados via foliar, na dose de 1g i.a. planta-1, regulam o crescimento de ramos vegetativos, mas apresentam tempo diferenciado de atividade nas mudas, sendo 20 dias para prohexadione-Ca, 30 dias para cloreto de chlormequat e 45 dias para etil-trinexapac, nas condições em que o experimento foi conduzido.The mango in the Brazilian semi-arid region stands out in the national scenario due to high yields and fruit quality, as well as to the possibility of all-year production due to climatic conditions and technologies which allow the management of plant growth and flowering through irrigation, pruning and use of plant growth regulators. Paclobutrazol applied to the soil is used for the production management of mangoes in most of the orchards. However, it is necessary to identify plant growth regulators which might be applied to the leaves, so as to minimize the risk of residues in the soil and to avoid inadequate application levels over several years. The present paper aimed at evaluating the effect of plant growth regulators applied to the leaves, regarding their efficiency for flowering management

  13. Perfluoroalkyl Substances, Sex Hormones, and Insulin-like Growth Factor-1 at 6–9 Years of Age: A Cross-Sectional Analysis within the C8 Health Project

    Science.gov (United States)

    Lopez-Espinosa, Maria-Jose; Mondal, Debapriya; Armstrong, Ben G.; Eskenazi, Brenda; Fletcher, Tony

    2016-01-01

    Background: Exposure to some perfluoroalkyl substances (PFAS), such as perfluorohexane sulfonate (PFHxS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA), may alter levels of sex hormones and insulin-like growth factor-1 (IGF-1) in animals. Human studies on this topic are scarce, and none have been conducted in young children. Objectives: We investigated the relationship between levels of PFAS and estradiol, total testosterone, and IGF-1 in 2,292 children (6–9 years of age) from the C8 Health Project who lived near a chemical plant in the Mid-Ohio Valley (USA) with local contamination from PFOA. Methods: Serum samples were collected in 2005–2006 and analyzed for PFAS, sex hormones, and IGF-1. Results from regression models were expressed as the adjusted percentage difference (95% CI) per sex-specific interquartile range (IQR) increment of each PFAS serum concentration. Analyses by PFAS quartiles were also conducted. Results: Median concentrations of PFHxS, PFOA, PFOS, and PFNA were 8, 35, 22, and 1.7 ng/mL in boys and 7, 30, 21, and 1.7 ng/mL in girls. In boys, PFOA concentrations were significantly associated with testosterone levels (–4.9%; 95% CI: –8.7, –0.8%); PFOS with estradiol (–4.0%; 95% CI: –7.7, –0.1%), testosterone (–5.8%; 95% CI: –9.4, –2.0%), and IGF-1 (–5.9%; 95% CI: –8.3, –3.3%); and PFNA with IGF-1 (–3.5%; 95% CI: –6.0, –1.0%). In girls, significant associations were found between PFOS and testosterone (–6.6%; 95% CI: –10.1, –2.8%) and IGF-1 (–5.6%; –8.2, –2.9%); and PFNA and IGF-1 (–3.8%; 95% CI: –6.4, –1.2%). In both sexes, the magnitudes of the associations decreased monotonically across quartiles for both testosterone and IGF-1 in relation to PFOS, and for IGF-1 and PFNA in girls. Conclusions: To our knowledge, this is the first study suggesting that PFAS are associated with lower levels of IGF-1 and sex hormones in young children. Citation: Lopez

  14. Squash inhibitor family of serine proteinases

    International Nuclear Information System (INIS)

    Otlewski, J.; Krowarsch, D.

    1996-01-01

    Squash inhibitors of serine proteinases form an uniform family of small proteins. They are built of 27-33 amino-acid residues and cross-linked with three disulfide bridges. The reactive site peptide bond (P1-P1') is between residue 5 (Lys, Arg or Leu) and 6 (always Ile). High resolution X-ray structures are available for two squash inhibitors complexed with trypsin. NMR solution structures have also been determined for free inhibitors. The major structural motif is a distorted, triple-stranded antiparallel beta-sheet. A similar folding motif has been recently found in a number of proteins, including: conotoxins from fish-hunting snails, carboxypeptidase inhibitor from potato, kalata B1 polypeptide, and in some growth factors (e.g. nerve growth factor, transforming growth factor β2, platelet-derived growth factor). Squash inhibitors are highly stable and rigid proteins. They inhibit a number of serine proteinases: trypsin, plasmin, kallikrein, blood clotting factors: X a and XII a , cathepsin G. The inhibition spectrum can be much broadened if specific amino-acid substitutions are introduced, especially at residues which contact proteinase. Squash inhibitors inhibit proteinases via the standard mechanism. According to the mechanism, inhibitors are substrates which exhibit at neutral pH a high k cat /K m index for hydrolysis and resynthesis of the reactive site, and a low value of the hydrolysis constant. (author)

  15. Phase I Study of SU5416, a Small Molecule Inhibitor of the Vascular Endothelial Growth Factor Receptor (VEGFR) in Refractory Pediatric Central Nervous System Tumors

    Science.gov (United States)

    Kieran, Mark W.; Supko, Jeffrey G.; Wallace, Dana; Fruscio, Robert; Poussaint, Tina Young; Phillips, Peter; Pollack, Ian; Packer, Roger; Boyett, James M.; Blaney, Susan; Prados, Michael; Geyer, Russ; Friedman, Henry; Goldman, Stewart; Kun, Larry E.; MacDonald, Tobey

    2009-01-01

    SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (Stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110mg/m2 while stratum II started at 48mg/m2. Thirty-three eligible patients were treated on stratum I (n=23) and stratum II (n=10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas and 2 choroid plexus carcinomas. The MTD in Stratum I was initially estimated to be 110mg/m2. The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145mg/m2 dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in Stratum I were 26.1 ± 12.5 liter/h/m2, 41.9 ± 21.4 liter/m2, and 1.11 ± 0.41 h, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum 1 patients. PMID:19065567

  16. An epithelial marker promoter induction screen identifies histone deacetylase inhibitors to restore epithelial differentiation and abolishes anchorage independence growth in cancers.

    Science.gov (United States)

    Tang, H M; Kuay, K T; Koh, P F; Asad, M; Tan, T Z; Chung, V Y; Lee, S C; Thiery, J P; Huang, Ry-J

    2016-01-01

    Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin. An expanded screen on 41 HDACi further identifies 28 compounds, such as class I-specific HDACi Mocetinosat, Entinostat and CI994, to restore E-cadherin and ErbB3 expressions in ovarian, pancreatic and bladder carcinoma cells. Mocetinostat is the most potent HDACi to restore epithelial differentiation with the lowest concentration required for 50% induction of epithelial promoter activity (EpIC-50).The HDACi exerts paradoxical effects on EMT transcriptional factors such as SNAI and ZEB family and the effects are context-dependent in epithelial- and mesenchymal-like cells. In vitro functional studies further show that HDACi induced significant increase in anoikis and decrease in spheroid formation in ovarian and bladder carcinoma cells with mesenchymal features. This study demonstrates a robust drug screening pipeline for the discovery of compounds capable of restoring epithelial differentiation that lead to significant functional lethality.

  17. Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy.

    Science.gov (United States)

    Mahernia, Shabnam; Hassanzadeh, Malihe; Sharifi, Niusha; Mehravi, Bita; Paytam, Fariba; Adib, Mehdi; Amanlou, Massoud

    2018-02-01

    Cancer cells are described with features of uncontrolled growth, invasion and metastasis. The epidermal growth factor receptor subfamily of tyrosine kinases (EGFR-TK) plays a crucial regulatory role in the control of cellular proliferation and progression of various cancers. Therefore, its inhibition might lead to the discovery of a new generation of anticancer drugs. In the present study, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations were applied to identify potential hits, which exhibited good inhibition on the proliferation of MCF-7 breast cancer cell line and favorable binding interactions on EGFR-TK. Selected compounds were examined for their anticancer activity against the Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line which overexpresses EGFR using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay. Compounds 1 and 2, with an isoindoline-1-one core, induced significant inhibition of breast cancer cells proliferation with IC[Formula: see text] values 327 and 370 nM, respectively.

  18. Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity.

    Science.gov (United States)

    Riemann, Anne; Güttler, Antje; Haupt, Verena; Wichmann, Henri; Reime, Sarah; Bache, Matthias; Vordermark, Dirk; Thews, Oliver

    2018-03-05

    Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications. CA IX was upregulated by hypoxia as well as acidosis in prostate cancer cells. This induction did not modulate intracellular pH but led to extracellular acidification. Pharmacological inhibition of CA IX activity by U104 (SLC-0111) resulted in a reduction in tumor cell growth and an increase in apoptotic cell death. Intracellular pH was reduced under normoxic and even more so under hypoxic conditions when CA IX level was high. However, although intracellular pH regulation was disturbed, targeting CA IX in combination with daunorubicin or cisplatin did not intensify apoptotic tumor cell death. Hence, targeting CA IX in prostate cancer cells can lead to intracellular pH dysregulation and, consequently, can reduce cellular growth and elevate apoptotic cell death. Attenuation of extracellular acidification by blocking CA IX might additionally impede tumor progression and metastasis. However, no beneficial effect was seen when targeting CA IX in combination with chemotherapeutic drugs.

  19. Radioactive Substances Act 1948

    International Nuclear Information System (INIS)

    1948-01-01

    This Act regulates the use of radioactive substances and radiation producing devices in the United Kingdom. It provides for the control of import, export, sale, supply etc. of such substances and devices and lays down the safety regulations to be complied with when dealing with them. (NEA) [fr

  20. Transport of radioactive substances

    International Nuclear Information System (INIS)

    2014-12-01

    The report on the transport of radioactive substances covers the following topics: facts on radioactive materials transport, safety of the transport of radioactive substances, legal regulations and guidelines: a multiform but consistent system, transport of nuclear fuels, safety during the transport of nuclear fuel, future transport of spent fuel elements and high-level radioactive wastes in Germany.

  1. Structure-based virtual screening toward the discovery of novel inhibitors for impeding the protein-protein interaction between HIV-1 integrase and human lens epithelium-derived growth factor (LEDGF/p75).

    Science.gov (United States)

    Panwar, Umesh; Singh, Sanjeev Kumar

    2017-10-23

    HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.

  2. Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

    International Nuclear Information System (INIS)

    Guo, Jun; Straub, Patrick; Pirotta, Nicoletta; Gogov, Sven; Huang, Yiran; Zhang, Xu; Zhou, Fangjian; Sun, Yinghao; Qin, Shukui; Ye, Zhangqun; Wang, Hui; Jappe, Annette

    2013-01-01

    In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC. An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011. A total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response. Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical

  3. Evaluation of anticancer effects of a novel proteasome inhibitor (Velcade), interferon (alpha-interferon) and anti myeloma antibodies on the growth of myeloma cells

    International Nuclear Information System (INIS)

    El shershaby, H.M.M.

    2013-01-01

    Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to deregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites, causing significant morbidity. Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow leading to impaired hematopoiesis and bone diseases, which includes mainly lytic lesions, pathological fractures, hypercalcaemia and osteoporosis. Chemotherapy is the systemic treatment of cancer with anticancer drugs. Chemotherapy uses powerful drugs that work by slowing or stopping the cancer cells from growing, spreading or multiplying to other parts of the body. Extensive studies were run all over the world during the last years to discovery some new drugs which possess anticancer effect with less toxicity and have the ability to increase the survival time. In the current study Bortezomib was employed as chemotherapeutic drug for the treatment of myeloma cells where a variable dose of Bortezomib (5, 10,20,30,50 and 100 nM/ml) were used for treatment of myeloma cells in vitro. The results obtained indicated that the T.C/ml was decreased by increasing the drug conc. compared to that of control group. These results illustrated the effect of Bortezomib on the growth of myeloma cells, where the myeloma cell division was decreased while the older cells were deteriorated so that the T.C/ml were decreased. Also the viability of myeloma cells were significantly decreased after 72 hours of addition at drug concentration 20, 30, 50 and 100 nM/ml).

  4. Pricing hazardous substance emissions

    Energy Technology Data Exchange (ETDEWEB)

    Staring, Knut; Vennemo, Haakon

    1998-12-31

    This report discusses pricing of emissions to air of several harmful substances. It combines ranking indices for environmentally harmful substances with economic valuation data to yield price estimates. The ranking methods are discussed and a relative index established. Given the relative ranking of the substances, they all become valued by assigning a value to one of them, the `anchor` substance, for which lead is selected. Valuations are provided for 19 hazardous substances that are often subject to environmental regulations. They include dioxins, TBT, etc. The study concludes with a discussion of other categories of substances as well as uncertainties and possible refinements. When the valuations are related to CO, NOx, SOx and PM 10, the index system undervalues these pollutants as compared to other studies. The scope is limited to the outdoor environment and does not include global warming and eutrophication. The indices are based on toxicity and so do not apply to CO{sub 2} or other substances that are biologically harmless. The index values are not necessarily valid for all countries and should be considered as preliminary. 18 refs., 6 tabs.

  5. Pricing hazardous substance emissions

    Energy Technology Data Exchange (ETDEWEB)

    Staring, Knut; Vennemo, Haakon

    1997-12-31

    This report discusses pricing of emissions to air of several harmful substances. It combines ranking indices for environmentally harmful substances with economic valuation data to yield price estimates. The ranking methods are discussed and a relative index established. Given the relative ranking of the substances, they all become valued by assigning a value to one of them, the `anchor` substance, for which lead is selected. Valuations are provided for 19 hazardous substances that are often subject to environmental regulations. They include dioxins, TBT, etc. The study concludes with a discussion of other categories of substances as well as uncertainties and possible refinements. When the valuations are related to CO, NOx, SOx and PM 10, the index system undervalues these pollutants as compared to other studies. The scope is limited to the outdoor environment and does not include global warming and eutrophication. The indices are based on toxicity and so do not apply to CO{sub 2} or other substances that are biologically harmless. The index values are not necessarily valid for all countries and should be considered as preliminary. 18 refs., 6 tabs.

  6. [Immunotoxicity and environmental substances].

    Science.gov (United States)

    Teshima, Reiko

    2014-01-01

    A well functioning immune system is essential in maintaining integrity of the organism, and malfunction may have severe health consequences. Environmental substances may pose direct toxicity to components of the immune system, often leading to immunosuppression and resulting reduced resistance to infections and tumors. Alternatively, such substances may be recognized by the immune system in a specific fashion, which may result in allergy and autoimmunity. A proper risk assessment of environmental substances in terms of immunotoxicity is necessary. In this manuscript, I reviewed recent three topics about immunotoxicity: (1) IPCS/WHO Guidance for immunotoxicity risk assessment for chemicals, (2) Intestinal immunotoxicity, and (3) Epicutaneous sensitization of food proteins.

  7. Epidermal growth factor receptor inhibitor PKI-166 governs cardiovascular protection without beneficial effects on the kidney in hypertensive 5/6 nephrectomized rats.

    Science.gov (United States)

    Ulu, Nadir; Mulder, Gemma M; Vavrinec, Peter; Landheer, Sjoerd W; Duman-Dalkilic, Basak; Gurdal, Hakan; Goris, Maaike; Duin, Marry; van Dokkum, Richard P E; Buikema, Hendrik; van Goor, Harry; Henning, Robert H

    2013-06-01

    Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

  8. Development of an imaging mitigation strategy for patient enrolment in the tanezumab nerve growth factor inhibitor (NGF-ab) program with a focus on eligibility assessment.

    Science.gov (United States)

    Roemer, Frank W; Miller, Colin G; West, Christine R; Brown, Mark T; Sherlock, Sarah P; Kompel, Andrew J; Diaz, Luis; Galante, Nicholas; Crema, Michel D; Guermazi, Ali

    2017-12-01

    Nerve growth factor antibodies (NGF-ab) have shown promising analgesic efficacy. Aim was to describe reader training efforts and present reliability data focusing on radiographic eligibility in the tanezumab program. A multi-step process was used for reader calibration and reliability testing. First, a reference standard set of cases was created and diagnostic performance was evaluated. A second exercise focused on agreement of ordinal assessment (Kellgren-Lawrence grading) of radiographic osteoarthritis. Subsequently, 11 readers were trained and read a test set of 100 cases focused on eligibility assessments. Additional reliability testing and calibration of five core readers assessing eligibility of 30 cases was performed 3 and 6 months after study start. Sensitivity for the reference standard readings ranged from 0.50 to 0.90 and specificity from 0.40 to 0.83. Overall agreement for Kellgren-Lawrence grading ranged from 71.4% to 82.9%. For the 11 reader exercise, in 76% of cases at least 8 of 11 readers agreed on eligibility status. For the reliability testing 3 months after study start, in 80.0% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.43 (95% CI: 0.32-0.54). For the reliability testing after 6 months, in 83.3% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.52 (95% CI: 0.41-0.63). After intense efforts spent in the development of an imaging program for an NGF-ab clinical program, the achieved reliability for eligibility assessment is substantial but not perfect. Ongoing efforts of calibration prior to including additional readers to the program and during study conduct between current readers will be needed to ensure agreement on potential adverse events and radiographic disease severity. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. EFFECT OF SUBSTANCE (1)

    African Journals Online (AJOL)

    OF HEALTH OFFICER AND MEDICAL STUDENTS OF JIMMA. UNIVERSITY ... cannabis or marihuana and khat (2, 3). Reports showed that these substances ... mainly through cancer especially lung cancer, of which about 90% of cases are ...

  10. Toxic substances handbook

    Science.gov (United States)

    Junod, T. L.

    1979-01-01

    Handbook, published in conjunction with Toxic Substances Alert Program at NASA Lewis Research Center, profiles 187 toxic chemicals in their relatively pure states and include 27 known or suspected carcinogens.

  11. Toxic substances alert program

    Science.gov (United States)

    Junod, T. L.

    1978-01-01

    A toxicity profile is provided, of 187 toxic substances procured by NASA Lewis Research Center during a 3 1/2 year period, including 27 known or suspected carcinogens. The goal of the program is to assure that the center's health and safety personnel are aware of the procurement and use of toxic substances and to alert and inform the users of these materials as to the toxic characteristics and the control measures needed to ensure their safe use. The program also provides a continuing record of the toxic substances procured, who procured them, what other toxic substances the user has obtained in the past, and where similar materials have been used elsewhere at the center.

  12. High plasma concentrations of transforming growth factor-β and tissue inhibitor of metalloproteinase-1. Potential non-invasive predictors for electroanatomical remodeling of atrium in patients with non-valvular atrial fibrillation

    International Nuclear Information System (INIS)

    Kim, Sook-Kyoung; Park, Jae-Hyung; Kim, Jong-Youn; Joung, Boyoung; Lee, Moon-Hyoung; Kim, Sung-Soon; Pak, Hui-Nam; Choi, Jong Il; Kim, Young-Hoon

    2011-01-01

    The degree of electroanatomical remodeling of the left atrial (LA) affects the clinical outcome after rhythm control of atrial fibrillation (AF). Our hypothesis was that plasma concentrations of transforming growth factor (TGF)-β and tissue inhibitor of metalloproteinase (TIMP)-1 reflect LA voltage and structural remodeling in patients with non-valvular AF. In the study, 242 patients (male 79.4%, 55.1±11.0 years old) with AF (155 paroxysmal AF, 87 persistent AF) underwent catheter ablation. Pre-ablation plasma concentrations of TGF-β and TIMP-1 and the degree of electroanatomical remodeling quantified by LA voltage map (NavX) and 3D-CT were evaluated. The mean LA voltage and volume were compared in patients with high TGF-β (±10.0 ng/ml, H-TGF) vs. low TGF-β ( 58%. In patients with non-valvular AF, high plasma concentrations TGF-β and TIMP-1 and low ejection fraction were closely related with electroanatomical remodeling of LA. (author)

  13. Australian athletes' knowledge of the WADA Prohibited Substances List and performance enhancing substances.

    Science.gov (United States)

    Orr, Rhonda; Grassmayr, Matthew; Macniven, Rona; Grunseit, Anne; Halaki, Mark; Bauman, Adrian

    2018-03-15

    This study investigated athlete knowledge of the World Anti-doping Agency (WADA) Prohibited Substances List and the effects of four well-known performance enhancing substances (PES). A sample of 1925 elite and sub-elite athletes (mean age 20.6 years) completed a questionnaire about the banned status of 30 substances/methods and their knowledge of the effects of amphetamines, anabolic steroids, growth hormone and erythropoietin. Athletes showed limited understanding of the WADA Prohibited Substances List, scoring 32.2% correct, 36.3% incorrect, and 31.4% indicated they did not know the status of 30 substances. Responses of >50% correct were given for only eight substances/method: anabolic steroids, amphetamines, blood doping, erythropoietin, caffeine, vitamins/minerals, protein powders and iron. Athletes demonstrated moderate knowledge of the desired effects of the four PES (49% correct), but poor knowledge of their adverse effects (29% correct). Age, sex, ethnicity, professional/amateur status, and current competition level were significant predictors of the number of correct responses (r 2  = 0.16, p wide range of substances and PES. Better targeted drug education towards younger and non-professional athletes and evaluation of current anti-doping programs are warranted. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

    Science.gov (United States)

    Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

    2011-02-10

    Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

  15. Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways

    Directory of Open Access Journals (Sweden)

    Chen J

    2014-07-01

    Full Text Available Jiezhong Chen,1,2 Renfu Shao,3 Li Li,4 Zhi Ping Xu,4 Wenyi Gu4 1School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, 2Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, 3GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Queensland, 4Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia Abstract: Colon cancer is the third most common cancer and the third largest cause of cancer-related death. Fluorouracil (5-FU is the front-line chemotherapeutic agent for colon cancer. However, its response rate is less than 60%, even in combination with other chemotherapeutic agents. The side effects of 5-FU also limit its application. Nanoparticles have been used to deliver 5-FU, to increase its effectiveness and reduce side effects. Another common approach for colon cancer treatment is targeted therapy against the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway. A recently-invented inhibitor of this pathway, BEZ-235, has been tested in several clinical trials and has shown effectiveness and low side effects. Thus, it is a very promising drug for colon cancer treatment. The combination of these two drugs, especially nanoparticle-packed 5-FU and BEZ-235, has not been studied. In the present study, we demonstrated that nanoparticles of layered double hydroxide (LDH loaded with 5-FU were more effective than a free drug at inhibiting colon cancer cell growth, and that a combination treatment with BEZ-235 further increased the sensitivity of colon cancer cells to the treatment of LDH-packed 5-FU (LDH-5-FU. BEZ-235 alone can decrease colon cancer HCT-116 cell viability to 46% of the control, and the addition of LDH-5-FU produced a greater effect, reducing cell survival to 8% of the control. Our data indicate that the combination therapy of

  16. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  17. Substance abuse in anaesthetists.

    Science.gov (United States)

    Garcia-Guasch, Roser; Roigé, Jaume; Padrós, Jaume

    2012-04-01

    Anaesthesiologists have a significantly higher frequency of substance abuse by a factor of nearly 3 when compared with other physicians. This is still a current problem that must be reviewed. Many hypotheses have been formulated to explain why anaesthesiologists appear to be more susceptible to substance abuse than other medical professionals (genetic differences in sensitivity to opioids, stress, the association between chemical dependence and other psychopathology or the second-hand exposure hypothesis). Environmental exposure and sensitization may be an important risk factor in physician addiction. There is a long debate about returning to work for an anaesthetist who has been depending on opioid drugs, and recent debates are discussed. Institutional efforts have been made in many countries and physician health programmes have been developed. As drug abuse among anaesthesiologists has continued, new studies have been conducted to know the theories about susceptibility. Written substance abuse policies and controls must be taken in place and in all countries.

  18. Detection of diffusible substances

    Energy Technology Data Exchange (ETDEWEB)

    Warembourg, M [Lille-1 Univ., 59 - Villeneuve-d' Ascq (France)

    1976-12-01

    The different steps of a radioautographic technique for the detection of diffusible substances are described. Using this radioautographic method, the topographic distribution of estradiol-concentrating neurons was studied in the nervous system and pituitary of the ovariectomized mouse and guinea-pig. A relatively good morphological preservation of structures can be ascertained on sections from unfixed, unembedded tissues prepared at low temperatures and kept-under relatively low humidity. The translocation or extraction of diffusible substances is avoided by directly mounting of frozen sections on dried photographic emulsion. Since no solvent is used, this technique excludes the major sources of diffusion artifacts and permits to be in favourable conditions for the localization of diffusible substances.

  19. Reacções cutâneas adversas aos inibidores do receptor do factor de crescimento epidérmico: estudo de 14 doentes Adverse cutaneous reactions to epidermal growth factor receptor inhibitors: a study of 14 patients

    Directory of Open Access Journals (Sweden)

    Felicidade Santiago

    2011-06-01

    Full Text Available FUNDAMENTOS: O cetuximab e o erlotinib, inibidores do receptor do factor de crescimento epidérmico, provocam frequentemente reacções cutâneas adversas peculiares. OBJETIVOS: Caracterizar do ponto de vista clínico-evolutivo as reacções cutâneas adversas e avaliar a sua abordagem terapêutica. METODOLOGIA: Entre março/2005 e setembro/2009 foram seguidos 14 doentes com idade média de 59,6 anos, em tratamento com cetuximab (7 ou erlotinib (7, por neoplasia pulmonar (10 ou colorrectal (4. Retrospectivamente foi avaliado o padrão clínico evolutivo de reacção cutânea, o intervalo entre a introdução do fármaco e o início dos sintomas e a resposta ao tratamento. RESULTADOS: Doze doentes apresentaram erupção papulopustulosa predominantemente na face, decote e dorso, em média 13,5 dias após o início do fármaco. Efectuaram tratamento oral com minociclina ou doxiciclina e tópico com metronidazol, peróxido de benzoílo e/ou corticoide. Ocorreu melhoria das lesões em todos os doentes. Cinco doentes, em média oito semanas após o início da terapia, apresentaram granulomas piogénicos periungueais, em quatro casos associados a paroníquia, melhorados com tratamento tópico (antibióticos, corticoides e antissépticos. Observou-se xerose em alguns doentes e, de forma isolada, outros efeitos adversos, como telangiectasias e angiomas, alterações dos cabelos e cílios e nevos melanocíticos eruptivos. Na maioria dos doentes, a terapêutica com o inibidor do receptor do factor de crescimento epidérmico foi mantida. CONCLUSÃO: Com o crescente uso destas terapêuticas-alvo, torna-se obrigatório reconhecer e tratar os seus efeitos cutâneos adversos, assegurando uma intervenção atempada de forma a permitir a manutenção desta terapêuticaBACKGROUND: Cetuximab and erlotinib, epidermal growth factor receptor inhibitors, often cause peculiar adverse cutaneous reactions. OBJECTIVES: Our aim was to evaluate adverse cutaneous reactions

  20. Is There a Survival Benefit of First-Line Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor Monotherapy Versus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer?: A Meta-Analysis.

    Science.gov (United States)

    Guetz, Gaetan Des; Landre, Thierry; Uzzan, Bernard; Chouahnia, Kader; Nicolas, Patrick; Morere, Jean-François

    2016-02-01

    Tyrosine-kinase inhibitors (TKIs) markedly improve progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) mutated for epidermal growth factor receptor (EGFR). Results on overall survival (OS) are less clear-cut. We performed a publication-based meta-analysis to address further this issue. We did a PubMed query using keywords simultaneously (lung neoplasm, tyrosine kinase inhibitors, epidermal growth factor receptor mutation, survival, and randomized controlled trials). We also searched for relevant abstracts in annual proceedings of ASCO, ESMO, and WCLC meetings. We cross-checked all references from all eligible articles. Only phase III randomized controlled trials comparing TKI monotherapy and platinum-based doublet chemotherapy in first-line treatment of metastatic or advanced NSCLC were included. We used EasyMA software to perform statistical analyses. A random effect model was used in case of heterogeneity between studies (and a fixed effect model in absence of heterogeneity). The eight eligible studies included 2962 patients (780 males, 2182 females, mostly Asian, median age 60 years), 2909 adenocarcinomas (98 %), 1739 mutated tumors (897 exon 19 deletion, 699 L858 mutation), 448 stage IIIB, and 2222 stage IV (75 %) tumours and 2453 never smokers (83 %). Four studies assessed gefitinib, two studies assessed erlotinib, and two studies assessed afatinib. Chemotherapies were doublets including a platinum salt. All studies included patients with EGFR mutations, but six studies included only EGFR mutated patients. OS was similar among patients who first received TKI or chemotherapy (HR 0.98, 95 % CI 0.87-1.10, fixed effect model). Conversely, compared with chemotherapy, EGFR TKIs significantly improved PFS in patients with EGFR-mutated tumours (HR 0.37, 95 % CI 0.29-0.49, random effect model). Concerning side effects, rash (RR 6.29, 95 % CI 4.05-9.77), diarrhoea (RR 3.51, 95 % CI 2.15-5.75), stomatitis (RR 3.57, 95 % CI 1

  1. Plasminogen activator inhibitor-I-related regulation of procollagen I (α1 and α2) by antitransforming growth factor-β1 treatment during radiation-impaired wound healing

    International Nuclear Information System (INIS)

    Schultze-Mosgau, Stefan; Kopp, Juergen; Thorwarth, Michael; Roedel, Franz; Melnychenko, Ivan; Grabenbauer, Gerhard G.; Amann, Kerstin; Wehrhan, Falk

    2006-01-01

    Purpose: Plasminogen activator inhibitor (PAI)-1 mediates transforming growth factor-β 1 (TGF-β 1 )-related signaling by stimulating collagen Type I synthesis in radiation-impaired wound healing. The regulation of α(I)-procollagen is contradictory in fibroblasts of different fibrotic lesions. It is not known whether anti-TGF-β 1 treatment specifically inhibits α(I)-procollagen synthesis. We used an experimental wound healing study to address anti-TGF-β 1 -associated influence on α(I)-procollagen synthesis. Methods and Materials: A free flap was transplanted into the preirradiated (40 Gy) or nonirradiated neck region of Wistar rats: Group 1 (n = 8) surgery alone; Group 2 (n = 14) irradiation and surgery; Group 3 (n = 8) irradiation and surgery and anti-TGF-β 1 treatment. On the 14th postoperative day, skin samples were processed for fibroblast culture, in situ hybridization for TGF-β 1 , immunohistochemistry, and immunoblotting for PAI-1, α 1 /α 2 (I)-procollagen. Results: Anti-TGF-β 1 significantly reduced TGF-β 1 mRNA (p 1 treatment in vivo significantly reduced α 1 (I)-procollagen protein (p 2 (I)-procollagen expression. Conclusion: These results emphasize anti-TGF-β 1 treatment to reduce radiation-induced fibrosis by decreasing α 1 (I)-procollagen synthesis in vivo. α 1 (I)-procollagen and α 2 (I)-procollagen might be differentially regulated by anti-TGF-β 1 treatment. Increased TGF-β signaling in irradiated skin fibroblasts seemed to be reversible, as shown by a reduction in PAI-1 expression after anti-TGF-β 1 treatment

  2. Epigallocatechin gallate from Camellia sinensis L. (Kuntze is a potential quorum sensing inhibitor in Chromobacterium violaceum

    Directory of Open Access Journals (Sweden)

    Joemar C. Taganna

    2008-06-01

    Full Text Available The problem on the widespread occurrence of antibiotic resistant strains of bacteria calls for novel methods of control of bacterial activity. One of the new viable alternatives to antibiotics is the use of substances that inhibit quorum sensing (QS – a bacterial communication system that has been known to regulate the expression of virulence genes during infection. In this study, epigallocatechin gallate (EGCG from green tea, Camellia sinensis L. (Kuntze was tested for its ability to inhibit QS in a test organism, Chromobacterium violaceum. This microorganism produces a violet-colored substance, violacein, through QS. This study aimed to detect inhibition of QS-regulated violacein production in C. violaceum by EGCG and to determine the dynamics of QS inhibition relative to the concentration of EGCG. The effect of increasing concentration of EGCG on both violacein production and cell density of treated and untreated C. violaceum was determined in a 96-well-microplate format and read at 570nm and 620nm for violacein production and growth, respectively. The results show that addition of EGCG increased the growth of the organism while there is concentration-dependent decrease in the QS-controlled production of violacein. This study thus establishes that EGCG is a potential QS inhibitor and can be further studied and developed for its use as an anti-pathogenic but non-toxic drug.

  3. Yellow substance (gelbstoff)

    International Nuclear Information System (INIS)

    Medina, A.

    1988-04-01

    The different values of the mean slope (S) of the absorption coefficient a(λ) of gelbstoff (yellow substance) for each region under the same hydrological conditions and the correlation between the quantity of absorption (CA) of gelbstoff and sea water parameter is discussed. 12 refs, 6 figs, 3 tabs

  4. Adolescent Substance Abuse.

    Science.gov (United States)

    Thorne, Craig R.; DeBlassie, Richard R.

    1985-01-01

    Cummings (1979), citing evidence from the National Institute of Drug Abuse, reports that one of every eleven adult Americans suffers from a severe addictive problem. Drug addiction is epidemic among teenagers; one of every six teenagers suffers from a severe addictive problem. This paper focuses on adolescent drug/substance abuse. (Author)

  5. Adolescent Suicidal Behavior and Substance Use: Developmental Mechanisms

    Directory of Open Access Journals (Sweden)

    Donald M. Dougherty

    2008-01-01

    Full Text Available Adolescent suicidal behaviors and substance use are disturbingly common. Research suggests overlap of some of the etiological mechanisms for both adolescent suicidal behavior and substance use, yet clear understanding of the complex relations between these behaviors and their causal underpinnings is lacking. A growing body of evidence and a diathesis model (Mann et al. 1999; Mann, 2003 highlight the importance of impulse control as a proximal risk factor for adolescent suicidal and substance use behaviors. This literature review extends current theory on the relationships between adolescent suicidal behavior and substance use by: (1 examining how, when, and to what extent adolescent development is affected by poor impulse control, stressful life events, substance use behavior, and biological factors; (2 presenting proposed causal mechanisms by which these risk factors interact to increase risk for suicidal behaviors and substance use; and (3 proposing specific new hypotheses to extend the diathesis model to adolescents at risk for suicide and substance use. More specifically, new hypotheses are presented that predict bidirectional relationships between stressful life events and genetic markers of 5-HT dysregulation; substance use behavior and impulsivity; and substance use behavior and suicide attempts. The importance of distinguishing between different developmental trajectories of suicidal and substance use behaviors, and the effects of specific risk and protective mechanisms are discussed. Use of new statistical approaches that provide for the comparison of latent growth curves and latent class models is recommended to identify differences in developmental trajectories of suicidal behavior and substance use. Knowledge gained from these prospective longitudinal methods should lead to greater understanding on the timing, duration, and extent to which specific risk and protective factors influence the outcomes of suicidal behavior and substance

  6. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  7. Aversion substance(s) of the rat coagulating glands

    Science.gov (United States)

    Gawienowski, Anthony M.; Berry, Iver J.; Kennelly, James J.

    1982-01-01

    The aversive substance(s) present in adult male urine were not found in castrate rat urine. Removal of the coagulating glands also resulted in a loss of the aversion compounds. The aversion substances were restored to the urine after androgen treatment of the castrate rats.

  8. Stroke And Substance Abuse

    OpenAIRE

    A Chitsaz

    2017-01-01

    Introduction: stroke in recreational substance users can be an indirect complication, like endocarditis and cardio embolism in parenteral drug users. With some drug like cocaine, stroke appear to be the result of a direct effect. In young subjects without other risk factors provide persuasive evidence for causality . OPIATES: Heroine is the most abused opiate drug, which is administered by injection, by snorting or by smoking. Stroke affects heroin users by diverse mechanisms,. Injec...

  9. Toxic Substances Control Act

    Energy Technology Data Exchange (ETDEWEB)

    1992-05-15

    This Reference Book contains a current copy of the Toxic Substances Control Act and those regulations that implement the statute and appear to be most relevant to DOE activities. The document is provided to DOE and contractor staff for informational purposes only and should not be interpreted as legal guidance. Questions concerning this Reference Book may be directed to Mark Petts, EH-231 (202/586-2609).

  10. Rust Inhibitor And Fungicide For Cooling Systems

    Science.gov (United States)

    Adams, James F.; Greer, D. Clay

    1988-01-01

    Mixture of benzotriazole, benzoic acid, and fungicide prevents growth of rust and fungus. Water-based cooling mixture made from readily available materials prevents formation of metallic oxides and growth of fungi in metallic pipes. Coolant remains clear and does not develop thick sludge tending to collect in low points in cooling systems with many commercial rust inhibitors. Coolant compatible with iron, copper, aluminum, and stainless steel. Cannot be used with cadmium or cadmium-plated pipes.

  11. Effect of new disinfectant substances on pseudomonas aeruginosa

    International Nuclear Information System (INIS)

    Majtan, V.

    1998-01-01

    The anti-bacterial effect of 13 new commercially manufactured disinfectant substances on P. aeruginosa strain was studied. The substances tested represent 9 quaternary ammonium salts QAT and 4 combined QAT with other ingredients. The antimicrobial efficacy was characterised by influencing the growth and reproduction of bacterial cells expressed either by MIC and ED 50 as well as and ED 50 , as well as by the inhibition of incorporation rate of incorporation rate of [ 14 C] adenine and [ 14 C] leucine. The method of inhibition of [ 14 C] precursors is suitable as one from possible evaluation criterion on anti-bacterial efficacy of synthetic disinfectant substances. (authors)

  12. Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-βl and Smad2/3 pathways in high-fat diet-induced obesity rat model.

    Science.gov (United States)

    Hong, Seul-Ki; Choo, Eun-Ho; Ihm, Sang-Hyun; Chang, Kiyuk; Seung, Ki-Bae

    2017-11-01

    Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-βl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-β1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-β1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-β1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-β1-induced collagen production and TGF-β1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-β1 and Smad2/3 pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Presence of pleural effusion is associated with a poor prognosis in patients with epidermal growth factor receptor-mutated lung cancer receiving tyrosine kinase inhibitors as first-line treatment.

    Science.gov (United States)

    Wang, Tso-Fu; Chu, Sung-Chao; Lee, Jen-Jyh; Yang, Gee-Gwo; Huang, Wei-Han; Chang, En-Ting; Low, Tissot; Wu, Yi-Feng; Kao, Ruey-Ho; Lin, Chih-Bin

    2017-08-01

    This study was conducted to evaluate the effect of clinical factors on the treatment outcomes of lung cancer patients with active epidermal growth factor receptor (EGFR) mutations treated by first-line tyrosine kinase inhibitors (TKIs). Patients of stage IIIb or IV lung adenocarcinoma harboring mutated EGFR were enrolled between March 2010 and June 2014 and followed up until December 2015. The effects of various clinical features, such as age, sex, smoking history, EGFR mutation types, TKIs used, presence of pleural effusion, metastatic sites on progression-free survival (PFS) and overall survival (OS), were analyzed retrospectively. A total of 104 patients were included in this study. Patients with pleural effusion at initial diagnosis had significantly shorter PFS and OS than those without pleural effusion (median PFS: 8.2 months vs 15.3 months, P = 0.0004; median OS: 16.3 months vs 28.2 months, P = 0.0003). Univariate analysis revealed that being male or a smoker was associated with short PFS, whereas smoking history, bony metastasis and malignant pleural effusion were associated with poor OS. Stepwise multivariate Cox regression analysis showed that the presence of pleural effusion and different TKI use were independent prognostic factors for PFS [hazard ratio [HR] = 2.50 (95% confidence interval [CI], 1.53-4.10), P = 0.0003 and HR = 0.55 (95% CI, 0.31-0.97), P = 0.0396, respectively], whereas the presence of pleural effusion and liver metastasis were associated with poor OS [HR = 2.79 (95% CI: 1.46-5.30), P = 0.0018 and HR = 2.12 (95% CI, 1.02-4.40), P = 0.0440, respectively]. The presence of pleural effusion predicts poor PFS and OS in lung adenocarcinoma patients receiving TKIs as the first-line treatment. Additional studies are warranted to elucidate the underlying mechanisms and determine novel strategies for improving the outcome of these patients. © 2017 John Wiley & Sons Australia, Ltd.

  14. The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials.

    Science.gov (United States)

    Li, Guifang; Gao, Shunji; Sheng, Zhixin; Li, Bin

    2016-01-01

    To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients. © 2016 S. Karger AG, Basel.

  15. Humic substances isolated from residues of sugar cane industry as root growth promoter Substâncias húmicas isoladas de resíduos da indústria da cana-de-açúcar como promotoras de crescimento radicular

    Directory of Open Access Journals (Sweden)

    Jader Galba Busato

    2010-04-01

    Full Text Available Plant growth promoting substances are widely used in modern agriculture. Several products in the market are humic substances isolated from different sources. The filter cake, a residue of sugar production, is a rich and renewable source of organic matter and these characteristics place the filter cake as a possible source of plant growth promoting substances. Humic acids (HA from filter cake were characterized, and their effects as root growth promoters were evaluated. Chemical features of the HA were evaluated through elemental composition, acidic functional groups, E4/E6 ratio and infrared spectroscopy analyzes. The biological activity of the HA was assessed using root architecture parameters and the P-type H+-ATPase activity. The lateral root development was directly related to the stimulation of plasma membrane ATPase activity. The ability of HA to promote root development indicate that HA from filter cake can be used as environmental plant growth stimulators.Substâncias promotoras do crescimento vegetal são amplamente utilizadas na agricultura moderna. Existem vários produtos no mercado, muitos dos quais são substâncias húmicas isoladas de diferentes fontes. A torta de filtro, um resíduo da produção do açúcar, é uma fonte rica e renovável de matéria orgânica e essas características a tornam uma possível fonte de substâncias promotoras do crescimento vegetal. Ácidos húmicos (AH da torta de filtro foram caracterizados, e foi avaliado seu efeito como promotor de crescimento radicular. As características químicas dos AH foram avaliadas por meio da composição elementar, grupos funcionais ácidos, relação E4/E6 e espectroscopia de infravermelho. A atividade biológica dos AH foi acessada avaliando-se a arquitetura radicular e a atividade da H+-ATPase de membrana plasmática. O desenvolvimento de raízes laterais foi diretamente relacionado ao estímulo da atividade da H+-ATPase. A habilidade dos AH em promover o

  16. Substance use in pregnancy.

    Science.gov (United States)

    Wong, Suzanne; Ordean, Alice; Kahan, Meldon

    2011-04-01

    To improve awareness and knowledge of problematic substance use in pregnancy and to provide evidence-based recommendations for the management of this challenging clinical issue for all health care providers. This guideline reviews the use of screening tools, general approach to care, and recommendations for clinical management of problematic substance use in pregnancy. Evidence-based recommendations for screening and management of problematic substance use during pregnancy and lactation. Medline, PubMed, CINAHL, and The Cochrane Library were searched for articles published from 1950 using the following key words: substance-related disorders, mass screening, pregnancy complications, pregnancy, prenatal care, cocaine, cannabis, methadone, opioid, tobacco, nicotine, solvents, hallucinogens, and amphetamines. Results were initially restricted to systematic reviews and randomized control trials/controlled clinical trials. A subsequent search for observational studies was also conducted because there are few RCTs in this field of study. Articles were restricted to human studies published in English. Additional articles were located by hand searching through article reference lists. Searches were updated on a regular basis and incorporated in the guideline up to December 2009. Grey (unpublished) literature was also identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on the Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). This guideline is intended to increase the knowledge and comfort level of health care providers caring for pregnant women who have substance use disorders. Improved access to

  17. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  18. SEARCH OF NEW SYNTHETIC INHIBITORS OF TYROSINASE

    Directory of Open Access Journals (Sweden)

    Yu. Shesterenko

    2017-11-01

    Full Text Available Melanin pigmentation of skin plays the most important role in the protection of organism against UV-irradiation, but the excessive accumulation of melanin brings to toxic melanodermia, melasma, lentigo and other skin lesions. Tyrosinase is the key enzyme of skin melanin pigment biosynthesis. In spite of certain progress in investigation of natural and synthetic tyrosinase inhibitors, actuality of such studies is of a high level, because the existing inhibitors are in some cases unstable, expensive, toxic, requires complex methods of synthesis or isolation from natural sources. The aim of the work is screening of new tyrosinase inhibitors, using the enzyme, isolated from Agaricus bisporus. Tyrosinase was isolated from Agaricus bisporus mushrooms by a modified method. It was found, that the introduction of polyethylene glycol 4000 in the extraction process promotes 3-fold reduction of polyphenol content, which leads to increase purity of enzyme with an increase in its activity by 25%. A search for new tyrosinase inhibitors among a wide range of compounds, including derivatives of 3-chloro-1,4-naphthoquinone, isatin, 3-hydroxy-2-naphthoic acid, etc was conducted. The studied substances did not displayed inhibitory effect at concentration of 0,1-0,5 mmol/dm3.

  19. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Directory of Open Access Journals (Sweden)

    Shohei Sakuda

    2014-03-01

    Full Text Available Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control.

  20. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Science.gov (United States)

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-01-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  1. Exogenous application of urea and a urease inhibitor improves drought stress tolerance in maize (Zea mays L.).

    Science.gov (United States)

    Gou, Wei; Zheng, Pufan; Tian, Li; Gao, Mei; Zhang, Lixin; Akram, Nudrat Aisha; Ashraf, Muhammad

    2017-05-01

    Drought is believed to cause many metabolic changes which affect plant growth and development. However, it might be mitigated by various inorganic substances, such as nitrogen. Thus, the study was carried out to investigate the effect of foliar-applied urea with or without urease inhibitor N-(n-butyl) thiophosphoric triamide (NBPT) on a maize cultivar under drought stress simulated by 15% (w/v) polyethylene glycol 6000. Foliar-applied urea resulted in a significant increase in plant dry weight, relative water content, and photosynthetic pigments under water stress condition. Furthermore, the activities of superoxide dismutase (SOD), peroxidase (POD), and hydrogen peroxidase (CAT), were enhanced with all spraying treatments under drought stress, which led to decreases in accumulation of hydrogen peroxide (H 2 O 2 ), superoxide anion ([Formula: see text]) and malondialdehyde (MDA). The contents of soluble protein and soluble sugar accumulated remarkably with urea-applied under drought stress condition. Moreover, a further enhancement in above metabolites was observed by spraying a mixture of urea and urease inhibitor as compared to urea sprayed only. Taken together, our findings show that foliar application of urea and a urease inhibitor could significantly enhance drought tolerance of maize through protecting photosynthetic apparatus, activating antioxidant defense system and improving osmoregulation.

  2. Substance abuse and child maltreatment.

    Science.gov (United States)

    Wells, Kathryn

    2009-04-01

    Pediatricians and other medical providers caring for children need to be aware of the dynamics in the significant relationship between substance abuse and child maltreatment. A caregiver's use and abuse of alcohol, marijuana, heroin, cocaine, methamphetamine, and other drugs place the child at risk in multiple ways. Members of the medical community need to understand these risks because the medical community plays a unique and important role in identifying and caring for these children. Substance abuse includes the abuse of legal drugs as well as the use of illegal drugs. The abuse of legal substances may be just as detrimental to parental functioning as abuse of illicit substances. Many substance abusers are also polysubstance users and the compounded effect of the abuse of multiple substances may be difficult to measure. Often other interrelated social features, such as untreated mental illness, trauma history, and domestic violence, affect these families.

  3. Blocking the proliferation of human tumor cell lines by peptidase inhibitors from Bauhinia seeds.

    Science.gov (United States)

    Nakahata, Adriana Miti; Mayer, Barbara; Neth, Peter; Hansen, Daiane; Sampaio, Misako Uemura; Oliva, Maria Luiza Vilela

    2013-03-01

    In cancer tumors, growth, invasion, and formation of metastasis at a secondary site play a pivotal role, participating in diverse processes in the development of the pathology, such as degradation of extracellular matrix. Bauhinia seeds contain relatively large quantities of peptidase inhibitors, and two Bauhinia inhibitors were obtained in a recombinant form from the Bauhinia bauhinioides species, B. bauhinoides cruzipain inhibitor, which is a cysteine and serine peptidase inhibitor, and B. bauhinioides kallikrein inhibitor, which is a serine peptidase inhibitor. While recombinant B. bauhinoides cruzipain inhibitor inhibits human neutrophil elastase cathepsin G and the cysteine proteinase cathepsin L, recombinant B. bauhinioides kallikrein inhibitor inhibits plasma kallikrein and plasmin. The effects of recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor on the viability of tumor cell lines with a distinct potential of growth from the same tissue were compared to those of the clinical cytotoxic drug 5-fluorouracil. At 12.5 µM concentration, recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor were more efficient than 5-fluorouracil in inhibiting MKN-28 and Hs746T (gastric), HCT116 and HT29 (colorectal), SkBr-3 and MCF-7 (breast), and THP-1 and K562 (leukemia) cell lines. Additionally, recombinant B. bauhinoides cruzipain inhibitor inhibited 40 % of the migration of Hs746T, the most invasive gastric cell line, while recombinant B. bauhinioides kallikrein inhibitor did not affect cell migration. Recombinant B. bauhinioides kallikrein inhibitor and recombinant B. bauhinoides cruzipain inhibitor, even at high doses, did not affect hMSC proliferation while 5-fluorouracil greatly reduced the proliferation rates of hMSCs. Therefore, both recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor might be considered for further studies

  4. Modelling the effects of pulse exposure of several PSII inhibitors on two algae.

    Science.gov (United States)

    Copin, Pierre-Jean; Chèvre, Nathalie

    2015-10-01

    Subsequent to crop application and during precipitation events, herbicides can reach surface waters in pulses of high concentrations. These pulses can exceed the Annual Average Environmental Quality Standards (AA-EQS), defined in the EU Water Framework Directive, which aims to protect the aquatic environment. A model was developed in a previous study to evaluate the effects of pulse exposure for the herbicide isoproturon on the alga Scenedesmus vacuolatus. In this study, the model was extended to other substances acting as photosystem II inhibitors and to other algae. The measured and predicted effects were equivalent when pulse exposure of atrazine and diuron were tested on S. vacuolatus. The results were consistent for isoproturon on the alga Pseudokirchneriella subcapitata. The model is thus suitable for the effect prediction of phenylureas and triazines and for the algae used: S. vacuolatus and P. subcapitata. The toxicity classification obtained from the dose-response curves (diuron>atrazine>isoproturon) was conserved for the pulse exposure scenarios modelled for S. vacuolatus. Toxicity was identical for isoproturon on the two algae when the dose-response curves were compared and also for the pulse exposure scenarios. Modelling the effects of any pulse scenario of photosystem II inhibitors on algae is therefore feasible and only requires the determination of the dose-response curves of the substance and growth rate of unexposed algae. It is crucial to detect the longest pulses when measurements of herbicide concentrations are performed in streams because the model showed that they principally affect the cell density inhibition of algae. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Bertran-Alamillo, Jordi; Molina, Miguel Angel

    2017-01-01

    Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms....... The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance......, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover...

  6. Radioactive substance solidifying device

    International Nuclear Information System (INIS)

    Sakoda, Kotaro.

    1979-01-01

    Purpose: To easily solidify radioactive substances adhering to the surfaces of solid wastes without scattering in the circumference by paints, and further to reduce surface contamination concentrations. Constitution: Solid wastes are placed on a hanging plate, and dipped in paints within a paint dipping treatment tank installed at the lower part of a treatment tank by means of a monorail hoist, and the surfaces of said solid wastes are coated with paints, thereby to solidify the radioactivity on the surfaces of the solid wastes. After dipping, the solid wastes are suspended up to a paint spraying tank to dry the paints. After drying, non-contaminated paints are atomized to apply through an atomizing tube onto the solid wastes. After drying the atomized paints, the solid wastes are carried outside the treatment tank by means of the monorail hoist. (Yoshino, Y.)

  7. Longitudinal associations between depression and problematic substance use in the Youth Partners in Care study.

    Science.gov (United States)

    McKowen, James W; Tompson, Martha C; Brown, Timothy A; Asarnow, Joan R

    2013-01-01

    Large-scale treatment studies suggest that effective depression treatment and reduced depression are associated with improved substance use outcomes. Yet information is limited regarding the longitudinal association between depressive symptoms and problematic substance use and its predictors, particularly in real-world practice settings. Using latent growth modeling, we examined the (a) longitudinal association between depressive symptoms and problematic substance use, (b) impact of depressive symptoms on problematic substance use, (c) impact of problematic substance use on depressive symptoms, and (d) role of co-occurring symptoms on depression and problematic substance use. Participants were part of the Youth Partners in Care study, an effectiveness trial evaluating a quality improvement intervention for youth depression through primary care. This ethnically diverse sample included youths aged 13 to 21 years screening positive for depression from 5 health care organizations. Participants were followed 4 times over an 18-month period and assessed for both depressive symptoms and problematic substance use. Both depressive symptoms and problematic substance use declined over time. Higher baseline depressive symptoms predicted a slower decline in problematic substance use, but baseline problematic substance use did not predict changes in depressive symptoms. These prospective associations remained robust controlling for co-occurring symptoms. Results support prior large-scale depression studies indicating depression burden negatively impacts substance use outcome and extends these findings to real-world practice settings. Findings underscore the importance of addressing depression severity in youth with concurrent substance use problems, even in the context of comorbid symptoms of anxiety, delinquency, and aggression.

  8. Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: An Evidence-Based Analysis.

    Science.gov (United States)

    2010-01-01

    In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: http://www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa(®)) or erlotinib (Tarceva(®)) in patients with advanced non-small cell lung cancer (NSCLC). TARGET POPULATION AND CONDITION With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer

  9. Monoamine Oxidase Inhibitors (MAOIs)

    Science.gov (United States)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for ... www.uptodate.com/home. Accessed May 16, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  10. Characterisation of inhibitory substances produced by two Pseudoalteromonas species and the cyanobacterial strain Flo1

    OpenAIRE

    Rau, Jan Erik

    2011-01-01

    In the present study the inhibitory substances of P. aurantia NCIMB 2052T and P. citrea NCIMB 1889T were investigated with respect to their substantial and functional nature, their inhibitory potential, their stability against various treatments as well as the growth phases and incubation conditions when the substances are produced. In addition, an inhibitory substance produced by strain Flo1 was examined regarding its structure, function, and inhibitory potential. Furthermore, its taxonomic ...

  11. Substance Use and Mental Health

    Science.gov (United States)

    ... and Alcohol Tobacco Learn More Substance Use and Mental Health Drugs and Alcohol Did you know that addiction ... Plus – also en Español Treatment Substance Abuse and Mental Health Administration (SAMHSA): SAMHSA’s National Helpline: 1-800-662- ...

  12. Stress corrosion inhibitors for type 18-10 stainless steels with low carbon content in hot and concentrated solutions of MgCl2. Study of some inorganic iodides

    International Nuclear Information System (INIS)

    Pinard, J.-L.

    1974-01-01

    Stress corrosion inhibitors for type Z2CN18-10 austenitic stainless steels with low carbon content in a solution of Cl 2 Mg at 105 deg C were investigated. It was established that iodides are the most adequate corrosion inhibitors because they react simultaneously upon the three main components of the alloy (Fe, Ni, Cr). A difference of behavior between I 2 Mg and the other iodides was observed (in electrochemistry and in simple stress corrosion experiments) and the influence of the metallic cation associated to I - was studied. The formation of the superficial film and the phenomena liable to occur at the interface film-corrosive solution were examined: film growth in MgCl 2 ; influence of certain substances added to the solution. A mechanism of inhibition by I - is suggested. It is similar to the mechanism proposed by BERGEN for the stress corrosion cracking by Cl - [fr

  13. Treatment with a JNK inhibitor increases, whereas treatment with a p38 inhibitor decreases, H2O2-induced calf pulmonary arterial endothelial cell death.

    Science.gov (United States)

    Park, Woo Hyun

    2017-08-01

    Oxidative stress induces apoptosis in endothelial cells (ECs). Reactive oxygen species (ROS) promote cell death by regulating the activity of various mitogen-activated protein kinases (MAPKs) in ECs. The present study investigated the effects of MAPK inhibitors on cell survival and glutathione (GSH) levels upon H 2 O 2 treatment in calf pulmonary artery ECs (CPAECs). H 2 O 2 treatment inhibited the growth and induced the death of CPAECs, as well as causing GSH depletion and the loss of mitochondrial membrane potential (MMP). While treatment with the MEK or JNK inhibitor impaired the growth of H 2 O 2 -treated CPAECs, treatment with the p38 inhibitor attenuated this inhibition of growth. Additionally, JNK inhibitor treatment increased the proportion of sub-G 1 phase cells in H 2 O 2 -treated CPAECs and further decreased the MMP. However, treatment with a p38 inhibitor reversed the effects of H 2 O 2 treatment on cell growth and the MMP. Similarly, JNK inhibitor treatment further increased, whereas p38 inhibitor treatment decreased, the proportion of GSH-depleted cells in H 2 O 2 -treated CPAECs. Each of the MAPK inhibitors affected cell survival, and ROS or GSH levels differently in H 2 O 2 -untreated, control CPAECs. The data suggest that the exposure of CPAECs to H 2 O 2 caused the cell growth inhibition and cell death through GSH depletion. Furthermore, JNK inhibitor treatment further enhanced, whereas p38 inhibitors attenuated, these effects. Thus, the results of the present study suggest a specific protective role for the p38 inhibitor, and not the JNK inhibitor, against H 2 O 2 -induced cell growth inhibition and cell death.

  14. Inhibitive effect of a naturally-occurring substance, tobacco, on the dissolution of mild steel in hydrochloric acid

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, K; Srivastava, P

    1980-12-01

    A number of naturally-occurring substances has been found to be effective inhibitors for the dissolution of mild steel in hydrochloric acid. The alkaloids nicotine and papaverine, contained in natural products such as tobacco leaves and black pepper, have proved themselves as excellent inhibitors. Considering the low cost of tobacco leaves, detailed studies were made with these, and they have been found to form an effective inhibitor under all practical conditions. Adsorption studies based on weight-loss measurements showed that adsorption of inhibitor obeys Freundlich's adsorption isoth

  15. Inhibition of crystallization caused by Proteus mirabilis during the development of infectious urolithiasis by various phenolic substances.

    Science.gov (United States)

    Torzewska, Agnieszka; Rozalski, Antoni

    2014-01-01

    Infectious urolithiasis is a consequence of persistent urinary tract infections caused by urease producing bacteria e.g. Proteus mirabilis. These stones are composed of struvite and carbonate apatite. Their rapid growth and high recurrence indicate that so far appropriate methods of treatment have not been found. In the present study, the inhibitory effect of phenolic compounds was investigated in vitro against formation of struvite/apatite crystals. The impact of these substances with different chemical structures on crystallization caused by clinical isolates of P. mirabilis was tested spectrophotometrically using a microdilution method. Among the 11 tested compounds resveratrol, epigallocatechin gallate, peralgonidin, vanillic and coffee acids at the concentrations 250-1000 μg/ml inhibited P. mirabilis urease activity and crystallization. However, only vanillic acid had such an effect on all tested strains of P. mirabilis. Therefore, using an in vitro model, bacterial growth, crystallization, urease activity and pH were examined for 24h in synthetic urine with vanillic acid. Effect of vanillic acid was compared with that of other known struvite/apatite crystallization inhibitors (acetohydroxamic acid, pyrophosphate) and it was shown that vanillic acid strongly inhibited bacterial growth and the formation of crystals. It can be assumed that this compound, after further studies, can be used in the treatment or prophylaxis of infectious urolithiasis. Copyright © 2013 Elsevier GmbH. All rights reserved.

  16. Radioiodination of humic substances

    Energy Technology Data Exchange (ETDEWEB)

    Franke, K.; Kupsch, H. [Inst. of Interdisciplinary Isotope Research, Leipzig (Germany)

    2010-07-01

    The known IODO-GEN trademark -method was adapted for radiolabeling of humic and fulvic acids with {sup 131}I. The water insoluble oxidizing agent 1,3,4,6tetrachloro-3{alpha},6{alpha}-diphenylglycoluril (IODO-GEN trademark) forms an iodous ion species (I{sup +}), which undergoes an electrophilic I/H-substitution on aromatic moieties of the humic and fulvic acids. This method offers mild conditions with a lesser extent of oxidative alterations of the target molecule, accompanied by an easy handling due to the virtual water-insolubility of the oxidizing agent. The method was optimized and different techniques were tested for the purification of the radioiodinated humic material. The yield of the labeling procedure varies between 45 and 75% depending on the provenance of the humic material and the applied purification method. A specific activity up to 40 MBq/mg was achieved. Furthermore, the known inherent photo-susceptibility of the iodinated humic substance and the influence of reducing agents were verified. An additional release of {sup 131}I up to 20% and up to 35%, respectively were observed. (orig.)

  17. Distillation of bituminous substances

    Energy Technology Data Exchange (ETDEWEB)

    du Buisson, M A.B.B.

    1845-06-23

    New and improved methods are described for the distillation of bituminous schistus and other bituminous substances, as well as for the purification, rectification, and preparation necessary for the employment of the productions obtained by such distillation for various useful purposes. This invention consists, first, in the arrangement and construction of furnace or apparatus for the distillation of schistus, and (any) other bituminous rocks. This furnace is made of circular brick-work, and is provided with the requisite number of fires placed round the circumference. The retort is of a conical or funnel shape, and when ready for use, has the appearance of one inverted cone being placed within a larger cone, in such a manner as to leave a space between the two cones for the reception of the schistus. Both cones are capable of being closed at their apexes, and their mouths, which are placed upwards, are connected together, and hermetically closed by a flat ring. The flame draft is caused to impinge against the lower portion of the outer cone and ascending, turns over the upper edge and descends within the inner cone to the mouth of the chimney, which is placed in the interior, and as low as may be convenient. A third cone is so placed within the inner cone as to cause the flame draft, in its descent, to bind against the surface of the retort.

  18. A method and apparatus for preparing the storage of noxious substances, in particular radioactive substances

    International Nuclear Information System (INIS)

    1974-01-01

    The invention relates to the storage of radioactive substances. It deals with a method for storing a substance, in particular a noxious or radioactive substance, comprising trapping said substance in a solid substance by bombarding said solid substance with ions of the above substance, so that the latter reaches a certain concentration level in the solid substance. This is applicable to the storage of radioactive wastes [fr

  19. Alexithymia in Egyptian Substance Abusers.

    Science.gov (United States)

    El Rasheed, Amany Haroun

    2001-03-01

    Alexithymia is thought of as a trait that predisposes to drug abuse. Moreover, it is suggested to be related to type of the substance abused, with the worst-case scenario including a worse prognosis as well as tendency to relapse or even not to seek treatment at all. To address this important subject in Egyptian patients, a sample of 200 Egyptian substance abusers was randomly selected from inpatients in the Institute of Psychiatry, Ain Shams University, Egypt. The study also included 200 group-matched controls. DSM-IV criteria were used for assessment of substance use disorders, and toxicologic urine analysis was used to confirm the substances of abuse. Toronto Alexithymia Scale (TAS)-Arabic version was used for assessment of alexithymia. It was found that alexithymia was significantly more prevalent in the substance use disorders group as compared to healthy controls. It was also found that among the substance use disorders group, alexithymics reported more polysubstance abuse, more opiate use (other than heroin IV), lower numbers of hospitalizations, lower numbers of reported relapses, and a lower tendency to relapse as a result of internal cues compared to patients without alexithymia. Statistically significant associations were also found between alexithymia and more benzodiazepine abuse and nonpersistence in treatment. The results suggest that alexithymia should be targeted in a treatment setting for substance use disorders.

  20. SGLT2 inhibitors.

    Science.gov (United States)

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Aromatase inhibitors in pediatrics.

    Science.gov (United States)

    Wit, Jan M; Hero, Matti; Nunez, Susan B

    2011-10-25

    Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

  2. Definition of Substance and Non-substance Addiction.

    Science.gov (United States)

    Zou, Zhiling; Wang, Huijun; d'Oleire Uquillas, Federico; Wang, Xiaomei; Ding, Jianrui; Chen, Hong

    2017-01-01

    Substance addiction (or drug addiction) is a neuropsychiatric disorder characterized by a recurring desire to continue taking the drug despite harmful consequences. Non-substance addiction (or behavioral addiction) covers pathological gambling, food addiction, internet addiction, and mobile phone addiction. Their definition is similar to drug addiction but they differ from each other in specific domains. This review aims to provide a brief overview of past and current definitions of substance and non-substance addiction, and also touches on the topic of diagnosing drug addiction and non-drug addiction, ultimately aiming to further the understanding of the key concepts needed for a foundation to study the biological and psychological underpinnings of addiction disorders.

  3. Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model.

    Science.gov (United States)

    Raben, David; Bianco, Cataldo; Damiano, Vincenzo; Bianco, Roberto; Melisi, Davide; Mignogna, Chiara; D'Armiento, Francesco Paolo; Cionini, Luca; Bianco, A Raffaele; Tortora, Giampaolo; Ciardiello, Fortunato; Bunn, Paul

    2004-08-01

    Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti-factor VIII-related antigen monoclonal antibody. ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis

  4. Stroke And Substance Abuse

    Directory of Open Access Journals (Sweden)

    A Chitsaz

    2017-02-01

    Full Text Available Introduction: stroke in recreational substance users can be an indirect complication, like endocarditis and cardio embolism in parenteral drug users. With some drug like cocaine, stroke appear to be the result of a direct effect. In young subjects without other risk factors provide persuasive evidence for causality . OPIATES: Heroine is the most abused opiate drug, which is administered by injection, by snorting or by smoking. Stroke affects heroin users by diverse mechanisms,. Injectors are at risk of infections endocarditis, which carries risk for both ischemic and hemorrhagic stroke. Cerebral or subarachnoid hemorrhage usually occurs after rupture of a septic (mycotic aneurysm. Heroine users can are also at risk for hemorrhagic stroke secondary to liver failure with deranged clotting and to heroin nephropathy with uremia or malignant hypertension. In some heroin users the drug it self is directly causal due to vasculitis, hypersensitivity and immunologic changes. Embolization of foreign material to brain due to mixed of heroine with quinine can cause cerebral embolism. AMPHETAMINE AND other psychostimulants: In abuser of amphetamine hemorrhagic stroke can occur, oral, intravenous, nasal, and inhalational routes of administration have been reported. Most were chronic user, but in several patients, stroke followed a first exposure. Some of amphetamine induced intracranial hemorrhages are secondary to acute hypertension, some to cerebral vacuities, and some to a combination of two. Decongestants and diet pills: Phenylpropanolamine (PPA, an amphetamine – like drug, in decongestants and diet pills, induce acute hypertension, sever headache, psychiatric symptoms, seizures and hemorrhagic stroke. Ephedrine and pseudo ephedrine are present in decongestants and bronchodilators and induce headache, tachyarrhythmia, hypertensive emergency, and hemorrhagic and occlusive stroke. Ecstasy, 3,4 Methylenedioxymethamphetamin (MDMA with amphetamine like can

  5. The role of vanillin and p-coumaric acid in the growth of Scotch pine seedlings

    Directory of Open Access Journals (Sweden)

    M. Michniewicz

    2015-01-01

    Full Text Available It was stated that vanillin and p-coumaric acid used at concentrations 10-8-10-5M stimulated the growth of pine seedlings. Most effective were these substances used at concentration 10-7M. Both phenolic compounds stimulated the elongation, fresh and dry weight in very young seedlings (up to 3-4 weeks and increased the fresh and dry weight only in older ones (7 weeks. The stimulation of growth processes in pine seedlings treated with vanillin and p-coumaric acid coincided with the increase of auxins in roots and with the decrease of free gibberellins in these plant organs. Neither vanillin nor p-coumaric acid influenced the level of ABA-like inhibitor both in the shoots and roots of pine seedlings.

  6. JAK inhibitors in autoinflammation.

    Science.gov (United States)

    Hoffman, Hal M; Broderick, Lori

    2018-06-11

    Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

  7. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  8. Ozone-depleting Substances (ODS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — This site includes all of the ozone-depleting substances (ODS) recognized by the Montreal Protocol. The data include ozone depletion potentials (ODP), global warming...

  9. Dermal uptake of petroleum substances

    NARCIS (Netherlands)

    Jakasa, Ivone; Kezic, Sanja; Boogaard, Peter J.

    2015-01-01

    Petroleum products are complex substances comprising varying amounts of linear and branched alkanes, alkenes, cycloalkanes, and aromatics which may penetrate the skin at different rates. For proper interpretation of toxic hazard data, understanding their percutaneous absorption is of paramount

  10. Chemical structure and properties of low-molecular furin inhibitors

    Directory of Open Access Journals (Sweden)

    T. V. Osadchuk

    2016-12-01

    Full Text Available The review is devoted to the analysis of the relationship between a chemical structure and properties of low-molecular weight inhibitors of furin, the most studied proprotein convertase, which is involved in the development of some pathologies, such as oncologic diseases, viral and bacterial infections, etc. The latest data concerning the influence of peptides, pseudo-peptides, aromatic and heterocyclic compounds, some natural ones such as flavonoids, coumarins, and others on enzyme inactivation are considered. The power of furin inhibition is shown to rise with the increasing number of positively charged groups in the structure of these compounds. Peptidomimetics (Ki = 5-8 pM are shown to be the most effective furin inhibitors. The synthesized substances, however, have not been used in practical application yet. Nowadays it is very important to find more selective inhibitors, improve their stability, bioavailability and safety for the human organism.

  11. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  12. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  13. **1**5N-NMR INVESTIGATION OF HYDROXYLAMINE DERIVATIZED HUMIC SUBSTANCES.

    Science.gov (United States)

    Thorn, Kevin A.; Arterburn, Jeffrey B.; Mikita, Michael A.

    1986-01-01

    Humic substances are the most abundant naturally occurring refactory organic compounds in soils and water. They have a broad range of physical, chemical and physiological properties. In soils, humic substances contribute to the cation exchange capacity, help maintain the physical structure, and play a role in plant growth and nutrition. In aquatic systems, humic substances serve to regulate the levels of inorganic constituents, yield trihalomethanes upon chlorination, and transport or concentrate organic and inorganic pollutants. The oxygen containing functional groups of humic and fulvic acids are believed to play a key role in the chemical properties of humic substances. This study was undertaken to gain additional information on the specific types of oxygen functionalities in humic substances. Since the analysis of hydroxyl moieties had been earlier established, we focused our attention on the analysis of ketone and aldehyde functional groups in humic substances.

  14. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes

    Czech Academy of Sciences Publication Activity Database

    Gudernová, I.; Veselá, Iva; Balek, L.; Buchtová, Marcela; Dosedělová, Hana; Kunová, M.; Pivnička, J.; Jelínková, I.; Roubalová, L.; Kozubík, Alois; Krejčí, P.

    2016-01-01

    Roč. 25, č. 1 (2016), s. 9-23 ISSN 0964-6906 R&D Projects: GA ČR(CZ) GA14-31540S Institutional support: RVO:67985904 ; RVO:68081707 Keywords : fibroblast growth factor receptor * tyrosine kinase domain * ERK MAP kinase Subject RIV: EA - Cell Biology Impact factor: 5.340, year: 2016

  15. Ecotoxicological assessment of the herbicide Winner Top and its active substances-are the other formulants truly inert?

    Science.gov (United States)

    Queirós, Libânia; Vidal, Tânia; Nogueira, António J A; Gonçalves, Fernando J M; Pereira, Joana Luísa

    2018-05-03

    Formulants used in Plant Protection Products (PPPs) to promote their efficiency are normally undisclosed in the PPP documentation, unless they bear a human health or environmental hazardous potential per se. PPP regulation also demands the assessment of putative interactions among formulants within each product recipe and consequent effects, but these results are often unavailable. Such a case is that of the herbicide Winner Top (Selectis®, Portugal), which we selected as a model commercial formulation in the present study specifically aiming at (i) characterising its aquatic toxicity towards sensitive eco-receptors (Raphidocelis subcapitata, Chlorella vulgaris, Lemna minor and Lemna gibba), as well as that of its active substances (a.s.) nicosulfuron and terbuthylazine; (ii) comparing the ecotoxicity among the commercial formulation, the corresponding mixture of its a.s. and this a.s.'s mixture increasingly enriched with the formulants. Single chemical testing revealed that terbuthylazine was the strongest microalgae growth inhibitor and nicosulfuron was the strongest macrophyte growth inhibitor. On the other hand, the commercial formulation was consistently less toxic than the corresponding mixture of the a.s., suggesting that Winner Top formulants (72.9% of the commercial formulation) interact with the a.s., promoting less than additive effects in the selected non-target species. Importantly, this environmentally protective effect of the formulation can be apparent. Because macrophytes share most physiological features with the weeds targeted by the studied herbicide, it is likely that increased application doses are required to reach desired efficacy levels with the consequent detrimental increase of PPP residues load in edge-of-field freshwater ecosystems.

  16. Dipeptidyl peptidase-4 inhibitor induced angioedema - an overlooked and potentially lethal adverse drug reaction?

    DEFF Research Database (Denmark)

    Scott, Susanne Irene; Andersen, Michelle Fog; Aagaard, Lise

    2018-01-01

    to vasodilatation and increase in vascular permeability in the capillaries. Objective To assess the risk and pathomechanism of angioedema due to inhibition of dipeptidyl peptidase-4 inhibitors when used as monotherapy and in combination with angiotensin converting enzyme-inhibitors. Method PubMed, Embase......, the Cochrane Library, PubMed Central, Web of Science, Google Scholar and clinicaltrials.gov were searched using different combinations of keywords "angioedema", "dipeptidyl peptidase 4", "dipeptidyl peptidase 4 inhibitors", "gliptins", "bradykinin", "substance P" and "angiotensin converting enzyme...

  17. IDENTIFICATION OF ODOR SUBSTANCES IN YAMABUSHITAKE MUSHROOM (Hericium erinaceum) CULTURE MEDIA CONTAINING 'SHOCHU' LEES AND STARCH WASTES, AND BASIC STUDIES ON THEIR DISAPPEARANCE

    Science.gov (United States)

    Yamauchi, Masahito; Matsumoto, Hirotaka; Yamada, Masayoshi; Yagi, Fumio; Murayama, Ryou; Yamaguchi, Yoshinori; Yamaguchi, Takashi

    In this study, odor substances from mushroom culture media containing 'shochu' lees and starch wastes were identified and determined. It was apparent that in the media, acetoin, butyric acid and diacetyl were found as main odor substances, and mixed with some other ordor substances to produce unpleasant odor. The main substances disappeared with growth of mycelia. It was not likely that these ordor substances were degraded by extracellular enzymes but suggested that they were degraded by mycelia. Further it was found with the growth of mycelia that odor quality changed from rancid ordor (unpleasant ordor) to mushroom smell (pleasant odor) and the odor index was decreasing.

  18. Acid corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  19. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  20. Humic substances in ground waters

    International Nuclear Information System (INIS)

    Paxeus, N.; Allard, B.; Olofsson, U.; Bengtsson, M.

    1986-01-01

    The presence of naturally occurring complexing agents that may enhance the migration of disposed radionuclikes and thus facilitate their uptake by plantsis a problem associated with the underground disposal of radioactive wastes in bedrock. The main purpose of this work is to characterized humic substances from ground water and compare them with humic substances from surface water. The humic materials isolated from ground waters of a borehole in Fjaellveden (Sweden) were characterized by elemental and functional group analyses. Spectroscopic properties, molecular weight distributions as well as acid-base properties of the fulvic and humic fractions were also studied. The ground water humic substances were found to be quite similar in many respects (but not identical) to the Swedish surface water humics concentrated from the Goeta River but appeared to be quite different from the American ground water humics from Biscayne Florida Aquifer or Laramie Fox-Hills in Colorado. The physico-chemical properties of the isolated humic materials are discussed

  1. NOSH–aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

    International Nuclear Information System (INIS)

    Chattopadhyay, Mitali; Kodela, Ravinder; Olson, Kenneth R.; Kashfi, Khosrow

    2012-01-01

    Highlights: ► NOSH–aspirin is the first dual acting NO and H 2 S releasing hybrid. ► Its IC 50 for cell growth inhibition is in the low nano-molar range. ► Structure–activity studies show that the sum of the parts does not equal the whole. ► NOSH–aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H 2 S) can increase mucosal defense mechanisms has led to the development of NO- and H 2 S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH–aspirin, which is an NO- and H 2 S-releasing agent. NOSH–aspirin inhibited HT-29 colon cancer growth with IC 50 s of 45.5 ± 2.5, 19.7 ± 3.3, and 7.7 ± 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH–aspirin inhibited cell proliferation, induced apoptosis, and caused G 0 /G 1 cell cycle block. Reconstitution and structure–activity studies representing a fairly close approximation to the intact molecule showed that NOSH–aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH–aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH–ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH–aspirin has strong anti-cancer potential and merits further evaluation.

  2. Process of treating carbonaceous substances

    Energy Technology Data Exchange (ETDEWEB)

    1938-12-16

    A process is described of removing halogens or halogen compounds (or both) from the products which form when carbonaceous substances are treated thermally in the presence of halogens or halogen compounds, consisting of passing the reaction products at the same temperature with a substance able to fix halogens or acid halides through an apparatus included between the receiver and the heat exchanger, which contains, in a relatively restricted space, internal elements obliquely disposed in relation to the direction of the flow, stretched in this direction and constituted preferably of helicoidal passages.

  3. 5 alpha-reductase inhibitors and prostatic disease.

    Science.gov (United States)

    Schröder, F H

    1994-08-01

    5 alpha-Reductase inhibitors are a new class of substances with very specific effects on type I and type II 5 alpha R which may be of use in the treatment of skin disease, such as male pattern baldness, male acne and hirsutism, as well as prostatic hyperplasia and prostate cancer. At least two types of 5 alpha R inhibitors with a different pH optimum have been described. cDNA encoding for both the type I and the type II enzyme has been cloned. Most of the orally effective 5 alpha R inhibitors belong to the class of 4-azasteroids. The radical substituted in the 17 position of the steroid ring seems to be related to species specific variations and to the types of 5 alpha R enzymes in different species and organ systems. 5 alpha R inhibitors lead to a decrease of plasma DHT by about 65% while there is a slight rise in plasma testosterone. The decrease of tissue DHT in the ventral prostate of the intact rat, the dog and in humans is more pronounced and amounts to about 85%. There is a reciprocal rise of tissue T in these systems. The application of an inhibitor of 5 alpha R type II leads to a shrinkage of BPH in men by about 30%. In the rat a similar shrinkage accompanied by a significant decrease of total organ DNA occurs. This decrease, however, is not as pronounced as can be achieved with castration.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Effect of Wall Shear Stress on Corrosion Inhibitor Film Performance

    Science.gov (United States)

    Canto Maya, Christian M.

    In oil and gas production, internal corrosion of pipelines causes the highest incidence of recurring failures. Ensuring the integrity of ageing pipeline infrastructure is an increasingly important requirement. One of the most widely applied methods to reduce internal corrosion rates is the continuous injection of chemicals in very small quantities, called corrosion inhibitors. These chemical substances form thin films at the pipeline internal surface that reduce the magnitude of the cathodic and/or anodic reactions. However, the efficacy of such corrosion inhibitor films can be reduced by different factors such as multiphase flow, due to enhanced shear stress and mass transfer effects, loss of inhibitor due to adsorption on other interfaces such as solid particles, bubbles and droplets entrained by the bulk phase, and due to chemical interaction with other incompatible substances present in the stream. The first part of the present project investigated the electrochemical behavior of two organic corrosion inhibitors (a TOFA/DETA imidazolinium, and an alkylbenzyl dimethyl ammonium chloride), with and without an inorganic salt (sodium thiosulfate), and the resulting enhancement. The second part of the work explored the performance of corrosion inhibitor under multiphase (gas/liquid, solid/liquid) flow. The effect of gas/liquid multiphase flow was investigated using small and large scale apparatus. The small scale tests were conducted using a glass cell and a submersed jet impingement attachment with three different hydrodynamic patterns (water jet, CO 2 bubbles impact, and water vapor cavitation). The large scale experiments were conducted applying different flow loops (hilly terrain and standing slug systems). Measurements of weight loss, linear polarization resistance (LPR), and adsorption mass (using an electrochemical quartz crystal microbalance, EQCM) were used to quantify the effect of wall shear stress on the performance and integrity of corrosion inhibitor

  5. Cadmium resistance in Drosophila: a small cadmium binding substance

    International Nuclear Information System (INIS)

    Jacobson, K.B.; Williams, M.W.; Richter, L.J.; Holt, S.E.; Hook, G.J.; Knoop, S.M.; Sloop, F.V.; Faust, J.B.

    1985-01-01

    A small cadmium-binding substance (CdBS) has been observed in adult Drosophila melanogaster that were raised for their entire growth cycle on a diet that contained 0.15 mM CdCl 2 . Induction of CdBS was observed in strains that differed widely in their sensitivity of CdCl 2 . This report describes the induction of CdBS and some of its characteristics. 17 refs., 4 figs., 1 tab

  6. Substance Abuse and the Family.

    Science.gov (United States)

    Murphy, John P.

    1984-01-01

    Examines the effect that a substance abuser may have on the family system and the maladaptive roles sometimes assumed by family members. Discusses dysfunctional family phases and therapeutic issues and presents 11 guidelines for counselors working with chemically dependent families. (JAC)

  7. Substance Use as Impression Management.

    Science.gov (United States)

    Sharp, Mark J.; Getz, J. Greg

    1996-01-01

    Examines the function of substance use as an impression management tactic. Introductory psychology students (n=377) responded to a survey instrument measuring self-monitoring, perceived success in impression management, interaction anxiety, and self-esteem. Results suggest that alcohol use may serve an impression management function. (JPS)

  8. [Acting out and psychoactive substances: alcohol, drugs, illicit substances].

    Science.gov (United States)

    Gillet, C; Polard, E; Mauduit, N; Allain, H

    2001-01-01

    In humans, some psychotropic agents (alcohol, drugs, illicit substances) have been suggested to play a role in the occurrence of major behavioural disorders, mainly due to the suppression of psychomotor inhibition. Behavioural disinhibition is a physiological mechanism which allows humans to behave appropriately according to a given environmental situation. The behavioural disinhibition induced by either therapeutic dosage or misuse involves the loss of restraint over certain types of social behaviour and may increase the risk of auto or hetero-aggression and acting out. The increased use of psychotropic agents in recent years and the occurrence of unwanted effects are worrying and must be detected and evaluated. The objective of the present study was to establish a causal relationship between psychoactive substance use and occurrence of major behavioural disorders, such as paradoxical rage reactions and suicidal behaviour, based on a literature analysis. It consisted of reviewing reports of drug-induced violent reactions in healthy volunteers and demonstrating, where possible, a cause-effect relationship. Patients with schizophrenia and psychopathic personalities were not included in our study since psychiatric comorbidity could influence behavioural responses. Psychotropic agents included drugs, licit and illicit substances already associated with violence in the past. Many reports used the "Go/No Go test" to evaluate the disinhibiting effect of psychotropic substances; this allows the "cognitive mapping" of drugs. The results suggest that only alcohol, antidepressants, benzodiazepines and cocaïne are related to aggressive behaviour. The best known precipitant of behavioural disinhibition is alcohol, which induces aggressive behaviour. However, there are large differences between individuals, and attentional mechanisms are now recognised as being important in mediating the effects of alcohol. Suicidal tendency as an adverse antidepressant reaction is rare

  9. IWR-1, a tankyrase inhibitor, attenuates Wnt/β-catenin signaling in cancer stem-like cells and inhibits in vivo the growth of a subcutaneous human osteosarcoma xenograft.

    Science.gov (United States)

    Martins-Neves, Sara R; Paiva-Oliveira, Daniela I; Fontes-Ribeiro, Carlos; Bovée, Judith V M G; Cleton-Jansen, Anne-Marie; Gomes, Célia M F

    2018-02-01

    Wnt/β-catenin or canonical Wnt signaling pathway regulates the self-renewal of cancer stem-like cells (CSCs) and is involved in tumor progression and chemotherapy resistance. Previously, we reported that this pathway is activated in a subset of osteosarcoma CSCs and that doxorubicin induced stemness properties in differentiated cells through Wnt/β-catenin activation. Here, we investigated whether pharmacological Wnt/β-catenin inhibition, using a tankyrase inhibitor (IWR-1), might constitute a strategy to target CSCs and improve chemotherapy efficacy in osteosarcoma. IWR-1 was specifically cytotoxic for osteosarcoma CSCs. IWR-1 impaired spheres' self-renewal capacity by compromising landmark steps of the canonical Wnt signaling, namely translocation of β-catenin to the nucleus and subsequent TCF/LEF activation and expression of Wnt/β-catenin downstream targets. IWR-1 also hampered the activity and expression of key stemness-related markers. In vitro, IWR-1 induced apoptosis of osteosarcoma spheres and combined with doxorubicin elicited synergistic cytotoxicity, reversing spheres' resistance to this drug. In vivo, IWR-1 co-administration with doxorubicin substantially decreased tumor progression, associated with specific down-regulation of TCF/LEF transcriptional activity, nuclear β-catenin and expression of the putative CSC marker Sox2. We suggest that targeting the Wnt/β-catenin pathway can eliminate CSCs populations in osteosarcoma. Combining conventional chemotherapy with Wnt/β-catenin inhibition may ameliorate therapeutic outcomes, by eradicating the aggressive osteosarcoma CSCs and reducing drug resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Prohibited anabolic substances, dangerous to human consumers, in accordance of E.U. regulations

    Directory of Open Access Journals (Sweden)

    Flavia A. Hanganu,

    2009-06-01

    Full Text Available Substances with anabolic effects are used to enhance feed conversion, growth rate or muscle tissue deposition in stock farming for several decades. The majority of these compounds have biochemical effects similar to sex steroids (androgens, estrogens, gestagens. However, in the E.U., the use of hormones for growth – promotion or fattening is prohibited. Monitoring of residues of hormonal growth-promotion in meat or milk, is essential for implementing such bans and to protect public health against the harmful effects of these substances, which incidentally is found in products of animal origin.

  11. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Chattopadhyay, Mitali; Kodela, Ravinder [Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States); Olson, Kenneth R. [Department of Physiology, Indiana University School of Medicine, South Bend, IN 46617 (United States); Kashfi, Khosrow, E-mail: kashfi@med.cuny.edu [Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer NOSH-aspirin is the first dual acting NO and H{sub 2}S releasing hybrid. Black-Right-Pointing-Pointer Its IC{sub 50} for cell growth inhibition is in the low nano-molar range. Black-Right-Pointing-Pointer Structure-activity studies show that the sum of the parts does not equal the whole. Black-Right-Pointing-Pointer NOSH-aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H{sub 2}S) can increase mucosal defense mechanisms has led to the development of NO- and H{sub 2}S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H{sub 2}S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC{sub 50}s of 45.5 {+-} 2.5, 19.7 {+-} 3.3, and 7.7 {+-} 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G{sub 0}/G{sub 1} cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation.

  12. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model.

    Science.gov (United States)

    Chattopadhyay, Mitali; Kodela, Ravinder; Olson, Kenneth R; Kashfi, Khosrow

    2012-03-16

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H(2)S) can increase mucosal defense mechanisms has led to the development of NO- and H(2)S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H(2)S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC(50)s of 45.5 ± 2.5, 19.7 ± 3.3, and 7.7 ± 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G(0)/G(1) cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. DGAT inhibitors for obesity.

    Science.gov (United States)

    Matsuda, Daisuke; Tomoda, Hiroshi

    2007-10-01

    Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis. Two isozymes of DGAT, DGAT1 and DGAT2, have been reported. Increased DGAT2 activity has a role in steatosis, while DGAT1 plays a role in very (V)LDL synthesis; increased plasma VLDL concentrations may promote obesity and thus DGAT1 is considered a potential therapeutic target of inhibition for obesity control. Several DGAT inhibitors of natural and synthetic origin have been reported, and their future prospect as anti-obesity drugs is discussed in this review.

  14. Perfluoroalkyl and polyfluoroalkyl substances and human fetal growth

    DEFF Research Database (Denmark)

    Bach, Cathrine Carlsen; Bech, Bodil Hammer; Brix, Nis

    2015-01-01

    original studies on pregnant women with measurements of PFOA or PFOS in maternal blood during pregnancy or the umbilical cord and associations with birth weight or related outcomes according to the PFAS level. Citations and references from the included articles were investigated to locate more relevant...... articles. Study characteristics and results were extracted to structured tables. The completeness of reporting as well as the risk of bias and confounding were assessed. Results: Fourteen studies were eligible. In utero PFOA exposure was associated with decreased measures of continuous birth weight in all...

  15. Effects of parental attitudes on the use of addictive substances in high school students.

    Science.gov (United States)

    Öztekin, C; Şengezer, T; Özkara, A

    2017-09-01

    Substance abuse is a major public health problem including social and economic aspects. Although multidimensional data about substance abuse are limited in our country, the fact that Turkey is located at the crossroads of Europe and Asia with a young population creating a promising market brings out the necessity of maintaining high awareness on substance abuse. Smoking, alcohol, and substance use are important health problems of adolescence period and families play a major role on adaptation to the changes in growth and development period. The research on substance abuse and dependence emphasizes on protective or risk-enhancing effects of family. The aim of this study was to provide evidence on the interventions that could be implemented about substance use by evaluating the relationship between parental attitude and attitudes of high school students toward substance use. This was a survey study. The study included randomly selected high school students who were willing to participate in the study from Ankara province. The students were applied the sociodemographic information questionnaire especially prepared for this research, the Addictive Substances Attitudes Scale for high school students, and the Parental Attitudes Scale. In the study, data of 707 students, 311 boys and 396 girls, with a mean age of 16.1 years were evaluated. According to the obtained findings, the rate of students with a negative attitude toward addictive substances increases as parental attitude changes from authoritative attitude to democratic attitude. The present study demonstrated that parental attitudes are related with the attitudes of high school students toward addictive substances. Students mostly adopted a negative attitude toward substance use in case of democratic parental attitude. Therefore, to protect children from substance abuse, parents should be advised to adopt a democratic attitude characterized with sincere love and constructive control.

  16. Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Bertran-Alamillo, Jordi; Molina, Miguel Angel

    2017-01-01

    Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms....

  17. Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects.

    Science.gov (United States)

    Brimhall, Darin B; Petri, Niclas; D'Angelo, Pina

    2018-05-01

    Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection. In this randomized, single-dose, crossover study, healthy adults aged 18 to 35 years received single 4-mg doses of somatropin via a needle-free device or SC injection, along with octreotide to suppress endogenous growth hormone production. Blood samples were analyzed for serum somatropin and insulin-like growth factor-1 (IGF-1) concentrations over 24 hours after somatropin dosing. Pharmacokinetic and pharmacodynamic parameters were evaluated by using noncompartmental methods, and bioequivalence was determined based on ln transformation of the AUC 0-24 , AUC 0-∞ , C max , area under the effect-time curve from time 0 to 24 hours (AUEC 0-24 ), and maximum effect concentration (E max ). Bioequivalence was concluded if the 90% CIs of the needle-free device compared with the SC injection, constructed by using the two 1-sided hypotheses at the α = 0.05 level, for these pharmacokinetic/pharmacodynamic parameters fell within the 80.00% to125.00% regulatory acceptance range. A total of 57 subjects completed both study periods and were included in the pharmacokinetic analyses. Point estimates (90% CIs) of the geometric mean ratio (needle-free device/SC injection) based on serum somatropin were 1.013 (0.987-1.040) for AUC 0-24 , 1.012 (0.986-1.038) for AUC 0-∞ , and 1.200 (1.137-1.267) for C max . For IGF-1, baseline-corrected point estimates (90% CIs) were 0.901 (0.818-0.993) for AUEC 0-24 and 0.867 (0.795-0.946) for E max . Non-baseline-corrected values were 0.978 (0.953-1.004) for AUEC 0-24 and 0.953 (0.923-0.984) for E max . Both treatments were well tolerated; blood glucose levels increased in nearly

  18. MAPK inhibitors, particularly the JNK inhibitor, increase cell death effects in H2O2-treated lung cancer cells via increased superoxide anion and glutathione depletion.

    Science.gov (United States)

    Park, Woo Hyun

    2018-02-01

    Reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), induce apoptosis in cancer cells by regulating mitogen-activated protein kinase (MAPK) signaling pathways. The present study investigated the effects of MAPK inhibitors on cell growth and death as well as changes in ROS and glutathione (GSH) levels in H2O2-treated Calu-6 and A549 lung cancer cells. H2O2 inhibited growth and induced death of Calu-6 and A549 lung cancer cells. All MAPK inhibitors appeared to enhance growth inhibition in H2O2-treated Calu-6 and A549 lung cancer cells and increased the percentage of Annexin V-FITC-positive cells in these cancer cells. Among the MAPK inhibitors, a JNK inhibitor significantly augmented the loss of mitochondrial membrane potential (MMP; ΔΨm) in H2O2-treated Calu-6 and A549 lung cancer cells. Intracellular ROS levels were significantly increased in the H2O2-treated cells at 1 and 24 h. Only the JNK inhibitor increased ROS levels in the H2O2-treated cells at 1 h and all MAPK inhibitors raised superoxide anion levels in these cells at 24 h. In addition, H2O2 induced GSH depletion in Calu-6 and A549 cells and the JNK inhibitor significantly enhanced GSH depletion in H2O2‑treated cells. Each of the MAPK inhibitors altered ROS and GSH levels differently in the Calu-6 and A549 control cells. In conclusion, H2O2 induced growth inhibition and death in lung cancer cells through oxidative stress and depletion of GSH. The enhanced effect of MAPK inhibitors, especially the JNK inhibitor, on cell death in H2O2-treated lung cancer cells was correlated with increased O2•- levels and GSH depletion.

  19. ORIGINAL ARTICLES An epidemiological perspective of substance ...

    African Journals Online (AJOL)

    2002-09-06

    Sep 6, 2002 ... advertising linking alcohol with the glamour of sport. This inculcates values that ... of substance use is a useful preventive strategy, hence the importance of ... substance use and associated factors (including age, gender,.

  20. Dual Diagnosis: Substance Abuse and Mental Illness

    Science.gov (United States)

    ... is a term for when someone experiences a mental illness and a substance use disorder simultaneously. Either disorder—substance use or mental illness—can develop first. People experiencing a mental health ...

  1. EPA Linked Open Data: Substance Registry Service

    Data.gov (United States)

    U.S. Environmental Protection Agency — Substance Registry Services (SRS) is the Environmental Protection Agency's (EPA) central system for information about substances that are tracked or regulated by EPA...

  2. Agency for Toxic Substances and Disease Registry

    Science.gov (United States)

    ... Z # Search Form Controls Search The CDC submit Agency for Toxic Substances and Disease Registry Note: Javascript ... gov . Recommend on Facebook Tweet Share Compartir The Agency for Toxic Substances and Disease Registry (ATSDR) , based ...

  3. Pulmonary Toxicity of Cholinesterase Inhibitors

    National Research Council Canada - National Science Library

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  4. Monitoring therapy with MEK inhibitor U0126 in a novel Wilms tumor model in Wt1 knockout Igf2 transgenic mice using 18F-FDG PET with dual-contrast enhanced CT and MRI: early metabolic response without inhibition of tumor growth.

    Science.gov (United States)

    Flores, Leo G; Yeh, Hsin-Hsien; Soghomonyan, Suren; Young, Daniel; Bankson, James; Hu, Qianghua; Alauddin, Mian; Huff, Vicki; Gelovani, Juri G

    2013-04-01

    during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50-100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased (18)F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in (18)F-FDG SUV was observed, as compared to pre-treatment levels (p endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.

  5. Abortion Legalization and Adolescent Substance Use

    OpenAIRE

    Charles, Kerwin Kofi; Stephens, Melvin, Jr

    2006-01-01

    We assess whether in utero exposure to legalized abortion in the early 1970's affected individuals' propensities to use controlled substances as adolescents. We exploit the fact that some states legalized abortion before national legalization in 1973 to compare differences in substance use for adolescents across birth cohorts in different states. We find that persons exposed to early legalization were, on average, much less likely to use controlled substances. We also assess how substance use...

  6. Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy

    Institute of Scientific and Technical Information of China (English)

    Shu-Ling; Wu; Dong-Mei; Zhan; Shu-Hong; Xi; Xiang-Lian; He

    2014-01-01

    AIM:To investigate the role of tissue plasminogen activator(t-PA) and plasminogen activator inhibitor(PAI)in proliferative diabetic retinopathy(PDR) and to discuss the correlations among t-PA, PAI and vascular endothelial growth factor(VEGF) expressions.METHODS:A total of 36 vitreous samples were collected from 36 patients with PDR(PDR group), and 17 vitreous samples from 17 patients with idiopathic macular hole were used as control. The concentrations of t-PA, PAI and VEGF in samples were determined by ELISA method. The correlations among t-PA, PAI and VEGF expressions were discussed.RESULTS:The concentrations of t-PA, PAI and VEGF in the PDR group were significantly higher than those in the control group(P <0.001). The t-PA and PAI expressions were highly correlated with the VEGF expression(P <0.001).CONCLUSION:In addition to VEGF, a variety of bioactive substances, such as t-PA and PAI, are involved in the pathogenesis involved in the angiogenesis of PDR.VEGF can activate t-PA expression, resulting in collagen tissue degradation and angiogenesis. VEGF may also activate the mechanism for endogenous anti-neovascularization.

  7. Substance Abuse in Aging Population

    Directory of Open Access Journals (Sweden)

    Alireza Jazayeri

    2006-10-01

    Full Text Available substance abuse' specially opiates and prescribed drugs are spreading among the older adults. Most of the time it begins as an attempt to medicate chronic pains, medical conditions and loneliness. In other instances, it simply is the continuation of a problem that begun in young adulthood. But scholars and specialists in both fields of Addiction and Gerontology, rather neglected this fast growing problem, to the extent that we almost have no data on the epidemiology, prevention and treatment modalities among the substance abusing old adults in Iran. This paper reflects the necessity of designing age specific programs to identify and treat this group. Besides, some of the most effictive methods of treatment in other countries are reviewed.

  8. Psychotropic substances in indoor environments.

    Science.gov (United States)

    Cecinato, Angelo; Romagnoli, Paola; Perilli, Mattia; Patriarca, Claudia; Balducci, Catia

    2014-10-01

    The presence of drugs in outdoor air has been established, but few investigations have been conducted indoors. This study focused on psychotropic substances (PSs) at three schools, four homes and one office in Rome, Italy. The indoor drug concentrations and the relationships with the outdoor atmosphere were investigated. The optimised monitoring procedure allowed for the determination of cocaine, cannabinoids and particulate fractions of nicotine and caffeine. In-field experiments were performed during the winter, spring and summer seasons. Psychotropic substances were observed in all indoor locations. The indoor concentrations often exceeded those recorded both outdoors at the same sites and at the atmospheric pollution control network stations, indicating that the drugs were released into the air at the inside sites or were more persistent. During winter, the relative concentrations of cannabinol, cannabidiol and tetrahydrocannabinol depended on site and indoor/outdoor location at the site. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. TOXICOLOGICAL ENDPOINTS OF DOPING SUBSTANCES

    OpenAIRE

    BASARAN, A. Ahmet

    2018-01-01

    Athletes and non athletes weighlifters have tried to gain an unfairadvantage through the use doping substances since ancient times. Dopingsubstances although enhance sports performance, represent a risk to the healthof individuals and violate the sprit of competition. The use of prohibitedperformance enhancing drugs (PED’s) or methods to improve results incompetitive sports is referred as doping. Among the PED’s used areandrogenic-anabolic steroids (AASs), diuretics and masking agents, narkot...

  10. The administration of radioactive substances

    International Nuclear Information System (INIS)

    Bourdillon, P.J.; Godfrey, B.E.; O'Brien, R.

    1983-01-01

    A brief history is given of the evolution of a system to approve the licensing of doctors and dentists to use radioactive medicinal products in man. Currently, the Administration of Radioactive Substances Advisory Committee (ARSAC) is appointed by UK Health Ministers to advise them on the granting, renewal, suspension, revocation and variation of certificates. The type of information requested on the application form for a certificate is outlined. (UK)

  11. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

    Directory of Open Access Journals (Sweden)

    Costanza Bogani

    Full Text Available BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN, usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001 and an ATP-competitive (PP242 mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib. mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with

  12. Substance misuse in Aboriginal Australians.

    Science.gov (United States)

    Gracey, M

    1998-01-01

    Australia's Aborigines lived in isolation from the rest of humanity as successful hunter-gatherers for tens of thousands of years. That isolation ended abruptly with British colonization in the late 18th century and was followed by a traumatic 200 years for Aborigines who are now seriously disadvantaged, socio-economically and in terms of their health standards. It has often been assumed that the Aborigines had no access to psychotropic substances before permanent European contact but several pieces of evidence dispute this view. The history of Aboriginal contact with and usage of intoxicating substances, including alcohol, is extremely complex and affected by a maze of restrictive government policies. These interact with a wide range of other Federal and State policies which have changed rapidly since the late 1960s when Aborigines were first granted the franchise; access to unrestricted drinking followed soon afterwards. Today Aborigines suffer disproportionately to other Australians from the physical and social consequences of excess alcohol consumption, tobacco usage, petrol and other solvent sniffing, usage of marijuana, amphetamines, cocaine and heroin, as well as other drugs. The Aboriginal population is dispersed in cities, towns, fringe settlements, rural and remote areas over this vast continent and there are different patterns of drug usage from place to place. This review attempts to synthesize some of this information in order to give an overview to the history, background, current status of substance misuse by Aborigines as well as some strategies being used to try to overcome this serious problem.

  13. Dermal uptake of petroleum substances.

    Science.gov (United States)

    Jakasa, Ivone; Kezic, Sanja; Boogaard, Peter J

    2015-06-01

    Petroleum products are complex substances comprising varying amounts of linear and branched alkanes, alkenes, cycloalkanes, and aromatics which may penetrate the skin at different rates. For proper interpretation of toxic hazard data, understanding their percutaneous absorption is of paramount importance. The extent and significance of dermal absorption of eight petroleum substances, representing different classes of hydrocarbons, was evaluated. Literature data on the steady-state flux and permeability coefficient of these substances were evaluated and compared to those predicted by mathematical models. Reported results spanned over 5-6 orders of magnitude and were largely dependent on experimental conditions in particular on the type of the vehicle used. In general, aromatic hydrocarbons showed higher dermal absorption than more lipophilic aliphatics with similar molecular weight. The results showed high variation and were largely influenced by experimental conditions emphasizing the need of performing the experiments under "in use" scenario. The predictive models overestimated experimental absorption. The overall conclusion is that, based on the observed percutaneous penetration data, dermal exposure to petroleum hydrocarbons, even of aromatics with highest dermal absorption is limited and highly unlikely to be associated with health risks under real use scenarios. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Energy Taxis Drives Campylobacter jejuni toward the Most Favorable Conditions for Growth

    DEFF Research Database (Denmark)

    Vegge, C.S.; Brondsted, L.; Li, Yiping

    2009-01-01

    Campylobacter jejuni is a serious food-borne bacterial pathogen in the developed world. Poultry is a major reservoir, and C. jejuni appears highly adapted to the gastrointestinal tract of birds. Several factors are important for chicken colonization and virulence, including a taxis mechanism...... identified as new attractants of C. jejuni, and we observed that chemical substances promoting tactic attraction are all known to support the growth of this organism. The attractants could be categorized as carbon sources and electron donors and acceptors, and we furthermore observed a correlation between...... an attractant's potency and its efficiency as an energy source. The tactic attraction was inhibited by the respiratory inhibitors HQNO (2-n-heptyl-4-hydroxyquinoline N-oxide) and sodium azide, which significantly reduce energy production by oxidative phosphorylation. These findings strongly indicate that energy...

  15. Substance misuse and substance use disorders in sex offenders: a review

    NARCIS (Netherlands)

    Kraanen, F.L.; Emmelkamp, P.M.G.

    2011-01-01

    Substance abuse has often been associated with committing sex offenses. In this article, the following will be reviewed: 1) studies that assessed substance abuse in sex offenders; 2) differences in substance abuse among different types of sex offenders; 3) differences in substance abuse between sex

  16. 21 CFR 172.510 - Natural flavoring substances and natural substances used in conjunction with flavors.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Natural flavoring substances and natural substances used in conjunction with flavors. 172.510 Section 172.510 Food and Drugs FOOD AND DRUG ADMINISTRATION....510 Natural flavoring substances and natural substances used in conjunction with flavors. Natural...

  17. 1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor.

    Science.gov (United States)

    Gu, Wan-gang; Ip, Denis Tsz-Ming; Liu, Si-jie; Chan, Joseph H; Wang, Yan; Zhang, Xuan; Zheng, Yong-tang; Wan, David Chi-Cheong

    2014-04-25

    Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. Copyright © 2014. Published by Elsevier Ireland Ltd.

  18. Kokumi Substances, Enhancers of Basic Tastes, Induce Responses in Calcium-Sensing Receptor Expressing Taste Cells

    Science.gov (United States)

    Maruyama, Yutaka; Yasuda, Reiko; Kuroda, Motonaka; Eto, Yuzuru

    2012-01-01

    Recently, we reported that calcium-sensing receptor (CaSR) is a receptor for kokumi substances, which enhance the intensities of salty, sweet and umami tastes. Furthermore, we found that several γ-glutamyl peptides, which are CaSR agonists, are kokumi substances. In this study, we elucidated the receptor cells for kokumi substances, and their physiological properties. For this purpose, we used Calcium Green-1 loaded mouse taste cells in lingual tissue slices and confocal microscopy. Kokumi substances, applied focally around taste pores, induced an increase in the intracellular Ca2+ concentration ([Ca2+]i) in a subset of taste cells. These responses were inhibited by pretreatment with the CaSR inhibitor, NPS2143. However, the kokumi substance-induced responses did not require extracellular Ca2+. CaSR-expressing taste cells are a different subset of cells from the T1R3-expressing umami or sweet taste receptor cells. These observations indicate that CaSR-expressing taste cells are the primary detectors of kokumi substances, and that they are an independent population from the influenced basic taste receptor cells, at least in the case of sweet and umami. PMID:22511946

  19. Phytotoxic substance with allelopathic activity in Brachiaria decumbens.

    Science.gov (United States)

    Kobayashi, Ai; Kato-Noguchi, Hisashi

    2015-05-01

    The grass Brachiaria decumbens becomes naturalized and quickly dominant in non-native areas. It was hypothesized that phytotoxic substances of plants may contribute to the domination and invasion of the plants. However, no potent phytotoxic substance has been reported in B. decumbens. Therefore, we searched for phytotoxic substances with allelopathic activity in this species. An aqueous methanol extract of B. decumbens inhibited the growth of roots and shoots of cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense) and ryegrass (Lolium multiflorum) seedlings. The extract was then purified using chromatographic methods and a phytotoxic substance with allelopathic activity was isolated and identified by spectral analysis as (6R,9S)-3-oxo-α-ionol. These results suggest that this compound may contribute to the allelopathic effect caused by the B. decumbens extract and may be in part responsible for the invasion and domination of B. decumbens. Two other Brachiaria species, B. brizantha and a Brachiaria hybrid were also confirmed to contain (6R,9S)-3-oxo-α-ionol. Therefore, this compound may play an important role in the phytotoxicity of the Brachiaria species.

  20. Zinc oxide nanoparticles as novel alpha-amylase inhibitors

    Science.gov (United States)

    Dhobale, Sandip; Thite, Trupti; Laware, S. L.; Rode, C. V.; Koppikar, Soumya J.; Ghanekar, Ruchika-Kaul; Kale, S. N.

    2008-11-01

    Amylase inhibitors, also known as starch blockers, contain substances that prevent dietary starches from being absorbed by the body via inhibiting breakdown of complex sugars to simpler ones. In this sense, these materials are projected as having potential applications in diabetes control. In this context, we report on zinc oxide nanoparticles as possible alpha-amylase inhibitors. Zinc oxide nanoparticles have been synthesized using soft-chemistry approach and 1-thioglycerol was used as a surfactant to yield polycrystalline nanoparticles of size ˜18 nm, stabilized in wurtzite structure. Conjugation study and structural characterization have been done using x-ray diffraction technique, Fourier transform infrared spectroscopy, UV-visible spectroscopy, and transmission electron microscopy. Cytotoxicity studies on human fibrosarcoma (HT-1080) and skin carcinoma (A-431) cell lines as well as mouse primary fibroblast cells demonstrate that up to a dose of 20 μg/ml, ZnO nanoparticles are nontoxic to the cells. We report for the first time the alpha-amylase inhibitory activity of ZnO nanoparticles wherein an optimum dose of 20 μg/ml was sufficient to exhibit 49% glucose inhibition at neutral pH and 35 °C temperature. This inhibitory activity was similar to that obtained with acarbose (a standard alpha-amylase inhibitor), thereby projecting ZnO nanoparticles as novel alpha-amylase inhibitors.

  1. Biological abatement of cellulase inhibitors

    Science.gov (United States)

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  2. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    -amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha...

  3. Corrosion inhibitors. Manufacture and technology

    International Nuclear Information System (INIS)

    Ranney, M.W.

    1976-01-01

    Detailed information is presented relating to corrosion inhibitors. Areas covered include: cooling water, boilers and water supply plants; oil well and refinery operations; fuel and lubricant additives for automotive use; hydraulic fluids and machine tool lubes; grease compositions; metal surface treatments and coatings; and general processes for corrosion inhibitors

  4. Autoradiographic localization of substance P receptors using 125I substance P

    International Nuclear Information System (INIS)

    Shults, C.W.; Quirion, R.; Jensen, R.T.; Moody, T.W.; O'Donohue, T.L.; Chase, T.N.

    1982-01-01

    This paper describes a method for localization of substance P receptors in the rat central nervous system using 125 I labeled substance P in an autoradiographic procedure. Particularly high densities of substance P receptors were observed in the olfactory bulb, dentate gyrus, amygdala, superior colliculus, and locus coeruleus. Surprisingly low densities of substance P receptors were found in the substantia nigra pars reticulata, a region which contains high concentrations of substance P

  5. A novel substance with allelopathic activity in Ginkgo biloba.

    Science.gov (United States)

    Kato-Noguchi, Hisashi; Takeshita, Sayaka; Kimura, Fukiko; Ohno, Osamu; Suenaga, Kiyotake

    2013-12-15

    Ginkgo (Ginkgo biloba) is one of the oldest living tree species and has been widely used in traditional medicine. Leaf extracts of ginkgo, such as the standardized extract EGb761, have become one of the best-selling herbal products. However, no bioactive compound directed at plants has been reported in this species. Therefore, we investigated possible allelopathic activity and searched for allelopathically active substances in ginkgo leaves. An aqueous methanol leaf extract inhibited the growth of roots and shoots of garden cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense) and ryegrass (Lolium multiflorum) seedlings. The extract was purified by several chromatographic runs and an allelopathically active substance was isolated and identified by spectral analysis to be the novel compound 2-hydroxy-6-(10-hydroxypentadec-11-enyl)benzoic acid. The compound inhibited root and shoot growth of garden cress and timothy at concentrations greater than 3 μM. The activity of the compound was 10- to 52-fold that of nonanoic acid. These results suggest that 2-hydroxy-6-(10-hydroxypentadec-11-enyl)benzoic acid may contribute to the allelopathic effect caused by ginkgo leaf extract. The compound may also have potential as a template for the development of new plant control substances. Copyright © 2013 Elsevier GmbH. All rights reserved.

  6. Proteolytic and Trypsin Inhibitor Activity in Germinating Jojoba Seeds (Simmondsia chinensis) 1

    Science.gov (United States)

    Samac, Deborah; Storey, Richard

    1981-01-01

    Changes in proteolytic activity (aminopeptidase, carboxypeptidase, endopeptidase) were followed during germination (imbibition through seedling development) in extracts from cotyledons of jojoba seeds (Simmondsia chinensis). After imbibition, the cotyledons contained high levels of sulfhydryl aminopeptidase activity (APA) but low levels of serine carboxypeptidase activity (CPA). CPA increased with germination through the apparent loss of a CPA inhibitor substance in the seed. Curves showing changes in endopeptidase activity (EPA) assayed at pH 4, 5, 6, 7, and 8 during germination were distinctly different. EPA at pH 4, 5, 6, and 7 showed characteristics of sulfhydryl enzymes while activity at pH 8 was probably due to a serine type enzyme. EPA at pH 6 was inhibited early in germination by one or more substances in the seed. Activities at pH 5 and later at pH 6 were the highest of all EPA throughout germination and increases in these activities were associated with a rapid loss of protein from the cotyledons of the developing seedling. Jojoba cotyledonary extracts were found to inhibit the enzymic activity of trypsin, chymotrypsin, and pepsin but not the protease from Aspergillus saotoi. The heat-labile trypsin inhibitor substance(s) was found in commercially processed jojoba seed meal and the albumin fraction of seed proteins. Trypsin inhibitor activity decreased with germination. PMID:16662104

  7. Proteolytic and Trypsin Inhibitor Activity in Germinating Jojoba Seeds (Simmondsia chinensis).

    Science.gov (United States)

    Samac, D; Storey, R

    1981-12-01

    Changes in proteolytic activity (aminopeptidase, carboxypeptidase, endopeptidase) were followed during germination (imbibition through seedling development) in extracts from cotyledons of jojoba seeds (Simmondsia chinensis). After imbibition, the cotyledons contained high levels of sulfhydryl aminopeptidase activity (APA) but low levels of serine carboxypeptidase activity (CPA). CPA increased with germination through the apparent loss of a CPA inhibitor substance in the seed. Curves showing changes in endopeptidase activity (EPA) assayed at pH 4, 5, 6, 7, and 8 during germination were distinctly different. EPA at pH 4, 5, 6, and 7 showed characteristics of sulfhydryl enzymes while activity at pH 8 was probably due to a serine type enzyme. EPA at pH 6 was inhibited early in germination by one or more substances in the seed. Activities at pH 5 and later at pH 6 were the highest of all EPA throughout germination and increases in these activities were associated with a rapid loss of protein from the cotyledons of the developing seedling.Jojoba cotyledonary extracts were found to inhibit the enzymic activity of trypsin, chymotrypsin, and pepsin but not the protease from Aspergillus saotoi. The heat-labile trypsin inhibitor substance(s) was found in commercially processed jojoba seed meal and the albumin fraction of seed proteins. Trypsin inhibitor activity decreased with germination.

  8. Discovery and Biological Evaluation of a Series of Pyrrolo[2,3-b]pyrazines as Novel FGFR Inhibitors.

    Science.gov (United States)

    Zhang, Yan; Liu, Hongchun; Zhang, Zhen; Wang, Ruifeng; Liu, Tongchao; Wang, Chaoyun; Ma, Yuchi; Ai, Jing; Zhao, Dongmei; Shen, Jingkang; Xiong, Bing

    2017-04-05

    Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3- b ]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors.

  9. Method for determining immunochemical substances

    International Nuclear Information System (INIS)

    O'connor, J.

    1980-01-01

    Drawing a method for detecting and measuring a predetermined specifically-bindable immunochemical substance in a liquid sample in a cuvette, comprising the steps of: (A) providing, in an immunoassay technique for the liquid sample in said cuvette, a component comprising a suspension of particles which may be agglutinated or insolubilized in relationship to the presence and concentration of the immunochemical substance in the sample; and (B) determining the presence and concentration of the immunochemical substance by measuring the electromagnetic radiation transmission properties of the sample using a calibrated radiation-measuring apparatus, said apparatus comprising: (1) a suitable electromagnetic radiation source capable of providing radiation at wavelengths equal to or less than the mean diameter of said particles; (2) means for concentrating and collimating radiation from the electromagnetic radiation source to form a beam; (3) means for filtering the beam to (I) eliminate radiation having wavelengths greater than the means diameter of the particles and (II) transmit radiation, which radiation has a range, whereby the upper wavelength is equal to or below the mean diameter of the particles, and the range is of at least about 100nm; (4) means for (I) positioning a sample-containing cuvette and for (II) allowing the filtered beam incident on the cuvette to be transmitted through the cuvette and sample, and for (III) receiving a portion of the filtered beam transmitted through the sample at two or more predetermined angles with respect to the beam; and (5) means for detecting and measuring the portion of the beam transmitted at a predetermined angle

  10. Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

    International Nuclear Information System (INIS)

    Ogura, Kenji; Shiga, Takanori; Yokochi, Masashi; Yuzawa, Satoru; Burke, Terrence R.; Inagaki, Fuyuhiko

    2008-01-01

    The solution structure of the growth factor receptor-bound protein 2 (Grb2) SH2 domain complexed with a high-affinity inhibitor containing a non-phosphorus phosphate mimetic within a macrocyclic platform was determined by nuclear magnetic resonance (NMR) spectroscopy. Unambiguous assignments of the bound inhibitor and intermolecular NOEs between the Grb2 SH2 domain and the inhibitor was accomplished using perdeuterated Grb2 SH2 protein. The well-defined solution structure of the complex was obtained and compared to those by X-ray crystallography. Since the crystal structure of the Grb2 SH2 domain formed a domain-swapped dimer and several inhibitors were bound to a hinge region, there were appreciable differences between the solution and crystal structures. Based on the binding interactions between the